A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice.
OBJECTIVE
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
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.
Toye
A A
AA
Medical Research Council, Harwell, Didcot, Oxfordshire, UK.
Lippiat
J D
JD
Proks
P
P
Shimomura
K
K
Bentley
L
L
Hugill
A
A
Mijat
V
V
Goldsworthy
M
M
Moir
L
L
Haynes
A
A
Quarterman
J
J
Freeman
H C
HC
Ashcroft
F M
FM
Cox
R D
RD
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics; D005215:Fasting; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005838:Genotype; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D018149:Glucose Intolerance / Q000097:blood / Q000235:genetics*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009154:Mutation; D009250:NADP Transhydrogenases / Q000235:genetics*; D010641:Phenotype; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics; D012044:Regression Analysis; D012737:Sex Factors; D014044:Tolbutamide / Q000494:pharmacology
D001786:Blood Glucose; D007328:Insulin; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D014044:Tolbutamide; D009250:NADP Transhydrogenases; D005941:Glucokinase; D005947:Glucose
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