FAM151A Regulates Insulin Secretion in Pancreatic β-Cells and Is Implicated in Pathogenesis of Type 2 Diabetes Mellitus

Background: The pathophysiology of type 2 diabetes mellitus (T2DM) is characterized by insulin resistance in peripheral tissues and dysfunction of β-cells. However, the molecular mechanisms underlying β-cell dysfunction remain incompletely understood. Methods: Analysis of single-cell RNA sequencing of T2DM islets was used to elucidate changes in family with sequence similarity 151 member A (Fam151a) expression. Deletion of Fam151a in INS-1E cells and mice was used to investigate the function of this gene in insulin secretion. Metabolic profiling and metabolomics analyses were used to decipher the effects of FAM151A on metabolic pathways. Results: Using single-cell RNA sequencing, we identified that Fam151a was significantly downregulated in pancreatic β-cells under T2DM conditions. We next investigated the potential functions of FAM151A in β-cells in vitro and in vivo. FAM151A was localized in the endoplasmic reticulum, and its expression was reduced by high-glucose treatment in INS-1E cells. Genetic deletion of Fam151a in INS-1E cells resulted in proinsulin accumulation, insulin vesicle retention, and impaired insulin secretion. A mouse model with pancreatic β-cell-specific deletion of Fam151a displayed reductions in glucose- and potassium chloride (KCl)-stimulated insulin secretion, and impaired glucose tolerance, without alterations in insulin sensitivity or islet morphology. Integrated metabolic profiling and metabolomics analyses revealed that cellular Fam151a deficiency affects the adenosine triphosphate/adenosine diphosphate ratio, glycolysis, the pentose phosphate pathway, and the purine synthesis pathway. Conclusion: Our study identifies FAM151A as a key regulator of insulin secretion in β-cells, providing a potential therapeutic target for the management of T2DM.