Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus. Paradoxical suppression of glucose utilization and lack of compensatory increase in glucose production, roles of insulin resistance, abnormal neuroendocrine responses, and islet paracrine interactions.

Abstract

Abs tract. To characterize glucose counterregulatory mechanisms in patients with noninsulin-dependent diabetes mellitus (NIDDM) and to test the hypothesis that the increase in glucagon secretion during hypoglycemia occurs primarily via a paracrine islet A-B cell interaction, we examined the effects of a subcutaneously injected therapeutic dose ofinsulin (0.15 U/kg) on plasma glucose kinetics, rates of glucose production and utilization, and their relationships to changes in the circulating concentrations of neuroendocrine glucoregulatory factors (glucagon, epinephrine, norepinephrine, growth hormone, and cortisol), as well as to changes in endogenous insulin secretion in 13 nonobese NIDDM patients with no clinical evidence of autonomic neuropathy. Compared with 11 age-weight matched nondiabetic volunteers in whom euglycemia was restored primarily by a compensatory increase in glucose production, in the diabetics there was no compensatory increase in glucose production (basal 2.08±0. plasma insulin concentrations were similar in both groups (peak values 22±2 vs. 23±2 ,U/ml in diabetics and nondiabetics, respectively). This abnormality in glucose production was nearly completely compensated for by a paradoxical decrease in glucose utilization after injection of insulin (basal 2.11±0.03 -+ 1.86±0.06 mg/kg per min at 2/2 h in diabetics vs. basal 2.08±0.04 --2.39±0.11 mg/ kg per min at 2'/2 h nondiabetics, P < 0.01), which could not be accounted for by differences in plasma glucose concentrations; the net result was a modest prolongation of hypoglycemia. Plasma glucagon (area under the curve [AUCG above base line, 12±3 vs. 23±3 mg/ml. 12 h in nondiabetics, P < 0.05), cortisol (AUC 2.2±0.5 vs. 4.0±0.7 mg/dl-12 h in nondiabetics, P < 0.05), and growth hormone (AUC 1.6±0.4 vs. 2.9±0.4 ,g/ml. 12 h in nondiabetics, P < 0.05) responses in the diabetics were decreased 50% while their plasma norepinephrine responses (AUC 49±12 vs. 21±5 ng/ml-12 h in nondiabetics, P < 0.05) were increased twofold (P < 0.05) and their plasma epinephrine responses were similar to those ofthe nondiabetics (AUC 106±17 vs. 1 12±10 ng/ml -12 h in nondiabetics). In both groups of subjects, increases in plasma glucagon were inversely correlated with plasma glucose concentrations (r = -0.80 in both groups, P < 0.01) and suppression of endogenous insulin secretion (r = -0.57 in nondiabetics and -0.64 Volume 73, June 1984, 1532-1541 Our results thus indicate that glucose counterregulatory mechanisms are abnormal in patients with NIDDM: impaired glucagon, growth hormone, cortisol, and perhaps epinephrine responses during hypoglycemia could all contribute to a lack of compensatory increase in glucose production while near normal (epinephrine) and increased (norepinephrine) release ofcatecholamines in the presence of resistance to insulin in peripheral tissues may explain the accompanying suppression of glucose utilization. The inverse relationship between increases in plasma glucagon and suppression of insulin secretion observed during hypoglycemia in ...

Effect of Intravenous Infusion of Exenatide (Synthetic Exendin-4) on Glucose-Dependent Insulin Secretion and Counterregulation During Hypoglycemia

“…Serum FFA concentrations were almost identical during both exenatide and placebo arms during the whole study. On balance, from the present study, it is difficult to speculate how the augmented glucagon response to hypoglycemia with exenatide may translate to patients with type 2 diabetes, keeping in mind that glucagon responses are commonly impaired in this patient population (30,31).…”

Hypoglycaemia: The limiting factor in the glycaemic management of Type I and Type II Diabetes*

“…As discussed above, regulated insulin and glucagon secretion, and without the latter epinephrine secretion, normally play key roles in the prevention of hypoglycaemia [12]. Glucagon responses to hypoglycaemia have been reported to be normal [48,49,50] or reduced but not absent [51,52,53] in studies of unselected patients with Type II diabetes. Epinephrine responses have not been found to be reduced.…”

Alpha cell function in health and disease: influence of glucagon-like peptide-1

“…A marked impairment is well documented in patients with type 1 diabetes [37] and those with long-standing type 2 diabetes [38], although the degree of impairment in patients with 'mild' type 2 diabetes is controversial [39], as are the relative contributions of altered pancreatic glucose sensing and autonomic failure [40]. Nonetheless, impaired alpha cell glucose sensing can result in inadequate glucagon secretion in response to decreases in plasma glucose, and thereby increased risk of severe hypoglycaemia, and in excessive glucagon secretion in the fasting [41] and postprandial states [42], which contribute to the development and progression of hyperglycaemia in type 2 diabetes.…”