title: Emerging roles of GLIS3 in neonatal diabetes, type 1 and type 2 diabetes.
abstract: GLI-similar 3 (GLIS3), a member of the Krüppel-like zinc finger protein subfamily, is predominantly expressed in the pancreas, thyroid and kidney. Glis3 mRNA can be initially detected in mouse pancreas at embryonic day 11.5 and is largely restricted to β cells, pancreatic polypeptide-expressing cells, as well as ductal cells at later stage of pancreas development. Mutations in GLIS3 cause a neonatal diabetes syndrome, characterized by neonatal diabetes, congenital hypothyroidism and polycystic kidney. Importantly, genome-wide association studies showed that variations of GLIS3 are strongly associated with both type 1 diabetes (T1D) and type 2 diabetes (T2D) in multiple populations. GLIS3 cooperates with pancreatic and duodenal homeobox 1 (PDX1), v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MAFA), as well as neurogenic differentiation 1 (NEUROD1) and potently controls insulin gene transcription. GLIS3 also plays a role in β cell survival and likely in insulin secretion. Any perturbation of these functions may underlie all three forms of diabetes. GLIS3, synergistically with hepatocyte nuclear factor 6 (HNF6) and forkhead box A2 (FOXA2), controls fetal islet differentiation via transactivating neurogenin 3 (NGN3) and impairment of this function leads to neonatal diabetes. In addition, GLIS3 is also required for the compensatory β cell proliferation and mass expansion in response to insulin resistance, which if disrupted may predispose to T2D. The increasing understanding of the mechanisms of GLIS3 in β cell development, survival and function maintenance will provide new insights into disease pathogenesis and potential therapeutic target identification to combat diabetes.
authors.affiliation: Division of EndocrinologyDepartment of Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.|Department of AnesthesiologyThe First People's Hospital of Foshan & Foshan Hospital of Sun Yat-sen University, Guangdong, China.
authors.forename: Xianjie
authors.initials: X
authors.lastname: Wen
authors.affiliation: Division of EndocrinologyDepartment of Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA yisheng.yang@case.edu.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000196:embryology / Q000378:metabolism; D005810:Multigene Family; D009154:Mutation; D011485:Protein Binding; D012097:Repressor Proteins; D013577:Syndrome; D015534:Trans-Activators; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C512851:GLIS3 protein, human; D007328:Insulin; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors
keywords: GLIS3; NGN3; insulin; neonatal diabetes; type 1 diabetes; type 2 diabetes