Physiological and behavioral aspects of glycemic control and hypoglycemia in diabetes.

Abstract: Homeostatic mechanisms that maintain blood glucose concentration within a narrow physiologic range are complex and redundant. Elaborate feedback loops involving insulin, glucagon, sympathoadrenal mediators, growth hormone, amylin, and incretins normally operate synchronously to keep blood glucose within a narrow set point. Individuals with diabetes have defects in glucose homeostatic pathways, including the counterregulatory pathways that oppose hypoglycemia and ensure sufficient glucose is available to serve the brain's metabolic needs. Because available interventions to manage hyperglycemia do not precisely mimic physiologic insulin secretion patterns, hypoglycemia can occur any time dosing exceeds demand. Focusing on the practical implications, we review the endocrinological principles underlying normal glucose homeostasis and the defects in regulation and counterregulation, including hypoglycemia unawareness, that occur with diabetes. Iatrogenic and behavioral factors that contribute to hypoglycemia risk and nocturnal hypoglycemia are discussed. A companion manuscript reviews the clinical symptoms and fundamentals of hypoglycemia prevention, recognition, and management.

Key Words: diabetes, hypoglycemia, glucose homeostasis, glucose counterregulation, behavior, insulin, glucagon

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In the last 25 years, the prevalence of diabetes in the US has more than doubled, (1) with newly diagnosed cases increasing 47% between 1997 and 2002. (2) The health benefits of achieving tight glycemic control have been clearly established in both Type 1 (T1DM) and Type 2 (T2DM) diabetes mellitus. (3-5) Specifically, the microvascular and, possibly, macrovascular complications of diabetes can be delayed if plasma glucose and hemoglobin A1c are maintained within narrow physiologic ranges. (6-8) In patients with T1DM, this control must be achieved with insulin therapy. In patients with T2DM, control is often not achieved with oral agents (ie, insulin secretagogues or insulin sensitizers alone or in combination), (9) and there is growing consensus that insulin therapy should be initiated earlier to delay the adverse medical sequelae associated with the progression of diabetes. (10-14)

Despite compelling evidence that tight glycemic control is crucial to delaying disease progression, concerns about iatrogenic hypoglycemia associated with such control have created unnecessary and sometimes formidable barriers to optimal diabetes management. (15-19) The risk of hypoglycemia increases with absolute or relative insulin excess (caused by exogenous insulin or agents that increase insulin secretion) or compromised glucose regulation. (15) In the earlier stages of T2DM when glucose counterregulatory responses are still functional, (20) hypoglycemia is less common than in patients with T1DM. (16) Most hypoglycemic episodes in these patients are minor and can be self-treated with a rapidly absorbed carbohydrate. However, since progressive [beta]-cell failure is a key pathophysiological feature of T2DM, (21) the characteristics of disease and frequency of hypoglycemic episodes eventually approach that of TIDM. (20) Also, in patients being treated for T2DM, long-acting sulfonylureas have the potential to cause prolonged and potentially severe hypoglycemia. (20,22)

In addition to therapeutic measures taken to improve glycemic control, physiologic, behavioral, and psychological factors can also influence hypoglycemia risk. (23,24) Primary care physicians, who treat the majority of patients with diabetes, should aim for tight glycemic control because of its proven benefits while minimizing risks for hypoglycemia. To achieve this goal, the mechanisms underlying glucose homeostasis must be well understood. This manuscript summarizes the current state of knowledge about the physiologic basis for deficient glycemic control in patients with diabetes as well as factors relevant to hypoglycemic risk. A companion manuscript reviews the fundamentals of hypoglycemia prevention, recognition, and management.

Glucose Homeostasis and the Normal Counterregulatory Response to Hypoglycemia

In individuals without diabetes, blood glucose concentrations are efficiently regulated to a tight set point (approximately 90 mg/dL [5.0 mmol/L]). As meals are ingested and blood glucose rises, this level is maintained throughout the day via elaborate feedback loops, primarily due to the complimentary actions of insulin and glucagon, a glucose counterregulatory hormone. Amylin (a pancreatic polypeptide), the incretins (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]), and other glucose counterregulatory hormones (epinephrine, norepinephrine, cortisol, and growth hormone) are part of this redundant and complex neuroendocrine network that contributes to maintaining this balance.

The basic endocrine processes that occur after ingestion of a meal are depicted in Figure 1A. Following intestinal absorption of nutrients, blood glucose rises and stimulates the pancreatic [beta]-cells to release insulin. This response, augmented by the incretins, (25) is known as first-phase insulin secretion. This increases circulating insulin sharply above the basal level, facilitating glucose transport in skeletal muscle and adipose tissue, and promotes uptake and storage of glucose as glycogen in the liver. Basal insulin secretion in persons without diabetes regulates hepatic glucose output. (26) Amylin, which participates in prandial glucose regulation, is cosecreted with insulin. (27) The incretin hormones further stimulate the late-phase of insulin secretion. (25)

Insulin suppresses the activity of glucagon, a key hormone secreted by pancreatic [alpha]-cells that counters the action of insulin. Amylin and GLP-1 also suppress glucagon secretion and thereby also indirectly facilitate insulin action. (27,28) About 2 hours after a meal, the concerted actions of insulin, amylin, and the incretins usually restore plasma glucose to a normal physiologic range. The mid-normal range for plasma glucose is 88 to 96 mg/dL (4.9-5.3 mmol/L), (29) although recent evidence suggests that men with normal fasting plasma glucose (FPG) levels >87 mg/dL are at progressively higher risk of developing T2DM as compared with men in the lowest quintile of normal plasma glucose values (<81 mg/dL [4.5 mmol/L]). (30) In fact, the American Diabetes Association now considers an FPG > 100 mg/dL as one indicator of prediabetes, estimated to affect 41 million Americans. (31)

[FIGURE 1 OMITTED]

The lower end of plasma glucose concentration is also tightly regulated in individuals without diabetes. The brain is unable to synthesize glucose or store more than minute quantities of glycogen and, therefore, depends on plasma glucose to support its metabolic demands. (32) Considerable redundancy exists in physiologic glucose control systems that serve the brain. (33) Three major glucose counterregulatory responses normally work in a well-orchestrated hierarchy to raise blood glucose in response to hypoglycemia; namely: (1) a reduction in insulin secretion and increases in (2) glucagon, and (3) epinephrine secretion (Fig. 1B).

When plasma glucose concentration falls to the lower end of normal (approximately 80 mg/dL [4.5 mmol/L]), pancreatic [beta]-cells and neurons sense this change. Insulin secretion decreases as the first defense to counter hypoglycemia. This favors hepatic and renal glucose production over peripheral uptake. When glucose levels fall below 68 to 70 mg/dL, (22) secretion of counterregulatory glucagon and epinephrine is activated. Falling insulin levels are the primary signal for [alpha]-cells to increase glucagon secretion; this occurs once a critical threshold is reached. (16)

Glucagon secreted from pancreatic [alpha]-cells is the second defense against hypoglycemia, stimulating hepatic glucose production via glycogenolysis and gluconeogenesis. Glycogenolysis requires stored glycogen, whereas lactate, amino acids, and glycerol are the necessary substrates for the synthesis of new ("neo") glucose. Epinephrine secretion by the adrenal glands is the third defense; its role is to inhibit insulin release, facilitate glucagon secretion, enhance hepatic glucose production, and mobilize gluconeogenic substrates. (22) Provided that sufficient glucagon is released from pancreatic [alpha]-cells to raise liver glucose production, epinephrine secretion is not critical, but provides a redundant safeguard. (32,33)

When an episode of hypoglycemia is prolonged, growth hormone (plasma glucose threshold of approximately 65 mg/dL) and cortisol (plasma glucose threshold of approximately 60 mg/dL) (22) counter the effects of hypoglycemia through stimulation of lipolysis and ketogenesis. These insulin-opposing hormones act after a lag period of several hours and do not correct acute hypoglycemia. (34,35)

Glucose autoregulation, defined as hypoglycemia directly stimulating glucose production, (22) and neural factors are believed to play minor roles in peripheral counterregulation of acute hypoglycemia. (33) Although hunger is one of the brain's responses to hypoglycemia, the urge to eat tends to occur at very low blood glucose concentrations (approximately 50 mg/dL [2.8 mmol/L]). Other neuroglycopenic symptoms (eg, weakness, tremulousness, motor impairment) and diminution of cognitive function also occur. The brain mediates local changes in blood flow, glucose metabolism, and transport across the blood-brain barrier. This involves vascular, neuronal, metabolic, and cellular systems that preserve function when hypoglycemia occurs. However, the role of specific brain neurons as "glucosensors" is complex and poorly understood. (36) Additional detail about glycemic responses and autonomic activation that occur as a result of very low glucose concentrations is provided by Cryer and colleagues. (16,32,37)

Careful regulation of glucose homeostasis in healthy individuals notwithstanding, factors including age, (38) obesity, (39) abnormal lipid profiles, (29) exercise, (40) alcohol intake, (41) some antihypertensive agents, (22) diurnal rhythms, (42) and gender (43) can influence normal glucose homeostatic responses. All of these factors should be considered when assessing the risk of hypoglycemia in patients with diabetes.

Glucose Counterregulation in Patients With Diabetes

The counterregulatory responses to hypoglycemia in both T1DM and T2DM are defective. Furthermore, in patients with T2DM using insulin ([+ or -]oral agents), the ability to blunt endogenous insulin release--the primary defense against hypoglycemia--is inoperative. Therefore, excess therapeutic insulin relative to physiologic demand is the primary cause of hypoglycemia. A falling insulin level, the fundamental signal for [alpha]-cells to release glucagon and the second defense against hypoglycemia, is absent in patients with T1DM and may eventually disappear in patients with T2DM. (20,32) Epinephrine secretion remains the sole defense against acute hypoglycemia, and if the response to epinephrine is blunted, glucose counterregulation will be severely compromised.

Hypoglycemia Unawareness and Hypoglycemia-associated Autonomic Failure

Many patients with diabetes do not recognize signs or perceive symptoms of hypoglycemia. The syndrome dubbed "hypoglycemia unawareness" is a major risk factor for hypoglycemia to progress from mild to severe. Hypoglycemia unawareness occurs because the threshold of the sympathoadrenal response (catecholamine secretion) to mild hypoglycemia is shifted to a lower plasma glucose concentration. (19,37) Unlike healthy individuals who begin to experience neurogenic symptoms of hypoglycemia (eg, tremulousness, sweating, weakness) at an average plasma glucose level of 68 mg/dL, (22) patients with diabetes and hypoglycemia unawareness may not experience such symptoms until their plasma glucose concentration is much lower. (15) This syndrome is worse in patients who have had frequent hypoglycemic episodes. Unawareness of symptoms combined with repeated hypoglycemic episodes promotes a vicious cycle of defective counterregulation known as hypoglycemia-associated autonomic failure (HAAF). Sleep and exercise potentiate HAAF, as depicted in an integrated model of this process (Fig. 2). (16,32,44)

Susceptibility to hypoglycemia unawareness can be influenced by external factors such as alcohol (41) or caffeine, (45) nonselective [beta]-adrenergic antagonists that may blunt autonomic warning symptoms, (22) and possibly by gender and the duration of diabetes. (46-49) Although individuals with early T2DM rarely exhibit hypoglycemia unawareness, normal counterregulatory mechanisms fail and the risk of unawareness increases as they approach the insulin-dependent end of the disease continuum. (50)

Brain glucose uptake is preserved in individuals who are frequently hypoglycemic, presumably an adaptation to recurrent glucose shortages in the brain that helps protect neural function. (51) However, with brain glucose demand adequately compensated for, neurogenic and neuroglycopenic symptoms become blunted, (52) explaining, in part, why hypoglycemia unawareness occurs, or why a patient's judgment about when to self-treat a hypoglycemic episode can be impaired. From a patient safety perspective, the glucoregulatory mechanisms that have developed as an adaptation to preserve neural function may be maladaptive, since symptoms may be triggered too late to prevent hypoglycemia-related seizures or coma. (52) The role of brain metabolism and brain glucose sensing mechanisms has been extensively reviewed by others. (36,53)

[FIGURE 2 OMITTED]

Additional Risk Factors for Hypoglycemia in Individuals With Diabetes

Much of the knowledge about risk factors for hypoglycemia comes from observations and studies in individuals with T1DM. Information about risk factors in patients with T2DM is less complete, (23) largely due to the relative infrequency of hypoglycemic episodes experienced by patients with T2DM as compared with patients with T1DM. However, as was recently articulated in a review about hypoglycemia in patients with T2DM, there is no evidence that the principal causes and risks of hypoglycemia are any different from T1DM. (20) Complex interactions and interdependence among risk factors exist, and may be grouped into iatrogenic, behavioral, and other factors for the purpose of discussion.

Iatrogenic factors. In most cases, hypoglycemia results from an excess of insulin, either absolute or relative to the available glucose substrate. The excess results either from inappropriate endogenous insulin secretion caused by insulin secretagogues (eg, primarily long-acting sulfonylureas) or from excess therapeutic insulin. Hormonal feedback loops in patients with diabetes are often defective and cannot offset the effects of excess insulin, thus exacerbating the risk. Any physiologic factor that prolongs the plasma half-life of therapeutic insulin (eg, compromised renal function) increases the risk of hypoglycemia. Therefore, renal function should always be taken into account when individualizing insulin dosing requirements. (54)

Patients who regularly experience large fluctuations in blood glucose (ie, wide glucose excursions) are more susceptible to hypoglycemia. The risk is comparable to that observed when targeting tight glycemic control. (55) Coexisting pathologies, such as the absence of a late-phase response to incretins or deposition of amyloid fibrils (formed from amylin aggregation, which are toxic to [beta]-cells in the islet) (56,57) are typically associated with hyperglycemia, but may render patients susceptible to wider glucose excursions than those experienced by healthy people. Even patients with T2DM managed with diet alone may experience routine afternoon hypoglycemia; the slope of the daily fall in blood glucose can correlate with fasting blood glucose level. (58) Therefore, it is imperative that treatment aims for optimal glucose pattern management by minimizing peaks and troughs.

Drugs that inhibit the hepatic metabolism of sulfonylureas or displace these molecules from plasma protein binding sites (dicoumarol, chloramphenicol, clofibrate, monoamine oxidase inhibitors, sulfaphenazole, phenylbutazone and salicylates, and sulfonamides) can also increase the risk of hypoglycemia. (22,59) Drugs that delay gastric emptying (eg, narcotic analgesics) (60) or increase insulin sensitivity (eg, some serotonergic drugs, angiotensin-converting enzyme [ACE] inhibitors, or antihyperlipidemic agents) are other agents that may increase the risk of hypoglycemia in patients using insulin. (61,62)

Behavioral factors. To a large extent, behavioral factors that increase the risk of hypoglycemia can be modified by the patient with appropriate caregiver intervention. Among the factors controlled by patients (missed meals, exercise, altered insulin dosing, and alcohol use), missed meals are the most common cause of hypoglycemia. (22,63,64) From the Diabetes Control and Complications Trial (DCCT), (63) which studied patients with T1DM, only missed meals were significantly associated with occurrence of severe hypoglycemia. In patients with T2DM, 53% of hypoglycemic episodes (for which a cause could be identified) were due to missing a meal and 24% were due to exercise. (65) Therefore, patients and healthcare providers need to be vigilant in monitoring meal and exercise habits.

Exercise, especially when sudden, vigorous, and not adequately planned for, may cause delayed hypoglycemia. The resultant hypoglycemic episodes tend to occur nocturnally and can be severe enough to cause coma and seizures. (66) Exercise depletes blood glucose by burning it as a fuel, and it also blunts the counterregulatory sympathetic response to hypoglycemia. (32) This, in turn, reduces glucagon, catecholamine, growth hormone, and pancreatic polypeptide secretion, as well as endogenous glucose production. (40) In controlled experiments, blunted counterregulatory responses to hypoglycemia after exercise were more pronounced in men compared with women. (67) This gender difference was not explained by levels of growth hormone, pancreatic polypeptide, or cortisol secretion, but by a more substantial dampening of sympathetic responses and lipolysis in men after exercise. Therefore, men may require a larger amount of glucose as metabolic fuel to protect against exercise-related hypoglycemia. In both sexes, insulin release from tissue injection sites may increase after exercise, explaining, in part, the delayed hypoglycemia that has been observed. (22) Increased insulin sensitivity as a result of weight loss or improved fitness may also predispose to hypoglycemia if the drug regimen is not appropriately adjusted. (68)

Alcohol inhibits the cortisol, glucagon, and growth hormone responses to hypoglycemia. (69) Alcohol also delays liver glucose production, lowers motor reaction time, impairs judgment, and reduces symptom awareness, each of which has the potential to exacerbate an episode of hypoglycemia. (41,70) When consumed in the evening, alcohol may predispose patients to hypoglycemia after breakfast the next morning, presumably as a result of reduced nocturnal growth hormone release. (71)

Most glucoregulatory networks are involved in the "stress response." The effects of stress on glucoregulatory systems that affect hypoglycemia risk are incompletely understood. Conflicting data exist as to whether prior cortisol release affects HAAF. Recent evidence has challenged a previously held view that cortisol secretion is the primary trigger for HAAF in T1DM. (72-74) Psychological/behavioral factors, which may be affected by stress hormones such as cortisol, can alter an individual's perception of impending hypoglycemia risk and the need to self-treat. (24)

Finally and importantly, tight control of the glycemic state, as evidenced by lower A1c levels, imparts a risk of hypoglycemia. (75) Glycemic goals that are too aggressive for the individual can contribute to this risk. (33) However, newer advances in pharmacotherapy and glucose monitoring systems can help reduce the inevitability of hypoglycemia that traditionally has accompanied tight control.

Other risk factors. In addition to behavioral factors subject to modification by patient and caregiver, the risk of hypoglycemia is also increased by factors not under the patient's control. For example, age affects hypoglycemia risk, with older people (22) and younger children (76) being the most vulnerable. In elderly patients, recent hospitalizations, polypharmacy, lower A1c levels, use of insulin, and previous hypoglycemia are contributing factors. (22,23) Children tend to be at higher risk than adolescents, not because of aggressive A1c targets, but because children and their parents exhibit poor overall ability to detect the warning signs of hypoglycemia. (76-78) Duration of disease and the presence of psychiatric disorders in older children are also associated with increased risk. (79)

Nocturnal Hypoglycemia

Hypoglycemia that occurs at nighttime during sleep (which is potentially the most dangerous form due to the high likelihood of not being sensed) is very common in patients with T1DM, (80) and also occurs in T2DM, (81,82) even in patients managed with single oral hypoglycemic agents. (83) The average episode of nocturnal hypoglycemia lasts 86 minutes. (84) A lack of food ingested during the night, changes in exercise patterns, or interruptions in daily routines increase the risk of nocturnal hypoglycemia. (66) Patients with both hypoglycemia unawareness and frequent episodes of severe daytime hypoglycemia are susceptible to experiencing more severe and longer durations of hypoglycemia during sleep. (85)

The phenomenon of nocturnal hypoglycemia results primarily from a mismatch between nighttime insulin requirements and the peak action of older intermediate or long-acting insulin preparations (eg, NPH, lente or ultralente, respectively). (86,87) Oral agents that affect insulin secretion or sensitivity presumably elicit nocturnal hypoglycemia because of a similar mismatch. For example, administration of a mixed regular plus NPH or lente insulin at suppertime to target a FBG of 125 to 145 mg/dL (approximately 7-8 mmol/L) could result in hypoglycemia between midnight and 3:00 AM. (87) Targeting a higher FBG of 180 to 200 mg/dL (approximately 10-12 mmol/L) does not entirely alleviate the risk of nocturnal hypoglycemia, even though optimal glycemic control is relinquished. Nocturnal secretion of growth hormone results in relative insulin resistance and increases basal insulin requirements just before awakening (known as the "dawn phenomenon"). In conjunction with waning insulin concentrations long after the evening injection of an intermediate-acting insulin, fasting hyperglycemia may occur.

Nocturnal hypoglycemia is unpredictable, occurring in 12 to 56% of patients who were enrolled in 11 clinical studies. (80) In 7 studies, 49 to 100% of the nocturnal hypoglycemic episodes were asymptomatic. (80) Because both the sympathetic response and hypoglycemia awareness are reduced during sleep, (88) and because most patients do not awake from symptoms, (86) nocturnal hypoglycemia often goes undetected. This explains the variability in the reported incidence and leads to a vicious cycle of hypoglycemia begetting hypoglycemia.

Conclusions/Summary

In persons without diabetes, the feedback loops that maintain glucose homeostasis are intricate and remarkably precise. Endogenous insulin, amylin, and incretins act in a concerted fashion with the glucose counterregulatory hormones--principally glucagon, catecholamines, and cortisol, to protect against high and low blood glucose excursions. Many elements of these mechanisms that maintain glucose homeostasis--physiologic, behavioral, or otherwise--are deficient in patients with diabetes. Treatment of these deficiencies to restore glucose homeostasis is vital to sustain brain function and life. Moreover, to delay the long-term medical complications of diabetes, this treatment must be aggressive. Because aggressive therapy in patients with diabetes is unchecked by normal feedback loops, the precise glycemic control seen in healthy individuals is lacking and hypoglycemia can occur. Patient behavior is a modifiable source of hypoglycemia risk. Insulin analogs and adjuvant therapies, including amylin analogs and incretin mimetic agents, have begun to remove barriers to tight glycemic control by lowering the risk of hypoglycemia. As the number of patients with diabetes in the US increases and as the breadth of therapeutic options expands, knowledge about the physiology of glucose homeostasis and the specific pathophysiological defects in diabetes will provide the basis for recognizing hypoglycemia and its risks, and for making treatment decisions that will help minimize those risks.

Acknowledgments

The authors would like to thank Novo Nordisk for funding that helped support preparation of this manuscript and Kathryn J. Lucchesi, PhD, RPh for writing and editorial support.

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Patrick J. Boyle, MD, and John Zrebiec, MSW, CDE 

From the Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM; and the Joslin Diabetes Center, Harvard Medical School, Boston, MA.

Reprint requests to Patrick J. Boyle, MD, Professor of Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131. Email: [e-mail]

Novo Nordisk of Princeton, NJ provided funding that helped support the preparation of this manuscript. The authors have received grant support/honoraria for speaking/consulting fees from Novo Nordisk. The authors have no financial interest in any drug, device, or equipment mentioned in this review.

Accepted July 13, 2006.

RELATED ARTICLE: Key Points

* Individuals with diabetes are unable to regulate blood glucose within a narrow healthy physiologic range because of defects in feedback loops that involve principally insulin, glucagon, amylin, incretins, and other glucose-counterregulatory hormones.

* Iatrogenic hypoglycemia occurs because most diabetic therapies (human insulin preparations and oral insulin secretagogues) do not precisely mimic the healthy physiologic state of insulin secretion.

* Behavioral factors (including missed meals, alcohol intake, unplanned exercise, and poor recognition of the need to self-treat) also contribute to hypoglycemia risk. These risk factors can be modified with patient education.

RELATED ARTICLE

Hypoglycemia unawareness is a major risk factor for the progression of hypoglycemia. Risk factors for hypoglycemia unawareness include:

* alcohol

* caffeine

* nonselective [beta]-beta adrenergic antagonists

* gender (possibly)

* duration of diabetes

Medications that may increase the risk of hypoglycemia in patients using insulin:

* Drugs that delay gastric emptying

-- narcotic analgesics

* Drugs that increase insulin sensitivity

-- serotonergic drugs

-- angiotensin-converting enzyme (ACE) inhibitors

-- antihyperlipidemic agents