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Loss of the Decrement in Intraislet Insulin Plausibly Explains Loss of the Glucagon Response to Hypoglycemia in Insulin-Deficient Diabetes

Documentation of the Intraislet Insulin Hypothesis in Humans

From the Division of Endocrinology, Metabolism and Lipid Research, and the General Clinical Research Center and Diabetes Research and Training Center, Washington University School of Medicine, St. Louis, Missouri

The intraislet insulin hypothesis for the signaling of the glucagon secretory response to hypoglycemia states that a decrease in arterial glucose a decrease in ß-cell insulin secretion a decrease in tonic -cell inhibition by insulin an increase in -cell glucagon secretion. To test this hypothesis in humans, a hyperinsulinemic- euglycemic (5.0 mmol/l [90 mg/dl] x 2 h) and then a hypoglycemic (3.0 mmol/l [55 mg/dl] x 2 h) clamp was performed in 14 healthy young adults on two occasions, once with oral administration of the ATP-sensitive potassium channel agonist diazoxide to selectively suppress baseline insulin secretion and once with the administration of a placebo. The decrement in plasma C-peptide during the induction of hypoglycemia was reduced by 50% in the diazoxide clamps (from 0.3 ± 0.0 to 0.1 ± 0.0 nmol/l [0.8 ± 0.1 to 0.4 ± 0.1 ng/ml]) compared with the placebo clamps (from 0.4 ± 0.0 to 0.1 ± 0.0 nmol/l [1.2 ± 0.1 to 0.4 ± 0.1 ng/ml]) (P = 0.0015). This reduction of the decrement in intraislet insulin during induction of hypoglycemia caused an 50% reduction (P = 0.0010) of the increase in plasma glucagon in the diazoxide clamps (from 29 ± 3 to 35 ± 2 pmol/l [102 ± 9 to 123 ± 8 pg/ml]) compared with the placebo clamps (from 28 ± 2 to 43 ± 5 pmol/l [98 ± 7 to 151 ± 16 pg/ml]). Baseline glucagon levels, the glucagon response to intravenous arginine, and the autonomic (adrenomedullary, sympathetic neural, and parasympathetic neural) responses to hypoglycemia were not altered by diazoxide. These data indicate that a decrease in intraislet insulin is a signal for the glucagon secretory response to hypoglycemia in healthy humans. The absence of that signal plausibly explains the loss of the glucagon response to falling plasma glucose concentrations, a key feature of the pathogenesis of iatrogenic hypoglycemia, in insulin-deficient (type 1 and advanced type 2) diabetes.

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