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Deletion of Nicotinamide Nucleotide Transhydrogenase

A New Quantitive Trait Locus Accounting for Glucose Intolerance in C57BL/6J Mice

¹ Mammalian Genetics Unit, Medical Research Council, Harwell, Oxfordshire, U.K
² University Laboratory of Physiology, Parks Road, Oxford, U.K

Address correspondence and reprint requests to Professor Roger D. Cox, Medical Research Council, Mammalian Genetics Unit, Harwell, Oxfordshire, OX11 0RD, U.K. E-mail: r.cox{at}har.mrc.ac.uk

Abbreviations: BAC, bacterial artificial chromosome; IPGTT, intraperitoneal glucose tolerance test; Nnt, nicotinamide nucleotide transhydrogenase; QTLs, quantitative trait loci

The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion. The genetic locus underlying this phenotype was mapped to nicotinamide nucleotide transhydrogenase (Nnt) on mouse chromosome 13, a nuclear-encoded mitochondrial protein involved in ß-cell mitochondrial metabolism. C57BL/6J mice have a naturally occurring in-frame five-exon deletion in Nnt that removes exons 7–11. This results in a complete absence of Nnt protein in these mice. We show that transgenic expression of the entire Nnt gene in C57BL/6J mice rescues their impaired insulin secretion and glucose-intolerant phenotype. This study provides direct evidence that Nnt deficiency results in defective insulin secretion and inappropriate glucose homeostasis in male C57BL/6J mice.

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