The C57BL/6J (B6J) strain is the most widely used mouse strain in metabolic research. B6J mice produce a truncated form of nicotinamide nucleotide transhydrogenase (NNT), an enzyme that pumps protons across the inner mitochondrial membrane. It has been proposed that this results in B6J mice having reduced insulin secretion and glucose intolerance compared with other strains of mice (e.g. C3H/HeH and DBA/2) that have a full-length NNT. The aim of this study was to determine whether truncated NNT was associated with reduced insulin secretion and glucose intolerance, comparing B6 substrains that differ in having a truncated NNT. C57BL/6N (B6N) mice have wild-type Nnt. We compared Nnt expression and activity levels as well as in vivo insulin secretion and glucose tolerance between these mice and B6J. Body weights and specific fat-pad depot masses were alike and Nnt expression and activity levels were similar between B6N and B6J mice. Glucose-mediated insulin secretion and insulin sensitivity were comparable between the two groups of mice, as were plasma glucose and insulin levels during the oral glucose tolerance test. The presence of a truncated Nnt did not affect insulin secretion or glucose tolerance on the C57BL/6 background. We suggest that low or normal levels of NNT (regardless of truncation) have little effect on insulin secretion. Rather, it is the increase in expression of Nnt that regulates and enhances insulin secretion. Our data confirm that B6J is a reasonable control strain for diabetes research; this is especially important considering that it is the strain commonly used to generate genetically modified animals.
Aims/hypothesis Insulin hypersecretion may be an independent predictor of progression to type 2 diabetes. Identifying genes affecting insulin hypersecretion are important in understanding disease progression. We have previously shown that diabetes-susceptible DBA/2 mice congenitally display high insulin secretion. We studied this model to map and identify the gene(s) responsible for this trait. Methods Intravenous glucose tolerance tests followed by a genome-wide scan were performed on 171 (C57BL/6 × DBA/2) × C57BL/6 backcross mice. Results A quantitative trait locus, designated hyperinsulin production-1 (Hip1), was mapped with a logarithm of odds score of 7.7 to a region on chromosome 13. Production of congenic mice confirmed that Hip1 influenced the insulin hypersecretion trait. By studying appropriate recombinant inbred mouse strains, the Hip1 locus was further localised to a 2 Mb interval, which contained only nine genes. Expression analysis showed that the only gene differentially expressed in islets isolated from the parental strains was Nnt, which encodes the mitochondrial proton pump, nicotinamide nucleotide transhydrogenase (NNT). We also found in five mouse strains a positive correlation (r 2 =0.90, p<0.01) between NNT activity and first-phase insulin secretion, emphasising the importance of this enzyme in beta cell function. Furthermore, of these five strains, only those with high NNT activity are known to exhibit severe diabetes after becoming obese. Conclusions/interpretation Insulin hypersecretion is associated with increased Nnt expression. We suggest that NNT must play an important role in beta cell function and that its effect on the high insulin secretory capacity of the DBA/2 mouse may predispose beta cells of these mice to failure.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.