ADCY5 couples glucose to insulin secretion in human islets
- David J. Hodson1,#,*,
- Ryan K. Mitchell1,#,
- Lorella Marselli3,
- Timothy J. Pullen1,
- Silvia Gimeno Brias1,
- Francesca Semplici1,
- Katy L. Everett2,
- Dermot M.F. Cooper2,
- Marco Bugliani3,
- Piero Marchetti3,
- Vanessa Lavallard4,
- Domenico Bosco4,
- Lorenzo Piemonti5,
- Paul R. Johnson6,
- Stephen J. Hughes6,
- Daliang Li7,
- Wen-Hong Li7,
- A.M. James Shapiro8 and
- Guy A. Rutter1,*
- 1Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London SW7 2AZ UK.
- 2Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, U.K.
- 3Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy
- 4Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
- 5Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.
- 6Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK.
- 7UT Southwestern Medical Center 5323 Harry Hines Boulevard Dallas, Texas 75390, USA.
- 8Clinical Islet Laboratory and Clinical Islet transplant program, University of Alberta, Edmonton, AB Canada.
- *Corresponding Author: Guy A. Rutter, E-mail: and David J. Hodson, E-mail:
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 beta 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 towards ATP at concentrations of the sugar >8 mM. However, calcium transient generation and functional connectivity between individual human beta 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 beta cell ADCY5 expression and impaired glucose signalling 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.
# Authors made equal contributions
- Received October 18, 2013.
- Accepted April 10, 2014.
- © 2014 by the American Diabetes Association.
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