Investigate the function of C2cd4a in metabolism

Type 2 diabetes (T2D) is caused by insulin resistance in peripheral tissues and pancreatic beta-cell dysfunction. Insulin resistance precedes beta-cell failure, and the beta-cell’s inability to keep up with the increased demand of insulin production and secretion leads to glucose intolerance and hyperglycemia. The human C2CD4B-C2CD4A-VPS13C locus harbors a pancreatic beta-cell super-enhancer and is heavily decorated by T2D risk-associated GWAS SNPs from virtually every ethnic group studied to date. There are only ~20 publications on “C2cd4a” in PubMed, the majority of which are association studies linking this locus to human diabetes susceptibility. Through a multi-omics approach followed by functional analysis in mice, we found that beta cell-specific C2cd4a ablation impairs insulin secretion. In this proposal, we will delve into the mechanism of C2cd4a-regulated beta cell function, and build a pathway centered on C2cd4a. Two aims are envisioned: in Aim 1, we will investigate the mechanism of exercise-induced hypoglycemia in beta cell-specific C2cd4a knockout mice and delve into metabolic flux in beta cells lacking C2cd4a. In Aim 2, we will identify transcription factor binding partners of C2cd4a in gene regulation to define the mechanistic action of C2cd4a in the nucleus. These aims will advance our understanding of C2cd4a as a human diabetes susceptibility gene and provide a blueprint to leverage human genetics data into biological insight that will eventually benefit patients.