Increased nicotinamide nucleotide transhydrogenase levels predispose to insulin hypersecretion in a mouse strain susceptible to diabetes

Abstract

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.

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

“…We found that in contrast to C57BL/6 mice, which have a genetic disruption in Nnt, and the 129T2 mice, which show low levels of expression, the diabetes-susceptible DBA/2 mice show a fivefold overexpression of this gene, which encodes the mitochondrial proton pump known as nicotinamide nucleotide transhydrogenase. Insulin secretion was elevated in DBA/2 mice relative to that in C57BL/6 and 129T2 mice [18][19][20] Interestingly, we found that other strains of mice (BALB/c, FVB/N) that have previously been shown to be susceptible to diabetes when subjected to genetically induced obesity and insulin resistance also displayed increased NNT activity. We suggest that reduced NNT levels in the C57BL/6 and 129T2 strains result in lowered insulin secretion and mild glucose intolerance [21], and that protection against the development of diabetes in response to genetically induced obesity and insulin resistance may paradoxically be due to a reduced ability of the beta cell to secrete insulin.…”

Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism

“…Of the genes associated with HbA1c levels, 70 were also associated with in vitro insulin secretion in human islets, further highlighting their role in glucose metabolism (Database S1). Of particular interest are the genes whose expression is associated with lower HbA1c levels and higher insulin secretion, such as RAS guanyl releasing protein 1 (RASGRP1) (6), transcription factor RFX3 (21), and nicotinamide nucleotide transhydrogenase (NNT) (22), all of which have been suggested to regulate insulin secretion (SI Appendix, Figs. S5-S7).…”

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

“…Islets were prepared for cDNA synthesis and subsequent mRNA analysis using the method as previously described (Aston-Mourney et al 2007). Total RNA (2 mg) was reverse transcribed using the Promega Reverse Transcription System kit with random primers (Promega Corporation) and any contaminating DNA removed by treatment with DNaseI (RNase-free; Ambion).…”