ADCY5 couples glucose to insulin secretion in human islets

Research output: Contribution to journalArticle

Authors

  • Ryan K Mitchell
  • Lorella Marselli
  • Timothy J Pullen
  • Silvia Gimeno Brias
  • Francesca Semplici
  • Katy L Everett
  • Dermot M F Cooper
  • Marco Bugliani
  • Piero Marchetti
  • Vanessa Lavallard
  • Domenico Bosco
  • Lorenzo Piemonti
  • Paul R Johnson
  • Stephen J Hughes
  • Daliang Li
  • Wen-Hong Li
  • A M James Shapiro
  • Guy A Rutter

Colleges, School and Institutes

External organisations

  • University of Oxford

Abstract

Single nucleotide polymorphisms (SNPs) within the ADCY5 gene, encoding adenylate cyclase 5, are associated with elevated fasting glucose and increased type 2 diabetes (T2D) risk. Despite this, the mechanisms underlying the effects of these polymorphic variants at the level of pancreatic β-cells remain unclear. Here, we show firstly that ADCY5 mRNA expression in islets is lowered by the possession of risk alleles at rs11708067. Next, we demonstrate that ADCY5 is indispensable for coupling glucose, but not GLP-1, to insulin secretion in human islets. Assessed by in situ imaging of recombinant probes, ADCY5 silencing impaired glucose-induced cAMP increases and blocked glucose metabolism toward ATP at concentrations of the sugar >8 mmol/L. However, calcium transient generation and functional connectivity between individual human β-cells were sharply inhibited at all glucose concentrations tested, implying additional, metabolism-independent roles for ADCY5. In contrast, calcium rises were unaffected in ADCY5-depleted islets exposed to GLP-1. Alterations in β-cell ADCY5 expression and impaired glucose signaling thus provide a likely route through which ADCY5 gene polymorphisms influence fasting glucose levels and T2D risk, while exerting more minor effects on incretin action.

Bibliographic note

© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Details

Original languageEnglish
Pages (from-to)3009-21
Number of pages13
JournalDiabetes
Volume63
Issue number9
Early online date16 Apr 2014
Publication statusPublished - Sep 2014

Keywords

  • Adenylate Cyclase, Calcium, Diabetes Mellitus, Type 2, Glucagon-Like Peptide 1, Glucose, Humans, Insulin, Insulin-Secreting Cells, Polymorphism, Single Nucleotide, RNA, Messenger, Risk