Role of amylin in insulin secretion and action in humans: antagonist studies across the spectrum of insulin sensitivity

Abstract

BACKGROUND: Amylin is a peptide co-secreted with insulin by pancreatic beta-cells. A role for amylin in the pathogenesis of type 2 diabetes mellitus (DM2) has been suggested by in vitro and in vivo studies indicating an effect of amylin to cause insulin resistance and/or inhibit insulin secretion. METHODS: We have determined the effect of endogenous amylin on insulin secretion and insulin action in humans by performing 4-h hyperglycemic clamps during infusion of placebo or a specific amylin receptor antagonist (ARA) in paired, double-blinded, crossover studies. We studied nine healthy lean, ten healthy obese (BMI>27) and ten obesity-matched DM2 subjects. RESULTS: Infusion of ARA alone had no effect on basal insulin, glucose or glucose turnover in any group. Under combined hyperglycemia and ARA infusion, lean subjects displayed a 32% augmentation in insulin levels [AUC 33,565+/-3556 (placebo) to 44,562+/-1379 (ARA) pmol/l/min, p<0.01]. The concomitant increase in glucose disposal rate (GDR) was proportionate, indicating no change in insulin sensitivity (ISI 27.7+/-2.7 vs 27.3+/-2.1, p=NS). In obese subjects, basal insulin and the rise in insulin during the clamp were greater (AUC I 44% increase from 82,054+/-15 407 to 117,922+/-27,085, p<0.01), and also accompanied by a proportionate rise in GDR reflecting an unchanged insulin sensitivity (ISI 12.1+/-2.9 vs 10.8+/-3.0, p=NS). In lean and obese subjects, the C-peptide response to hyperglycemia was also augmented by ARA (p=0.007). No effect of ARA on insulin secretion or action was observed in diabetic subjects. CONCLUSIONS: The present data are consistent with an effect of endogenous amylin on the beta-cell to modulate and/or restrain insulin secretion, and indicate that endogenous amylin does not affect insulin action. These observations provide the first human evidence that amylin plays a role in the modulation of insulin secretion.