Multiple defects in counterregulation of hypoglycemia in modestly advanced type 2 diabetes mellitus.

In type 2 diabetes mellitus (T2DM), little is known about hormonal responses to hypoglycemia. In particular, beta-cell responses to hypoglycemia have not been carefully investigated and potentially because of confounding factors or insufficient power, conflicting data have been obtained regarding growth hormone responses. We therefore compared hormonal responses including rates of insulin secretion during a 2-hour hyperinsulinemic hypoglycemic clamp in a relatively large number of nondiabetic (n=21) and moderately insulin-deficient subjects with T2DM (homeostasis model assessment of beta-cell function [HOMA-%B], 751+/-160 vs 1144+/-83 [pmol/L]/[mmol/L], P<.04) (n=14) matched for age, sex, and body mass index. Subjects with T2DM were excluded for antecedent hypoglycemia, and baseline glycemia was controlled by a variable infusion of insulin overnight. Although both groups of subjects had indistinguishable plasma glucose levels at baseline and virtually identical levels of plasma insulin and glucose throughout the hypoglycemic clamp, insulin secretion decreased more slowly in the subjects with T2DM. The time required for insulin secretion to decline to half its baseline level was markedly increased (38.9+/-4.9 vs 22.3+/-1.3 minutes [SD], P<.01), and insulin secretion decreased to a lesser extent (-0.79+/-0.17 vs -1.51+/-0.09 [pmol/L]/kg per minute, P<.002). Moreover, responses of glucagon (28.3+/-7.3 vs 52.8+/-7.0 ng/L, P<.05) and growth hormone (2.9+/-0.8 vs 6.3+/-0.9 ng/mL, P<.04) were reduced in the subjects with T2DM, whereas responses of epinephrine, norepinephrine, and cortisol were similar to those in nondiabetic subjects (all P>0.6). We conclude that multiple defects exist in hormonal responses to hypoglycemia in T2DM with moderate beta-cell failure. These include delayed and reduced decreases in insulin secretion, and impaired increases of plasma glucagon and growth hormone.

Increasing the decrement in insulin secretion improves glucagon responses to hypoglycemia in advanced type 2 diabetes.

OBJECTIVE: In advanced beta-cell failure, counterregulatory glucagon responses may be impaired due to a reduced decrement in insulin secretion during the development of hypoglycemia. The present studies were therefore undertaken to test the hypothesis that these may be improved by increasing this decrement in insulin secretion. RESEARCH DESIGN AND METHODS: Twelve subjects with type 2 diabetes who have been insulin requiring were studied as a model of advanced beta-cell failure. Glucagon responses were examined during a 90-min hypoglycemic clamp (approximately 2.8 mmol/l) on two separate occasions. On one occasion, tolbutamide was infused for 2 h before the clamp so that the decrement in insulin secretion during the induction of hypoglycemia would be increased. On the other occasion, normal saline was infused as a control. RESULTS: Before the hypoglycemic clamp, infusion of tolbutamide increased insulin secretion approximately 1.9-fold (P < 0.001). However, during hypoglycemia, insulin secretion decreased to similar rates on both occasions (P = 0.31) so that its decrement was approximately twofold greater following the tolbutamide infusion (1.63 +/- 0.20 vs. 0.81 +/- 0.17 pmol x kg(-1) x min(-1), P < 0.001). This was associated with more than twofold-greater glucagon responses (42 +/- 11 vs. 19 +/- 8 ng/l, P < 0.002) during the hypoglycemic clamp but unaltered glucagon responses to intravenous arginine immediately thereafter (449 +/- 50 vs. 453 +/- 50 ng/l, P = 0.78). CONCLUSIONS: Increasing the decrement in insulin secretion during the development of hypoglycemia improves counterregulatory glucagon responses in advanced beta-cell failure. These findings further support the concept that the impaired counterregulatory glucagon responses in advanced beta-cell failure may at least partially be due to a reduced decrement in insulin secretion.