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Diabetologia
Published in: Diabetologia 4/2005

01-04-2005 | Article

A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice

Authors: A. A. Toye, J. D. Lippiat, P. Proks, K. Shimomura, L. Bentley, A. Hugill, V. Mijat, M. Goldsworthy, L. Moir, A. Haynes, J. Quarterman, H. C. Freeman, F. M. Ashcroft, R. D. Cox

Published in: Diabetologia | Issue 4/2005

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Abstract

Aims/hypothesis

C57BL/6J mice exhibit impaired glucose tolerance. The aims of this study were to map the genetic loci underlying this phenotype, to further characterise the physiological defects and to identify candidate genes.

Methods

Glucose tolerance was measured in an intraperitoneal glucose tolerance test and genetic determinants mapped in an F2 intercross. Insulin sensitivity was measured by injecting insulin and following glucose disposal from the plasma. To measure beta cell function, insulin secretion and electrophysiological studies were carried out on isolated islets. Candidate genes were investigated by sequencing and quantitative RNA analysis.

Results

C57BL/6J mice showed normal insulin sensitivity and impaired insulin secretion. In beta cells, glucose did not stimulate a rise in intracellular calcium and its ability to close KATP channels was impaired. We identified three genetic loci responsible for the impaired glucose tolerance. Nicotinamide nucleotide transhydrogenase (Nnt) lies within one locus and is a nuclear-encoded mitochondrial proton pump. Expression of Nnt is more than sevenfold and fivefold lower respectively in C57BL/6J liver and islets. There is a missense mutation in exon 1 and a multi-exon deletion in the C57BL/6J gene. Glucokinase lies within the Gluchos2 locus and shows reduced enzyme activity in liver.

Conclusions/interpretation

The C57BL/6J mouse strain exhibits plasma glucose intolerance reminiscent of human type 2 diabetes. Our data suggest a defect in beta cell glucose metabolism that results in reduced electrical activity and insulin secretion. We have identified three loci that are responsible for the inherited impaired plasma glucose tolerance and identified a novel candidate gene for contribution to glucose intolerance through reduced beta cell activity.
Appendix
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Metadata
Title
A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice
Authors
A. A. Toye
J. D. Lippiat
P. Proks
K. Shimomura
L. Bentley
A. Hugill
V. Mijat
M. Goldsworthy
L. Moir
A. Haynes
J. Quarterman
H. C. Freeman
F. M. Ashcroft
R. D. Cox
Publication date
01-04-2005
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 4/2005
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-005-1680-z

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