Defective insulin secretory response to intravenous glucose in C57BI/6J compared to C57BI/6N mice

Objective: The C57BI/6J (BI/6J) mouse is the most widely used strain in metabolic research. This strain carries a mutation in nicotinamide nucleotide transhydrogenase (NO, a mitochondrial enzyme involved in NADPH production, which has been suggested to lead to glucose intolerance and beta-cell dysfunction. However, recent reports comparing BI/6J to BI/6N (carrying the wild-type Nnt allele) under normal diet have led to conflicting results using glucose tolerance tests. Thus, we assessed glucose-stimulated insulin secretion (GSIS), insulin sensitivity, clearance and central glucose-induced insulin secretion in BI/6J and N mice using gold-standard methodologies. Methods: GSIS was measured using complementary tests (oral and intravenous glucose tolerance tests) and hyperglycemic clamps. Whole body insulin sensitivity was assessed using euglycemic-hyperinsulinemic clamps. Neurally-mediated insulin secretion was measured during central hyperglycemia. Results: BI/6J mice have impaired GSIS compared to BI/6N when glucose is administered intravenously during both a tolerance test and hyperglycemic clamp, but not in response to oral glucose. First and second phases of GSIS are altered without changes in whole body insulin sensitivity, insulin clearance, beta-cell mass or central response to glucose, thereby demonstrating defective beta-cell function in BI/6J mice. Conclusions: The BI/6J mouse strain displays impaired insulin secretion. These results have important implications for choosing the appropriate test to assess beta-cell function and background strain in genetically modified mouse models. (C) 2014 The Authors Published by Elsevier GmbH.