Roles of HNF1alhpa and HNF4alpha in Pancreatic beta-Cells: Lessons from a Monogenic Form of Diabetes (MODY)

摘要

Mutations in the genes encoding hepatocyte nuclearfactor (HNF)1 a and HNF4alpha cause a monogenic form of diabetes mellitus known as maturity-onset diabetes of the young (MODY). The primary cause of MODY is an impairment of glucose-stimulated insulin secretion by pancreatic (3-cells, indicating the important roles of HNF1alpha and HNF4alpha in beta-cells. Large-scale genetic studies have clarified that the common variants of HNF1alpha and HNF4alpha genes are also associated with type 2 diabetes, suggesting that they are involved in the pathogenesis of both diseases. Recent experimental studies revealed that HNF1alpha controls both beta-cell function and growth by regulating target genes such as glucose transporter 2, pyruvate kinase, collectrin, hepatocyte growth factor activator, and HNF4a. In contrast, HNF4alpha mainly regulates the function of beta-cells. Although direct target genes of HNF4alpha in beta-cells are largely unknown, we recently identified Anks4b as a novel target of HNF4alpha that regulates beta-cell susceptibility to endoplasmic/eticulum stress. Studies of MODY have led to a better understanding of the molecular mechanism of glucose-stimulated insulin secretion by pancreatic (3-cells.