Hypoglycemia-Associated Autonomic Failure in Advanced Type 2 Diabetes

Abstract

We tested the hypotheses that the glucagon response to hypoglycemia is reduced in patients who are approaching the insulin-deficient end of the spectrum of type 2 diabetes and that recent antecedent hypoglycemia shifts the glycemic thresholds for autonomic (including adrenomedullary epinephrine) and symptomatic responses to hypoglycemia to lower plasma glucose concentrations in type 2 diabetes. Hyperinsulinemic stepped hypoglycemic clamps (85, 75, 65, 55, and 45 mg/dl steps) were performed on two consecutive days, with an additional 2 h of hypoglycemia (50 mg/dl) in the afternoon of the first day, in 13 patients with type 2 diabetes-7 treated with oral hypoglycemic agents (OHA R X ; mean [؎SD] HbA 1c 8.6 ؎ 1.1%) and 6 requiring therapy with insulin for an average of 5 years and with reduced C-peptide levels (insulin R X , HbA 1c 7.5 ؎ 0.7%)-and 15 nondiabetic control subjects. The glucagon response to hypoglycemia was virtually absent (P ‫؍‬ 0.0252) in the insulin-deficient type 2 diabetic patients (insulin R X mean [؎SE] final values of 52 ؎ 16 vs. 93 ؎ 15 pg/ml in control subjects and 98 ؎ 16 pg/ml in type 2 diabetic patients, OHA R X on day 1). Glucagon (P ‫؍‬ 0.0015), epinephrine (P ‫؍‬ 0.0002), and norepinephrine (P ‫؍‬ 0.0138) responses and neurogenic (P ‫؍‬ 0.0149) and neuroglycopenic (P ‫؍‬ 0.0015) symptom responses to hypoglycemia were reduced on day 2 after hypoglycemia on day 1 in type 2 diabetic patients; these responses were not eliminated, but their glycemic thresholds were shifted to lower plasma glucose concentrations. In addition, the glycemic thresholds for these responses were at higher-than-normal plasma glucose concentrations (P ‫؍‬ 0.0082, 0.0028, 0.0023, and 0.0182, respectively) at baseline (day 1) in OHA R X type 2 diabetic patients, with relatively poorly controlled diabetes. Because the glucagon response to falling plasma glucose levels is virtually absent and the glycemic thresholds for autonomic and symptomatic responses to hypoglycemia are shifted to lower glucose concentrations by recent antecedent hypoglycemia, patients with advanced type 2 diabetes, like those with type 1 diabetes, are at risk for hypoglycemia-associated autonomic failure and the resultant vicious cycle of recurrent iatrogenic hypoglycemia. Diabetes 51:724 -733, 2002

Regulation of α-Cell Function by the β-Cell in Isolated Human and Rat Islets Deprived of Glucose: the “Switch-off” Hypothesis

“…Loss of the glucagon response to hypoglycemia is an important problem for patients with type 1 diabetes and for patients with diabetes who require insulin-based therapy for glycemic control (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Cryer et al (15) attributed loss of the glucagon response in diabetes to an absence of an essential signal from the ␤-cell.…”

Attenuation of Counterregulatory Responses to Recurrent Hypoglycemia by Active Thalamic Inhibition

“…Hypoglycemia in diabetes is the result of the interplay of therapeutic insulin excess and compromised physiological and behavioral defenses against falling plasma glucose concentrations (1)(2)(3). The key feature of the latter is an attenuated sympathoadrenal response to hypoglycemia that causes the clinical syndromes of hypoglycemia unawareness, which is largely the result of a reduced sympathetic neural response (4), and defective glucose counterregulation, which is the result of a reduced adrenomedullary epinephrine response in the setting of absent decrements in insulin and absent increments in glucagon in insulin-deficient diabetes--type 1 diabetes and advanced (i.e., absolutely insulin deficient) type 2 diabetes.…”

Preoperative Glycemic Control for Adult Diabetic Patients Undergoing Elective Surgery

“…This is especially important in patients with hypoglycemic unawareness, a loss of the signs of hypoglycemia, due to long-standing diabetes [25]. Alternatively, patients achieving the 80-180 mg/dL perioperative standard may experience hypoglycemic symptoms if they generally have uncontrolled diabetes, and thus, should closely monitor their blood glucose [25].…”

“…This is especially important in patients with hypoglycemic unawareness, a loss of the signs of hypoglycemia, due to long-standing diabetes [25]. Alternatively, patients achieving the 80-180 mg/dL perioperative standard may experience hypoglycemic symptoms if they generally have uncontrolled diabetes, and thus, should closely monitor their blood glucose [25]. One study looked at fasting diabetes patients who had hypoglycemic symptoms while driving to have routine labs drawn, and found a 68% reduction in risk when patients were properly educated on fasting precautions [26].…”