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

Abstract

ObjectiveThe 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.MethodsGSIS 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.ResultsBl/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.ConclusionsThe 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.

An Acetate-Specific GPCR, FFAR2, Regulates Insulin Secretion

“…One-step hyperglycemic clamps were performed on conscious animals as previously described (29). A 20% dextrose solution was infused through the jugular vein to clamp plasma glucose at approximately 350 mg/dL for 60 minutes and was adjusted based on glucose measurements (Roche Accu-Check; Roche).…”

Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

“…On the other hand, NNT deficiency had the opposite effect; with very little CORT secretion because of adrenal cortex dysfunction (31), NNT deficiency was associated with severe hyperglycemia. Peripheral insulin resistance and impaired insulin secretion likely contribute to this effect (29,33) and could explain why psychological stress during the Trier social stress test (TSST) in humans preferentially favors hyperglycemia in those with preexisting diabetes and insulin resistance (49). Furthermore, stress-related cortisol levels also exhibit racial and ethnic differences (50), although the underlying mechanisms remain unclear.…”

“…On the other hand, although NNT deficiency was associated with hypocortisolemia, it caused the most severe hyperglycemic response to stress (Fig. 4A), possibly as a result of impaired insulin secretion and action (33). Because stress-induced CORT and glucose increases were measured concurrently, we could analyze their relationships as representing an aspect of the organism's sensitivity to CORT.…”

Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease

“…The differences between our results may be related to the genetic background of the mice (C57BL/6J vs. C57BL/6N used in this study) and/or the prevention of acidosis in our study. C57BL/6J mice carry a mutation in nicotinamide nucleotide transhydrogenase, a mitochondrial enzyme involved in NADPH production, and have reduced insulin secretion relative to that seen in the C57BL/6N strain, without changes in insulin sensitivity (77). Furthermore, overproduction of H 2 O 2 , indicative of alterations in NADPH-dependent oxidases, plays a critical role in urea-induced insulin resistance in adipocytes (15).…”