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

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 of insulin (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 ± 0.04 → 1.79 ± 0.07 mg/kg per min at 2 1/2 h in diabetics vs. basal 2.06 ± 0.04 → 2.32. ± 0.11 mg/kg per min at 2 1/2 h in nondiabetics, P < 0.01) despite the fact that plasma insulin concentrations were similar in both groups (peak values 22 ± 2 vs. 23 ± 2 μ 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 1/2 h in diabetics vs. basal 2.08 ± 0.04 → 2.39 ± 0.11 mg/kg per min at 2 1/2 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 [AUC] 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 μg/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 of the nondiabetics (AUC 106 ± 17 vs. 112 ± 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 in diabetics, both P < 0.05). The slope for the relationship between plasma glucagon responses and plasma glucose concentrations was reduced in the diabetics (1.2 vs. 2.3 in nondiabetics), suggesting decreased pancreatic A cell sensitivity to glucose. 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 of catecholamines 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 both nondiabetic and diabetic subjects is incompatible with the concept that deinhibition of glucagon secretion via a paracrine islet A-B cell interaction is a major factor responsible for the increase in glucagon secretion during hypoglycemia. Our results suggest that the plasma glucagon response to hypoglycemia is predominantly the result of a stimulatory effect of decreased extracellular glucose concentrations on the A cell.