THE IMPACT OF INS AND STARD10 GENE MUTATIONS ON INSULIN PROCESSING, SECRETION AND PANCREATIC BETA-CELL FUNCTION IN DIABETES

Abstract

Diabetes can be caused by genetic mutations that result in defective insulin processing and secretion by pancreatic beta-cells. Here, I will study two genes involved in β-cell function: insulin (INS) and STARD10. Heterozygous INS gene mutations are reported to cause neonatal diabetes in humans, while polymorphisms in the STARD10 gene, which encodes a lipid-transfer protein, are associated with increased T2D risk. Through various experimental models, we showed that the dominant negative effects of mutant human INS expression are evident after nine weeks of expression, as shown by the decline in insulin secretory capacity. We also showed that STARD10 gene knockout downregulated cell cycle gene expression and perturbed several lipid species in STARD10-/- stem cell-derived beta-like cells. Our results provided deeper insight into the mechanisms of beta-cell dysfunction caused by INS and STARD10 gene perturbations. Modulation of mutant INS or its consequences on ER stress can potentially restore the function of WT INS allele for patients with heterozygous INS mutations. Addressing lipid alterations or indirect effects on beta-cell identity caused by STARD10 gene polymorphisms could also potentially improve beta-cell function in these T2D patients.