title: Obesity-related abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D.
abstract: The incidence of adult-onset T1D in low-risk non-HLA type has increased several folds, whereas the contemporaneous incidence in high-risk HLA-type remains stable. Various factors behind this selective increase in T1D in young adults remain unclear. Obesity and its associated abnormalities appear to be an important determinant; however, the underlying mechanism involved is not understood. Recently, we have developed two novel transgenic obese mice models, Mito-Ob and m-Mito-Ob, by expressing a pleiotropic protein prohibitin (PHB) and a phospho mutant form of PHB (Y114F-PHB or m-PHB) from the aP2 gene promoter, respectively. Both mice models develop obesity in a sex-neutral manner, independent of diet; but obesity associated chronic low-grade inflammation and insulin resistance in a male sex-specific manner. Interestingly, on a high fat diet (HFD) only male m-Mito-Ob mice displayed marked mononuclear cell infiltration in pancreas and developed insulitis that mimic adult-onset T1D. Male Mito-Ob mice that share the metabolic phenotype of male m-Mito-Ob mice, and female m-Mito-Ob that harbor m-PHB similar to male m-Mito-Ob mice, did not develop insulitis. Thus, insulitis development in male m-Mito-Ob in response to HFD requires both, obesity-related abnormalities and m-PHB. Collectively, this data provides a proof-of-concept that obesity-associated abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D and reveals PHB as a potential susceptibility gene for T1D.
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: K Hoa
authors.initials: KH
authors.lastname: Nguyen
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Sudharsana R
authors.initials: SR
authors.lastname: Ande
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada; Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, Canada. Electronic address: suresh.mishra@umanitoba.ca.
authors.forename: Suresh
authors.initials: S
authors.lastname: Mishra
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D059305:Diet, High-Fat; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics*; D000091402:Prohibitins; D012097:Repressor Proteins / Q000235:genetics*; D012737:Sex Factors
chemical_list: D000091402:Prohibitins; D012097:Repressor Proteins
keywords: Chronic low-grade inflammation; High fat diet; Metabolic dysregulation; Obesity; Prohibitin; Transgenic mice