ABSTRACT

 

The major cause of hypoglycemia is iatrogenic. Treatment with an insulin secretagogue, including sulfonylureas or glinides, or insulin, particularly when coupled with compromised defenses against the resulting falling plasma glucoseconcentrations, is the limiting factor in the glycemic management of diabetes. It causes recurrent morbidity in most peoplewith type 1 diabetes mellitus (T1DM) and many with advanced type 2 diabetes mellitus (T2DM) and is sometimes fatal. Low blood glucose also impairs physiological and behavioral defenses against subsequent hypoglycemia, further increasing the risk of hypoglycemia and its complications including adverse cardiovascular effects. Strategies to reduce hypoglycemia are based on the individual’s age, regimen, and comorbidities. A patient-centered approach, newer insulin analogues, novel insulin delivery devices, and continuous glucose monitoring help reduce the risk of hypoglycemia and optimize glycemia.

 

THE CLINICAL PROBLEM OF HYPOGLYCEMIA IN DIABETES 

 

The problem of iatrogenic hypoglycemia in diabetes has been reviewed in detail (1–6).

 

Glycemic Control

 

In the context of comprehensive treatment, including weight, blood pressure, and blood lipid control among other measures, normoglycemia makes a difference for people with diabetes. Improved glycemic control reduces microvascular complications (retinopathy, nephropathy, and neuropathy) in both type 1 diabetes mellitus (T1DM) (7) and type 2 diabetes mellitus (T2DM) (8,9). Follow-up of patients with T1DM (10) and T2DM (11) suggests that an improved earlier period of glycemic control may also reduce subsequent macrovascular complications. Thus, safe and long-term maintenance of physiologic normoglycemia is in the best interest of people with diabetes.

 

The Limiting Factor

 

Iatrogenic hypoglycemia, fundamentally but not exclusively usually results from treatment with an insulin secretagogue or insulin either alone or in combination with other glucose lowering medications, and is the major limitingfactor in the goal of near normoglycemia in the management of diabetes (1). Iatrogenic hypoglycemia causes recurrent morbidity in most people with T1DM and many with advanced T2DM and is sometimes fatal (4). It impairs defensesagainst subsequent falling plasma glucose concentrations and results in a vicious cycle of recurrent hypoglycemia. It generally precludes maintenance of euglycemia over a lifetime of diabetes and, thus, full realization of the benefits of glycemic control.

 

Type 1 and Type 2 Diabetes

 

Iatrogenic hypoglycemia commonly occurs in the overwhelming majority of people with T1DM who must, of course, be treated with insulin. Most have untold numbers of episodes of asymptomatic hypoglycemia. These are not benign sincethey impair defenses against subsequent hypoglycemia (1). Individuals with T1DM suffer an average of two episodes of symptomatic hypoglycemia per week – thousands of such episodes over a lifetime of diabetes – and about one episode of disabling severe (i.e., requiring assistance) hypoglycemia per year. Hypoglycemia causes brain fuel deprivation that, if unchecked, results in functional brain failure that is typically corrected after the plasma glucose concentration is raised (12). Rarely, if low blood glucose is profound and prolonged, it can result in brain death (12). Hypoglycemia may lead to cardiac arrhythmias, especially in patients with preexisting cardiac abnormalities (13,14). Additionally, hypoglycemia has been demonstrated to be pro-coagulant and pro-atherothrombotic (15,16). Furthermore, severe hypoglycemia has beenassociated with increased risk of death extending many months and up to one year after the sentinel episode (17). Of concern, roughly from 2 to 10 percent of deaths of people with diabetes were the result of hypoglycemia (4,5,14,18,19).Regardless of the actual rate, the fact that there is an iatrogenic hypoglycemia mortality rate is alarming.

 

Overall, for a given individual, iatrogenic hypoglycemia is less frequent in T2DM (1,20,21). However, due to the greatly increased numbers of individuals with T2DM, the prevalence of hypoglycemic episodes is actually greater than in T1DM. Drugs that can cause endogenous or exogenous (insulin) hyperinsulinemia unregulated by glucose can cause hypoglycemia. On the other hand, insulin sensitizers (metformin or a thiazolidinedione), α-glucosidase inhibitors, sodium glucose cotransporter 2 inhibitors, and drugs such as dipeptidyl peptidase-IV inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) that cause glucose-dependent hyperinsulinemia should not, and probably do not, causehypoglycemia. They do, however, increase the risk of hypoglycemia if used with an insulin secretagogue or with insulin. Even during treatment of T2DM with insulin, hypoglycemia event rates are about one-third of those in T1DM overall (20).However, for reasons discussed shortly (see Glucose Counterregulatory Physiology and its Pathophysiology inDiabetes), the incidence of iatrogenic hypoglycemia increases over time, approaching that in T1DM, as people approach the insulin deficient end of the spectrum of T2DM (21). Because T2DM is roughly 20-fold more prevalent than T1DM and many, perhaps most, people with T2DM ultimately require treatment with insulin, most episodes of hypoglycemia, including those of severe hypoglycemia, occur in individuals with T2DM. Insulin secretagogue and insulin induced hypoglycemia can be fatal in T2DM although precise hypoglycemic mortality rates are as yet known. As many as 10% of patients with severe sulfonylurea-induced hypoglycemia die (22).

 

DEFINITION AND CLASSIFICATION OF HYPOGLYCEMIA

 

The American Diabetes Association and the International Hypoglycemia Study Group (Table 1) define clinicallysignificant hypoglycemia as a blood glucose <54 mg/dl (3.0 mmol/L) which is detected by the individual’s self-monitoring blood glucose (SMBG) as well as by continuous glucose monitoring ((CGM), glucose values of <54 mg/dl(3.0 mmol/L) for at least 20 min), or laboratory measurement of plasma glucose which is sufficiently low to indicate clinically significant hypoglycemia (23,24). Blood glucose ≤70 mg/dl (3.9 mmol/L) is considered a hypoglycemia alert value, which represents an important lower glucose cutoff value for treatment with fast-acting carbohydrates and doseadjustments of antidiabetic medications. Severe hypoglycemia is defined as a low glucose value with severe cognitiveimpairment that requires assistance from another person in order to achieve recovery (25). Relative hypoglycemia or pseudohypoglycemia represents an event during which the person with diabetes reports any of the typical symptoms of hypoglycemia and interprets those as indicative of hypoglycemia with a measured plasma glucose concentration >70 mg/dL (>3.9 mmol/L).

 

Table 1. Classification of Hypoglycemia in Diabetes (23,24)
Level	Glycemic criteria
Hypoglycemia alert value	≤70 mg/dl (3.9 mmol/L)	Sufficiently low for treatment with fast
(level 1)		acting carbohydrate and dose adjustment
		of glucose lowering therapy
Clinically significant hypoglycemia (level 2)	<54 mg/dl (3.0 mmol/L)	Sufficiently low to indicate serious, clinically important hypoglycemia
Severe hypoglycemia (level 3)	No specific glucose threshold	Hypoglycemia associated with severe cognitive impairment requiring external assistance for recovery

 

COMPLICATIONS OF HYPOGLYCEMIA

 

Increased mortality has been observed in randomized controlled trials during more aggressive compared with less aggressive glucose-lowering therapy in patients with T2DM (26) and in patients with hypoglycemia in intensive care units (27). In addition, intensive glycemic control has not been shown to improve cardiovascular outcomes in patients with T2DM (28). The associations between increased hypoglycemia and increased morbidity and mortality during aggressive glycemic therapy in these and other (18,29,30)  trials have been thought to be multifactorial (31). A possible explanation is that aggressive reduction of blood glucose increases the risk of hypoglycemia. The latter can trigger sympathoadrenal activation with the release of catecholamines, cause abnormal cardiac repolarization, and lead to myocardial ischemia. Hypoglycemia-induced ECG changes include ST-segment depression, atrial and ventricular ectopic beats, P- and T-wave abnormalities, and QT-interval prolongation (32). Low blood glucose creates procoagulant and prothrombotic states and induces inflammation and oxidative stress (33,34).

 

The association of hypoglycemia with cognitive function appears to be more complicated. Among older individuals with type 2 diabetes, a history of severe hypoglycemia was associated with a greater risk of dementia (37). The ACCORD study reported that cognitive impairment at baseline and a continuing decline in cognitive function among individuals were associated with a greater risk for dementia following hypoglycemia (35). It should be noted however that in DCCT/EDIC, which involved much younger participants, no association of severe hypoglycemia and cognitive decline was found (25, 39).

 

Hypoglycemic episodes can create fear of subsequent hypoglycemia and negatively affect the quality of life in T1DM as well as T2DM (36). Some of the consequences may include anxiety, shortness of breath, palpitations, tremors, symptoms of depression, and reduced ability to function.

 

GLUCOSE COUNTERREGULATORY PHYSIOLOGY AND ITS PATHOPHYSIOLOGY IN DIABETES

 

Physiology

 

In nondiabetic individuals, there are a number of physiological defenses against falling plasma glucose concentrations. These include reductions in insulin secretion, which occur as glucose levels decline within the physiological range. This allows for increased hepatic (and renal) glucose production, and increments in glucagon and epinephrine secretion, which occur as glucose levels fall just below the physiological range and stimulate hepatic glucose production (1,2,37)(Figure 1). Increased epinephrine levels also normally mobilize gluconeogenic precursors from muscle and fat, stimulate renal glucose production, limit glucose utilization by muscle and fat, and limit insulin secretion (2). The behavioral defense against falling plasma glucose concentrations is carbohydrate ingestion prompted largely by the perception ofneurogenic (autonomic) symptoms (e.g., palpitations, tremor, and anxiety/arousal which are catecholamine-mediated or adrenergic and sweating, hunger, and paresthesias which are sympatho-adrenal mediated or cholinergic) (38,39) (Figure 1). These are largely sympathetic neural, rather than adrenomedullary, in origin (39). The extent to which mild neuroglycopenic symptoms such as altered mentation or psychomotor changes contribute to the patient’s recognition of hypoglycemia is unclear; awareness of hypoglycemia is largely prevented by pharmacological antagonism of neurogenicsymptoms (38). Severe neuroglycopenic symptoms include frank confusion, acute focal or central neurologic deficits, seizure and/or loss of consciousness. All of these defenses can be compromised in T1DM and advanced T2DM (1,40,41).

 

Pathophysiology

 

Episodes of therapeutic hyperinsulinemia, the result of glucose unregulated delivery of endogenous (insulin secretagoguetherapy) or exogenous (insulin therapy) insulin into the circulation, initiate the sequence that may, or may not, culminate in an episode of hypoglycemia (1). Absolute therapeutic insulin excess of sufficient magnitude can cause isolated episodes of hypoglycemia despite intact glucose counterregulatory defenses against hypoglycemia (Figure 2). But that isan uncommon event. Iatrogenic hypoglycemia is typically the result of the interplay of mild-moderate absolute therapeutic insulin excess, reduced glucose intake, exercise, increased insulin sensitivity, sleep, and existing or induced compromised physiological and behavioral defenses against falling plasma glucose concentrations in T1DM (1,40) and T2DM (1,41). In T1DM, because of β-cell failure, insulin levels do not decrease as glucose levels fall; the first physiological defense is lost. Furthermore, glucagon levels do not increase as glucose levels fall (42); the second physiological defense is lost. That, too, is possibly attributable to a β-cell signaling failure since a decrease in β-cell secretion, coupled with a low α-cell glucose concentration, normally signals α-cell glucagon secretion (3,43,44). Finally, the increase in epinephrine levels as glucose levels fall is also attenuated ((1,41); and thus, the three major physiological defenses are compromised.

 

 

Although it is often caused by recent antecedent hypoglycemia (40,46) or by prior exercise (47) or sleep (48–50), the mechanism of the attenuated sympathoadrenal response to falling glucose levels is unknown (3). Nonetheless, theattenuated epinephrine response is a marker of an attenuated sympathetic neural response (39) and the latter largely results in the reduction of the symptoms of hypoglycemia causing hypoglycemia unawareness (or impaired awareness of hypoglycemia) and thus loss of the behavioral defense, i.e., carbohydrate ingestion. In the setting of therapeutichyperinsulinemia, falling plasma glucose concentrations, absent decrements in insulin, absent increments in glucagon, and attenuated increases in epinephrine cause the clinical syndrome of defective glucose counter-regulation (1,40), whichis associated with a 25-fold (51) or greater (52) increased risk of iatrogenic hypoglycemia. The attenuated sympathoadrenal, particularly the attenuated sympathetic neural response, causes the clinical syndrome of hypoglycemiaunawareness (1) which is associated with a 6-fold increased risk of iatrogenic hypoglycemia (53).

 

The pathophysiology of glucose counter-regulation is the same in T1DM and T2DM albeit with different time courses. β-cell failure, and therefore loss of the insulin and glucagon responses to falling plasma glucose concentrations, develops early in T1DM but more gradually in T2DM. Thus, iatrogenic hypoglycemia, becomes a common problem early in T1DMand later in T2DM.

 

The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes (1,3,5,40,41) (Figure 2) posits that recentantecedent hypoglycemia, as well as prior moderate exercise or sleep, causes both defective glucose counter-regulation(by reducing increments in epinephrine in the setting of absent decrements in insulin and absent increments in glucagon during subsequent hypoglycemia) and hypoglycemia unawareness (by reducing sympathoadrenal and resulting neurogenic symptom responses during subsequent hypoglycemia) and, therefore, a vicious cycle of recurrent hypoglycemia. Supporting this concept is the finding, that as little as 2-3 weeks of scrupulous avoidance of hypoglycemia reverses hypoglycemia unawareness and improves the attenuated epinephrine component of defective glucose counter-regulation in most affected patients. (54–57).

 

The mechanism(s) of the attenuated sympathoadrenal response to falling glucose levels, the key feature of HAAF, is not known (3). It must involve the central nervous system or the afferent or efferent components of the sympathoadrenal system. Theories include increased blood-to-brain transport of a metabolic fuel, effects of a systemic mediator such as cortisol on the brain, altered hypothalamic mechanisms, and activation of an inhibitory cerebral network mediated through the thalamus (3).

 

 

RISK FACTORS FOR HYPOGLYCEMIA IN DIABETES

 

Conventional Risk Factors

 

The conventional risk factors are based on the premise that relative to low rates of glucose delivery into the circulation, high rates of glucose efflux out of the circulation, or both, or absolute therapeutic hyperinsulinemia is the soledeterminant of risk (1). They include (but are not limited to):

 

1. Insulin (or insulin secretagogue) doses are excessive, ill-timed, or of the wrong type.
2. Exogenous glucose delivery is decreased (as following missed meals and during the overnight fast, with gastroparesis or celiac disease).
3. Glucose utilization and sensitivity to insulin are increased (as during and shortly after exercise, in the middle of the night, following weight loss, or improved glycemic control).
4. Endogenous glucose production is decreased (as following alcohol ingestion or in liver failure).
5. Insulin clearance is decreased (as in renal failure).
6. Classical diabetic autonomic

 

Patients with diabetes and their caregivers must consider each of these risk factors carefully whenever hypoglycemia is a problem (58).

 

Risk Factors Indicative of Hypoglycemia-Associated Autonomic Failure (HAAF)

 

These risk factors stem directly from the pathophysiology of glucose counter-regulation and the concept of HAAF in diabetes (1,40,41). They include:

 

1. The degree of absolute endogenous insulin deficiency. This determines the extent to which insulin levels will notdecrease and glucagon levels will not increase as plasma glucose concentrations fall in response to therapeutic It is in part a function of the duration of diabetes.
2. A history of severe hypoglycemia, hypoglycemia unawareness, or both as well as recent antecedent hypoglycemia, prior exercise or sleep.
3. Aggressive glycemic therapy per se (lower A1C levels, lower glycemic goals). Studies with a control group treated to higher mean glycemia consistently document higher rates of hypoglycemia in individuals treated to lower mean glycemia (e.g. (4)). Mean glycemia is a risk factor for hypoglycemia. However, severe hypoglycemia can occur in individuals with any A1C level, and the fact that mean glycemia is a risk factor does not mean that one cannot both lower mean glycemia and reduce the risk of hypoglycemia in individual patients (6).

 

PREVENTION OF HYPOGLYCEMIA IN DIABETES

 

The prevention of hypoglycemia can be viewed as a process with four steps (1,6). The first step is acknowledging the problem; the second - considering the conventional risk factors in diabetes; the third – considering the risk factors indicative of HAAF in diabetes; and the fourth - application of the relevant principles of intensive glycemic therapy of diabetes.

 

Acknowledge the Problem

 

The issue of hypoglycemia should be addressed at every contact with a patient treated with an insulin secretagogue or with insulin (6). In addition to the patient’s comments and review of the individual’s SMBG data (as well as any CGM data) we find it especially helpful to inquire what is the glucose level when each patient can detect hypoglycemia andwhat are the symptoms and signs at various hypoglycemic levels. It is also often helpful to question close associates of the patient since they may have observed clues to episodes of hypoglycemia. Patient concerns about the reality, or even the possibility, of hypoglycemia can be a barrier to glycemic control (59,60). Their concerns need to be discussed and addressed if hypoglycemia is a real or perceived problem.

 

Consider the Conventional Risk Factors for Hypoglycemia in Diabetes

 

Each of the risk factors that result in relative or absolute therapeutic hyperinsulinemia, as just discussed, should be considered carefully in any patient with iatrogenic hypoglycemia. Those include the dose, timing, and type of the insulinsecretagogue or insulin preparations(s) used, and conditions in which exogenous glucose delivery or endogenous glucose production is decreased, glucose utilization or insulin sensitivity is increased or insulin clearance is decreased.

 

Consider the Risk Factors Indicative of HAAF in Diabetes

 

As detailed earlier, the risk factors indicative of HAAF include the degree of absolute endogenous insulin deficiency, ahistory of severe hypoglycemia, impaired awareness of hypoglycemia, or both as well as any relationship between iatrogenic hypoglycemia and recent antecedent hypoglycemia, prior exercise or sleep, and lower glycemic goals. A history of severe hypoglycemia is a clinical red flag. Without a fundamental adjustment of the treatment regimen, the likelihood of another episode is high (7,61).

 

Apply the Relevant Principles of Intensive Glycemic Therapy

 

The principles of intensive glycemic therapy relevant to minimizing the risk of iatrogenic hypoglycemia in diabetes include drug selection, selective application of diabetes treatment technologies, individualized glycemic goals, structured patient education, and short-term scrupulous avoidance of hypoglycemia (6). Based on the premise that the risk of hypoglycemia is modifiable, the International Hypoglycemia Study Group recommended that people with diabetes treated with a sulfonylurea, a glinide, or insulin should be educated about hypoglycemia, should treat self- monitored plasma glucose (SMPG) <70 mg/dL (<3.9 mmol/L) to avoid progression to clinical iatrogenic hypoglycemia, and should regularly be queried about hypoglycemia, including the glucose level at which symptoms develop (6).

 

Drug selection relevant to minimizing the risk of hypoglycemia includes avoidance, if possible, of sulfonylureas or glinides, the use of more physiological insulin regimens (62), and the use of long-acting or even ultra-long-acting daily basal insulin analogues and rapid-acting prandial insulin analogues in lieu of human insulins (63–66). Insulin analogues reduce the frequency of at least nocturnal hypoglycemia (63–65) including severe nocturnal hypoglycemia (65) compared to human insulins. In insulin-requiring T2DM, basal insulins are associated with less hypoglycemia than prandial insulin regimens. Furthermore, the combination of a long-acting basal insulin with a glucose-lowering drug with low hypoglycemic potential (e.g., a GLP-1 receptor agonist) may result in less hypoglycemia than with the use of basal-bolus insulin therapy (67).

 

Relevant diabetes treatment technologies include continuous subcutaneous insulin infusion (CSII), continuous glucose monitoring (CGM), and combinations of CSII and CGM. Although earlier meta-analyses disclosed little (68) or no (69)advantage of CSII, recent evidence suggest that CSII treatment is superior in achieving glucose control compared to multiple daily injections (70,71). CGM devices alone have been shown to improve glycemic control and decrease duration of hypoglycemia in patients with diabetes mellitus (72,73). As their accuracy is continuously improving, several CGM systems have been approved by the FDA, and other regulatory authorities to even replace point of care blood glucose testing (74,75). Real-time CGM systems have also been found to improve hypoglycemia awareness, without achange in A1C, in a small group of patients with T1DM (76). A favorable experience with CSII has also been reported (77,78). The combination of CSII and real-time CGM – sensor augmented pump therapy, particularly that including an insulin pump programmed to stop insulin infusion for up to two hours when CGM values fall to a selected glucose level (“low glucose suspend”) – has been reported to reduce the frequency of severe hypoglycemia in T1DM (79–81). Recentinnovations have included cessation of insulin delivery during hypoglycemia. Several promising studies have investigated approaches for leading closed-loop insulin (or insulin and glucagon) replacement. The development of automated closed-loop insulin pumps represents an area of ongoing research and fully closed-loop insulin (82) or insulin and glucagon replacement (83) and pancreatic islet transplantation (84) will undoubtedly eliminate hypoglycemia andimprove overall glycemic control. A hybrid-not fully automated -system (as only basal insulin is automatically adjusted) has received approval by the FDA (85).

 

Special circumstances relevant to drug selection and treatment technologies in the prevention of hypoglycemia in diabetes include exercise, the overnight period, the elderly, drivers, and pregnancy. Especially in insulin-treated patients’ hypoglycemia can occur during or shortly after exercise (86) or late after exercise (87,88). Measures to avoid early-onset exercise hypoglycemia include interspersing episodes of intense exercise (which tends to raise plasma glucose concentrations), adding carbohydrate ingestion, and reducing insulin doses (89). A consistent observation since the DCCT (7) is that more than half of episodes of hypoglycemia, including severe hypoglycemia, occur during the night. That is typically the longest interval between meals and between SMPG and includes the time of maximal sensitivity to insulin. In addition to the use of insulin analogues, sensor augmented pump therapy or closed-loop insulin or insulin and glucagon replacement, all discussed earlier, approaches to the prevention of nocturnal hypoglycemia include attempts to produce sustained delivery of exogenous carbohydrate or sustained endogenous glucose production (90). With respect to the former approach, a conventional bedtime snack or bedtime administration of uncooked cornstarch have not been found to be consistently effective (90). With respect to the latter approach an experimental treatment is bedtime administration of a β2-adrenergic agonist such as terbutaline (90–92). In addition to HAAF, comorbidities including renal insufficiency, polypharmacy, and impaired cognition are more relevant to the development of hypoglycemia in older individuals (93). Drivers with diabetes and a history of recurrent hypoglycemia-related driving mishaps have been found to have greater driving simulator impairments (94). Finally, up to 45% of pregnant women with type 1 diabetes experience severe hypoglycemia especially in the first trimester (95).

 

Individualized Glycemic Goal

 

Glycemic goals should be individualized in patients with diabetes (4,96). The selection of a glycemic goal in a person with diabetes is a trade-off between the benefits of glycemic control – partial prevention or delay of microvascularcomplications – and the risk of recurrent morbidity, and potential mortality, of hypoglycemia (4). A reasonable individualized glycemic goal is the lowest A1C that does not cause severe hypoglycemia and preserves awareness of hypoglycemia, preferably with little or no symptomatic or even asymptomatic hypoglycemia, at a given stage in the evolution of the individual’s diabetes (4). Thus, the glycemic goal should be linked not only to the level of glycemic control (i.e., the A1C) but also to the risk of hypoglycemia, specifically the drugs used (a sulfonylurea, a glinide, or insulin), the degree of endogenous insulin deficiency, and the anticipated benefit of the targeted level of glycemic control. A nondiabetic A1C would be reasonable in a patient with early T2DM treated effectively with lifestyle changes and/or drugsthat do not cause hypoglycemia. For the majority of non-pregnant adults, a reasonable goal for an A1C is <7% (53 mmol/mol). For selected individuals with long life expectancy, without significant comorbidities (especially cardiovascular disease), stringent A1c goals (<6.5% (48 mmol/mol)) should be targeted, if this can be achieved without significant hypoglycemia (23). For children and adolescents, an A1C of <7.5% (58 mmol/mol) should be the goal, although a lower target (<7% (53 mmol/mol)) should be reasonable if it can be achieved without excessive hypoglycemia (97). Howevermuch higher levels of A1C (7.5%-8.0% (58-64 mmol/mol)) may be appropriate in elderly patients where hypoglycemia may be harmful. Even higher targets (A1C<8.5% (69 mmol/mol)) may be appropriate in individuals with very limited life expectancy (93).

 

Of note, it needs to be underscored that severe hypoglycemia can and does occur at A1C levels between 8-10% (64-86 mmol/mol) or higher in either T1DM or T2DM. Thus, severe hypoglycemia is not just a consequence of “low or near normal” A1C values. Of concern are recent data that severe hypoglycemia occurring in T2DM individuals >60 years withelevated A1C may have greater serious adverse events and increased mortality compared to individuals with improved glycemic control and lower A1C values.

 

Thus, attempts to improve glycemic control with insulin in T2DM individuals that have been resistant or proven challenging to strategies to lower glucose levels may be at greater risk for severe hypoglycemia and associated serious adverse events (18,26,29,30).

 

Structured Patient Education

 

The core approach, applicable to virtually all patients with diabetes treated with a sulfonylurea, a glinide, or insulin in whom hypoglycemia becomes a problem, is thorough, structured patient education (often re- education) that teaches the patient how and when their drugs can cause hypoglycemia, how to adjust their medications, meal plans, and exercise to optimize glycemic control and minimize hypoglycemia, and how to recognize and treat hypoglycemia (6). Based conceptually on earlier inpatient education programs (98), there is increasing evidence that outpatient structured education programs decrease hypoglycemia, often with a decrease in A1C (99–103). For example, a structured patient education program in flexible insulin therapy led to a reduction of impaired awareness of hypoglycemia (45% of those with impaired awareness initially were aware at one year) and a reduction in severe hypoglycemia (from 1.9 to 0.6 episodes per patient-year and a small but significant decrease in A1C in patients with type 1 diabetes (101). Patient education needs to cover a broad range of information and skill training and often include a motivational element (6).

 

Short-Term Scrupulous Avoidance of Hypoglycemia

 

In patients with impaired awareness of hypoglycemia structured patient education should be combined with 2- to 3-weeks of scrupulous avoidance of hypoglycemia – which may require acceptance of somewhat higher glycemic goals in the short-term – since that can be expected to restore awareness of hypoglycemia in most affected patients (54–57).

 

In summary, people with diabetes treated with a sulfonylurea, a glinide, or insulin should be educated about hypoglycemia, should treat SMPG (or CGM) glucose levels <70 mg/dL (<3.9 mmol/L) to avoid progression to clinical iatrogenic hypoglycemia, and should regularly be queried about hypoglycemia, including the SMPG (or CGM) level at which symptoms develop (6).

 

TREATMENT OF HYPOGLYCEMIA IN DIABETES

 

Most episodes of asymptomatic hypoglycemia, detected by routine SMBG or CGM, or of mild- moderate symptomatic hypoglycemia are effectively self-treated by ingestion of glucose tablets or carbohydrate containing juice, soft drinks, candy, other snacks, or a meal (1,104). A reasonable dose is 20 g of carbohydrate (104). The dose can be repeated in 15 to 20 minutes, if necessary. Since the glycemic response to oral glucose is transient – roughly two hours in the setting of ongoing hyperinsulinemia (104) – the ingestion of a more substantial snack or meal shortly after the plasma glucose level is raised is generally advisable.

 

When a hypoglycemic patient is unwilling (because of neuroglycopenia) or unable to take carbohydrate orally, parenteral therapy is required. That is often glucagon injected subcutaneously or intramuscularly by an associate of the patient whohas been trained to recognize and treat severe hypoglycemia. The usual glucagon dose is 1.0 mg; that can be life-saving although it causes substantial, albeit transient, hyperglycemia (104) and can cause nausea, and even vomiting. Smaller doses (e.g., 150 mcg), repeated, if necessary, have been found to be effective without side effects in adolescents (105). Recent advances include 1) approval of nasal glucagon and of a device to deliver glucagon intranasally (106), that would obviate the need for parenteral injection and 2) a glucagon that is stable in solution (107), that would obviate the need to reconstitute the drug prior to administration. Because it also stimulates insulin secretion, glucagon might be less effectivein patients with early T2DM. In a medical setting intravenous glucose, 25 g initially, is the standard parenteral therapy(1). The glycemic response to intravenous glucose is, of course, transient. A subsequent glucose infusion is generally needed, and food should be provided as soon as the patient is able to ingest it safely.

 

The duration of a hypoglycemic episode is a function of its cause. While that caused by a short-acting insulin secretagogue or a rapid-acting insulin can be measured in hours, that caused by a long-acting insulin secretagogue or insulin can last for days requiring hospitalization for prolonged therapy. The duration of secretagogue-induced hypoglycemia can be shortened by administration of octreotide (108,109).

 

In the UK, the Joint British Diabetes Societies for Inpatient Care have produced guidance on the management of hypoglycemia for hospital inpatients, although these can be used in the community setting as necessary (110).

 

ACKNOWLEDGMENTS AND DISCLOSURES

 

Hugh A. Davis has no disclosures to report.

 

Elias K. Spanakis has received research support (CGM supplies) from DEXCOM (San Diego, CA) for the conduction of inpatient CGM clinical studies.

 

Maka Siamashvili has no disclosures to report.

 

Stephen N. Davis- This work has received support from the NIH, NHLBI, NIDDK, JDRF and VA.

 

 

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ABSTRACT

 

Complementary and Integrative Health (CIH) approaches, otherwise known as non-mainstream practices or Complementary and Alternative Medicine (CAM), are commonly used by patients with diabetes. Natural products, including dietary supplements, are the most frequently used complementary approach by patients with diabetes. While popular, there are regulatory, safety, and efficacy concerns regarding natural products. Commonly used dietary supplements for diabetes can be categorized as hypoglycemic agents, carbohydrate absorption inhibitors, and insulin sensitizers. Hypoglycemic agents of interest include banaba, bitter melon, fenugreek, and gymnema. American ginseng, banaba, berberine, chromium, cinnamon, gymnema, milk thistle, prickly pear cactus, soy, and vanadium are insulin sensitizers that have been studied in patients with diabetes. The carbohydrate absorption inhibitors aloe vera gel, fenugreek, flaxseed, prickly pear cactus, soy, and turmeric may be used in patients with diabetes. Mind body therapies including yoga, massage, and Tai Chi have preliminary evidence to support use in patients with diabetes. Deceptive marketing tactics may be employed by sellers of natural products. Consumers and clinicians must be aware of potential risks and make informed choices. Resources such as the Food and Drug Administration’s (FDA’s) MedWatch may be helpful. The FDA’s online health fraud website informs consumers on various types of fraud and how to avoid them.

 

COMPLEMEMTARY AND INTEGRATIVE HEALTH APPROACHES BACKGROUND        

 

This chapter reviews information regarding Complementary and Integrative Health (CIH) approaches used to treat diabetes. First, background information on complementary health approaches (sometimes referred to as Complementary and Alternative Medicine or CAM) will be presented. This will be followed by a description of non-mainstream practices used by patients with diabetes. An evidence-based description of specific natural products used to treat diabetes will be next. Mind body practices will be addressed. The chapter will conclude with specific ways clinicians can assist patients in choosing safe natural products. Please note information regarding therapies to treat comorbidities of diabetes are covered elsewhere in this text.

 

To help clarify the contents of this chapter, nomenclature definitions relevant to CIH will be provided as defined by the National Institute of Health (NIH) National Center for Complementary and Integrative Health (NCCIH). Table 1 provides definitions of commonly used terms. Complementary medicine is defined as non-mainstream practices that are used together with conventional medicine. In contrast, alternative medicine describes non-mainstream practices used instead of conventional medicine. Complementary health approaches are non-mainstream practices. The term integrative medicine refers to medicine that brings complementary and conventional health approaches together in a coordinated manner. Integrative health describes complementary approaches that are incorporated into mainstream healthcare. Lastly, the term natural products refer to herbs, vitamins, minerals, and probiotics (1).

 

Table 1. Definitions of Terms Relevant to Complementary and Alternative Medicine (1)
Term	Definition
Alternative Medicine	Non-mainstream practice used instead of conventional medicine
Complementary Health Approaches	Non-mainstream practices
Complementary Medicine	Non-mainstream practice used together with conventional medicine
Integrative Health	Complementary approaches being incorporated into mainstream healthcare
Integrative Medicine	Medicine that brings complementary and conventional health approaches together in a coordinated fashion
Natural Products	Herbs, vitamins, minerals, and probiotics

 

“Complementary health approaches” is an umbrella term for non-mainstream practices. Complementary health approaches can be classified by their primary therapeutic input, or method of delivery (Table 2). A graphic representation of the examples of complementary health approaches and their categorization is provided in Figure 1 (1).

 

Table 2. Classification of Complementary Health Approaches (1)
Primary Therapeutic Input	Examples
Nutritional	Special diets, dietary supplements, herbs, and probiotics
Psychological	Mindfulness
Physical	Osteopathic manipulative therapy, chiropractic spinal manipulation, massage therapy, physical therapy
Combinations	Psychological and physical, e.g., yoga, Tai Chi, acupuncture, dance or art therapies, or psychological and nutritional, e.g., mindful eating

 

The complementary health approach classification system has its limitations and, therefore, a five-domain system has been proposed to organize CIH. The domains include: (1) biologically based therapies; (2) mind-body interventions; (3) manipulative and body-based therapies; (4) alternative or whole medical systems; and (5) energy therapies. Examples of each domain are provided in Table 3 (1, 2).

 

Table 3. Domains to Classify Complementary and Integrative Health
Domain	Examples
Biologically based therapies	Dietary interventions, vitamins, minerals, supplements, herbal/botanical medicines
Mind–body interventions	Meditation, relaxation and breathing techniques, guided imagery, hypnosis, biofeedback, yoga, Tai Chi, qigong, expressive arts therapies, spiritual practices, and other forms of “directed” attention
Manipulative and body-based methods	Osteopathic manipulative therapy, chiropractic spinal manipulation, massage therapy, physical therapy
Alternative or whole medical systems	Traditional Chinese medicine, ayurveda, naturopathic medicine, homeopathy, Polynesian medicine, Unani-Tibb medicine, traditional African medicine, traditional Mayan medicine
Energy therapies	Acupuncture, Tai Chi, qigong, reiki, therapeutic or healing touch, bioenergetic therapy, and other methods that affect the body’s “bioelectric” field

 

REGULATIONS OF DIETARY SUPPLEMENTS AND NATURAL PRODUCTS

 

Background Information

 

The Dietary Supplement Health and Education Act (DSHEA) was passed in 1994. This legislation created the category of dietary supplements. Prior to DSHEA, natural products (herbs, vitamins, minerals, probiotics) were classified as either food or drug. Even though natural products are biologically active, they are considered food products and are exempt from the same approval process as drugs (3).

 

Under DSHEA, natural product manufacturers are not allowed to sell any adulterated or misbranded product. Manufacturers are expected to ensure natural products are effective and safe. However, manufacturers are not required to provide proof of efficacy or safety before marketing and selling a particular product (3).

 

When DSHEA was passed, it required that good manufacturing practices (GMPs) be established. Several years later the Food and Drug Administration (FDA) provided these standards. The standards say products must be labeled correctly and be free of impurities or adulterants (4).

 

Labeling requirements for dietary supplements exist. Products sold as dietary supplements must contain certain informational pieces on their labels. Items such as the product name, the word “supplement”, the net content quantity, the name and place of business of the manufacturer/packer/distributor, directions for use, a “Supplement Facts” panel, and a listing of all nondietary ingredients must be included. Table 4 reviews labeling requirements and Figure 2 is an example “Supplement Facts” panel (5).

 

Table 4. Information Required to Appear on Dietary Supplement Labels (5)
Dietary Supplement Labeling Requirements
Product Name
The word “supplement” or a statement the product is a supplement
Net content quantity
Manufacturer’s, packer’s, or distributor’s name
Manufacturer’s, packer’s, or distributor’s place of business
Directions for use
“Supplement Facts” panel listing serving size, dietary ingredients, amount per serving size, and percent daily value (if established)
Nondietary ingredients such as fillers, artificial colors, sweeteners, binders,

 

Dietary supplement products are allowed to make claims about maintaining structure or function of the body.  However, products are not allowed to make claims about diagnosis, treatment, cure, or prevention of a disease. For example, a product may claim to “maintain a healthy pancreas.” Conversely, a product may not claim to “treat diabetes.” If a product does make a health maintenance claim, the label must include the following statement: “This statement has not been evaluated by the Food and Drug Administration (FDA). This product is not intended to diagnose, treat, cure, or prevent any disease” (5).

 

Reporting of Adverse Events

 

The Dietary Supplement and Nonprescription Drug Consumer Protection Act was signed into law in 2006. This act required manufacturers to report adverse events for dietary supplements and nonprescription drugs. In addition, individuals are encouraged to report supplement and nonprescription drug adverse events to the FDA (6). Despite the Dietary Supplement and Nonprescription Drug Consumer Protection Act, there is concern of underreporting of adverse events.

 

Safety Concerns

 

Safety surrounding dietary supplements and natural products is a concern for clinicians and consumers alike. Despite DSHEA and the Dietary Supplement and Nonprescription Drug Consumer Protection Act, adverse events and safety issues regarding natural products abound. In fact, an article published in 2015 in The New England Journal of Medicineestimated 23,005 emergency room visits annually were a result of adverse effects related to dietary supplements (7).

 

The FDA publishes recalls for prescription drugs, nonprescription drugs, and dietary supplements. The most serious recalls are classified as Class I. A Class I drug recall is one where the product in question has “reasonable probability that the use of or exposure to . . . will cause serious adverse health consequences or death” (8). From 2008 to 2012, half of all Class I drug recalls were from dietary supplements (9).

 

INTEGRATIVE HEALTH USE IN THE UNITED STATES

 

According to the Council for Responsible Nutrition (CRN), Americans spend an estimated $35 billion on dietary supplements each year. The market appears to be growing each year. CRN estimates 74% of adults in the United States use supplements (10).

 

Most users of natural products take a multivitamin. Other commonly used supplements include specific vitamins (D, C, and B), calcium, omega-3 fatty acids/fish oil, probiotics, green tea, protein bars, whey protein powders, and energy drinks. Mass merchandizers and pharmacies are the most common places where dietary supplements are purchased (10,11).

 

Reasons for dietary supplement use vary. The most popular was to support overall health and wellness. Other popular reasons include filling nutrient gaps, heart health, healthy aging, immune health, energy, bone health, preventing illness, and joint health (11).

 

Integrative Health Use Amongst Patients with Diabetes

 

According to a meta-analysis published in 2021, 51% of patients with diabetes globally use some form of CAM. Use prevalence was highest in Europe, where 76% of patients with diabetes in France use CAM; prevalence was lowest in North America, where 45% of patients used CAM (12). Reasons for CAM use specific to the United States (US) include overall wellness (28% of users), treatment of diabetes (15%), or a combination of the two (57%) (13). Figure 3 illustrates the reasons for CAM use in patients with diabetes.

 

 

Overall, the most common forms of CAM used in US patients with diabetes were herbal therapies (56.7% of users), chiropractic (25.3%), and massage (20.2%). See Figure 4 for an illustration. For those citing treatment alone as their reason for complementary health approach use, the most common types were chiropractic, herbal therapies, and massage. Those that cited wellness alone as their reason, the most common types of CAM utilized were herbal therapies, massage, and chiropractic (13).

 

 

 

Sociodemographically, there are several differences in US CAM users with diabetes. The racial/ethnic group most likely to utilize complementary health approaches were non-Hispanic Whites. Those employed and with higher education attainment were also more likely to use CAM (13).

 

Due to the high usage, clinicians should gather comprehensive complementary health approach use histories from patients. This may prevent dangerous CAM-herb and CAM-disease interactions.

 

Older Adults

 

In particular, older adults with diabetes that utilize CAM can present unique challenges. Older adults tend to have more chronic medical conditions and diabetes complications. Additionally, older adults tend to use more medications compared to the general population.

 

One-quarter of older adults with diabetes utilize complementary, alternative, or integrative medicine (14). Of these older adults, 62.8% utilize herbal therapies specifically. Chiropractic (23.9%), massage (14.7%), acupuncture (10.2%), and yoga (5.2%) were the other most popular therapies used (14).

 

Clinicians should query older adult patients with diabetes on active CAM use. This may prevent dangerous CAM-herb and CAM-disease interactions.

 

NATURAL PRODUCTS  

 

Natural products have been used for thousands of years. Natural products were depicted on clay tablets in ancient Mesopotamia (2600 BC). An ancient Egyptian pharmaceutical record, the Ebers Papyrus, dates to 2900 BC and documents hundreds of natural therapies. Documented records of natural product use have also been found in China (the Chinese Materia Medica) and Greece (from the physician Dioscorides) (15).

 

This section will discuss natural products that are commonly used in patients with type 2 diabetes mellitus (T2DM) for glycemic control. A brief description of each product will be followed by an overview of proposed mechanisms of action. Next, currently available evidence for the product will be reviewed. A brief discussion of adverse effects and drug interactions will also be included.

 

While botanical products are often hypothesized to work by multiple mechanisms, each product is categorized below by the major mechanism thought to exert its effect. For your convenience, an alphabetized table of botanical products is also presented.

 

Hypoglycemic Agents

 

The natural products covered in this section are all agents that theoretically lower blood glucose. Each individual product may have additional mechanisms of action, which are also covered.

 

BANABA (LAGERSTROEMIA SPECIOSA)

 

Banaba is a crepe myrtle species indigenous to Southeast Asia. The first published report of banaba use is from 1940. Banaba is used for diabetes and weight loss. See Figure 5 for an illustration of the banaba plant. The banaba leaf is the portion thought to exert beneficial effects. It is thought the active constituents of the banaba leaf are corosolic acid and ellagitannins (lagerstroemin, flosin B, and reginin A) (16-18).

 

 

Mechanism of Action

 

It is hypothesized that banaba lowers blood glucose by increasing insulin secretion and stimulating glucose uptake of cells (insulin-like effect). Additional proposed mechanisms include alpha-glucosidase inhibition and subsequent reduction in nutrient load; increasing insulin sensitivity via increased expression of liver peroxisome proliferator‐activated receptor‐α (PPAR‐α) mRNA and adipose tissue peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) mRNA; decreased gluconeogenesis; and increased glycolysis by increasing glucokinase activity (17-21).

 

Evidence

 

A randomized controlled trial studied the activity of 1% corosolic acid (an active constituent of banaba) on glucose control in patients with type 2 diabetes. This was a dose-response study of 10 subjects aged 55-70 years. Subjects did not use any oral hypoglycemic medications for 45 days prior to the clinical trial. Five subjects in each group received either a hard or soft gelatin capsule containing 1% corosolic acid of 16, 32, and 48 mg doses (equivalent to 0.16 mg, 0.32 mg, and 0.48 mg of corosolic acid). Doses were given sequentially with a 10-day wash-out period between dose escalation.  Blood glucose levels were measured via finger-prick sample. Compared to control blood glucose levels, 1% corosolic acid from a soft gelatin capsule resulted in a statistically significant percent reduction in blood glucose levels at the 32 mg (10.7% ± 1.4) and 48 mg (30.0% ± 3.4) doses (p <0.05). The hard gel formulation resulted in a significant (p <0.05) percentage reduction in blood glucose for only the 48 mg dose (20.2% ± 1.29). Results are summarized in Table 5 (18).

 

Table 5. Percent Reduction in Basal Blood Glucose Levels in Patients with Type 2 Diabetes After 15 Days of Treatment with Different Doses of 1% Corosolic Acid (18)
Dosage Form	Dose of 1% Corosolic Acid (Equivalent Corosolic Acid Dose)	Percent Reduction in Blood Glucose Levels (± SD)	p-value
	32 mg (0.32 mg)	10.7 ± 1.4	≤0.01
	48 mg (0.48 mg)	30.0 ± 3.4	≤0.002
	32 mg (0.32 mg)	6.5 ± 1.13	≤0.09
	48 mg (0.48 mg)	20.2 ± 1.29	≤0.001

 

Fukushima and colleagues performed a double-blind cross-over design trial in 31 subjects with type 2 diabetes. In this study, subjects were not randomized. Subjects received oral supplementation with a 10 mg corosolic acid (an active constituent of banaba) capsule or placebo five minutes prior to a 75-g oral glucose tolerance test. The majority of the subjects had type 2 diabetes (n=19) while seven had impaired glucose tolerance, one had impaired fasting glucose, and four had normal glucose according to 1998 WHO criteria. Subjects with diagnosed hypertension, hepatic, or renal disease; engaged in heavy exercise; or took any medication were excluded. Thirty minutes after the oral glucose tolerance test, there were no differences in plasma glucose levels. The corosolic acid treatment group showed lower glucose levels from 60 minutes until 120 minutes after glucose administration. Statistical significance was reached at 90 minutes (p<0.05) (22).

 

Adverse Effects and Warnings

 

Banaba extract appears to be well tolerated when used orally. Dizziness, headache, tremor, weakness, diaphoresis, and nausea have been reported (23).

 

Interactions

 

As banaba lowers blood glucose, it should be used with caution in those using other hypoglycemic agents. Banaba may also lower blood pressure and may have an additive effect with other antihypertensives (18, 23).

 

Summary

 

Banaba is possibly effective for the treatment of type 2 diabetes. Data from human studies investigating banaba demonstrate corosolic acid’s potential to lower blood glucose. Small sample size and short study duration limit applicability of results.

 

BITTER MELON (MOMORDICA CHARANTIA)

 

Bitter melon is a plant cultivated in India, Asia, South America, and the Caribbean. Local nomenclature for Bitter melon varies – in India it is known as karela, bitter melon, and bitter gourd. It can also be known as wild cucumber, ampalaya, and cundeamor (24, 25). A member of the melon family, bitter melon is consumed in Asian cuisine and used both orally and topically. Uses for bitter melon include diabetes, cancer, and HIV (26). See Figure 6 for an image of the bitter melon plant.

 

 

Mechanism of Action

 

It is thought bitter melon has insulin-like properties. More specifically, it is hypothesized bitter melon: 1) inhibits mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in pancreatic cells; 2) promotes glucose and fatty acid catabolism; 3) stimulates fatty acid absorption; 4) induces insulin production; 5) improves insulin resistance; 6) stimulates activated protein kinases (AMPK); and 6) inhibits fructose-1,6-bisphosphate and glucose-6-phosphatase (27, 28).

 

Evidence

 

In 2024, a meta-analysis was published that aimed to examine the impact of bitter melon on glycemic control and lipid profiles in individuals with T2DM. Eight randomized controlled trials were included (n=423). The authors found bitter melon was associated with significant reductions in fasting blood glucose (weighted mean distribution [WMD] of -15.3 mg/dL; 95% CI: -25.9 to -4.7; p = 0.005; I²= 73.4 %); postprandial glucose (WMD: -41.0 mg/dL; 95% CI: -60.3 to -21.8; p = 0.000; I² = 66.9 %); and glycosylated hemoglobin A1c (HbA1c) (WMD: -0.38%; 95% CI: -0.53 to -0.23; p = 0.000; I²= 37.6 %). Total cholesterol was also significantly reduced (WMD: -6.8 mg/dL; 95% CI: -12.6 to -1.3; p = 0.017; I² = 63.6 %). No significant differences were observed in terms for triglycerides (TG), high-density lipoproteins (HDL), and low-density lipoprotein (LDL) (29).

 

A 2019 meta-analysis was conducted to evaluate the efficacy of bitter melon in lowering elevated plasma glucose levels in patients with prediabetes and T2DM. Ten studies were included in the meta-analysis and ranged from 4 to 16 weeks in follow up. Overall, bitter melon lowered fasting plasma glucose by 13 mg/dL (95% CI: -23.9 to -2.2). Postprandial glucose decreased by 25.7 mg/dL (95% CI: -39.2 to -12.1) and HbA1c decreased by 0.26% (95% CI, -0.49 to 0.03). Of note, the studies had overall bias risk of moderate to high. The study authors rated the evidence quality low due to risk of bias and inadequate sample size (30).

 

A 2012 Cochrane Review of four randomized controlled trials found no statistically significant difference in glycemic control with bitter melon compared to placebo. Additionally, there was no significant change in glycemic control compared to metformin and sulfonylureas. Of note, no significant interactions were noted (31).

 

Adverse Effects and Warnings

 

Adverse effects reported include abdominal discomfort, pain, and diarrhea (32).

 

Bitter melon has been used as an abortifacient agent. Animal research confirms two proteins isolated from the plant possess abortifacient properties and may decrease fertility (33).

 

Interactions

 

As bitter melon may lower blood glucose, it should be used with caution in those using other hypoglycemic agents.

 

Bitter melon may increase levels of drugs that are P-glycoprotein substrates. For example, levels of apixaban, cimetidine, corticosteroids, diltiazem, erythromycin, fexofenadine, linagliptin, rivaroxaban, and verapamil may be increased with concurrent bitter melon use.

 

Those with G6PD deficiency should avoid use due to risk of developing favism (27).

 

Summary

 

Bitter melon is commonly used medicinally and in cuisine. There is mixed regarding bitter melon’s blood glucose lowering efficacy in patients with type 2 diabetes. Bitter melon has abortifacient properties and should be avoided in pregnancy.

 

FENUGREEK (TRIGONELLA FOENUM-GRAECUM)

 

Fenugreek, a member of the Fabaceae family, is an aromatic herb native to the Mediterranean region, northern Africa, southern Europe, and western Asia. The plant appears clover-like and its leaves are used in southeast Asian cuisine (see Figure 7 for an illustration). The seed is considered to be the pharmaceutically active portion of Trigonella foenum-graecum. If consuming fenugreek seeds, one must crush them to release the viscous gel fiber to increase efficacy. The flavor and fragrance of the seed is similar to maple syrup. Fenugreek seeds are approximately 50% fiber (30% soluble and 20% insoluble fiber) (21, 34).

 

 

Mechanism of Action

 

Fenugreek is thought to lower blood glucose via multiple mechanisms. As fenugreek seeds are fiber rich, it is thought this may slow postprandial glucose absorption (34, 35). Bioactive compounds in fenugreek include 4-hydroxyisoleucine (which accounts for the majority), saponins, alkaloids, and coumarins (36). 4-hydroxyisoleucine increases glucose-dependent insulin secretion in human beta-islet cells (21, 37). Fenugreek may play a role in regulating glucagon-like peptide-1 (GLP-1) through the action of an active compound N55, which is thought to bind to GLP-1 and enhance its potency in stimulating GLP-1 receptor signaling (35). Fenugreek, along with other herbal products used for the treatment of type 2 diabetes, contains biguanide-related compounds. In fact, the history of metformin can be traced back to the use of French lilac as herbal medicine in medieval Europe (38).

Evidence

 

A systematic review and meta-analysis published in 2023 evaluated fourteen trials (n=894) on the effect of fenugreek on hyperglycemia. Twelve of the trials included patients with T2DM; the two remaining trials included patients with pre-diabetes and that were classified as overweight, respectively. The meta-analysis demonstrated a non-significant reduction in fasting blood glucose levels (WMD -3.70 mg/dL; 95% CI: −27.02 to 19.62; p = 0.76) and postprandial blood glucose (WMD of −10.61 mg/dL; 95% CI: −68.48 to 47.26; p = 0.72). A significant reduction in HbA1c was seen (WMD of −0.88%; 95% CI: −1.49 to −0.27; p < 0.05) with fenugreek consumption. See Table 6 for a summary of the results of the meta-analysis (39).

 

Table 6. Fenugreek Meta-Analysis Results (39)
Parameter	Weighted Mean Difference (95% CI)	p-value Weighted Mean Difference	Heterogeneity (I2)	p-value Heterogeneity
HbA1c	-0.88% (-1.49 to -0.27)	<0.05	74.9%	< 0.01
Fasting blood glucose	-3.70 mg/dL (−27.02 to 19.62)	0.76	99.4%	< 0.01
Postprandial glucose	−10.61 mg/dL (−68.48 to 47.26)	0.72	99.1%	< 0.01

 

An earlier meta-analysis evaluated ten trials of fenugreek found both fasting blood glucose and HbA1c significantly decreased with fenugreek compared to placebo. The weighted mean difference in HbA1c was -0.58% (95% CI: -0.99 to -0.17; p<0.05). The same analysis found a difference in fasting blood glucose of – 12.94 mg/dL (95% CI: -21.39 to -4.49; p<0.05) (40).

 

A study evaluating the effect of fenugreek on glycemic control enrolled 25 patients with T2DM. Baseline fasting glucose was less than 200 mg/dL in all study participants. Half of patients received 1 g of hydroalcoholic extract of fenugreek seeds while the other half received placebo. At the end of two months, the fenugreek group’s fasting and two hour post prandial glucose levels were not different from placebo. There was, however, a difference favoring fenugreek in area under the curve of blood glucose (2375 +/- 574 vs 27597 +/- 274) as well as insulin (2492 +/- 2536 vs. 5631 +/- 2428) (p < 0.001). Homeostatic model assessment for insulin resistance (HOMA-IR) was lower in the fenugreek group (86.3 +/- 32 vs. 70.1 +/- 52) and insulin sensitivity increased (112.9 +/- 67 vs 92.2 +/- 57) (p < 0.05) (41).

 

Adverse Effects and Warnings

 

Adverse effects of fenugreek include diarrhea, heartburn, and flatulence (34).

 

Fenugreek is aromatic and smells similar to maple syrup. Consumption prior to delivery may cause the neonate to have this odor, which may lead to confusion with maple syrup urine disease (42).

 

Patients with chickpea allergies should use fenugreek with caution as there is potential for cross-reactivity. Furthermore, fenugreek may cause uterine contractions and should be avoided in pregnancy (34).

 

Interactions

 

Fenugreek preparations may contain coumarin and increase the risk of bleeding with anticoagulants. Theophylline levels may be decreased with concomitant use. As fenugreek may lower blood glucose levels, it should be used cautiously with other agents that decrease glucose (34).

 

Summary

 

Fenugreek is a commonly used herb that is possibly effective for the treatment of hyperglycemia in patients with type 2 diabetes. Due to the risk of uterine contractions, fenugreek should not be used in pregnancy. Fenugreek may contain coumarin and should be used cautiously with anticoagulants.

 

GYMNEMA (GYMNEMA SYLVESTRE)

 

Gymnema is a plant native to tropical and subtropical regions of Asia, Africa, and Australia. Ayurvedic medicine has long utilized gymnema and its Hindi name is gurmar, which means “destroyer of sugar” (43). The pharmaceutically active parts of the gymnema plant are the leaves and roots. See Figure 8 for an image of the gymnema plant (44).

 

 

Mechanism of Action

 

The active constituents of gymnema appear to be gymnemosides, saponins, stigmasterol, and various amino acid derivatives. In terms of glucose lowering, it appears gymnema reduces intestinal absorption of glucose. It may also increase enzymes that promote cellular glucose update. It is hypothesized gymnema impacts beta cells – particularly by increasing cell quantity and by stimulation of insulin release (45-47).

 

Evidence

 

In 2023, a systematic review and meta-analysis of six studies sought to determine the impact of gymnema on various cardiometabolic risk factors, including glycemic control. Participants had T2DM, metabolic syndrome, and/or impaired glucose tolerance. Fasting blood glucose significantly changed by -4.96 mg/dL (CI 95%: -7.65 to -2.27, p<0.001). HbA1c had a non-significant change of -1.78% (95% CI: -4.09 to 0.53, p=0.131). Results are shown in Table 7 (48).

 

Table 7. 2023 Gymnema Systematic Review and Meta-Analysis Results (48)
Parameter	Weighted Mean Difference (95% CI)	p-value Weighted Mean Difference	Heterogeneity (I2)	p-value Heterogeneity
HbA1c	-1.78% (-4.09 to 0.53	0.131	98.9%	< 0.01
Fasting blood glucose	-4.96 mg/dL (-7.65 to -2.27)	<0.001	97.0%	< 0.01

 

An earlier systematic review and meta-analysis of ten studies (n=419) aimed to determine the effect of gymnema on glycemic control in individuals with T2DM. The study found that gymnema significantly reduced fasting blood glucose by 1.57 mg/dl (CI 95%: -2.22 to -0.93, p < .0001) and postprandial blood glucose by 1.04 mg/dl (CI 95%: -1.53 to -0.54, p < .0001). HbA1c was reduced by 3.91% (CI 95%: -7.35 to -0.16%, p < .0001), however heterogeneity did not show significance (see Table 8) (49). 

 

Table 8. 2021 Gymnema Systematic Review and Meta-Analysis Results (49)
Parameter	Weighted Mean Difference (95% CI)	Heterogeneity (I2)	p-value Heterogeneity
HbA1c	-3.91% (-7.35 to -0.16%,)	99%	>0.05
Fasting blood glucose	-1.57 mg/dl (-2.22 to -0.93	90%	< 0.01
Postprandial glucose	−1.04 mg/dl (-1.53 to -0.54)	80%	< 0.01

 

Gymnema was studied in 64 patients with type 1 diabetes in an open-label, non-randomized, controlled trial. The study group received 200 mg twice daily of a water-soluble extract of gymnema by mouth for 6 to 60 months. All participants remained on insulin throughout the duration of the study. Insulin requirements were reduced by 50% in those in the gymnema group. Additionally, blood glucose and HbA1c levels were reduced (50).

 

An open-label and non-randomized trial studied gymnema in 47 patients with T2DM. In addition to conventional oral hypoglycemic agents, 400 mg of a water-soluble extract of gymnema was administered for 18 to 20 months to 22 of the participants.  At the conclusion of the study, the gymnema group had significantly lower fasting glucose (29% reduction, p<0.001). HbA1c levels were also significantly (p<0.001) lower in the gymnema group (baseline 11.9% to 8.48%). Results are summarized in Table 9 (51).

 

Table 9. Effect of Gymnema on Patients with Type 2 Diabetes Mellitus (51)
	Gymnema Group			Control Group
	Baseline	18-20 months	p-value	Baseline	18-20 months	p-value
Fasting blood glucose (mg/dL)	174 ± 7	124 ± 5	<0.001	150 ± 4	157 ± 4	>0.05
HbA1c (%)	11.91 ± 0.30	8.48 ± 0.13	<0.001	10.24 ± 0.15	10.47 ± 0.14	>0.05

 

Adverse Effects and Warnings

 

A case of acute hepatitis secondary to gymnema use has been reported (43).

 

Interactions

 

Gymnema may potentiate the effects of other agents that lower glucose. There is evidence to suggest gymnema can inhibit and induce certain liver enzymes. For example, gymnema may inhibit cytochrome P450 (CYP) 1A2 and increase circulating levels of medications such as clozapine, cyclobenzaprine, mexiletine, olanzapine, propranolol, theophylline, and zolmitriptan. Gymnema may induce CYP 2C9 and decrease levels of concurrently used medications such as nonsteroidal anti-inflammatory drugs, glipizide, losartan, and warfarin (51).

 

Summary

 

Gymnema has been long used in Ayurvedic medicine. It is thought to lower blood glucose via multiple mechanisms. There are minimal human studies evaluating gymnema’s efficacy, but preliminary evidence shows promise.

 

Insulin Sensitizers

 

The natural products contained in this section are known to be insulin sensitizers. This means they improve the sensitivity of cells to the effects of insulin. Products may also employ other mechanisms of action, which are addressed.

 

AMERICAN GINSENG (PANAX QUINQUEFOLIUS)

 

American ginseng is from the Panax genus. While named similarly, American ginseng (Panax quinquefolius) is different from Asian ginseng (Panax ginseng). American ginseng, as its name suggests, is found mostly in North America and is considered endangered in some areas (53). Currently in the United States, only eighteen states allow for the harvesting of American ginseng. See Figure 9 for an image of the American ginseng plant (54).

 

 

Mechanism of Action

 

The root of the American ginseng plant is the portion that exerts a pharmaceutical effect. Saponins, specifically ginsenosides, are hypothesized to reduce glucose levels 55-57). The primary mechanism is thought to be insulin sensitization, but increased insulin secretion and prevention of beta-cell loss may also play a role (56, 57).

 

Evidence

 

Vuksan and colleagues performed a randomized, double-blind, cross-over trial to evaluate the efficacy and safety of American ginseng as complementary therapy in patients with T2DM using conventional therapy. Participants (n=24) received either 1 g of American ginseng extract or placebo for 8-weeks while continuing their original conventional therapies. After a 4-week washout period, participants were crossed over to the opposite 8-week treatment arm. American ginseng reduced HbA1c by 0.29% (p = 0.041) and plasma blood glucose by 12.8 mg/mL (p=0.008). The safety parameters studied, liver and kidney function, were not affected (58). 

 

Vuksan and colleagues performed a randomized, single-blind, controlled study in ten patients to evaluate the efficacy of various doses of American ginseng. Participants received either placebo or 3, 6, or 9 g of American ginseng prior to a 25-g oral glucose challenge. Capillary glucose was measured during the study duration. Compared to placebo, American ginseng significantly decreased glucose (p<0.05) for the 3, 6, and 9 g doses. Glucose area under the curve was also reduced (19.7% for the 3 g dose, 15.3% for the 6 g dose, and 15.9% for the 9 g dose). There was no difference between the various American ginseng doses (56).

 

Due to concern over varying ginsenoside concentrations in different products, a follow up study was completed. The objective of this study was to determine the efficacy of American ginseng with a different ginsenoside profile. Twelve participants received 6 g of American ginseng or placebo after a 75-g oral glucose load. There was no significant difference in venous blood glucose levels at -40, 0, 15, 30, 45, 60, 90, and 120 minutes between the groups. There was also no difference in plasma insulin levels. The American ginseng used in this study contained 1.66% total ginsenosides with the breakdown being 0.90% protopanaxodiol ginsenosides (PPD) and 0.75% protopanaxatriol ginsenosides (PPT) (59).

 

Adverse Effects and Warnings

 

Headache is the most common side effect reported with American ginseng use (60).

 

American ginseng should not be confused for Asian ginseng (Panax ginseng), Siberian ginseng (Eleutherococcus senticosus) (53).

 

Interactions

 

American ginseng may stimulate immune function and may theoretically decrease the effect of immunosuppressants (61).

 

American ginseng can decrease the efficacy of warfarin. Concomitant use is not advised (62).

 

As American ginseng can lower glucose, it should be used cautiously with other glucose lowering agents (56). 

 

Summary

 

Limited trials suggest American ginseng (Panax quinquefolius) may lower blood glucose. However, variability of product ginsenoside profile can impact efficacy. Concomitant warfarin use is not recommended due to decreased warfarin effectiveness. American ginseng is often confused with Asian (Panax ginseng) or Siberian ginseng (Eleutherococcus senticosus).

 

BANABA (LAGERSTROEMIA SPECIOSA)

 

Banaba is a natural product with multiple mechanisms. It was previously covered in the “Hypoglycemia Agents” section.

 

BERBERINE

 

Berberine is a bitter tasting plant alkaloid extracted from various plants. Goldenseal, goldthread, Oregon grape, European barberry, phellodendron, and tree turmeric are all sources. See Figure 10 for an image of European barberry, a source of berberine. Berberine is used for glucose lowering, dyslipidemia, hypertension, and infections (63, 64).

 

 

Mechanism of Action

 

Berberine’s glucose lowering properties are thought to be from increased insulin secretion, increased glycolysis, increased levels of GLUT-4 and GLP-1, activation of PPAR gamma receptors, and alpha-glucosidase inhibition (65-68).

 

Evidence

 

The effect of berberine on metabolic profiles in patients with T2DM was studied in a systematic review and meta-analysis. Thirty-seven randomized controlled trials with 3,048 patients were included.  with at least 60 participants over the age of 18 were included. Compared to the control group, berberine was associated with a significant reduction in fasting plasma glucose (-14.8 mg/dL; 95% CI: -17.1 to -0.12.6; p<0.05), HbA1c (-0.63%; 95% CI: -0.72 to -0.53; p<0.05), and two-hour post prandial blood glucose (-20.9 mg/dL; 95% CI: -24.5 to -17.3; p<0.05). There was significant heterogeneity with each of the three outcomes. Adverse effects were included in 14 of the included studies. Analysis revealed incidence of adverse effects was lower with berberine compared to the control groups. Hypoglycemia was reported in nine studies with no significant difference between the berberine and control groups (fixed effects model; RR = 0.48; 95% CI: 0.21 to 1.08; p = 0.08). Results are presented in Table 10 (69).

 

Table 9. Berberine Systematic Review and Meta-Analysis Results (69)
Parameter	Weighted Mean Difference (95% CI)	Heterogeneity (I2)	p-value Heterogeneity
HbA1c	-0.63% (-0.72 to -0.53)	52%	< 0.001
Fasting blood glucose	14.8 mg/dL (-17.1 to -0.12.6)	60%	< 0.00001
Postprandial glucose	-20.9 mg/dL (-24.5 to -17.3)	68%	< 0.001

 

The analysis also concluded that berberine alone or in combination with oral hypoglycemic agents did not significantly increase the incidence of total adverse events (RR = 0.73; 95% CI: 0.55 to 0.97; p = 0.03) and the risk of hypoglycemia (RR = 0.48, 95% CI 0.21 to 1.08; p = 0.08).

 

Berberine has also been studied in a randomized controlled trial compared to metformin, a medication in the biguanide class. In this study, 36 patients that were recently diagnosed with T2DM were randomized to either berberine 500 mg three times daily or metformin 500 mg three times daily for three months. In the berberine group, HbA1c decreased from 9.5 ± 0.5% to 7.5 ± 0.4% (p<0.01). Fasting blood glucose changed from 191 ± 16 mg/dL to 124 ± 9 mg/dL (p<0.01). Postprandial glucose also decreased from 357 ± 31 mg/dL to 214 ± 16 mg/dL (p<0.01). These differences were similar to metformin. At the end of the trial, the HbA1c lowering effect of berberine was similar to metformin (70).

 

Adverse Effects and Warnings

 

Gastrointestinal side effects are most common with berberine (diarrhea, constipation, flatulence, abdominal pain, and vomiting).

 

Uterine contractions are an adverse effect of berberine. Berberine is also thought to cross the placenta and neonatal kernicterus may result when ingested during pregnancy. Use in pregnancy is not recommended. Berberine can be transferred through breastmilk (71, 72).

 

Interactions

 

Berberine may inhibit cytochrome P450 3A4, 2D6, and 2C9 and should be used cautiously with other agents that are substrates, inhibitors, or inducers of these hepatic enzymes. Of note, cyclosporine levels can be increased and concomitant use is not advised.

 

As berberine lowers glucose, caution should be exercised when used with other agents that lower glucose. Berberine may increase the risk of bleeding when used with anticoagulants (64).

 

Summary

 

Berberine is an alkaloid extract derived from various plants. There is evidence to suggest berberine lowers fasting glucose, postprandial glucose, and HbA1c. Berberine may cause uterine contractions and kernicterus so should be avoided during pregnancy. There is concern that berberine inhibits several CYP enzymes and may contribute to multiple drug interactions.

 

CHROMIUM

 

Chromium is a mineral essential to humans. It is found naturally in brewer’s yeast (where it was first discovered), oysters, mushrooms, liver, potatoes, beef, cheese, and fresh vegetables. Chromium exists in two valences – trivalent and hexavalent. Trivalent chromium (Cr⁺³ or Cr III) is the biologically active form found in food and supplements. Hexavalent chromium (Cr⁺⁶ of Cr VI) is a toxic manufacturing byproduct and may cause lung cancer, dermatologic issues, and perforated nasal septum with chronic exposure (73, 74). Chromium in this section will refer to the commercially available trivalent chromium.

 

Chromium may be referred to as glucose tolerance factor (74, 75). However, glucose tolerance factor is a complex that contains, amongst other molecules, chromium. There is an apparent association between low chromium levels and impaired glycemic control (76).

 

The Food and Nutrition Board of the Institute of Medicine determined there was not sufficient evidence to set an Estimated Average Requirement for chromium consumption. However, they did suggest Adequate Intake (AI) levels. For adults, the AI is 35 mcg per day for men and 25 mcg per day for women. Due to the fact few serious adverse effects are associated with excess chromium from food, there is no designated Tolerable Upper Intake Level (74).

 

Chromium is typically found in the chloride, nicotinate, and picolinate salt forms. It is thought the picolinate salt is absorbed by humans best (73, 77).

 

Mechanism of Action

 

The exact mechanism of chromium has not been elucidated. Chromium has an insulin sensitizing effect by reducing the content and activity of the tyrosine phosphatase PTP-1B (78). Alternatively, chromium might act directly on the insulin receptor (79, 80).

 

Evidence

 

Despite plausible mechanisms of action, there is mixed evidence surrounding chromium for the treatment of diabetes (75, 81).

 

A systematic review and meta-analysis of ten studies (n=509) was published in 2021 to determine the effect of chromium supplementation on blood glucose and lipid levels in patients with T2DM. The weighted mean difference in HbA1c indicated a significant reduction in HbA1c (-0.54%; 95% CI: -0.98 to -0.09; p = 0.02). No difference in fasting plasma glucose was found (-29.65 mg/dL; 95% CI: -68.62 to 9.31; p=0.14). There was no difference found in triglycerides, total cholesterol, low-density lipoproteins, and high-density lipoproteins. Results are summarized in Table 10 (82).

 

Table 10. 2021 Meta-Analysis Results of the Effect of Chromium on Glycemic Control in Patients with Diabetes (82)
Parameter	Weighted Mean Difference (95% CI)	Heterogeneity (I2)	p-value Heterogeneity
HbA1c	-0.54% (-0.98 to -0.09)	84%	< 0.01
Fasting blood glucose	-29.65 mg/dL (-68.62 to 9.31)	97%	< 0.00001

 

A meta-analysis of 28 randomized controlled studies aimed to investigate the effect of chromium on glycemic control in patients with T2DM was published in 2020. The revealed significant reductions in HbA1c (-0.71%; p = 0.004) and fasting blood glucose (-19.0 mg/dL; p = 0.030) with chromium use. Insulin levels (-12.35 pmol/L, p <0.001) and homeostatic model assessment for insulin resistance (HOMA-IR) were also significantly lower with chromium. HOMA-IR levels decreased by 1.53 (p <0.001). There was significant heterogeneity between studies for HbA1c, fasting blood glucose, insulin, and HOMA-IR. Results are shown in Table 11 (83).

 

Table 11. 2020 Meta-Analysis Results of the Effect of Chromium on Glycemic Control in Patients with Diabetes (83)
Parameter	Weighted Mean Distribution (95% CI)	p-value Weighted Mean Distribution	Heterogeneity (I2)	p-value Heterogeneity	p-value Begg’s test
HbA1c (%)	-0.71 (-1.19 to -0.23)	0.004	99.2%	<0.001	0.143
Fasting blood glucose (mg/dL)	-19.0 (-36.15 to -1.85)	0.030	99.8%	<0.001	0.086
Insulin level (pmol/L)	-12.35 (-17.86 to -6.83)	<0.001	98.1%	<0.001	0.363
HOMA-IR	-1.53 (-2.35 to -0.72)	<0.001	89.9%	<0.001	0.466

 

Another meta-analysis of 25 randomized controlled trials evaluating the efficacy of chromium supplementation was published in 2014. Of these trials, 22 studied chromium monosupplementation, while two trials studied chromium in combination with biotin and one trial studied chromium with vitamins C and E. Trial duration varied from four to 24 weeks. In the 14 included trials that assessed HbA1c, there was a statistically significant change of -0.55% (95% CI: -0.88 to -0.22). Twenty-four studies evaluated fasting glucose and the pooled mean change was -20.7 mg/dL (95% CI: -33.1 to -8.5). Monosupplementation with chromium significantly decreased triglycerides (-26.6 mg/dL; p=0.002) and increased high density lipoprotein concentration (4.6 mg/dL; p=0.01). There was no change in total cholesterol or low-density lipoprotein concentrations. The meta-analysis authors concluded chromium supplementation had favorable effects on HbA1c and fasting glucose in patients with diabetes (75). Results from this meta-analysis are presented in Table 12.

 

Table 12. Meta-Analysis Results of the Effect of Chromium on Glycemic Control in Patients with Diabetes (75)
Parameter	Pooled Mean Difference (95% CI)	Heterogeneity P-Value
HbA1c (%)	-0.55% (-0.88 to -0.22)	<0.00001
Fasting glucose (mg/dL)	-20.7 mg/dL (-33.1 to -8.5)	<0.00001

 

A meta-analysis from 2002 of 15 randomized controlled trials was conducted to determine the efficacy of chromium on glycemic control. Doses in the included trials ranged from 10 to 1,000 micrograms of chromium daily and varied in terms of source (brewer’s yeast, chromium chloride, chromium nicotinate, chromium picolinate, or chromium-niacin). Study duration ranged from one to 16 months. In terms of fasting glucose, 14 studies and 463 patients were included (n=38 with diabetes and n=425 without diabetes). For all included patients, the fasting glucose pooled mean difference was 0.5 mg/dL (95% CI: -1.6 to 2.7) with no evidence of heterogeneity (p=0.97).  The effect of chromium supplementation on two-hour OGTT results were included in five of the 14 trials. The majority of patients did not have a diabetes diagnosis (n=133 versus 8 with a diabetes diagnosis). The pooled mean difference was 4.7 mg/dL (95% CI, -4.3 to 13.7) with no evidence of heterogeneity (p=0.98). Fasting insulin levels were recorded in 10 of the studies (8 patients with diabetes and 326 without diabetes). The pooled mean difference in fasting insulin with chromium use was 0.28 pmol/L (95% CI, -7.0 to 7.5, heterogeneity p=0.097). Three of the trials assessed HbA1c (33 healthy subjects, 24 with glucose intolerance, and 155 with diabetes). There was no association between chromium supplementation and HbA1c in the study of healthy subjects. The single study that included subjects with glucose intolerance showed chromium supplementation was associated with a nonsignificant reduction in HbA1c (mean difference -0.30%; 95% CI: -0.86 to 0.25). The study that included subjects with diabetes showed a reduction in HbA1c for different chromium doses (mean difference for 1000 micrograms: -1.90%; 95% CI: -2.34 to -1.46; mean difference for 200 micrograms: -1.00%; 95% CI: -1.55 to -0.45). Data from the meta-analysis is presented in the following table. The authors of the meta-analysis concluded there was no effect of chromium on glucose or insulin concentrations in subjects without diabetes. The data for those with diabetes was inconclusive. Table 13 summarizes these results (81).

 

Table 13. Meta-Analysis Results of the Impact of Chromium on Glycemic Control (81)
Parameter	Number of Studies	N Patients with Diabetes	N Patients without Diabetes	Chromium Supplementation Pooled Mean Difference (95% CI)	Heterogeneity p Value
Fasting glucose (mg/dL)	14	38	425	0.5 (-1.6 to 2.7)	0.97
2-hour glucose tolerance test (mg/dL)	5	8	133	4.7 (-4.3 to 13.7)	0.98
Fasting insulin (pmol/L)	10	8	326	0.28 (-7.0 to 7.5)	0.097

 

Adverse Effects and Warnings

 

Trivalent chromium has demonstrated safety in large doses (74, 75). The picolinate form may cause cognitive, perceptual, and moto dysfunction (84).

 

Hexavalent chromium is toxic and is listed as a known carcinogen (74).

           

Interactions

 

There is a theoretical interaction between chromium and iron (74).

 

Summary

 

Chromium is a mineral essential to humans and may be referred to as glucose tolerance factor. There is conflicting evidence in terms of efficacy. Meta-analyses published in 2020 and 2014 suggested chromium decreased HbA1c and fasting glucose in patients with diabetes. Another meta-analysis published in 2002 found chromium to have no impact on glycemic control in those without diabetes. 

 

CINNAMON (CINNAMOMUM AROMATICUM, CINNAMOMUM CASSIA)

 

Cinnamon is a natural product derived from the dried inner bark of the evergreen tree. It is commonly used in many cuisines. Cinnamon commonly found in grocery stores for culinary purposes is usually Cinnamomum cassia, but may be Ceylon cinnamon (85, 86).

 

Mechanism of Action

 

Procyanidin polymers appear to be responsible for cinnamon’s insulin sensitizing actions. It is hypothesized that these compounds increase phosphorylation of the insulin receptor, therefore, increasing sensitivity to insulin. Cinnamon may also stimulate insulin release and increase GLP-1 and GLUT-4 levels. Evidence also suggests cinnamon increases cellular glucose uptake (87-90).

 

Evidence

 

Cinnamon has shown mixed results in various trials in patients with diabetes (91-94).

 

In 2012, a Cochrane Review was published evaluating the effectiveness of cinnamon in patients with T2DM. The primary outcomes included fasting glucose, postprandial glucose, and adverse effects. Change in HbA1c was a secondary outcome. There was no change in fasting glucose (-1.4 mg/dL; 95% CI: -6.1 to 3.2), post-prandial glucose (-7.0; 95% CI: -14.9 to 0.9), or HbA1c (-0.06%; 95% CI: -0.29 to 0.18]. There was no difference in adverse effects between users and non-users of cinnamon (OR 0.83; 95% CI: 0.22 to 3.07), p = 0.77; n = 264; 4 trials). Table 14 presents the results from this review (95).

 

Table 14. Cochrane Review Results of the Effect of Cinnamon on Glycemic Control in Patients with Diabetes (95)
Parameter	Weighted Mean Distribution (95% CI)	p-value Weighted Mean Distribution	Heterogeneity (I2)	Number of Trials
HbA1c (%)	-0.06% (-0.29 to 0.18)	0.63	0%	6
Fasting blood glucose (mg/dL)	-1.4 (-6.1 to 3.2)	0.06	0%	8
Postprandial glucose (mg/dL)	-7.0 (-14.9 to 0.9)	0.08	n/a	1

 

More recently, a systematic review and meta-analysis by Moridpour and colleagues was published in 2024 that aimed to assess the effects of cinnamon supplementation in managing glycemic control in patients with T2DM. Twenty-four randomized controlled trials were included. The pooled results indicated cinnamon had a statistically significant (p<0.05) reduction in fasting blood glucose (-1.32 mg/dL; 95 % CI: -1.77 to -0.87; p<0.001), HbA1c (-0.67%; 95 % CI: -1.18 to -0.15; p=0.011), and HOMA-IR (-0.44; 95 % CI: -0.77 to -0.10; p<0.001). Results are summarized in Table 15 (94).

 

Table 15. Systematic Review and Meta-Analysis of the Effect of Cinnamon on Glycemic Control in Patients with Diabetes (94)
Parameter	Weighted Mean Distribution (95% CI)	p-value Weighted Mean Distribution	Heterogeneity (I2)	p-value Heterogeneity	Number of Trials
Fasting blood glucose (mg/dL)	-1.32 (-1.77 to -0.87)	<0.001	94.0%	<0.001	23
HbA1c (%)	-0.67% (-1.18 to -0.15)	0.011	94.7%	<0.001	18
HOMA-IR	-0.44 (-0.77 to -0.10)	<0.001	79.1%	<0.001	8

 

A systematic review and meta-analysis by Deyno and colleagues was published to evaluate the efficacy of cinnamon in patients with type 2 diabetes mellitus and pre-diabetes. Sixteen randomized controlled studies were included in the meta-analysis. There was no significant change in weighted mean difference of HbA1c and lipid profiles. There was, however, a statistically significant difference in fasting blood glucose and HOMA-IR. High heterogeneity was observed in the included studies and cinnamon doses ranged from 1 g to 14.4 g a day. Results can be found in Table 16 (96).

 

Table 16. Meta-Analysis Results for the Effect of Cinnamon on Glycemia and Lipoprotein Levels (96)
Parameter	Weighted Mean Difference (95% CI)	Heterogeneity (I2)
Glycemic
Fasting plasma glucose (mg/dL)	-9.8 (-16.4 to -3.2)	83.6%
HbA1c (%)	-0.104 (-0.138 to 0.110)	69.6%
HOMA-IR	-0.714 (-1.388 to -0.04)	84.4%
Lipoprotein
Total Cholesterol (mg/dL)	-3.6 (-7.3 to 0.2)	86.4%,
Low density lipoprotein concentration (mg/dL)	-2.1 (-4.9 to 0.7)	86.0%
High density lipoprotein concentration (mg/dL)	-0.1 (-1.1 to 0.9)	81.0%
Triglycerides (mg/dL)	-1.8 (-4.0 to 0.4)	69.0%

 

A randomized, double-blind, placebo-controlled trial evaluated the effect of cinnamon on 66 Chinese patients with type 2 diabetes (HbA1c greater than 7% and fasting glucose greater than 144 mg/dL). Patients were not receiving insulin or other glucose-lowering agents aside from glicazide, a sulfonylurea, of which all participants were taking 30 mg daily. Patients were randomized to 120 mg daily of cinnamon, 360 mg daily of cinnamon, or placebo for 12 weeks. Both the 120 mg and 360 mg cinnamon groups experienced significantly lower HbA1c and fasting plasma glucose measurements. There was no significant change in either parameter for the placebo group. Results are provided in Table 17 (97).

 

Table 17. Effect of Various Cinnamon Doses on Glycemic Parameters (97)
	Cinnamon 120 mg Daily Group	Cinnamon 360 mg Daily Group	Placebo Group
Change in HbA1c (%) (95% CI)	-0.67 (-1.1 to -0.25)	-0.93 (-1.38 to -0.47)	0.00 (-0.61 to 0.61)
Change in fasting plasma glucose (mg/dL) (95% CI)	-18.4 (-29.0 to -7.57)	-29.2 (-41.8 to -16.8)	-3.96 (-24 to 16)

 

Adverse Effects and Warnings

 

Cinnamon is typically tolerated well (98-100).

 

Cinnamon is a natural source of coumarin and use therefore presents a theoretical risk of hepatic injury (101).

 

Interactions

 

Due to concerns of hepatic injury when large doses of cinnamon are used, use cautiously with other hepatotoxic agents.

 

Cinnamon may decrease glucose levels and should be used cautiously with other agents that lower glucose.

 

Summary

 

Cinnamon is derived from the dried inner bark of evergreen trees and is commonly used as a spice in cuisine. In terms of glycemic lowering, cinnamon studies have shown varying results. A 2012 Cochrane review found cinnamon to be no more effective than placebo; a 2024 meta-analysis found cinnamon to have statistically significant improvements on fasting plasma glucose and HbA1c. Cinnamon is typically well tolerated.

 

GYMNEMA (GYMNEMA SYLVESTRE)

 

Gymnema has multiple mechanisms of action is addressed under the “Hypoglycemic Agents” section.

 

MILK THISTLE (SILYBUM MARIANUM)

 

Milk thistle (Silybum marianum) is a member of the aster family which also includes daisies and thistles (102). The plant itself is edible and was native to Europe before introduction to North America. Currently, milk thistle is found in Europe, North America, India, China, South America, Africa, and Australia (103).

 

Milk thistle has a long history of medicinal use. Use dates back to the time of ancient Greece. Milk thistle is used for diabetes, liver support, and menstrual support. An image of the milk thistle plant can be found in Figure 11 (103, 104).

 

 

Mechanism of Action

 

The mechanism of action of milk thistle for glycemic control is not fully understood. The pharmaceutically active portions of the plant are the seeds and the above ground portions. Milk thistle seed extract is comprised primarily (up to 80%) of silymarin. Silymarin contains various flavonolignans, the most active being silybin or silibinin (102, 103, 105, 106).

 

Silymarin decreases insulin resistance and may have a protective pancreatic effect through a mechanism thought to involve antioxidant properties (107, 108). Some studies suggest that silymarin may also regenerate pancreatic beta cells and enhance insulin sensitivity of liver and muscle cells (106). Carbohydrate-induced glycolysis is decreased by silibinin through pyruvate kinase inhibition (103, 109).

 

Evidence

 

Milk thistle has been studied in randomized controlled trials. Soleymani and colleagues published a meta-analysis of 30 studies to determine the effects of milk thistle on cardiometabolic syndrome. Adults (with and without diabetes) were included. The study demonstrated that milk thistle significantly reduced the levels of fasting plasma glucose (WMD: -17.96 mg/dL; 95% CI: -32.91 to -3.02); HbA1c (WMD: -1.25%; 95% CI: -2.34 to -0.16); total cholesterol (WMD: -17.46 mg/dL; 95% CI: -30.98 to -3.95); triglycerides (WMD: -25.70 mg/dL; 95% CI: -47.23 to -4.17); low-density lipoproteins (WMD: -10.53 mg/dL; 95% CI: -19.12 to -1.94). High-density lipoprotein levels increased (WMD: 3.36 mg/dL; 95% CI: 0.88 to 5.84). There was no difference in BMI. The majority of patients included in the meta-analysis had type 2 diabetes mellitus. Results are summarized in Table 18 (106).

 

Table 18. Effect of Various Cinnamon Doses on Glycemic Parameters (106)
Parameter	Weighted Mean Difference (95% CI)	p-value Weighted Mean Difference	Heterogeneity (I2)	p-value Heterogeneity
Glycemic
Fasting plasma glucose (mg/dL)	-17.96 (-32.91 to -3.02)	<0.05	82.4%	<0.001
HbA1c (%)	-1.25% (-2.34 to -0.16)	<0.05	92.9%	<0.001
Lipoprotein
Total Cholesterol (mg/dL)	-17.46 (-30.98 to -3.95)	<0.05	62.9%	0.006
Low density lipoprotein concentration (mg/dL)	-10.53 (-19.12 to -1.94)	<0.05	37.5%	0.119
High density lipoprotein concentration (mg/dL)	3.36 (0.88 to 5.84)	<0.05	81.0%
Triglycerides (mg/dL)	-25.70 (-47.23 to -4.17)	<0.05	54.3%	0.025
Body Mass Index (kg/m2)	0.07 kg (-0.7, 0.83)	>0.05	0%	0.94

 

In 2020, a meta-analysis was published to evaluate the efficacy and safety of milk thistle in patients with glucose or lipid metabolic dysfunction. Sixteen studies (n=1358) were included in the analysis. Fasting blood glucose levels and HbA1c were reduced significantly in milk thistle users compared to placebo. There was no difference between the groups in liver enzymes, creatinine phosphokinase, or creatinine. Results are shown in Table 19 (110).

 

Table 19. Effect of Silymarin on Glucose and Lipid Parameters (110)
Parameter	Weighted Mean Difference (95% CI)	p-value
Glycemic
Fasting plasma glucose (mg/dL)	-22.9 mg/dL (-32 to -13.7)	<0.001
HbA1c (%)	-1.88 (-2.57 to -1.20)	<0.001

 

A meta-analysis of trials was published in 2011 that evaluated the impact of milk thistle on glycemic control in patients with type 2 diabetes. Two studies (n=89) were identified that met analysis criteria. The mean pooled difference in fasting glucose was -38.1 mg/dL (95% CI: -66.6 to -9.5). The mean pooled difference in HbA1c was -1.92% (95% CI: -3.32 to -0.51). Heterogeneity for both had p-values of less than 0.05. The authors concluded milk thistle may improve glycemic control in patients with type 2 diabetes.

 

The two studies included in the aforementioned meta-analysis each individually showed statistically significant change in fasting glucose as well as HbA1c (107, 111). Results are shown in the Tables 20 and 21.

 

Table 20. The Effect of Milk Thistle on Glycemic Control (107)
Parameter	Milk Thistle Treatment (SD)	Control (SD)	P-Value
Fasting glucose (mg/dL)	133 (39)	188 (48)	0.001
HbA1c (%)	6.8 (1.1)	9.5 (2.2)	0.001

 

Table 21. The Effect of Milk Thistle on Fasting Glucose and HbA1c (111)
Parameter	Milk Thistle Treatment (SD)	Control (SD)	P-Value
Fasting glucose (mg/dL)	167.58 (9.9)	193.14 (16.1)	<0.01
HbA1c (%)	7.45 (0.8)	8.71 (0.63)	<0.05

 

Milk thistle has also been studied in combination with berberine. The combination of the two was more effective than berberine alone in reducing HbA1c in type 2 diabetes patients (112).

 

Adverse Effects and Warnings

 

Milk thistle is typically well tolerated. Side effects include nausea, diarrhea, and abdominal bloating (113).

 

As milk thistle is a member of the aster family, cross reactivity may exist with other plants. Those with a daisy or ragweed allergy may experience a cross reaction with milk thistle use (102).

 

Interactions

 

Milk thistle may inhibit certain cytochrome P450 isoenzymes. The isoenzymes 2C8, 2C9, 2D6, 3A4, and 3A5 may all be inhibited with concomitant use (114, 115).

 

As milk thistle may lower glucose levels, it should be used cautiously with other hypoglycemia agents. Increased warfarin levels may occur with concomitant use (116).

 

Summary

 

Milk thistle is a member of the aster family and is used for lowering glucose, liver support, and menstrual support. There is modest evidence to suggest milk thistle may lower glucose in patients with diabetes.

 

PRICKLY PEAR CACTUS (OPUNTIA FICUS-INDICA AND OTHER OPUNTIA SPECIES), NOPAL

 

Prickly pear cactus is native to Mexico and found widely in the southwestern United States, Africa, Australia, and the Mediterranean. The berries of the cactus are oval, edible, and may vary in color (117, 118). Prickly pear cactus has been used historically in Mexican cultures as a treatment for type 2 diabetes. Figure 12 illustrates the prickly pear cactus plant (119).

 

 

Mechanism of Action

 

Much of the prickly pear cactus plant is pharmaceutically active – the leaves, flowers, stems, and fruit are all thought to exert an effect. The plant contains carbohydrate, protein, fat, and fiber (120). It is thought prickly pear cactus lowers glucose by acting as an insulin sensitizer and by slowing carbohydrate absorption (117, 120, 121).

 

Evidence

 

A systematic review that included 20 articles investigated the effects of various parts of the prickly pear cactus plant on glucose and insulin. Studies that used prickly pear cactus fruit generally did not impact serum glucose or insulin. Studies that used the cladode portion of the plant (flat, leaf-like stem) predominantly demonstrated reductions in glucose and insulin (122).

 

A randomized, double-blind, placebo-controlled study was conducted to evaluate and effect of prickly pear cactus in obese patients with pre-diabetes. Patients received either 200 mg of a proprietary prickly pear product (n=15) or placebo (n=14). Patients underwent two different oral glucose tolerance tests – one without prickly pear cactus to determine baseline values and one half an hour after prickly pear cactus ingestion. There was a significant difference (p<0.05) in plasma glucose concentrations at 60, 90, and 120 minutes following the glucose tolerance test for the prickly pear cactus group. There was no difference in HbA1c, insulin levels, high sensitivity C-Reactive Protein, body weight, or fat mass. There was also no difference in comprehensive metabolic profile parameters (123).

 

Most prickly pear cactus trials were published in Spanish only with abstracts available in English. Two trials showed a decrease in postprandial glucose from prickly pear administration (124, 125). Another trial showed when added to a high-carbohydrate or high-soy-protein breakfast, prickly pear cactus decreased glucose area under the curve (126).

 

Adverse Effects and Warnings

 

Prickly pear cactus is generally tolerated well when used orally. Side effects include nausea, diarrhea, and headache (120).

 

Interactions

 

Prickly pear cactus may lower glucose levels and should be used cautiously with other agents that impact glycemic control (123, 126).

 

Summary

 

Prickly pear cactus was used historically in Mexican cultures and is gaining popularity. There is preliminary data to suggest prickly pear cactus may be effective in lowering glucose. Some parts of the plant, i.e., the cladode, may be more efficacious than others, i.e., fruit. However, more studies are needed to determine efficacy. Prickly pear cactus is usually well tolerated.

 

SOY (GLYCINE MAX)

 

Soy comes from the soybean, a legume originating from Asia. In fact, prior to the 1950s soybean was seldom grown outside of the region. Now soybeans are grown in other regions such as North and South America. Soybeans are used in various food preparations such as edamame, tofu, and soymilk. An image of a soybean plant can be found in Figure 13 (127.

 

 

Mechanism of Action

 

The portion of soy that is pharmaceutically active is the bean. Soybeans are protein-rich and contain calcium, iron, potassium, amino acids, vitamins, and fiber (128). Soybeans contain phytoestrogens (isoflavones and lignans) and phytosterols, which are biologically active (129. 130).

 

Soy works via various mechanisms. Soy has insulin sensitizing properties and may slow carbohydrate absorption due to its fiber content. It is hypothesized that the fiber content of soy helps reduce glucose levels (128, 131).

 

Evidence

 

Results on the efficacy of soy in type 2 diabetes are conflicting. A systematic review and meta-analysis summarizing the association of soy intake and the risk of type 2 diabetes was published in 2020. Fifteen studies were included (n = 565,810) and multivariable-adjusted relative risks were determined. The relative risk of incidence of type 2 diabetes was 0.83 (95% CI: 0.68 to 1.01; p>0.05) for total soy. The relative risk for soy milk was 0.89 (95% CI: 0.71 to 1.11; p>0.05); tofu was 0.92 (95% CI: 0.84 to 0.99; p<0.05); soy protein was 0.84 (95% CI: 0.75 to 0.95; p<0.05); and soy isoflavones was 0.88 (95% CI: 0.81 to 0.96; p<0.05). High heterogeneity was observed in the total soy (I² = 90.8%) and soy milk (I²= 91.7%) categories. Inverse linear associations were observed for the tofu, soy protein, and soy isoflavone groups. The quality of evidence was rated as low for the total soy, soy milk, tofu, soy protein, and soy isoflavone groups. The study authors suggested dietary intake of tofu, soy protein, and soy isoflavones are inversely associated with type 2 diabetes incidence. They found no association between total soy intake and incidence of type 2 diabetes. The authors cautioned that the overall quality of evidence was low (132).

 

In 2020, Zuo and colleagues conducted a systematic review and meta-analysis regarding the intake of soy and the association with type 2 diabetes mellitus and cardiovascular disease events. The review included 29 studies with 16,521 individuals with T2DM and 54,213 individuals with cardiovascular disease events. The follow up duration of the studies ranged from 2.5 to 24 years. In groups with the highest soy consumption compared to the lowest soy consumption, there was a significant reduction in the risk of T2DM (17%; total relative risk [TRR] = 0.83; 95% CI: 0.74 to 0.93); cardiovascular disease events (13%; TRR = 0.87; 95% CI: 0.81 to 0.94); coronary heart disease (21%; TRR = 0.79; 95% CI: 0.71 to 0.88); and stroke (12%; TRR = 0.88; 95% CI: 0.79 to 0.99). Daily tofu intake of 26.7 g of reduced cardiovascular disease event risk by 18% (TRR = 0.82; 95% CI: 0.74 to 0.92) and daily intake of 11.1 g of natto lowered cardiovascular disease event risk by 17% (TRR = 0.83; 95% CI: 0.78 to 0.89). The authors concluded that soy consumption was negatively associated with the risk of developing T2DM and cardiovascular disease events (133).

 

In 2018, a meta-analysis was published that aimed to evaluate the efficacy of soy in preventing diabetes. Eight studies were included in the meta-analysis. Soy intake decreased the risk of type 2 diabetes with an overall risk reduction of 0.77 (95% CI: 0.66 to 0.97). Soy protein and isoflavone intake lowered the risk of diabetes with risk reduction of 0.77 (95% CI: 0.80 to 0.97). A subgroup analysis looked at the relationship of soy intake in women and Asian populations. Women had a risk reduction of 0.65 (95% CI: 0.49 to 0.87) and Asian populations had a risk reduction of 0.73 (95% CI: 0.61 to 0.88). The study authors concluded soy intake may be associated with a decreased risk of type 2 diabetes (134).

 

Yang and colleagues performed a meta-analysis evaluating the impact of soy on glycemic control and lipoproteins in patients with type 2 diabetes. Eight studies were included and found there was no association between soy consumption and fasting glucose and HbA1c. There was, however, a significant reduction in serum cholesterol, triacylglycerol, and LDL-C, associated with soy use (p<0.001 for all). The authors concluded there was no significant effect of soy on fasting glucose, insulin, or HbA1c, but there was a favorable effect on serum lipids (135).

 

Another meta-analysis was published in 2011 examining the impact of soy intake on glycemic control. Twenty-four trials were included (n=1,518). The pooled mean change in fasting glucose was -0.69 mg/dL (95% CI, -1.65 to 0.27). Fasting insulin concentrations decreased by 0.18 mg/dL (95% CI, -0.70 to 0.34). The authors concluded there was no significant overall effect of soy on fasting glucose and insulin, but there was a favorable change in studies that used whole soy foods or soy diet (136).

 

Adverse Effects and Warnings

 

Soy is generally well tolerated with side effects being nausea, diarrhea, and bloating. There is concern that soy may alter thyroid function, but this appears to occur in those with iodine deficiency (137-139).

 

Interactions

 

Fermented soy products such as tofu may contain small amounts of tyramine. Tyramine should be avoided in those using monoamine oxidase inhibitors (140). 

 

Summary

 

Soy comes from the soybean plant and contains phytoestrogens and phytosterols. There is some data to suggest soy consumption may decrease the risk of type 2 diabetes. Two meta-analyses showed soy did not significantly decrease fasting glucose of HbA1c in patients with type 2 diabetes. 

 

VANADIUM

 

Vanadium is a mineral found in food sources such as mushrooms, shellfish, black pepper, parsley, dill seed, and certain prepared foods. Beer and wine are also sources. Grains account for 13 to 30 percent of vanadium in adult diets (74).

 

Mechanism of Action

 

Vanadium increases sensitivity to insulin and may mimic insulin’s actions. It may stimulate glucose oxidation and transport, stimulate hepatic glycogen synthesis, inhibit hepatic gluconeogenesis, and increase glucose uptake. Vanadium inhibits phosphotyrosine phosphatase enzymes which impact the insulin receptor (141, 142).

 

Evidence

 

A systematic review of five trials (n=48) evaluated vanadium’s impact in glycemic control. Doses varied from 50 mg to 300 mg of vanadium over three to six weeks. All trials reported reductions in fasting glucose values. However, none of the trials included controls (85).

 

A study of vanadium’s role in glycemic control enrolled 11 patients with type 2 diabetes. Patients were treated with 150 mg of vanadyl sulfate (a salt form of vanadium) for 6 weeks. Treatment with vanadyl sulfate decreased fasting glucose from 194 mg/dL ± 16 to 155 mg/dL ± 15. There was no change in body weight. Patients had an increased rate of hepatic glucose production (HGP) compared with controls (4.1 ± 0.2 vs. 2.7 ± 0.2 mg/kg lean body mass/min; p< 0.001), which was closely correlated with fasting glucose (r = 0.56; p< 0.006). Vanadyl sulfate reduced HGP by about 20% (P < 0.01), and the decline in HGP was correlated with the reduction in FPG (r = 0.60; p<0.05). Vanadyl sulfate also caused a modest increase in insulin-mediated glucose disposal (from 4.3 ± 0.4 to 5.1 ± 0.6 mg/kg lean body mass/min; p< 0.03), although the improvement in insulin sensitivity did not correlate with the decline in fasting glucose after treatment (r = -0.16; p>0.05). Thus, vanadyl sulfate at a dose of 150 mg/day for 6 weeks improves hepatic and muscle insulin sensitivity in patients with type 2 diabetes. The glucose-lowering effect of vanadyl sulfate correlated well with the reduction in HGP, but not with insulin-mediated glucose disposal, suggesting that liver, rather than muscle, is the primary target of vanadyl sulfate action at therapeutic doses (143).

 

Li and colleagues conducted a case-control study to explore the association of plasma vanadium with gestational diabetes mellitus. They included 252 newly diagnosed gestational diabetes mellitus cases with 252 controls matched by age, parity, and gestational age. Plasma concentrations of vanadium were significantly lower in the gestational diabetes mellitus group compared to the control group (p<0.001). The authors concluded there was an inverse association between plasma vanadium and gestational diabetes mellitus (144).  

 

Adverse Effects and Warnings

 

Acute vanadium toxicity does not appear to be a common concern. Mild gastrointestinal effects such as abdominal cramps and loose stools may occur. Animal studies suggest vanadium may cause anemia. However, this has not been shown in humans (74).

 

Interactions

 

There is theoretical concern that vanadium may increase the risk of bleeding in anticoagulant agents (145).

 

Summary

 

Vanadium is a mineral that may increase sensitivity to insulin. There is a lack of human data to support the use of vanadium as a glucose lowering agent, but there is promise. 

 

Carbohydrate Absorption Inhibitors

 

The natural products contained in this section are known to be carbohydrate absorption inhibitors. This means they theoretically lower plasma glucose by preventing the absorption of ingested carbohydrate. Products may also employ other mechanisms of action, which are addressed.

 

ALOE VERA GEL

 

Aloe is a desert plant that appears similar to a cactus and typically grows in hot and dry climates. See Figure 14 for an image of the aloe plant. Aloe byproducts are commonly used in cosmetics and medicine. The byproducts aloe vera gel and aloe latex are common (146).

 

 

Mechanism of Action

 

The portion of the aloe extract that is thought to be pharmaceutically active is the leaf. Aloe gel is clear and can be extracted from the leaf (147, 148). Monosaccharides, polysaccharides, tannins, sterols, enzymes, amino acids, salicylic acid, arachidonic acid, lipids, vitamins, and minerals are all found in aloe vera gel (148). Studies in mice suggest aloe gel may stimulate beta-cells, while human studies show conflicting evidence. Aloe latex contains anthraquinones and may be toxic. Aloe latex should not be confused with aloe gel (149, 150).

 

Evidence

 

In 2021, an analysis of four systematic reviews analyzing the metabolic effects of aloe vera in individuals with type 2 diabetes and pre-diabetes was published. Fasting blood glucose was significantly lower in the aloe vera group compared to placebo (-5.61 mg/dL; 95% CI: -7.94 to -3.28; p<0.001); HbA1c was also lower in the aloe vera group (-0.95%; 95% CI: -1.76 to -0.14; p=0.02). There was no significant change in total cholesterol, low-density lipoproteins, triglycerides, or high-density lipoproteins. Results are summarized in Table 22 (151).

 

Table 22. Effect of Aloe Vera on Metabolic Parameters (151)
Parameter	Pooled Mean Difference (95% CI)	p-value Pooled Mean Difference	Heterogeneity (I2)	p-value Heterogeneity
Glycemic
Fasting plasma glucose (mg/dL)	-5.61 (-7.94 to -3.28)	<0.001	98%	<0.001
HbA1c (%)	-0.95% (-1.76 to -0.14)	0.02	78%	0.004
Lipoprotein
Total Cholesterol (mg/dL)	-6.79 (-44.07 to 30.48)	0.72	96%	<0.001
Low density lipoprotein concentration (mg/dL)	24.49 (-13.70 to 62.67)	0.21	99%	<0.00001
High density lipoprotein concentration (mg/dL)	4.44 (-4.24 to 13.12)	0.32	98%	<0.00001
Triglycerides (mg/dL)	28.04 (-41.90 to 97.98)	0.43	100	<0.001

 

A meta-analysis was published in 2016 evaluating the impact of aloe vera on fasting glucose and HbA1c in patients with type 2 diabetes. Nine studies were included in the fasting glucose analysis. Aloe vera use decreased fasting glucose by 26.6 mg/dL (p<0.001). Five studies were included in the HbA1c analysis. HbA1c decreased by 1.05% in aloe vera treated individuals (p<0.004). Results suggested patients with higher fasting glucose levels may benefit more from aloe vera use (these patients demonstrated a decrease of 109.9 mg/dL; p<0.01). The authors concluded their results support the use of aloe vera for decreasing fasting glucose and HbA1c in patients with diabetes (152).

 

Aloe vera has also been studied in pre-diabetes. Alinejad-Mofrad and colleagues compared aloe vera to placebo in patients with prediabetes (n=72). Patients were randomized to three groups: aloe vera 300 mg daily, aloe vera 500 mg daily, and placebo for eight weeks. Treatment with aloe vera (both 300 mg and 500 mg daily) decreased fasting glucose and HbA1c compared to placebo. Results are presented in Table 23 (153).

 

Table 23. Comparison Fasting Glucose and HbA1c with use of Aloe Vera in Patients with Prediabetes (153)
Parameter	Time	Placebo	Within Group p-Value	Aloe Vera 300 mg Group	Within Group p-Value	Aloe Vera 500 mg Group	Within Group p-Value	Between Group p-value
Fasting glucose (mg/dL)	Baseline	110 ± 3.91	n/a	112 ± 2.5	n/a	111 ± 4.1	n/a	0.69
	8 weeks	110 ± 4.22	0.19	108 ± 2.78*	0.001	104 ± 4.2*	<0.001	0.001*
HbA1c (%)	Baseline	6.01 ± 0.16	n/a	6 ± 0.24	n/a	6 ± 0.23	n/a	0.37
	8 weeks	6.03 ± 0.14	0.059	5.8 ± 0.21*	0.042	5.6 ± 0.33*	0.011	0.04*

* indicates statistical significance compared to placebo (p<0.05)

 

A meta-analysis and systematic review of randomized controlled trials evaluated aloe vera in patients with type 2 diabetes and prediabetes. Eight trials were included (five enrolled patients with diabetes and three enrolled patients with prediabetes). In patients with diabetes, both fasting glucose (-21 mg/dL; p<0.05) and HbA1c (-1%; p=0.01) decreased significantly. In patients with prediabetes, fasting glucose decreased statistically significantly, but in a very small amount (-4 mg/dL; p<0.0001). There was no change in HbA1c in the prediabetes patients (154).

 

Adverse Effects and Warnings

 

Aloe vera gel, when used orally, is well tolerated. Aloe latex, however, can cause abdominal pain and cramps. Unlike aloe vera gel, aloe latex contains anthraquinones which may be toxic (148).

 

Interactions

 

Aloe vera gel may decrease glucose and should be used cautiously with other products with the same effect. It may also increase the risk of bleeding when used with anticoagulant or antiplatelet drugs (148).

 

Summary

 

Aloe vera gel is derived from the leaf of the aloe plant. There is preliminary evidence to suggest it lowers glucose in those with diabetes and prediabetes. Aloe vera gel is typically well tolerated.

 

FENUGREEK (TRIGONELLA FOENUM-GRAECUM)

 

Fenugreek has multiple mechanisms of action is addressed under the “Hypoglycemic Agents” section.

 

FLAXSEED (LINUM USITATISSIMUM)

 

Flaxseed is a grain that is native to Europe, Asia, and the Mediterranean. Flax is a blue flowering crop and the seeds exist in brown, yellow, and green colors (see Figure 15). Whole flaxseeds primarily contain fat (41%), dietary fiber (28%), and protein (21%). The oil contained in flaxseeds is particularly rich in polyunsaturated fat (73%) and lower in monounsaturated (18%) and saturated (9%) fats. Flaxseed oil is a rich source of the omega-3 fatty acid alpha linolenic acid (ALA) (155).

 

 

Mechanism of Action

 

The pharmaceutically active portion of flaxseed is the seed and the oil. The high soluble fiber content is thought to decrease carbohydrate absorption. The high omega-3 fatty acid content (ALA) is also thought to play a crucial role as these acids have been shown improve insulin sensitivity and glycemic control. ALA has been shown to increase plasma GLP-1 levels (156). Flaxseeds contain lignans, which have been proven to have antioxidant effects (157-159).

 

Evidence

 

A systematic review and meta-analysis of randomized controlled trials aimed at determining the impact of flaxseed supplementation in patients with type 2 diabetes mellitus was published in 2023. Thirteen studies were included in the analysis. HbA1c was significantly reduced in the flaxseed supplementation group (-0.19%; 95% CI: -0.38 to 0.00; p=0.045). The authors found no significant change in fasting plasma glucose, insulin, HOMA-IR, lipid parameters, body weight, BMI, or blood pressure (160).

 

A single-blinded, randomized, controlled trial evaluated the impact of flaxseed in 53 patients with type 2 diabetes that also had constipation. Patients either received cookies with flaxseed twice a day or cookies free of flaxseed twice daily for 12 weeks. Constipation scores, weight (-3.8 kg), and fasting plasma glucose (-26.7 mg/dL) all decreased from baseline in the flaxseed group (p<0.05). Constipation scores, weight (-3.8 versus 0 kg), fasting plasma glucose (-26.7 versus 1.9 mg/dL), and HbA1c (-0.8% versus 1.0%) were significantly different in the flaxseed group compared to placebo (p<0.05) (161).

 

A placebo-controlled, crossover study evaluated the impact of flaxseed on diabetes. Seventy-three patients with type 2 diabetes took either placebo or 360 mg daily of flaxseed for 12 weeks. After an eight-week washout period, patients crossed over to the other group. HbA1c decreased a small, but statistically significant, amount (0.1%; p=0.01). There was no significant change in fasting plasma glucose or lipoprotein levels (162).

 

An open-label study evaluated the effect of flaxseed in patients with type 2 diabetes (n=29). Patients received 10 g of flaxseed daily (n=18) or placebo (n=11). Fasting glucose decreased 28.9 mg/dL in the flaxseed group (p=0.02) and slightly increased in the placebo group. HbA1c decreased 0.59% (from 8.75% to 8.16%) in the flaxseed group (p=0.009) and increased 0.1% in the placebo group. Triglycerides and LDL-C also decreased significantly in the flaxseed group (1630.

 

Flaxseed has also been studied in patients with prediabetes. Hutchins and colleagues randomized 25 patients with prediabetes to take 26 g of flaxseed, 13 g of flaxseed, or placebo for 12 weeks. After a 2-week washout period, patients were crossed over to another group. Fasting glucose levels did not decrease significantly in the 26 g group compared to placebo. However, fasting glucose decreased significantly in the 13 g group compared to placebo (-2 mg/dL, p=0.036). Insulin levels also decreased significantly in the 13 g group (p=0.021) (164).

 

Adverse Effects and Warnings

 

Few adverse effects are reported with flaxseed use.¹⁶¹ Gastrointestinal side effects are the most commonly reported (155).

 

Interactions

 

Oil from flaxseeds is shown to decrease platelet aggregation and may, therefore, increase the risk of bleeding in users of anticoagulants and antiplatelets (165).

 

Theoretically, flaxseed may decrease the absorption of acetaminophen and ketoprofen. However, this interaction has not been shown in human studies (166).

 

Summary

 

Flaxseed is rich in fat (primarily omega-3 fatty acids) and fiber. There are conflicting results regarding flaxseed’s efficacy in glycemic control. Most individuals tolerate flaxseed well.

 

PRICKLY PEAR CACTUS (OPUNTIA FICUS-INDICA), NOPAL

 

Prickly pear cactus has multiple mechanisms of action is addressed under the “Insulin Sensitizers” section.

 

SOY (GLYCINE MAX)

 

Soy has multiple mechanisms of action is addressed under the “Insulin Sensitizers” section.

 

TURMERIC (CURCUMA LONGA, CURCUMA DOMESTICA, CURCUMA AROMATIC) 

 

Turmeric is a member if the Zingiberaceae (ginger) family (167). Turmeric has a long history of use in Ayurvedic and Chinese medicine (see Figure 16). Curcumin is considered the active constituent of turmeric and is yellow-colored and fragrant. Curcumin is typically what is used as a flavoring and coloring agent in turmeric-containing products (168).

 

 

Mechanism of Action

 

Turmeric has multiple proposed mechanisms of action relating to glycemia. Turmeric can induce peroxisome proliferator-activated receptor-gamma activation. It may also activate hepatic enzymes associated with glycolysis and gluconeogenesis. Turmeric may also enhance tumor necrosis factor alpha (168).

 

Evidence

 

In 2023, a systematic review and network meta-analysis of randomized controlled trials was published that compared the effectiveness of different herbs in the management of T2DM. Turmeric (curcumin) was one of the herbs studied. Forty-four trials were included in the review. Compared to controls, turmeric use was correlated with a statistically significant reduction in fasting plasma glucose (-13.15 mg/dL; 95% CI: -23.64 to -2.66; p<0.05). The authors found no change in HbA1c associated with turmeric use (169).

 

A systematic review and meta-analysis published in 2021 was conducted to evaluate the effect of curcumin on glycemic and lipid profiles in patients with type 2 diabetes. There was a statistically significant difference in HbA1c in turmeric users (-0.42%, 95% CI -0.72 to -0.11; p< 0.05). There was non-significant (p = 0.107) moderate heterogeneity (I² = 42.42) (170).

 

The effect of turmeric in delaying the development of type 2 diabetes was studied in patients with prediabetes in a randomized, double-blinded, placebo-controlled trial. Subjects (n=240) were randomly assigned to curcumin capsules or placebo for nine months. After nine months, 16.4% of subjects in the placebo group were diagnosed with type 2 diabetes. No subjects in the curcumin group were diagnosed in this timeframe (p<0.05). Markers of insulin sensitivity also showed favor for the curcumin group (higher HOMA-beta and lower HOMA-IR; p<0.05) (171).

 

Adverse Effects and Warnings

 

Turmeric is usually well tolerated. Itching, constipation, and vertigo have been reported with use (171).

 

Interactions

 

There is a risk of increased bleeding when turmeric is combined with anticoagulants (172).

 

Summary

 

Turmeric and its active constituent, curcumin, have been long used medicinally. There is limited evidence in humans to suggest curcumin use may delay the onset of type 2 diabetes in patients with prediabetes. Turmeric is typically well tolerated.

 

Summary of Natural Products

 

A summary of the natural products is presented alphabetically in Table 24.

 

Table 24. Summary of Natural Products Used for Diabetes Listed Alphabetically
Natural Product	Adverse Effects	Interactions
Aloe Vera Gel	Aloe vera gel is typically well tolerated Aloe latex (which contains anthraquinones) can cause abdominal pain and cramps	May decrease glucose and should be used cautiously with other products with the same effect
Banaba (Lagerstroemia speciosa)	Dizziness, headache, tremor, weakness, diaphoresis, nausea	Additive effect with antihypertensives Use with caution in those using hypoglycemic agents
Berberine	Diarrhea, constipation, flatulence, abdominal pain, and vomiting Uterine contractions May cross the placenta and result in neonatal kernicterus when ingested during pregnancy	May inhibit cytochrome P450 3A4 and should be used cautiously with other agents that are substrates, inhibitors, or inducers of this hepatic enzyme As berberine lowers glucose, caution should be exercised when used with other agents that lower glucose
Bitter melon	Abdominal discomfort, pain, and diarrhea May contain abortifacient proteins	Use with caution in those using other hypoglycemic agents Those with G6PD deficiency should avoid use due to risk of developing favism
Chromium	Chromium picolinate may cause cognitive, perceptual, and motor dysfunction	There is a theoretical interaction between chromium and iron
Cinnamon	Cinnamon is typically tolerated well Cinnamon is a natural source of coumarin and use, therefore, presents a theoretical risk of hepatic injury	May contain coumarin and increase the risk of bleeding with anticoagulants Use cautiously with other hepatotoxic agents due to concerns of hepatic injury when large doses are used May decrease glucose levels and should be used cautiously with other agents that lower glucose
Fenugreek (Trigonellafoenum-graecum)	Diarrhea, heartburn, and flatulence Fenugreek smells similar to maple syrup; consumption prior to delivery may cause the neonate to have this odor, which may lead to confusion with maple syrup urine disease Patients with chickpea allergies should use fenugreek with caution as there is potential for cross-reactivity Fenugreek may cause uterine contractions and should be avoided in pregnancy	May contain coumarin and increase the risk of bleeding with anticoagulants Theophylline levels may be decreased with concomitant use Use cautiously with other agents that decrease glucose
Flaxseed (Linumusitatissimum)	Gastrointestinal side effects are the most commonly reported	Flaxseed may decrease the absorption of acetaminophen and ketoprofen Flaxseed oil may increase the risk of bleeding with antiplatelets and anticoagulants
American Ginseng(Panax quinquefolius)	Headache	May stimulate immune function and theoretically decrease the effect of immunosuppressants Can decrease the efficacy of warfarin; concomitant use is not advised Use cautiously with other glucose lowering agents
Gymnema (Gymnemasylvestre)	A case of acute hepatitis secondary to gymnema use has been reported	May potentiate the effects of other agents that lower glucose
Milk thistle (Silybummarianum)	Nausea, diarrhea, and abdominal bloating may occur with use Those with a daisy or ragweed allergy may experience a cross reaction with milk thistle use	May inhibit certain cytochrome P450 isoenzymes; the isoenzymes 2C8, 2C9, 2D6, 3A4, and 3A5 may all be inhibited with concomitant use Increased warfarin levels may occur with concomitant use May lower glucose levels and should be used cautiously with other hypoglycemia agents
Prickly Pear Cactus(Opuntia ficus-indica andother Opuntia species),Nopal	Prickly pear cactus is generally tolerated well when used orally Side effects include nausea, diarrhea, and headache	Prickly pear cactus may lower glucose levels and should be used cautiously with other agents that impact glycemic control
Soy	Soy is generally well tolerated May cause nausea, diarrhea, and bloating Soy may alter thyroid function, but this appears to occur in those with iodine deficiency	Fermented soy products such as tofu may contain small amounts of tyramine; tyramine should be avoided in those using monoamine oxidase inhibitors
Turmeric (Curcuma longa, Curcuma domestica, Curcuma aromatic)	Itching, constipation, and vertigo have been reported with use	There is a risk of increased bleeding when turmeric is combined with anticoagulants
Vanadium	Mild gastrointestinal effects such as abdominal cramps and loose stools may occur Animal studies suggest vanadium may cause anemia	Theoretical concern that vanadium may increase the risk of bleeding in anticoagulant agents

 

MIND BODY PRACTICES FOR TYPE 2 DIABETES

 

According to the National Institute of Heath, mind body practices include, but are not limited to, yoga, chiropractic and osteopathic manipulation, meditation, massage, acupuncture, Tai Chi, healing touch, hypnotherapy, and movement manipulation (1). Mind body practices are used for overall health and to help with specific disease states. There is recent interest in studying the impact of mind body practices on type 2 diabetes.

 

Yoga has been studied in patients with type 2 diabetes. Preliminary studies indicate yoga may reduce BMI, improve glycemic control, improve lipid levels, and improve body composition. Yoga may also decrease blood pressure (173-177).

 

The impact of massage on glycemic control in patients with diabetes has been studied. One study showed parent-provided full body massage at bedtime improved serum glucose levels and decreased anxiety of both the massage giver and receiver (178). Another study compared changes in metabolic parameters of individuals with type 2 diabetes between a control group, a routine massage group, and an abdominal massage group. The control group had no significant change in fasting plasma glucose, postprandial plasma glucose, or HbA1c. The routine massage and abdominal massage groups had significant reductions in fasting plasma glucose, postprandial plasma glucose, and HbA1c (69).

 

A meta-analysis exploring the impact of Tai Chi on glucose and lipid metabolism in patients with T2DM was conducted and included 16 randomized controlled trials. Tai Chi significantly reduced fasting plasma glucose and HbA1c (179). Individual studies on Tai Chi have shown it may decrease fasting glucose values in patients with diabetes. However, Tai Chi does not appear to reduce glucose more than other types of gentle exercise (180-182).

 

RELIABLE RESOURCES FOR PROVIDERS AND PATIENTS

 

Clinicians need to be aware of the deceptive marketing tactics employed by natural product manufacturers. Patients and clinicians need reliable and dependable resources regarding integrative medicine.

 

MedWatch is a website developed and updated by the FDA. MedWatch provides timely safety information on dietary supplements as well as medications and cosmetics. MedWatch can be accessed at: https://www.fda.gov/Safety/MedWatch/.

 

The FDA also has a health fraud online resource. The website describes health fraud and provides actionable ways patients can protect themselves. The FDA’s health fraud website can be accessed at: https://www.fda.gov/consumers/health-fraud-scams

 

In terms of efficacy, primary literature is a reasonable resource. The US National Library of Medicine has an online database that can be searched free of change. The database can be accessed at: https://www.ncbi.nlm.nih.gov/pubmed.

 

Additional online resources are provided in Table 25.

 

Table 25. Complementary Health Approach Online Resources for Patients and Clinicians
Source	Description	Website Address
American Botanical Council	Non-profit, international member-based organization providing education using evidence-based and traditional information to promote the responsible use of herbal medicine	http://abc.herbalgram.org/site/PageServer
ConsumerLab.com	Independent testing site that reviews natural products and specific manufacturers	http://www.consumerlab.com
National Center for Complementary and Integrative Health (NCCIH)	National (US) center that supports and disseminates research results on complementary health approaches	https://www.nccih.nih.gov
National Institute of Health Office of Dietary Supplements (ODS)	National (US) center that supports and disseminates research results on dietary supplements	http://ods.od.nih.gov/index.aspx
Natural Medicines	A scientifically-based and practical database on natural medicines (Subscription required)	https://naturalmedicines.therapeuticresearch.com
The Cochrane Library	An electronic database designed to provide high quality scientific evidence	https://www.cochranelibrary.com
United States Food and Drug Administration Health Fraud Website	The website describes health fraud and provides actionable ways patients can protect themselves.	https://www.fda.gov/consumers/health-fraud-scams
United States Food and Drug Administration MedWatch	MedWatch provides timely safety information on dietary supplements as well as medications and cosmetics.	https://www.fda.gov/Safety/MedWatch/
United States Food and Drug Administration Office of Nutritional Products, Labeling, and Dietary Supplements	FDA office responsible for developing policy and regulations for dietary supplements, medical foods, and related areas, as well as for their scientific evaluation	http://www.fda.gov/Food/DietarySupplements/default.htm
WebMD Health	WebMD provides comprehensive health information and tools for managing health care for health care professionals and their patients	http://diabetes.webmd.com/default.htm

 

IDENTIFYING POTENTIALLY HARMFUL PRODUCTS

 

According to the FDA’s health fraud website, there are certain red flags that can alert a consumer to potentially harmful natural products, including dietary supplements. Red flags to be wary of include: claims that a product is a cure-all for a wide variety of ailments; suggestions that a product can treat or cure diseases; promotions using words such as "scientific breakthrough" or "miraculous cure"; undocumented testimonies by consumers or doctors claiming amazing results; limited availability and advance payment requirements; promises of no-risk, money-back guarantees; promises of an "easy" fix; and claims that the product is "natural" or "non-toxic" (which doesn't necessarily mean safe) (183). These safety alerts are provided in Table 26. Additionally, the FDA fraud website warms to avoid websites that fail to list the company’s name, physical address, phone number, or other contact information.

 

Table 26. FDA Health Fraud Indicators a Natural Product May Be Ineffective or Unsafe (183)
Claims that a product is a quick, effective cure-all or a diagnostic tool for a wide variety of ailments
Suggests that a product can treat or cure diseases
Promotions using words such as "scientific breakthrough," "miraculous cure," "secret ingredient," and "ancient remedy"
Text with impressive-sounding terms such as: "hunger stimulation point" and "thermogenesis" for a weight loss product
Undocumented case histories by consumers or doctors claiming amazing results
Limited availability and advance payment requirements
Promises of no-risk, money-back guarantees
Promises of an "easy" fix
Claims that the product is "natural" or "non-toxic" (which doesn't necessarily mean safe)

 

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ABSTRACT

 

Diabetes presents a significant risk factor for all kinds of infections. It has been well described to increase rates of outpatient infection as well as the incidence of infections requiring hospitalization. This appears to be related to deficits in the immune system, particularly changes seen in innate immunity. Respiratory infections, skin and soft tissue infections, gastrointestinal and genitourinary infections all appear to occur more frequently in patients with DM. Not only are they more frequent, but these infections appear to have a poorer response to therapy and more rapid progression to severe forms of infection. There is good evidence that reduction of hyperglycemia can improve outcomes. Among the antihyperglycemic agents available, translational and clinical data exists that insulin can help to improve immune function and potentially metformin as well.

 

INTRODUCTION

 

The 2020 release of the US Centers for Disease Control and Prevention National Diabetes Statistics Report revealed that in 2018, 34.2 million individuals had diabetes mellitus (DM), representing approximately 10.5% of the US population and a total cost of care in excess of US $300 billion (1). Part of these numbers reflects the impact of DM on infection rates and morbidity/mortality. Both type 1 and type 2 DM are associated with a significantly higher risk of infection, both in the outpatient and inpatient context, and the outcomes are generally worse than in those without diabetes. We will discuss here the impact of diabetes on the immune system, specific infections which are commonly seen in diabetes, and the influence of various therapies targeted both at glycemic control and also on immunomodulation on infection outcomes.

 

EPIDEMIOLOGY

 

DM, both type 1 and type 2, is associated with a high risk of infection. A large retrospective study of primary care patients revealed that diabetes is likely to account for 6% of infection-related hospitalizations and 12% of infection-related deaths, with the strongest associations being for bone and joint infections, development of sepsis, and cellulitis (2).

 

Outpatient

 

A number of studies have been performed on the rate of infection among patients with diabetes in the primary care and other outpatient settings. In a Canadian cohort of 1,779 patients with DM matched to 11,066 without DM the patients with DM had an increased risk of infection (adjusted odds ratio 1.21, adjusted for confounding variables). with skin and soft tissue infections having the strongest association with having DM. Interestingly, DM was not found in this study to be associated with head and neck, musculoskeletal, or viral infections (3). Another large Canadian study including more than a million individuals matched those with DM to those without, and assessed all physician and hospital claims for infectious disease. It found that almost half of all individuals with DM had a claim for an infectious disease within a cohort year compared with 38% of those without DM. The risk ratio was skewed most towards those with DM for upper respiratory tract infections, cystitis, and pneumonia (4).

 

Inpatient

 

In one study, having diabetes led to a 2-fold increased risk for hospitalization when presenting with an infection to the emergency room, and up to 12% of inpatient admissions in patients with diabetes were the consequence of an infection (5). A South Korean showed that those with diabetes had a significantly greater risk of infection-related ICU admission and death when hospitalized with infections of skin or soft tissue, central nervous system infection, or bone and joints (6). The previously-mentioned Canadian retrospective cohort study showed that, while the overall risk ratio for infection in those with diabetes versus without was 1.21, this number rose to 2.17 and 1.92 when considering infection which led to hospitalization and death, respectively (4). These and other studies (7,8) have revealed that not only is diabetes associated with (and causative of) an increased risk of infection, but also with higher rates of hospitalization, ICU stays, and death related to these infections. Of note, many of these patients with DM have other comorbidities which may not be able to be fully controlled for in these epidemiologic studies demonstrating higher estimates of the risk of infection with DM.

 

One important entity to consider in the inpatient arena is sepsis. The studies on sepsis are not consistent — though some show worse outcomes from DM, others have suggested either no effect or even a protective effect from DM (9). Data for the latter come from studies assessing acute respiratory failure and respiratory distress syndrome in the ICU, and it may be that the blunted immune response that we see in some patients with DM are responsible for the findings (i.e., reduced inflammation and injury related to impaired neutrophil function as described in section on Innate Immunity) (10). More studies are needed to better understand in what specific clinical contexts DM results in higher risk.

 

PATHOPHYSIOLOGY OF DIABETES AND IMMUNE SYSTEM

 

There is well-known disruption of the immune system in diabetes which occurs at multiple levels. Innate and adaptive immunity are affected along with cytokine signaling within both. This dysregulation occurs both in those with type 1 and 2 DM. Microvascular complications such as neuropathy also increase susceptibility to an accidental lesion in the barrier of the skin which forms one of the first lines of defense. Furthermore, poor vascular flow to sites of infection can further compromise an appropriate immune response and healing leading to worsening or secondary infections (11,11b). In our discussion on alterations of the immune system, it is important to note that we have focused on alterations in function as opposed to baseline differences in the number of immune cells or cytokine levels between those with and without DM. Table 1 provides a summary of the alterations in immune dysfunction that are known.

 

Innate Immunity

 

COMPLEMENT SYSTEM

The complement system plays a critical role in both innate and adaptive immunity and leads to the opsonization, lysis and phagocytosis of pathogens along with recruitment of immune cells to the site of infection. There is known to be a reduction in the complement factor 4 (C4) level in those with type 1 DM, although it is unclear if that alone can precipitate an increased risk of infection (12). A variety of studies demonstrate that hyperglycemia can inhibit phagocytosis through the system, potentially by reducing complement binding to immunoglobulins. Glycosylation of C3 can also impair its ability to attach to the pathogen surfaces (13).

 

Table 1. Impact of Diabetes and Hyperglycemia on the Immune System
Innate Immunity
Complement System	-  Reduction in C4 levels (Unclear relevance for infection risk) -  Reduction complement binding to immunoglobulins -  Glycosylation of C3 can impair binding to pathogen surface
Recruitment and Pathogen Recognition	-  Reduced CAM expression leading to reduced leukocyte recruitment -    In setting of hyperglycemia reduced production of chemokine in response to bacterial LPS -    Advanced glycation end products inhibit neutrophil transendothelial migration -  Reduced expression TLR (which allows for recognition LPS)
Cellular Dysfunction	-    Reduced H2O2 production leading to reduced bactericidal ability in both macrophage and neutrophils -    Impairment of macrophage phagocytic ability through complement pathway -  Impaired metabolism of glucose in macrophages reducing activity -    NK cell activity reduced through reduced expression activating receptors NKG2D and NKp46
Adaptive Immunity	-  Depletion and dysfunction memory CD4+ cells -  Not as well described as alterations in innate immunity
Cytokine Signaling	- Deficiency of IL-1, IL-2, IL-6, IL-10, IL-22, IFN-γ, TNF α
Skin and Mucosal Barriers	-  Vascular compromise leading to impaired healing -  Neuropathy making breakage of the skin more likely

 

RECRUITMENT AND PATHOGEN RECOGNITION

 

A number of older studies reported reduced chemotaxis of polymorphonuclear leukocytes (PMNs) in patients who have DM (14,15). One of the mechanisms appears to be related to disruption of cellular adhesion molecules (CAMs) which are critical for the recruitment of leukocytes to the site of infection. This was seen when db/db (a diabetic mouse model) and wild type mice were infected with West Nile Virus and subsequent analysis of the brains of the db/db showed less leukocyte recruitment consistent with reduced CAM expression compared with the brains of the wild type mice (16). When hyperglycemia was induced in mice exposed to Klebsiella pneumoniae, there was a reduced recruitment of granulocytes to the site of infection as compared with control mice. This was felt to be related to a reduction in the chemokine production able to be induced by the bacterial lipopolysaccharide (LPS) (17). There are also in vitro data which reveal that advanced glycation end products are able to inhibit neutrophil transendothelial migration (18). A reduction in the expression of Toll- like receptors (TLR, which bind to LPS and allow for pathogen recognition) in patients with poorly controlled diabetes has been described as well (19).

 

SPECIFIC CELLULAR DYSFUNCTION

 

Multiple immune cells are impacted in DM. Neutrophil recruitment is not only reduced, but there are also good data demonstrating their reduced phagocytic activity and hydrogen peroxide production, leading to reduced bactericidal ability (20-23). The mechanism for the alteration appears may be partially linked to impaired metabolism of glucose and glutamine, as was demonstrated in streptozotocin-induced diabetic rats (24). Macrophages are also similarly affected. Examination of cells from patients with type 2 DM have revealed that there is impairment of both the complement and Fc-gamma receptor-mediated pathways by which macrophages are able to phagocytize pathogens (25). When macrophages from diabetic mice were cultured in normal versus high glucose, there was a reduction in the phagocytic and bactericidal activity, apparently through a defect similar to that seen in neutrophils, specifically impaired metabolism of glucose (26). NK cell activity is also known to be reduced in a manner which is related to level of glycemic control, demonstrated in multiple studies comparing NK cells from patients with DM, prediabetes, and also without DM (27). The mechanism of the reduced activity may be in part related to decreased expression of activating receptors NKG2D and NKp46 on the NK cells in patients with DM (28).

 

Adaptive Immunity

 

The adaptive immune system is activated in response to specific pathogens and involves the immunologic memory for those pathogens. There are two components of adaptive immunity, the humoral and cellular, which carry out the major purposes of generating an antibody and cellular (involving B and T cells) response to a specific antigen. The adaptive humoral immunity is involved in antibody production. This appears to be preserved in those with DM on the basis of overall appropriate response to various vaccines (29,30). However, there may be some dysregulation of the adaptive cellular immunity. There is a depletion of memory CD4+ cells that has been noted prior to the development of type 1 DM (31). Furthermore, a dysfunction of and an impaired response of these cells to Streptococcus pneumoniae has been described (32). However, the dysfunction seen in DM with innate immunity is better understood than that the dysfunction in adaptive immunity (33).

 

Cytokine Signaling Defects

 

Cytokines play a vital role in the signaling cascades which underpin the immune system, allowing for full activation of both innate and adaptive immune responses. Multiple points of dysregulation have been identified in DM. With stimulation, multiple of these cytokines have been shown to be secreted at lower levels than would be typical with stimulation. In vitro studies done on monocytes isolated from patients without DM showed suppression of IL-1, IL-2, IL-6, and IL-10 secretion in the presence of hyperglycemia (34-36). In diabetic mice, there was noted to be immune dysregulation and also inflammation which was related to IL-22 deficiency reversed with provision of IL-22 (37). There is also evidence for impaired interferon gamma (IFN-γ) and TNF alpha production from T cells in the setting of methylglyoxal, a compound which is increased in those with DM (38). The end result of these deficits is that there is attenuation of the phagocytic and cellular immune response.

 

COMMON INFECTIONS, OUTCOMES, AND GENERAL DRUG OF CHOICE

 

In addition to many infections having a worse course in those with diabetes, specific types of infections are also significantly more common in those with diabetes. We will review these diabetes-predominant infections (39-42). Table 2 also provides an overview of common infections and considerations in those with DM.

 

 

Table 2. Common infections seen in patients with diabetes with attention to diagnosis, common responsible organisms, management, and outcomes
Respiratory Infections
Pneumonia	-  Higher rates of hospitalization and also mortality in those with DM compared with those without -  Less commonly presents with purulent cough and pleuritic chest pain, more commonly with altered consciousness -  Aspiration and skin colonization common etiologies -  S pneumonia, S aureus, and K pneumoniae among most common organism -  Rx with amoxicillin/clavulanate or cephalosporin + macrolide/doxycycline vs fluoroquinolone
Tuberculosis	-  Higher risk contracting with risk corresponding with level of glycemic control -  Higher risk of treatment failure -  Isoniazid needs to be taken with pyridoxine to prevent neuropathy -  Rifampin can cause hyperglycemia and also induces cyp450 leading to increased clearance of various DM agents
Skin and Soft Tissue
Cellulitis/Abscess	-  Most common SSTI seen in those with DM -  Most common organism Staph species -  For abscess culture is needed to determine organism and resistance -  Oral abx: Doxycycline, clindamycin, TMP-SMX, cephalexin -  Presence SIRS or other complication: IV vancomycin, linezolid, ceftaroline
Necrotizing Fasciitis	-  Comorbid DM much more common -  Limb loss seen more often -  Polymicrobial typically but can be only K pneumoniae -  Surgical rx most common and need broad spectrum coverage
Fournier Gangrene	-  More commonly seen in those with DM -  Anaerobic and aerobic bacteria such as S aureus and Pseudomonas species -  Debridement a must -  Seen with SGLT2 inhibitors
Sternal Wound Infection	-  DM one of strongest predictors for infection -  Improved glycemic control with insulin shown to reduce rate of infection
Gastrointestinal
Hepatitis	- HCV outcomes worse with more frequent cirrhosis and failure of Antivirals
Emphysematous Cholecystitis	-  Diagnosis through sonography or CT typically as first step -  Most common organism C perfringens and E coli -  Rx is typically cholecystectomy but can try abx in mild case
Genitourinary
Urinary Tract Infection	-  Higher rate of infection and failure/relapse with rx -  Most common organism E choli and Enterobacteriaceae -  Urine culture is strongly recommended -  Do not treat asx bacteriuria -  Decision for abx is based on local organism and resistance trend -    Higher risk of progression to pyelonephritis which is more severe and often bilateral
Head and Neck
Necrotizing Otitis Externa	-  DM higher risk of abscess formation requiring draining -    Vascular compromise and pseudomonal vasculitis much more commonly seen in DM -  P aeruginosa most common organism -  Confirm with CT -    Systemic abx with antipseudomonal action and local therapy to the canal including cleaning/debridement
Fungal Infections
Onychomycosis	-  Potentially up to 1/3 of all patients with DM impacted -  Diagnosis based on fungal culture/microscopy -  Oral agents most effective
Genitourinary	-  Most common Candida specie -  Increased ability to bind with receptor in DM UTI -  Communicate with lab on culture that Candida specie is suspected -  If symptomatic, then fluconazole first line
Mucormycosis	-  Causative agents are the mucormycetes -  Most commonly sinus +/- cerebrum/orbits -  Respiratory tract second most common -  Skin third most common and has ulcerative necrotic lesion -    Tissue biopsy needed and imaging helpful to identify extent of infection -  Debulking of infection with adjuvant

 

 

Abbreviations: Rx (Treatment), Abx (Antibiotics), Asx (Asymptomatic), SSTI (Skin and soft tissue infections), UTI (Urinary tract infection)

 

 

Respiratory Infections

 

Pneumonia is a frequently-seen infection in those with DM. In a large Danish population-based case-control study of 34,239 patients, the relative risk for hospitalization from community-acquired pneumonia was 1.26 compared with patients without DM. Furthermore, the risk appeared to be correlated with level of glycemic control with relative risk (RR) for those with HbA1c <7% being 1.22, versus a RR of 1.6 when HbA1c was ≥9% (43). A Portuguese study similarly showed DM prevalence was higher in those with pneumonia and that outcomes were worse with a longer hospital stay and significantly higher mortality in patients with DM versus those without (15.2% vs 13.5%) (44). These trends were also seen in another Danish study which showed mortality was greater in those with type 2 DM compared with other patients at both 30 and 90 days after the initial pneumonia episode (45). The presentation of pneumonia is potentially different in those with DM as typically bacterial pneumonia presents with a purulent cough and pleuritic chest pain, symptoms which are less commonly seen in those with DM. The hypothesis is that the lowered immune defense results in a decreased inflammatory response and symptoms. Notably, altered consciousness is more common on presentation with pneumonia in those with DM. The causative agent of pneumonia is similar in those with and without DM with the most common being Streptococcus pneumoniae (46). However, there is an over-representation of organisms such as Staphylococcus aureus and Klebsiella pneumoniae related to skin colonization and more frequent aspiration in those with DM. Management is using combination therapy with amoxicillin/clavulanate or cephalosporin and a macrolide or doxycycline versus monotherapy with respiratory fluoroquinolone (47). Use of certain DM medications like metformin have been shown to reduce the risk of development of bacterial pneumonia (odds ratio 0.89) and also morbidity and mortality when pneumonia develops, hypothesized to be related to improvement in function of the innate immune system and reduction in levels of inflammation which is explored later in this chapter (47b).

 

Diabetes also represents an important risk factor for contracting tuberculosis (TB). The odds of developing tuberculosis appear to be higher in those with DM compared to those without with the odds ratio ranging from 2.44-8.33 in various studies. Furthermore, severity of DM appears to be correlated with greater risk of contracting TB based on studies comparing the incidence of TB in those with insulin-dependent versus non-insulin dependent DM. Risk of treatment failure despite good adherence to medication regimen and also death from tuberculosis all appear to be increased (48). There are side effects of medications targeted at tuberculosis with particular relevance in DM. Isoniazid can cause peripheral neuropathy that could be mistaken for diabetic neuropathy, and pyridoxine should be administered to ameliorate this risk. Rifampicin has the ability to cause hyperglycemia. Rifampicin also is a powerful inducer of the cytochrome P450 system leading to increased clearance of multiple DM agents (i.e., sulfonylurea, pioglitazone, meglitinides). Hence while the regimen to treat TB seen in patients with DM is the same as the regimen in those without, special attention must be paid to these DM specific issues.

 

Skin and Soft Tissue Infections (SSTI)

 

There is a significantly increased risk of skin and soft tissue infections (SSTI) in DM. Up to 80% of patients with DM will experience a skin complication related to DM during their lifetime, many of which are SSTIs (48b). Using a large administrative claims database (HealthCore Integrated Research Database), Suaya et al were able to demonstrate complications from SSTI were five times higher, and hospitalization four times higher, in patients with DM than those without DM in their cohort (49). The most common agent of infection is Staphylococcus aureus (S aureus). The foot represents the most common site of infection as well which has been expertly covered in another chapter (50). In the last few years, a number of therapies directed at improving immune function, blood flow, and better restoring integrity of the barrier of the skin have been developed that likely have implications for other non-foot related infections (50b).

 

For cellulitis, the diagnosis is typically clinical, as opposed to an abscess which often is cultured for organism identification and resistance profiling. The decision for antibiotics in cellulitis and with abscess is often empiric, and in those with DM it is imperative that the choice cover Staphylococcus species. Potential first line therapy for outpatient oral antibiotics includes doxycycline, clindamycin, trimethoprim-sulfamethoxazole, and cephalexin. If there is admission due to SIRS criteria being present or a suspected complication, then the recommendations change to IV predominant choices including vancomycin, linezolid, and ceftaroline (51).

 

Necrotizing fasciitis is a life-threatening condition involving the subcutaneous fat and deep fascial layers. A retrospective report of 59 necrotizing fasciitis cases at a single center revealed that 11 of the cases had DM, and another study showed that 51% of 84 patients in the cohort with necrotizing fasciitis had DM (52,53). Though most commonly a polymicrobial infection, Klebsiella pneumoniae is also commonly seen as a single isolate (53). Prognosis appears to be poorer in those with DM, with a higher rate of limb loss than that seen in those without DM. Broad spectrum antibiotics are utilized, related to the frequent polymicrobial nature of the infection. However, ischemia compromises appropriate antibiotic concentration at the site, therefore the management is primarily surgical involving a combination of debridement, necrosectomy, and fasciotomy frequently (54).

 

Fournier gangrene represents a particularly serious SSTI, defined as a necrotizing skin infection of the scrotum and penis or vulva. Typically, patients are between the age of 50-60 years and DM represents a serious risk factor for development. Usually, the infection will begin in the perianal or retroperitoneal region and then spreads to the genitalia or as a urinary tract infection which then also moves towards the genitalia. There will be necrosis and crepitus which is an indication of involvement of the underlying skin and soft tissue. The etiology is usually a mix of aerobic and anaerobic bacteria which can commonly include S aureus and Pseudomonas (51). Surgical debridement is typically necessary. This condition has become of particular relevance with the release of a warning from the US Food and Drug Administration in August 2018 that Fournier’s represented a rare but serious complication of sodium-glucose cotransporter 2 inhibitors (SGLT2i), a newer but increasingly utilized class of DM medications (55). There were 55 cases of Fournier’s reported to the FDA between March 2013 and January 2019 (56). However, it is important to note that while this number appears to be higher than for other anti-hyperglycemic agents, that there has not been a clear establishment of causality here. In fact, other studies including a meta-analysis of randomized controlled trials involving SGLT2i and a “real-world” study using IBM MarketScan were unable to confirm an increased risk of Fournier’s Gangrene for those using SGLT2i versus those who did not (57,58). Intriguingly, a single center retrospective review of cases of Founier Gangrene admitted actually suggested use of SGLT2i and metformin were both protective in reducing length of ICU and hospital stay (58b).

 

Sternal wound infections after surgery are also known to occur more frequently in those with DM. After coronary artery bypass, presence of DM is one the strongest predictors for a deep sternal wound infection (odds ratio 2.6) (59). Improved glycemic control in the post-operative period has been shown to be able to significantly reduce the rate of sternal wound infection (60-62). Furnary et al in their seminal study were able to demonstrate in a prospective manner that use of an IV insulin infusion to keep glucose <200 mg/dL resulted in a 66% reduction in risk of sternal infection compared with nonrandomized historical controls (60).

 

Gastrointestinal Infections

 

The presence of DM has been known to worsen viral hepatitis. The outcome in chronic hepatitis C infection is worse in those with DM as compared to those without, corresponding to a significantly increased risk for cirrhosis and a reduced response to antiviral therapy in those with DM and hepatitis C (63). Emphysematous cholecystitis is a rare progression of acute cholecystitis, defined as presence of gas in the gallbladder wall for which DM serves as a major risk factor. The prevalence of DM among those with emphysematous cholecystitis has been described as high as 50% in the literature (64). Sonography is able to detect the presence of gas within the gallbladder wall and an abdominal radiograph will show a curvilinear lucency around the gallbladder. CT can also detect the condition with nearly 100% sensitivity. The two most common causative agents are Clostridium perfringens and Escherichia coli. The treatment is often surgical with prompt cholecystectomy although for a mild case antibiotic therapy can be initiated but without improvement within 3-4 days then the recommendation is still for cholecystectomy (65).

 

Genitourinary Infections

 

Urinary tract infections (UTI) are significantly more common in patients with DM with a large UK study showing an incidence of UTI of 46.9 per 1000 person- years among those who had type 2 DM versus 29.9 for those without DM (66). The most common pathogens in those with DM are Escherichia coli and the Enterobacteriaceae (Klebsiella, Proteus, Enterobacter, etc.). There is an increased risk of drug- resistant organisms being present. In making the diagnosis, beyond the typical clinical symptoms of dysuria and increased frequency, it is important to note that a urine culture really should be obtained in all individuals with DM prior to therapy (67). Outcomes are worse in those with DM, being associated with increased relapse and reinfection (at 7.1% and 15.9% respectively in those with DM versus 2% and 4.1% in those without) (68). Asymptomatic bacteriuria should not be treated even in those with DM. In those with symptoms, trimethoprim-sulfamethoxazole and ciprofloxacin are good choices but the general consensus is to follow local infection and resistance trends and tailor antibiotic therapy towards those organisms (67). From a lower UTI, there is also more risk of progression to pyelonephritis (both emphysematous and nonemphysematous) which tends to be more severe requiring hospitalization and are often bilateral in those with DM (69,70).

 

It would be important to note that the class of medications called SGLT2i, previously mentioned under the section of Fournier gangrene, was initially thought to be associated with increased risk of UTIs. The purported mechanism is the increased glucose level in the urine, favoring the growth of microorganisms. However, database-driven studies and meta-analyses have not borne out this association (70b,70c). The initial observation of increased rates of UTI may have been related to surveillance bias or mycotic infections being mistaken for UTI in patients on SGLT2i.

 

Head and Neck Infections

 

Consistent with the findings in many types of infections, head and neck infections are more common and appear to be more severe in those with DM. An assessment of 185 patients at the National Taiwan University Hospital with deep neck infections found that those with DM had a significantly higher rate of abscess formation than those without (89.3% vs 71.3%) and that surgical drainage was required more frequently as well (86% vs 65.2%) (71). One concerning entity commonly associated with DM is necrotizing external otitis. This term references an infection which has spread to the temporal and adjacent bones at the base of the skull. The causative agent is often Pseudomonas aeruginosa. The increased frequency of this in those with DM appears to be related in part to the vascular compromise seen in DM combined with a pseudomonal vasculitis (72,72b). A certain level of suspicion for this condition needs to be present when there is external otitis in a patient at risk of necrotizing progression. Imaging is often needed to confirm with CT used. Systemic antibiotics are a requirement along with local treatment of the canal (i.e., cleaning, antimicrobial topicals, etc.). The antibiotic chosen needs to have antipseudomonal action such as the fluoroquinolones with the understanding that poor vascularization of the area often means higher doses are required (72).

 

Fungal Infections

 

Infection with Candida species is common in those with DM (73). Skin and soft tissue along with mucosa can be commonly impacted. Assessment of mouth swabs from patients with and without DM revealed that there was a higher frequency of Candida infection in the patients with DM (74). This appears to be related to decreased salivary pH and salivary flow which promoted colonization with the yeast. But there is also the possibility that in DM there is increased ability of Candida to bind to its receptor (75). Onychomycosis, a fungal infection of the nails, is also very common with DM with some studies suggesting up to 1/3 of individuals with DM are impacted. Diagnosis is made based on a positive fungal culture for a dermatophyte or microscopy showing fungus prior to initiation of therapy. Oral agents tend to be the most efficacious but topical lacquers are used as well (76).

 

Beyond the skin and mucosa, there is a high rate of genitourinary infections with Candida species. Among fungal infections of the urinary tract system, the vast majority involve Candida species. For both outpatient and inpatient urinary tract infections where Candida species was the causative agent, DM is present as a comorbid condition in 29% and 39% of cases respectively. Initial work-up would be similar to that of any other for urinary tract infection including urinalysis and culture. If there is a concern for Candida then that should be communicated with the reporting lab as there can be slow growth on certain cultures. It is important to remember that symptomatic urinary tract infections with Candida are rare. However, if truly a symptomatic infection is felt to be present, then fluconazole is typically the first line therapy of choice because of its ability to accumulate in high concentrations within the urine. If there is progression to pyelonephritis then speciation and sensitivities will be required given the presence of resistant strains and often dual agent therapy is required (77).

 

Mycotic genital infections are driven by Candida species. in both men and women (78). A very large percentage of women will experience symptomatic vulvovaginal candidiasis within their lifetime, and DM represents a risk factor for development of infection, with worsening glycemic control predisposing to an even higher risk (73). This appears to be related to known defects in immune cell function (PMNs and macrophages) and the impact of glucose in the urine, leading to worsening virulence in addition to improved adherence of yeast. Clinically, women present with pruritis and discomfort. Diagnosis is best made with microscopy and can be suspected in those with a negative amine (“whiff”) test and normal pH. Treatment is typically with a short course of intravaginal imidazole or triazole as opposed to oral fluconazole (78). For male patients, a similar finding of increased risk of balanitis (i.e., inflammation of the glans penis and prepuce) with DM and with increasing HbA1c is noted (73,79). This condition also occurs almost exclusively in males who have not been circumcised. Diagnosis is best made based on clinical presentation (burning and itching of penis worse after intercourse) in combination with a subpreputial culture. Imidazole or triazole creams represent the mainstay of therapy (78). 

 

It is worth mentioning that SGLT2i as a class are known to be associated with genital infections, particularly mycotic genital infections caused by Candida species. Using information from two US based health insurance databases, Dave et al were able to demonstrate in a retrospective cohort study that use of an SGLT2i compared with dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists led to an approximately three-fold increase in risk of genital infection (80). This might be mitigated in part by improved hygiene (i.e., rinsing the genital area with water after every episode of urination and before going to bed) (81). Interestingly, the association between use of SGLT2i and genital infections does not appear to extend to UTIs (82). This may be related to increased volume and flow through the urinary tract preventing excess bacterial load from developing (83). As SGLT2i are increasingly a mainstay of therapy for patients with type 2 DM, this association with mycotic genital infections needs to be carefully considered.

 

Mucormycosis is a rare but life-threatening fungal infection caused by a mucormycetes, a group of molds (commonly the mucor and rhizppus species). A metanalysis of cases of mucormycosis showed that DM was the commonest underlying condition present in 40% of cases (84). Frequently the DM associated is type 2 and uncontrolled. It carries with it a high fatality rate which ranges from 32-57%. The most common site of infection (66% of cases in a large 929 case series) is the sinus-cavity leading to rhinocerebral infection which can also impact the orbits. In these cases, there are often symptoms of sinus congestion/inflammation, fever, facial swelling along with ophthalmoplegia, cellulitis, and cranial nerve palsies. Necrotic eschars in the nasal cavity and on the hard palate are classic findings and also indicate a rapidly progressive infection. The respiratory tract is the second most commonly affected location (16%) with endobronchial lesions commonly found in those with DM. The subsequent invasion of the vasculature can lead to more distant infection. Finally, the third most common site is the skin (10%). Cutaneous mucormycosis presents with erythematous or ulcerative necrotic lesions which can also lead to osteomyelitis (85,86). Tissue biopsy is a requirement for diagnosis while various imaging modalities can help provide further evidence of an infection. Debulking of the infection through surgery is necessary. Amphotericin B and isavuconazole have been utilized as adjunctive therapies (85,87).

 

COVID-19 and DM

 

There is clearly a significant interaction between DM and SARS-CoV-2 (causative agent of coronavirus disease 2019 (COVID-19)). Multiple risk factors for contracting and having a more severe course of COVID-19 have been identified, including advanced age and male gender, but both type 1 and type 2 DM are now known to be important risk factors for morbidity and mortality with the disease (88). An assessment of patients who contracted COVID-19 and were tested within the Vanderbilt University Medical system demonstrated that there was a significantly increased risk for hospitalization in those with DM compared to without DM (odds ratio 3.36 for type 2 and 3.9 for type 1) and also for more severe disease course (odds ratio 3.42 for type 2 and 3.35 for type 1) (89). From a cohort of patients in England, there is evidence that poorly-controlled DM as compared with well-controlled DM (HbA1c 6.5-7% versus  greater than 10%) results in significantly increased mortality in both type 1 and type 2 DM (hazard ratio 2.23 and 1.61 respectively) (90). Increased mortality has also been seen in another English cohort (83). A more comprehensive review on this topic is offered by Lim et al, where the multiple points at which COVID-19 and DM interact – including the impact of glucotoxicity on the lungs, increased thromboembolic risk, worsened oxidative stress. and inappropriately high levels of cytokine production leading to organ damage – are outlined (91).

 

 

IMPACT OF GLYCEMIC CONTROL AND OTHER THERAPIES

 

Glycemic Control and Diabetes Therapies

 

There is good evidence that glycemic control is correlated with infection. A study of 69,318 patients with type 2 DM in Denmark revealed an association between increased risk for community- and hospital- treated infection in those with higher HbA1c ≥10.5% compared with HbA1c 5.5-<6.4% (92). Similarly, in a large English cohort there was an increasing risk of infection in parallel with HbA1c for patients with both type 1 and type 2 (2). In a Taiwanese study looking at outcomes from a community-based health screening program, the authors found that fasting plasma glucose >200 mg/dL and DM was associated with the highest risk of infection and also a 3-fold higher risk of death than those without DM (93). Looking at an older population, the risk of certain infections was significantly higher in those with poor glycemic control HbA1c >8.5% compared with good glycemic control (relative risk infections ranging from 1.28-2.38) (94). Intervening to lower glucose appears to mitigate the risks. Zerr et al assessed incidence of sternal wound infection in patients with and without DM before and after implementation of a postoperative continuous IV insulin protocol to keep blood glucose <200 mg/dL. They found that lower glucose in the first 2 days postoperatively was associated with a decrease in deep wound infection from 2.4% to 1.5% (62).

 

Insulin, in both translational and clinical studies, has been suggested to have a protective effect against infection risk in those with DM (Table 3). A large surgical ICU trial assessing tight (80-110 mg/dL) versus conventional (treatment with insulin only if glucose >215 mg/dL) glycemic control using IV insulin found a lower mortality with tight glycemic control, and the greatest reduction in mortality was seen in those with sepsis leading to multi-organ dysfunction. In those treated with IV insulin, there was a significant reduction in the risk of developing sepsis (46%) (95).

 

While these data were later brought into question by the findings of the NICE-SUGAR trial (96) which demonstrated increased mortality with intensive glycemic control using IV insulin, other studies have suggested that there is improvement in rates of infection with use of insulin (60,97) particularly in the post-cardiac surgery setting for sternal wound infections. Furthermore, the increased risk of mortality in the intensive glycemic control arm in NICE-SUGAR is felt to be related to an excess of hypoglycemia seen in the cohort compared with normal care. If improved glycemic control can be achieved without causing a significant increase in hypoglycemia, a different outcome may be able to be achieved (98). Translational studies have been able to show in vivo that T cells which lack insulin receptor expression are unable to proliferate and produce cytokines properly and that insulin enables the cells to take up nutrient which supports their function (99). As mentioned earlier chemotaxis of PMNs is impaired in patients with DM and it has been noted that provision of glucose and insulin can restore these to baseline (15).

 

While data for immune function improvement and infection using other antihyperglycemic medications are relatively sparse, there are some suggestions that therapies beyond insulin can have an immune- restorative effect (Table 3). Metformin has demonstrated an ability to increase the number and action of CD8+ tumor-infiltrating lymphocytes, resulting in improved production of cytokines IL-2, TNFα, and IFNγ (100). In a mice model with an absence of the TNF receptor-associated factor 6 (TRAF6), there is a relative inability to generate memory T cells that is related to defects in fatty acid metabolism. When TRAF6-deficient antigen specific effector T cells and TRAF6-deficient mice were exposed to metformin, there was a restoration of the production of memory T cells (101). While a number of other diabetes therapies have well-established anti- inflammatory effects (i.e., peroxisome proliferator- activated receptor-γ agonists, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors) data are lacking as to their specific impact on immune function with regards to infection risk apart from their reduction of hyperglycemia (102-104).

 

Immunomodulating Therapies

 

There are data showing that the use of granulocyte- colony stimulating factor (G-CSF), which induces differentiation and release of PMN from marrow, is able to assist with healing in foot infections (105). While a subsequent meta-analysis did not show that the use of G-CSF was able to significantly impact the resolution or healing of wounds, there was a reduction in risk of needing amputation or surgical intervention (106).

 

While not a “medication”, physical activity has long been known to be associated with improvement in the immune system which are known to extend as well to those with DM (107). In diabetic rats, exercise was able to improve the neutrophil and lymphocyte count significantly (108).

 

Table 3. Anti-Hyperglycemic Agents Associated with a Reduced Risk of Infection
Insulin	-    T cells in vivo which lack insulin receptor are unable to proliferate and produce cytokines due to the inability to take up nutrients -  Chemotaxis in PMNs impaired in DM which is restored with glucose and Insulin
Metformin	-    Increase number of tumor-infiltrating lymphocytes and improved cytokine production -  Restoration of production of memory T cells from effector T cells

 

 

CONCLUSION

 

Diabetes represents an incredibly important risk factor for infection raising the likelihood of infection for both outpatient treated conditions and those which lead to hospitalization. Beyond raising the risk for contracting an infection, prognosis is frequently worse for many of these conditions which increases the frequency of rare and life-threatening infectious processes seen in those with DM. This is the consequence of disturbances in the immune system which have been well described involving both innate and adaptive immunity. However, glucose lowering therapies appear to be able to counteract some of the increased risk of infection and worsened prognosis by improving function of immune cells. More work is needed to fully elucidate if and how newer diabetes agents may be able to reduce risk of infection.

 

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