Hypoglycemia-associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes

Abstract

Hypoglycemia remains a major barrier to the achievement of target levels of glycemic control for most individuals with insulin-dependent type 1 diabetes (T1D). Both the loss of β cells and an accompanying defect in the α cell response to hypoglycemia predispose patients with T1D to the development of low blood glucose. Increased glucose variability, exposure to hypoglycemia, and impaired awareness of hypoglycemia all contribute to increased risk of experiencing severe hypoglycemia, which is explained by progressive impairment in epinephrine secretion and autonomic symptom generation in response to hypoglycemia leading to defective glucose counterregulation and hypoglycemia unawareness that characterize hypoglycemia-associated autonomic failure (HAAF). Interruption of HAAF requires interfering with the mechanisms of brain adaptation to low blood glucose that affect central glucose sensing and the autonomic response to hypoglycemia, or avoidance of hypoglycemia that may allow for eventual recovery of counterregulatory and autonomic symptom responses. Strategies for hypoglycemia avoidance that include continuous glucose monitoring may reduce, but do not eliminate, clinically significant hypoglycemia, with ongoing counterregulatory defects and impaired awareness of hypoglycemia. Complete avoidance of hypoglycemia can be achieved following pancreatic islet transplantation and allows for the restoration of counterregulatory and autonomic symptom responses that evidences the potential for reversing HAAF in T1D.

Keywords: glucose counterregulation; hypoglycemia unawareness; hypoglycemia-associated autonomic failure; type 1 diabetes.

Figure 1.

Proportion of patients with type 1 diabetes (T1D) experiencing a severe episode of hypoglycemia resulting in seizure or loss-of-consciousness in the prior 3 months according to most recent HbA_1c as reported in the T1D Exchange Registry and Clinic Network of specialized diabetes care practices in the United States. Data are from Foster et al.

Figure 2.

Risk factors for experiencing severe hypoglycemia in patients with type 1 diabetes.

Figure 3.

Vicious cycle of hypoglycemia begets hypoglycemia in patients with type 1 diabetes (T1D). Sympathoadrenal responses refer to an increase in epinephrine secretion and the generation of autonomic symptoms that are critical for defense against hypoglycemia in T1D. Adapted from Cryer.

Figure 4.

Mechanisms for brain adaptation to hypoglycemia leading to hypoglycemia-associated autonomic failure (HAAF). In red are strategies for interrupting HAAF based on central signaling pathways. In blue are strategies for preventing/reversing HAAF based on hypoglycemia avoidance.

Figure 5.

Recovery of counterregulatory responses to insulin-induced hypoglycemia following islet transplantation in patients with type 1 diabetes (T1D) and hypoglycemia unawareness prior to transplant. Response measures are taken from the final hour of a hypoglycemic clamp and expressed as a percentage of normally derived measures from a nondiabetic control group using data reported by Rickels et al. The hashed area gives the range of responses that were both significantly greater than pretransplant and not statistically different than normal.