title: Roles of HNF1α and HNF4α in pancreatic β-cells: lessons from a monogenic form of diabetes (MODY).
abstract: Mutations in the genes encoding hepatocyte nuclear factor (HNF)1α and HNF4α 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 β-cells, indicating the important roles of HNF1α and HNF4α in β-cells. Large-scale genetic studies have clarified that the common variants of HNF1α and HNF4α genes are also associated with type 2 diabetes, suggesting that they are involved in the pathogenesis of both diseases. Recent experimental studies revealed that HNF1α controls both β-cell function and growth by regulating target genes such as glucose transporter 2, pyruvate kinase, collectrin, hepatocyte growth factor activator, and HNF4α. In contrast, HNF4α mainly regulates the function of β-cells. Although direct target genes of HNF4α in β-cells are largely unknown, we recently identified Anks4b as a novel target of HNF4α that regulates β-cell susceptibility to endoplasmic reticulum stress. Studies of MODY have led to a better understanding of the molecular mechanism of glucose-stimulated insulin secretion by pancreatic β-cells.
authors.affiliation: Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. Electronic address: k-yamaga@kumamoto-u.ac.jp.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yamagata
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D059865:Endoplasmic Reticulum Stress; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D009154:Mutation; D010179:Pancreas / Q000166:cytology / Q000473:pathology / Q000502:physiology / Q000503:physiopathology
chemical_list: C496487:HNF1A protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin
keywords: Anks4b; Collectrin; Diabetes; Gene; HNF1β; HNF4α; Hepatocyte growth factor activator; Hepatocyte nuclear factor 1α; Insulin secretion; Maturity-onset diabetes of the young; Transcription factor