Decreased STARD10 Expression Is Associated with Defective Insulin Secretion in Humans and Mice

Gaelle R Carrat, Ming Hu, Marie-Sophie Nguyen-Tu, Pauline Chabosseau, Kyle J Gaulton, Martijn van de Bunt, Afshan Siddiq, Mario Falchi, Matthias Thurner, Mickaël Canouil, Francois Pattou, Isabelle Leclerc, Timothy J Pullen, Matthew C Cane, Priyanka Prabhala, William Greenwald, Anke Schulte, Piero Marchetti, Mark Ibberson, Patrick E MacDonaldJocelyn E Manning Fox, Anna L Gloyn, Philippe Froguel, Michele Solimena, Mark I McCarthy, Guy A Rutter

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)
316 Downloads (Pure)

Abstract

Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in β cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, β-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca(2+) dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult β cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in β cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the β cell.

Original languageEnglish
Pages (from-to)238-256
Number of pages19
JournalAmerican Journal of Human Genetics
Volume100
Issue number2
Early online date26 Jan 2017
DOIs
Publication statusPublished - 2 Feb 2017

Fingerprint

Dive into the research topics of 'Decreased STARD10 Expression Is Associated with Defective Insulin Secretion in Humans and Mice'. Together they form a unique fingerprint.

Cite this