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Mechanisms of Hypoglycemia Counterregulation

Authors: Arun S Rajan, MD, MBAFaculty and Disclosures


The Diabetes Control and Complications Trial (DCCT) convincingly established the benefits of tight glucose control in the avoidance of long-term diabetic complications. However, a pitfall of the aggressive management of diabetes using intensive insulin regimens is an increased frequency of hypoglycemia. At the 62nd Scientific Sessions of the American Diabetes Association, several symposia were dedicated to the discussion of issues related to the pathogenesis and treatment of impaired hypoglycemia counterregulation in diabetes.


Normal Glucose Counterregulatory Mechanisms

Normally during insulin-induced hypoglycemia, the sequence of primary hormone counterregulatory responses is as follows:


  • Suppression of insulin release (occurring at a threshold glucose concentration of ~ 4 mM).  
  • Activation of the rapid-acting counterregulatory hormones glucagon and epinephrine (occurring at a threshold glucose concentration of ~ 3.9 mM) -- a major effect.  
  • Release of slow-acting growth hormone and cortisol (during chronic hypoglycemia of 3-4 hours) -- a minor effect.  


Intensively Treated Patients With Type 1 Diabetes Have Impaired Glucagon and Epinephrine Responses to Hypoglycemia

In patients with type 1 diabetes of long duration (> 5 years), epinephrine constitutes the main defense against hypoglycemia, because the pancreatic alpha cell glucagon secretory response to hypoglycemia is irreversibly lost. However, clinical studies have shown that the epinephrine response is also impaired in type 1 patients undergoing intensive insulin treatment. This "double whammy" (lack of glucagon and epinephrine response) places intensively treated type 1 diabetes patients at significant risk for recurrent hypoglycemia. In addition, frequent antecedent hypoglycemia reduces the counterregulatory responses to future hypoglycemia by 50% -- creating a vicious cycle of iatrogenic hypoglycemia-associated autonomic failure, where hypoglycemia induces further hypoglycemia.

Using hyperinsulinemic, hypoglycemic clamp studies (where glucose levels can be held constant at any desired level of glycemia) and microneurography (an index of muscle sympathetic nerve activity), Stephen Davis, MD, Vanderbilt University, Nashville, Tennessee, and colleagues[1] observed that antecedent hypoglycemia blunted the counterregulatory responses (epinephrine and sympathetic nerve activity) in type 1 diabetic men (compared with healthy controls) and that this impairment was proportional to the magnitude of the antecedent hypoglycemia. In addition, the responses were blunted in women (healthy and diabetic) by ~50%. In other studies, it has been observed that type 1 diabetics that are well controlled (ie, intensively treated) have greater brain glucose uptake compared with more poorly controlled diabetics. This finding suggests that the impaired epinephrine response during intensive treatment may in part be attributed to a "hypoglycemic unawareness" by the brain, since it is bathed in higher levels of glucose.


Cortisol/Stress as a Causative Factor in Hypoglycemia-associated Autonomic Failure

Another series of studies was based on the observation that glucocorticoids blunt stress responses in animals, raising the question of whether cortisol is associated with hypoglycemia-associated autonomic failure. Using hyperinsulinemic, glycemic clamps, Dr. Davis and colleagues observed a substantial blunting of the hormonal (epinephrine, norepinephrine, and glucagon) responses and sympathetic nerve activity in subjects preinfused with cortisol, suggesting that prevention of cortisol secretion during hypoglycemia should preserve counterregulatory responses. This finding was verified in patients with Addison's disease (primary adrenocortical failure), for whom hyperinsulinemic, hypoglycemic clamp studies showed no blunting of epinephrine levels, glycerol (a marker for lipolysis which is activated by the counterregulatory hormones), nonesterified fatty acids, or sympathetic nerve activity. Furthermore, in rat studies involving direct infusion of cortisol into the third ventricle of the brain, it was observed that brain cortisol impairs the epinephrine, glucagon, and norepinephrine responses to antecedent hypoglycemia. These studies suggest that cortisol (stress) is a major determinant of hypoglycemia-associated autonomic failure.


Exercise Impairs Glucose Counterregulation in Type 1 Diabetes

Hypoglycemia can occur during and after exercise, confounding glycemic control in patients with type 1 diabetes. This has been attributed to increased insulin levels originating from subcutaneous depots and increased insulin sensitivity that prevent glycogen breakdown to glucose. To examine whether failed glucose counterregulation to exercise may contribute to hypoglycemia, Dr. Davis and colleagues performed hyperinsulinemic, hypoglycemic clamps in exercising type 1 diabetes patients. They observed blunted glucagon, epinephrine, norepinephrine, muscle sympathetic nerve activity, and lipolytic responses in these patients, which were associated with a deficiency in endogenous glucose production. Thus, antecedent exercise is also a causative factor in hypoglycemia-associated autonomic failure.


Resolution of Hypoglycemic Unawareness Syndrome by Preventing Hypoglycemia

The vicious cycle of prior hypoglycemia begetting hypoglycemic unawareness implies that strategies to prevent hypoglycemia may be beneficial in restoring the hormonal, neuronal, and cognitive impairments of deficient counterregulation.

Geremia Bolli, MD, University of Perugia, Italy, and colleagues[2] used different approaches to test this hypothesis. First they studied insulinoma patients, who exhibit recurrent episodes of hypoglycemic and hypoglycemia unawareness. In hyperinsulinemic, hypoglycemic clamp studies, these subjects had blunted hormonal (eg, glucagon, epinephrine, norepinephrine) counterregulatory responses and deficient neuroglycopenic and autonomic symptoms in response to hypoglycemia. However, when these subjects were studied 1 week after surgery to remove the insulinoma, the counterregulatory hormonal and neural symptoms were restored to normal and comparable to those seen in nondiabetic controls.

In another approach, type 1 diabetes patients with a short duration of disease were compared before and after 3 months of tight glycemic control using insulin, frequent self-monitoring of blood glucose, and patient education techniques. Patients under this regimen showed a reduced frequency of hypoglycemic episodes and a good recovery of epinephrine, hypoglycemia symptom awareness, and glycemic threshold for recognition of hypoglycemia.

To examine whether the improvements in hypoglycemic unawareness could be sustained long term, further studies were performed after 1 year of tight glucose control in patients with a varying but more prolonged duration of diabetes. Here again, there was a marked recovery of autonomic and neuroglycopenic symptoms and epinephrine responses at 3 months. It was noted that the degree of improvement was inversely correlated with the duration of diabetes.

These studies suggest that hypoglycemic unawareness can be resolved and glucose counterregulation can be achieved by preventing the occurrence of hypoglycemia.


Rational Insulin Therapy to Prevent Hypoglycemia

Conventional insulin therapy to manage daytime glycemia generally entails use of a mixture of NPH and regular insulin at mealtime. Unfortunately, the peak effect of regular insulin is late, and this results in episodes of hyperinsulinism and hypoglycemia between meals. These undesirable effects of regular insulin can be avoided by the use of a rapid-acting insulin analog (eg, insulin lispro or aspart) whose peak mimics physiologic insulin release at mealtime. Using this approach and hyperinsulinemic, hypoglycemic clamp studies, Dr. Bolli and colleagues observed a one-third reduction in the frequency of hypoglycemic episodes and decreased impairment of epinephrine counterregulatory response and symptoms. Thus, in addition to preventing postprandial hypoglycemia, mealtime rapid-acting insulin analogs may aid glucose counterregulation and hypoglycemic awareness.

Nighttime glycemic control is difficult because of the greater incidence of hypoglycemia associated with higher insulin sensitivity. To avoid the effects of the delayed peak of activity of NPH insulin given at dinnertime, Dr. Bolli recommends the use of insulin pumps or the new long-acting, peakless insulin analog glargine. In clinical studies, Dr. Bolli and coworkers observed a 50% reduction in the incidence of nocturnal hypoglycemia in patients on bedtime insulin glargine.

The availability of new insulin analogs may permit a rational regimen of insulin therapy with the dual purpose of controlling glycemia (glycosylated hemoglobin < 7%) and avoiding hypoglycemia and hypoglycemic unawareness.


Impaired Glucose Counterregulation in Intrahepatic Islet Transplant Recipients

Highly successful clinical outcomes of insulin independence have resulted in type 1 diabetic patients undergoing intrahepatic islet transplantation using the Edmonton protocol. (See "Perspectives on Islet Transplantation.") Prior clinical studies to examine hypoglycemia counterregulation in patients who had undergone whole pancreas transplantation demonstrated recovery of the counterregulatory responses posttransplantation. However, similar studies by R. Paul Robertson, MD, University of Washington, Seattle, and colleagues,[3] using stepped hypoglycemic clamps in intrahepatic islet transplant recipients, revealed a surprising result. The islet transplant recipients exhibit an impaired counterregulatory hormonal response. Since this impairment was not observed with intraperitoneally implanted islets (in dog studies), the investigators have concluded that the defect may in part be due to the intrahepatic implantation site. More important, one should be wary of the possibility of increased hypoglycemic recurrence if these patients require supplemental exogenous insulin posttransplantation.


Glucose Sensing in the Brain Mimics That in Pancreatic Islets

The pancreatic islet beta cells have an intricate molecular machinery to "sense" changes in blood glucose. Thus, in response to an elevation in blood glucose, glucose is transported into and metabolized in beta cells, resulting in an increase in the intracellular ATP/ADP ratio. This, in turn, results in closure of cell surface ATP-sensitive K+ (KATP) ion channels, and the accumulated cellular K+ causes membrane depolarization of the cell. Voltage-dependent Ca2+ channels are activated, Ca2+ action potentials are generated, and the resulting Ca2+ influx into the cell triggers exocytosis of insulin. The oral antidiabetic sulfonylureas act through the same pathway by binding and inactivating KATP channels to stimulate insulin secretion.

The conversion of glucose-generated metabolic signals to electrical signals in beta cells may serve as a paradigm for glucose sensing in the brain. With the recent identification of KATP channels in specialized neurons in the brain, it is plausible that these molecules may transduce the glucose signal in neurons, similar to their role in beta cells. To test this hypothesis, Mark L. Evans, MD, Yale University School of Medicine, New Haven, Connecticut, and colleagues[4] examined the effect of glyburide or tolbutamide (blockers of KATP channels) on the hormone counterregulatory response to neuroglycopenia in rats. The drug was delivered into the lateral ventricles through indwelling catheters. The investigators observed a marked attenuation of the glucagon and epinephrine response to a glucopenic stimulus in the presence of the sulfonylureas. In addition, when the studies were repeated using the KATP channel opener diazoxide, enhanced glucagon and epinephrine responses to neuroglycopenia were observed.

Thus, as in pancreatic beta cells, KATP channels may sense changes in brain glucose and thereby play a role in hypoglycemia counterregulation and possibly serve as a therapeutic target.


Brain Insulin Signaling in Hypoglycemia Counterregulation

Simon J. Fisher, MD, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, and colleagues[5] have postulated a role for brain insulin receptors in normal glucose counterregulation. Using NIRKO mice (a mouse model where insulin receptors in the brain have been specifically ablated) and hypoglycemic clamp studies, they observed an impaired epinephrine and corticosterone response to induced hypoglycemia. Glucagon responses to the hypoglycemic stimulus were preserved and were comparable to those in control mice. These studies implicate a role for brain insulin receptors in the hypothalamic-pituitary-adrenal axis counterregulatory hormone response to hypoglycemia.


Summary: Implications for Clinical Practice

  • Long-standing type 1 diabetes is associated with an impairment in the hormonal counterregulatory response to a hypoglycemic challenge. This includes defects in glucagon, epinephrine, and norepinephrine responses aimed at restoring euglycemia.  
  • Cortisol and stress may blunt the counterregulatory response and contribute to hypoglycemia-associated autonomic failure in type 1 diabetes.  
  • Exercise may impede the counterregulatory response and contribute to hypoglycemia-associated autonomic failure in type 1 diabetes.  
  • Antecedent hypoglycemia increases the risk for future hypoglycemia recurrence, resulting in a vicious cycle. Prevention of iatrogenic hypoglycemia can result in rescue of the impaired counterregulatory defects in type 1 diabetes.  
  • A rational insulin regimen of mealtime short-acting insulin analogs combined with basal insulin using insulin pumps or insulin glargine reduces hypoglycemia and preserves glucose counterregulation.  
  • Brain KATP channels (molecules involved in glucose sensing in pancreatic islets) may be involved in brain glucose sensing and glucose counterregulation and may serve as a therapeutic target.  
  • Brain insulin receptors may be involved in glucose counterregulation mediated by the hypothalamic-pituitary-adrenal axis.  



  1. Davis S. Pathophysiology of defective glucose counterregulation. Symposium: Clinical issues in the treatment of hypoglycemia. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association. June 14-18, San Francisco, California. Diabetes, Volume 51, Supplement 2.
  2. Bolli G. Restoring defective hypoglycemia counterregulation. Symposium: Clinical issues in the treatment of hypoglycemia. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association; June 14-18, 2002; San Francisco, California. Diabetes, Volume 51, Supplement 2.
  3. Robertson RP. Does islet transplantation cure hypoglycemia? Symposium: Clinical issues in the treatment of hypoglycemia. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association; June 14-18, 2002; San Francisco, California. Diabetes, Volume 51, Supplement 2.
  4. Evans ML, Keshavarz T, Flanagan DV et al. ICV brain glibenclamide suppresses counterregulatory responses to brain glucopenia in rats: evidence for a role for brain KATP channels in hypoglycemia sensing. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association; June 14-18, 2002; San Francisco, California. Abstract 293-OR. Diabetes, Volume 51, Supplement 2.
  5. Fisher SJ, Bruning J, Lannon S, et al. Insulin signaling in central nervous system is critical for normal counterregulatory response to hypoglycemia. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association; June 14-18, 2002; San Francisco, California. Abstract 294-OR. Diabetes, Volume 51, Supplement 2.