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

Jochen Seufert, Timothy J. Kieffer, Colin A. Leech, George G. Holz, Wolfgang Moritz, Camillo Ricordi, Joel F. Habener

Research output: Contribution to journalArticle

244 Scopus citations

Abstract

Previously we demonstrated the expression of the long form of the leptin receptor in rodent pancreatic β-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 β-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 β-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 β-cells. We suggest that dysregulation of the adipoinsular axis in obese individuals due to defective leptin reception by β-cells may result in chronic hyperinsulinemia and may contribute to the pathogenesis of adipogenic diabetes.

Original languageEnglish (US)
Pages (from-to)670-676
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume84
Issue number2
DOIs
StatePublished - 1999

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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