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Mol Metab. 2014 Sep 28;3(9):848-54. doi: 10.1016/j.molmet.2014.09.006. eCollection 2014 Dec.

Defective insulin secretory response to intravenous glucose in C57Bl/6J compared to C57Bl/6N mice.

Author information

1
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, QC H3T 1J4, Canada ; Rodent Metabolic Phenotyping Core of Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada.
2
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, QC H3T 1J4, Canada ; Imaging and Cell Biology Core of Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada.
3
Centre des Sciences du Goût et de l'Alimentation, Unité Mixte de Recherche CNRS, INRA, Université de Bourgogne, Dijon, France.
4
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, QC H3T 1J4, Canada.
5
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, QC H3T 1J4, Canada ; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada ; Department of Nutrition, Université de Montréal, Montréal, QC H3T 1J4, Canada.
6
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, QC H3T 1J4, Canada ; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada ; Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada.
7
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, QC H3T 1J4, Canada ; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada ; Department of Pathology and Cell Biology, Université de Montréal, Montréal, QC H3T 1J4, Canada ; Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada.

Abstract

OBJECTIVE:

The C57Bl/6J (Bl/6J) mouse is the most widely used strain in metabolic research. This strain carries a mutation in nicotinamide nucleotide transhydrogenase (Nnt), a mitochondrial enzyme involved in NADPH production, which has been suggested to lead to glucose intolerance and beta-cell dysfunction. However, recent reports comparing Bl/6J to Bl/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 Bl/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:

Bl/6J mice have impaired GSIS compared to Bl/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 Bl/6J mice.

CONCLUSIONS:

The Bl/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.

KEYWORDS:

Beta-cell; DI, disposition index; FSIVGTT, frequently sampled intravenous glucose tolerance test; GIR, glucose infusion rate; GSIS, glucose-stimulated insulin secretion; Genetic background; IDE, insulin degrading enzyme; IVGTT, intravenous glucose tolerance test; Insulin secretion; Insulin sensitivity; MI, insulin sensitivity index; Mouse strain; NNT, nicotinamide nucleotide transhydrogenase; OGTT, oral glucose tolerance test

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