Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus

J Clin Endocrinol Metab. 1999 Feb;84(2):670-6. doi: 10.1210/jcem.84.2.5460.

Abstract

Previously we demonstrated the expression of the long form of the leptin receptor in rodent pancreatic beta-cells and an inhibition of insulin secretion by leptin via activation of ATP-sensitive potassium channels. Here we examine pancreatic islets isolated from pancreata of human donors for their responses to leptin. The presence of leptin receptors on islet beta-cells was demonstrated by double fluorescence confocal microscopy after binding of a fluorescent derivative of human leptin (Cy3-leptin). Leptin (6.25 nM) suppressed insulin secretion of normal islets by 20% at 5.6 mM glucose. Intracellular calcium responses to 16.7 mM glucose were rapidly reduced by leptin. Proinsulin messenger ribonucleic acid expression in islets was inhibited by leptin at 11.1 mM, but not at 5.6 mM glucose. Leptin also reduced proinsulin messenger ribonucleic acid levels that were increased in islets by treatment with 10 nM glucagon-like peptide-1 in the presence of either 5.6 or 11.1 mM glucose. These findings demonstrate direct suppressive effects of leptin on insulin-producing beta-cells in human islets at the levels of both stimulus-secretion coupling and gene expression. The findings also further indicate the existence of an adipoinsular axis in humans in which insulin stimulates leptin production in adipocytes and leptin inhibits the production of insulin in beta-cells. We suggest that dysregulation of the adipoinsular axis in obese individuals due to defective leptin reception by beta-cells may result in chronic hyperinsulinemia and may contribute to the pathogenesis of adipogenic diabetes.

Publication types

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

MeSH terms

  • Calcium / metabolism
  • Carrier Proteins / analysis
  • Cells, Cultured
  • Diabetes Mellitus / metabolism*
  • Gene Expression / drug effects*
  • Glucagon / pharmacology
  • Glucagon-Like Peptide 1
  • Glucose / pharmacology
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / chemistry
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Leptin
  • Obesity*
  • Peptide Fragments / pharmacology
  • Potassium Channels / drug effects
  • Potassium Channels / physiology
  • Proinsulin / genetics*
  • Protein Precursors / pharmacology
  • Proteins / pharmacology*
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface*
  • Receptors, Leptin

Substances

  • Carrier Proteins
  • Insulin
  • Leptin
  • Peptide Fragments
  • Potassium Channels
  • Protein Precursors
  • Proteins
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Leptin
  • leptin receptor, human
  • Glucagon-Like Peptide 1
  • Glucagon
  • Proinsulin
  • Glucose
  • Calcium