ADCY5 couples glucose to insulin secretion in human islets

Diabetes. 2014 Sep;63(9):3009-21. doi: 10.2337/db13-1607.

David J Hodson ¹, Ryan K Mitchell ², Lorella Marselli ³, Timothy J Pullen ², Silvia Gimeno Brias ², Francesca Semplici ², Katy L Everett ⁴, Dermot M F Cooper ⁴, Marco Bugliani ³, Piero Marchetti ³, Vanessa Lavallard ⁵, Domenico Bosco ⁵, Lorenzo Piemonti ⁶, Paul R Johnson ⁷, Stephen J Hughes ⁷, Daliang Li ⁸, Wen-Hong Li ⁸, A M James Shapiro ⁹, Guy A Rutter ¹

Affiliations

1 Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, U.K. d.hodson@imperial.ac.uk g.rutter@imperial.ac.uk.
2 Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, U.K.
3 Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
4 Department of Pharmacology, University of Cambridge, Cambridge, U.K.
5 Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
6 Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy.
7 Nuffield Department of Surgical Sciences, University of Oxford, Oxford, U.K. Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, U.K. National Institute of Health Research Oxford Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
8 University of Texas Southwestern Medical Center, Dallas, TX.
9 Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada.

PMID: 24740569 DOI: 10.2337/db13-1607

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.

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