title: Exploring the role of the HNF-1αG319S polymorphism in β cell failure and youth-onset type 2 diabetes: Lessons from MODY and Hnf-1α-deficient animal models.
abstract: The prevalence of youth-onset type 2 diabetes (T2D) is rapidly increasing worldwide, disproportionately affecting Indigenous youth with Oji-Cree heritage from central Canada. Candidate gene screening has uncovered a novel and private polymorphism in the Oji-Cree population in the hepatocyte nuclear factor-1 alpha (HNF-1α) gene, where a highly conserved glycine residue at position 319 is changed to a serine (termed HNF-1αG319S or simply G319S). Oji-Cree youth who carry one or two copies of the "S-allele" present at diagnosis with less obesity, reduced indicators of insulin resistance, and lower plasma insulin levels at diagnosis, suggestive of a primary defect in the insulin-secreting β cells. Few studies on the impact of the HNF-1αG319S variant on β cell function have been performed to date; however, much can be learned from other clinical phenotypes of HNF-1α-deficiency, including HNF-1α mutations that cause maturity-onset diabetes of the young 3 (MODY3). In addition, evaluation of Hnf-1α-deficient murine models reveals that HNF-1α plays a central role in the regulation of insulin secretion by regulating the expression of key genes involved in β cell glucose-sensing, mitochondrial function, and the maintenance of the β cell phenotype in differentiated β cells. The overall goal of this minireview is to explore the impact of HNF-1α-deficiency on the β cell to better inform future research into the mechanisms of β cell dysfunction in Oji-Cree youth with T2D.
authors.affiliation: d Children's Hospital Research Institute of Manitoba, 715 McDermot Avenue, Winnipeg MB R3E 3P4, Canada.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Jonasson
authors.affiliation: b Department of Pediatrics and Child Health, University of Manitoba, CE-208 Childrens Hospital, 840 Sherbrook Street, Health Sciences Centre, Winnipeg, MB R3A 1S1, Canada.|d Children's Hospital Research Institute of Manitoba, 715 McDermot Avenue, Winnipeg MB R3E 3P4, Canada.
authors.forename: Brandy A
authors.initials: BA
authors.lastname: Wicklow
authors.affiliation: b Department of Pediatrics and Child Health, University of Manitoba, CE-208 Childrens Hospital, 840 Sherbrook Street, Health Sciences Centre, Winnipeg, MB R3A 1S1, Canada.|d Children's Hospital Research Institute of Manitoba, 715 McDermot Avenue, Winnipeg MB R3E 3P4, Canada.
authors.forename: Elizabeth A C
authors.initials: EA
authors.lastname: Sellers
authors.affiliation: c Department of Pharmacology and Therapeutics, A203 Chown Bldg., 753 McDermot Avenue, University of Manitoba, Winnipeg, MB R3E 0T6, Canada.|d Children's Hospital Research Institute of Manitoba, 715 McDermot Avenue, Winnipeg MB R3E 3P4, Canada.
authors.forename: Vernon W
authors.initials: VW
authors.lastname: Dolinsky
authors.affiliation: a College of Medicine, Faculty of Health Sciences, Department of Physiology & Pathophysiology, 432 Basic Medical Sciences Building, 745 Bannatyne Avenue, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.|d Children's Hospital Research Institute of Manitoba, 715 McDermot Avenue, Winnipeg MB R3E 3P4, Canada.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Doucette
mesh_terms: D000818:Animals; D002170:Canada; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D009154:Mutation; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha
keywords: HNF-1α; cellules β; diabète juvénile; insulin; insuline; youth-onset type 2 diabetes; β cell