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

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 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.

The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

“…The characteristic decrease of plasma proinsulin:insulin ratio observed in human carriers of the risk alleles at this locus [22], and the observation of a similar phenotype in βStard10KO mice [10], suggest an action of STARD10 on proinsulin processing in the β-cell. We therefore next investigated this hypothesis by performing a metabolic labelling pulse-chase experiment in isolated islets from WT and βStard10KO mice.…”

“…Mice homozygous for floxed Stard10 (Stard10 fl/fl ) alleles were crossed to mice expressing Cre recombinase from the endogenous Ins1 locus (Ins1-Cre mice). This generated Stard10 fl/fl :Ins1Cre + (βStard10KO) mice as in [10].…”

“…As an initial approach to determining the target membranes for STARD10 action, we first explored the impact of deleting the Stard10 gene on β-cell ultrastructure. We have previously shown that crossing of Stard10 floxed mice to Ins1Cre knock-in mice [20] efficiently and selectively deletes STARD10 in the pancreatic β-cell [10]. Transmission electron microscopy images of β-cells in islets isolated from βStard10KO mice revealed a dramatic change in insulin granule morphology with a significant increase in "atypical" granules with a "rod-shaped" core ( Figure 1A and B; Cre+: 12.05 ± 1.67% versus Cre-: 2.78 ± 0.36%; p<0.001, Student's t test, n = 3 animals).…”

“…We have recently examined a T2D-associated locus adjacent to STARD10 on chromosome 11q13 [10,11]. Risk variants at this locus were associated with a decrease in STARD10 mRNA in human islets, with no concomitant change in the liver.…”

A transcription start site map in human pancreatic islets reveals functional regulatory signatures

“…We observed significant activity of the TC element that overlaps rs1552224 in our STARR-seq assay (Z score = 4.90, Z score P value = 4.78x10 -7 ). A previous study showed evidence for rs11603334 to be the causal variant (Kulzer et al 2014), whereas another study pointed towards an indel rs140130268 as more likely causal (Carrat et al 2017). These studies nominating different causal variants highlight the complexity at this locus.…”