Altered Glucose-dependent Secretion of Glucagon and ACTH is Associated with Insulin Resistance, Assessed by Population Analysis

This study aimed to characterize how the dysregulation of counter-regulatory hormones can contribute to insulin resistance and potentially to diabetes. Therefore, we investigated the association between insulin sensitivity and the glucose- and insulin-dependent secretion of glucagon, adrenocorticotropic hormone (ACTH), and cortisol in non-diabetic individuals using a population model analysis. Data, from hyperinsulinemic-hypoglycemic clamps, were pooled for analysis, including 52 individuals with a wide range of insulin resistance (reflected by glucose infusion rate 20-60 min; GIR20-60min). Glucagon secretion was suppressed by glucose and, to a lesser extent, insulin. The GIR20-60min and BMI were identified as predictors of the insulin effect on glucagon. At normoglycemia (5 mmol/L), a 90% suppression of glucagon was achieved at insulin concentrations of 16.3 and 43.4 µU/mL in individuals belonging to the highest and lowest quantiles of insulin sensitivity, respectively. Insulin resistance of glucagon secretion explained the elevated fasting glucagon for individuals with a low GIR20-60min. ACTH secretion was suppressed by glucose and not affected by insulin. The GIR20-60min was superior to other measures as a predictor of glucose-dependent ACTH secretion, with 90% suppression of ACTH secretion by glucose at 3.1 and 3.5 mmol/L for insulin-sensitive and insulin-resistant individuals, respectively. This difference may appear small but shifts the suppression range into normoglycemia for individuals with insulin resistance, thus, leading to earlier and greater ACTH/cortisol response when the glucose falls. Based on modeling of pooled glucose-clamp data, insulin resistance was associated with generally elevated glucagon and a potentiated cortisol-axis response to hypoglycemia, and over time both hormonal pathways may therefore contribute to dysglycemia and possibly type 2 diabetes.