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

Kieren J. Mather, Giancarlo Paradisi, Rosalind Leaming, Ginger Hook, Helmut O. Steinberg, Naomi Fineberg, Rochelle Hanley, Alain D. Baron

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Background. Amylin is a peptide co-secreted with insulin by pancreatic β-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 β-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.

Original languageEnglish (US)
Pages (from-to)118-126
Number of pages9
JournalDiabetes/Metabolism Research and Reviews
Volume18
Issue number2
DOIs
StatePublished - May 15 2002

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Keywords

  • Amylin
  • Glucose disposal rate
  • Hyperglycemic clamp
  • Insulin resistance
  • Insulin sensitivity

ASJC Scopus subject areas

  • Endocrinology
  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

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