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 K ATP 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.

1. The effects of alterations of the protein and zinc concentrations of a semi-synthetic diet on the food intake and dietary preferences of Zn-deficient and normal rats have beencompared.2. The voluntary food intake of Zn-deficient rats fell to 70% 96 of that of the controls. The day-to-day variation of intake increased markedly and was associated with a cyclical pattern of food consumption. When the food intake of deficient rats was slightly restricted the troughs of the cycles disappeared.3. Concurrent with the fall in food intake, Zn-deficient rats ceased to gain weight, but a similar change was found with pair-fed controls.4. Force-feeding Zn-deficient rats with 140 % of their voluntary intake rapidly induced signs of ill-health.5. Reduction of the protein content of the diet from 20 to 5 % resulted in an increased food intake and the disappearance of the cyclical pattern of intake. Growth, however, was not renewed.6. Zn-deficient rats responded to a Zn-supplemented diet within 1–2 h by an increased food intake.7. Zn-deficient rats were able to discriminate between diets containing 6 and I ppm Zn when both diets were offered simultaneously.8. The responses of Zn-deficient rats to Zn-containing diets did not occur if the diets did not contain protein.

I . The effects of changes in zinc intake on weight gain, plasma Zn concentration and the development of clinical lesions of Zn deficiency have been studied in Zn depletion and repletion studies with calves and lambs.2. A basal diet, the principal components of which are urea, dried egg white, starch, glucose, cellulose and arachis oil has been developed for trace element deficiency studies with ruminants.3. Weight gain ceased abruptly in both calves and lambs when either the unsupplemented basal diet was given or when Zn supplements provided only 0.05 mg Zn/kg live weight per day. Mean plasma Zn concentrations in these animals fell from pre-experiment values of between 0.8 and 1.2 yg Zn/ml to below 0.4 pg Zn/ml after I week on these treatments.4. Supplements providing 0.2 mg Zn/kg live weight per day were sufficient to maintain a good rate of growth but insufficient to prevent a fall in plasma Zn. Growth arrest occurring within z weeks and a rapid fall in plasma Zn occurring withinI week after Zn supplements were withheld from calves and lambs that had previously received 0.7 mg Zn/kg live weight per day for 6 and 14 wceks respectively indicated that these species have only a limited capacity to store Zn in a form that can be utilized during periods of inadequate Zn intake.6. Tentative estimates are presented of the Zn requirements of calves maintained on this type of basal diet and the influence of ration composition on Zn availability is discussed.7. The possible value and the limitations of plasma Zn determination as an aid to the field diagnosis of Zn deficiency are considered.

No abstract

No abstract