Whole‐body glucose tolerance is impaired in male and female congenic mice lacking nicotinamide nucleotide transhydrogenase ( NNT )

Abstract

Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial redox protein. Previous reports of NNT deficiency impairing glucose tolerance in young male mice were potentially confounded by background strain differences. This study investigated whether an NNT deletion specifically in a congenic mouse model induces glucose intolerance across sexes and ages. Indirect calorimetry, oral glucose tolerance tests, and tissue analyses were performed in adult (6‐month‐old) and old (24‐month‐old) male and female congenic mice with ( Nnt ^WT ) and without ( Nnt ^Δ ) NNT ( n  = 8–15). While older mice exhibited increased body weight and higher fasted insulin levels ( p  < 0.0001), NNT deficiency did not affect these parameters, energy expenditure, or substrate utilization in either sex. Following glucose ingestion, glucose tolerance worsened in Nnt ^Δ mice of both sexes. Glucose‐stimulated serum insulin was unaffected in adult females, but was lower in 24‐month Nnt ^Δ females ( p  = 0.009) and 6‐month Nnt ^Δ males ( p  = 0.0303). However, there were no effects of genotype on glucose‐stimulated signaling pathways (including PI3K, STAT3, phosphorylated‐AKT, sarcolemmal GLUT4 localization) in skeletal muscle ( p  > 0.295) collected 30 min following glucose administration. Similarly, glucose‐stimulated AKT phosphorylation ratio did not differ between genotypes within liver or mesenteric white adipose tissue (mWAT). Combined, congenic NNT deficiency induces whole‐body glucose intolerance in both male and female adult and old mice.