The Deletion Variant of Nicotinamide Nucleotide Transhydrogenase (Nnt) Does Not Affect Insulin Secretion or Glucose Tolerance

Abstract

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.

Cofactor Balance by Nicotinamide Nucleotide Transhydrogenase (NNT) Coordinates Reductive Carboxylation and Glucose Catabolism in the Tricarboxylic Acid (TCA) Cycle

“…NNT has also been speculated to regulate insulin secretion and glucose homeostasis, and some studies show that NNT mutant C57BL/6J mice exhibit glucose intolerance and impaired insulin secretion (32,35), whereas other studies have challenged this hypothesis (36,37). Being involved in NADPH production and proton translocation, NNT has been viewed mostly through the lens of reactive oxygen species detoxification and stress response (24), with mutations in NNT being reported in individuals with familial glucocorticoid deficiency (38).…”

The New Zealand obese mouse model of obesity insulin resistance and poor breeding performance: evaluation of ovarian structure and function

“…The NZO mouse is an inbred polygenic model of obesity and therefore does not have an appropriate control strain (Andrikopoulos et al 2000a). We have used the C57BL/6J strain for this study as it is generally used as a control strain for many metabolic studies; it is the preferred strain for the generation of genetically modified models (Wong et al 2010) and, according to the JAX website, is considered a good breeder (http://jaxmice.jax.org/strain/ 000664.html). The metabolic features and the well-known poor reproductive rate of the NZO mouse (Bielschowsky & Bielschowsky 1956, Koza et al 2004 provided us with reason to study it further.…”

Identification of ABCC8 as a contributory gene to impaired early-phase insulin secretion in NZO mice

“…Animal source and maintenance C57BL/6J (B6) (Wong et al 2010) and NZO/Wehi mice were purchased from the Walter and Eliza Hall Institute (Kew, Victoria, Australia). For genetic studies, we mated NZO to B6 mice and backcrossed F1 mice to the B6 parental strain to generate backcross (BC) mice for initial testing.…”