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

Grace Fergusson, Mélanie Éthier, Mélanie Guévremont, Chloé Chrétien, Camille Attané, Erik Joly, Xavier Fioramonti, Marc Prentki, Vincent Poitout, Thierry Alquier
Molecular Metabolism. 2014-12-01; 3(9): 848-854
DOI: 10.1016/j.molmet.2014.09.006

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1. 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.

Fergusson G(1), Ethier M(1), Guévremont M(2), Chrétien C(3), Attané C(4), Joly
E(2), Fioramonti X(3), Prentki M(5), Poitout V(6), Alquier T(7).

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.

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.