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

Diabetes Metab Res Rev. Mar-Apr 2002;18(2):118-26. doi: 10.1002/dmrr.263.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Amyloid / blood
  • Amyloid / physiology*
  • Area Under Curve
  • Blood Glucose / metabolism*
  • Body Mass Index
  • C-Peptide / blood
  • Diabetes Mellitus / blood
  • Diabetes Mellitus / physiopathology*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Female
  • Glucagon / blood
  • Glucose Clamp Technique
  • Humans
  • Insulin / metabolism
  • Insulin / physiology*
  • Insulin Secretion
  • Islet Amyloid Polypeptide
  • Male
  • Obesity / blood
  • Obesity / physiopathology*
  • Receptors, Islet Amyloid Polypeptide
  • Receptors, Peptide / antagonists & inhibitors
  • Receptors, Peptide / blood
  • Reference Values

Substances

  • Amyloid
  • Blood Glucose
  • C-Peptide
  • Insulin
  • Islet Amyloid Polypeptide
  • Receptors, Islet Amyloid Polypeptide
  • Receptors, Peptide
  • Glucagon