ADCY5 Couples Glucose to Insulin Secretion in Human Islets

• Published in: Diabetes (New York, N.Y.) Vol. 63; no. 9; pp. 3009 - 3021
• Main Authors: HODSON, David J, MITCHELL, Ryan K, LAVALLARD, Vanessa, BOSCO, Domenico, PIEMONTI, Lorenzo, JOHNSON, Paul R, HUGHES, Stephen J, DALIANG LI, LI, Wen-Hong, SHAPIRO, A. M. James, RUTTER, Guy A, MARSELLI, Lorella, PULLEN, Timothy J, BRIAS, Silvia Gimeno, SEMPLICI, Francesca, EVERETT, Katy L, COOPER, Dermot M. F, BUGLIANI, Marco, MARCHETTI, Piero
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-09-2014
• Subjects: Adenosine triphosphatase; Adenylyl Cyclases - physiology; Biological and medical sciences; Calcium; Calcium - metabolism; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucagon-Like Peptide 1 - physiology; Glucose; Glucose - metabolism; Glucose - pharmacology; Humans; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Islet Studies; Medical sciences; Polymorphism; Polymorphism, Single Nucleotide; Risk; Risk assessment; RNA, Messenger - metabolism; Endocrinopathy; Human; Pancreatic hormone; Secretion; Diabetes mellitus; Glucose; Insulin
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db13-1607

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.