title: High fat feeding unmasks variable insulin responses in male C57BL/6 mouse substrains.
abstract: Mouse models are widely used for elucidating mechanisms underlying type 2 diabetes. Genetic background profoundly affects metabolic phenotype; therefore, selecting the appropriate model is critical. Although variability in metabolic responses between mouse strains is now well recognized, it also occurs within C57BL/6 mice, of which several substrains exist. This within-strain variability is poorly understood and could emanate from genetic and/or environmental differences. To better define the within-strain variability, we performed the first comprehensive comparison of insulin secretion from C57BL/6 substrains 6J, 6JWehi, 6NJ, 6NHsd, 6NTac and 6NCrl.In vitro, glucose-stimulated insulin secretion correlated withNntmutation status, wherein responses were uniformly lower in islets from C57BL/6J vs C57BL/6N mice. In contrast,in vivoinsulin responses after 18 weeks of low fat feeding showed no differences among any of the six substrains. When challenged with a high-fat diet for 18 weeks, C57BL/6J substrains responded with a similar increase in insulin release. However, variability was evident among C57BL/6N substrains. Strikingly, 6NJ mice showed no increase in insulin release after high fat feeding, contributing to the ensuing hyperglycemia. The variability in insulin responses among high-fat-fed C57BL/6N mice could not be explained by differences in insulin sensitivity, body weight, food intake or beta-cell area. Rather, as yet unidentified genetic and/or environmental factor(s) are likely contributors. Together, our findings emphasize that caution should be exercised in extrapolating data fromin vitrostudies to thein vivosituation and inform on selecting the appropriate C57BL/6 substrain for metabolic studies.
authors.affiliation: Veterans Affairs Puget Sound Health Care SystemSeattle, Washington, USA.|Division of MetabolismEndocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hull
authors.affiliation: Veterans Affairs Puget Sound Health Care SystemSeattle, Washington, USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Willard
authors.affiliation: Division of MetabolismEndocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Matthias D
authors.initials: MD
authors.lastname: Struck
authors.affiliation: Veterans Affairs Puget Sound Health Care SystemSeattle, Washington, USA.
authors.forename: Breanne M
authors.initials: BM
authors.lastname: Barrow
authors.affiliation: Veterans Affairs Puget Sound Health Care SystemSeattle, Washington, USA.
authors.forename: Gurkirat S
authors.initials: GS
authors.lastname: Brar
authors.affiliation: Department of MedicineUniversity of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.
authors.forename: Sofianos
authors.initials: S
authors.lastname: Andrikopoulos
authors.affiliation: Veterans Affairs Puget Sound Health Care SystemSeattle, Washington, USA zraikas@uw.edu.|Division of MetabolismEndocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Sakeneh
authors.initials: S
authors.lastname: Zraika
mesh_terms: D000818:Animals; D001835:Body Weight / Q000502:physiology; D059305:Diet, High-Fat; D004435:Eating / Q000502:physiology; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D013045:Species Specificity
chemical_list: D007328:Insulin; D005947:Glucose
keywords: C57BL/6 substrains; high-fat diet; insulin secretion; islet