Glucose-Dependent Granule Docking Limits Insulin Secretion and Is Decreased in Human Type 2 Diabetes

Research output: Contribution to journalArticle

Abstract

Glucose-stimulated insulin secretion is biphasic, with a rapid first phase and a slowly developing sustained second phase; both are disturbed in type 2 diabetes (T2D). Biphasic secretion results from vastly different release probabilities of individual insulin granules, but the morphological and molecular basis for this is unclear. Here, we show that human insulin secretion and exocytosis critically depend on the availability of membrane-docked granules and that T2D is associated with a strong reduction in granule docking. Glucose accelerated granule docking, and this effect was absent in T2D. Newly docked granules only slowly acquired release competence; this was regulated by major signaling pathways, but not glucose. Gene expression analysis indicated that key proteins involved in granule docking are downregulated in T2D, and overexpression of these proteins increased granule docking. The findings establish granule docking as an important glucose-dependent step in human insulin secretion that is dysregulated in T2D. Insulin secretion is disturbed in type 2 diabetes (T2D). Gandasi et al. show that insulin granule docking to the plasma membrane is necessary for exocytosis and sustained insulin secretion and that this process is dysregulated in T2D.

Details

Authors
  • Nikhil R. Gandasi
  • Peng Yin
  • Muhmmad Omar-Hmeadi
  • Emilia Ottosson Laakso
  • Petter Vikman
  • Sebastian Barg
Organisations
External organisations
  • Uppsala University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes

Keywords

  • biphasic secretion, dense core vesicle, docking, exocytosis, genome-wide association, GLP-1, insulin secretion, priming, somatostatin, type 2 diabetes
Original languageEnglish
Pages (from-to)470-478.e4
JournalCell Metabolism
Volume27
Issue number2
Publication statusPublished - 2018 Feb 6
Publication categoryResearch
Peer-reviewedYes