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

Fergusson G, Ethier M, Guévremont M, Chrétien C, Attané C, Joly E, Fioramonti X, Prentki M, Poitout V, Alquier T - Mol Metab (2014)

Bottom Line: 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.GSIS was measured using complementary tests (oral and intravenous glucose tolerance tests) and hyperglycemic clamps.Neurally-mediated insulin secretion was measured during central hyperglycemia.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus

Hyperglycemic clamps. Glucose (A), glucose infusion rate (GIR 30–60 min) (B), plasma insulin levels (C and D) during the course of the hyperglycemic clamp in 12–14 weeks old Bl/6J and N mice. (E) Area under the curve (AUC) for insulin. (F) C-peptide levels at 45 min. (G) Beta-cell mass. Values are expressed as means ± SEM of 7–8 mice per group. *p < 0.05, **p < 0.01 and ***p < 0.001 compared to Bl/6N mice.
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fig2: Hyperglycemic clamps. Glucose (A), glucose infusion rate (GIR 30–60 min) (B), plasma insulin levels (C and D) during the course of the hyperglycemic clamp in 12–14 weeks old Bl/6J and N mice. (E) Area under the curve (AUC) for insulin. (F) C-peptide levels at 45 min. (G) Beta-cell mass. Values are expressed as means ± SEM of 7–8 mice per group. *p < 0.05, **p < 0.01 and ***p < 0.001 compared to Bl/6N mice.

Mentions: To validate the IVGTT results, insulin secretion was measured using hyperglycemic clamps. The glucose infusion rate (GIR, Figure 2B) required to maintain glycemia at ∼320 mg/dl (Figure 2A) was significantly decreased in Bl/6J compared to Bl/6N. Hyperglycemia induced a biphasic insulin secretion in Bl/6N mice, a response which was almost absent in Bl/6J mice (Figure 2C). First and second phase of insulin secretion were respectively decreased by ∼5 and ∼3 fold in Bl/6J compared to Bl/6N mice (Figure 2E). In addition, potentiation of insulin secretion by arginine was ∼3 fold lower in Bl/6J vs. Bl/6N mice (Figure 2D and E). Accordingly, C-peptide level during the steady-state was significantly decreased in Bl/6J animals (Figure 2F). Importantly, beta-cell mass was not different between Bl/6J and Bl/6N mice suggesting that the impairment in insulin secretion does not involve a decrease in beta-cell mass (Figure 2G). These results are in line with those of Wong et al. [11] reporting similar pancreatic insulin content in Bl/6J and N mice.


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

Fergusson G, Ethier M, Guévremont M, Chrétien C, Attané C, Joly E, Fioramonti X, Prentki M, Poitout V, Alquier T - Mol Metab (2014)

Hyperglycemic clamps. Glucose (A), glucose infusion rate (GIR 30–60 min) (B), plasma insulin levels (C and D) during the course of the hyperglycemic clamp in 12–14 weeks old Bl/6J and N mice. (E) Area under the curve (AUC) for insulin. (F) C-peptide levels at 45 min. (G) Beta-cell mass. Values are expressed as means ± SEM of 7–8 mice per group. *p < 0.05, **p < 0.01 and ***p < 0.001 compared to Bl/6N mice.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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Show All Figures
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fig2: Hyperglycemic clamps. Glucose (A), glucose infusion rate (GIR 30–60 min) (B), plasma insulin levels (C and D) during the course of the hyperglycemic clamp in 12–14 weeks old Bl/6J and N mice. (E) Area under the curve (AUC) for insulin. (F) C-peptide levels at 45 min. (G) Beta-cell mass. Values are expressed as means ± SEM of 7–8 mice per group. *p < 0.05, **p < 0.01 and ***p < 0.001 compared to Bl/6N mice.
Mentions: To validate the IVGTT results, insulin secretion was measured using hyperglycemic clamps. The glucose infusion rate (GIR, Figure 2B) required to maintain glycemia at ∼320 mg/dl (Figure 2A) was significantly decreased in Bl/6J compared to Bl/6N. Hyperglycemia induced a biphasic insulin secretion in Bl/6N mice, a response which was almost absent in Bl/6J mice (Figure 2C). First and second phase of insulin secretion were respectively decreased by ∼5 and ∼3 fold in Bl/6J compared to Bl/6N mice (Figure 2E). In addition, potentiation of insulin secretion by arginine was ∼3 fold lower in Bl/6J vs. Bl/6N mice (Figure 2D and E). Accordingly, C-peptide level during the steady-state was significantly decreased in Bl/6J animals (Figure 2F). Importantly, beta-cell mass was not different between Bl/6J and Bl/6N mice suggesting that the impairment in insulin secretion does not involve a decrease in beta-cell mass (Figure 2G). These results are in line with those of Wong et al. [11] reporting similar pancreatic insulin content in Bl/6J and N mice.

Bottom Line: 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.GSIS was measured using complementary tests (oral and intravenous glucose tolerance tests) and hyperglycemic clamps.Neurally-mediated insulin secretion was measured during central hyperglycemia.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus