Homozygous deletion of the gene of the neuronal glucose transporter GLUT3 (Slc2a3) in mice results in embryonic lethality, whereas heterozygotes (Slc2a3...) are viable. Here, we describe the ...characterization of heterozygous mice with regard to neuronal function, glucose homeostasis, and, since GLUT3 might be a component of the neuronal glucose-sensing mechanism, food intake and energy balance. Levels of GLUT3 mRNA and protein in brain were reduced by 50% in Slc2a3... mice. Electrographic features examined by electroencephalographic recordings give evidence for slightly but significantly enhanced cerebrocortical activity in Slc2a3... mice. In addition, Slc2a3... mice were slightly more sensitive to an acoustic startle stimulus (elevated startle amplitude and reduced prepulse inhibition). However, systemic behavioral testing revealed no other functional abnormalities, e.g., in coordination, reflexes, motor abilities, anxiety, learning, and memory. Furthermore, no differences in body weight, blood glucose, and insulin levels were detected between wild-type and Slc2a3... littermates. Food intake as monitored randomly or after intracerebroventricular administration of 2-deoxyglucose or D-glucose, or food choice for carbohydrates/fat was not affected in Slc2a3... mice. Taken together, our data indicate that, in contrast to Slc2a1, a single allele of Slc2a3 is sufficient for maintenance of neuronal energy supply, motor abilities, learning and memory, and feeding behavior. (ProQuest: ... denotes formulae/symbols omitted.)
Objective: We have previously reported that a high-fat, carbohydrate-free diet prevents diabetes and β-cell destruction in the New Zealand Obese (NZO) mouse strain. Here we investigated the effect of ...diets with and without carbohydrates on obesity and development of β-cell failure in a second mouse model of type 2 diabetes, the db/db mouse. Results: When kept on a carbohydratecontaining standard (SD; with (w/w) 5.1, 58.3, and 17.6% fat, carbohydrates and protein, respectively) or high-fat diet (HFD; 14.6, 46.7 and 17.1%), db/db mice developed severe diabetes (blood glucose >20 mmol/l, weight loss, polydipsia and polyurea) associated with a selective loss of pancreatic β-cells, reduced GLUT2 expression in the remaining β-cells, and reduced plasma insulin levels. In contrast, db/db mice kept on a high-fat, carbohydrate-free diet (CFD; with 30.2 and 26.4% (w/w) fat or protein) did not develop diabetes and exhibited near-normal, hyperplastic islets in spite of a morbid obesity (fat content >60%) associated with hyperinsulinaemia. Conclusion: These data indicate that in genetically different mouse models of obesity-associated diabetes, obesity and dietary fat are not sufficient, and dietary carbohydrates are required, for β-cell destruction.
Type 2 diabetes is a polygenic disease resulting from a combination of different disease alleles reflecting obesity, insulin resistance, and hyperglycemia. Using a positional cloning strategy with ...different inbred strains of mice, we mapped a disease locus for obesity-associated diabetes on chromosome 4. We analyzed all genes in this region and identified distinct differences in the expression levels of the transcription factor Zfp69. The expression of this gene mediated diabetes progression in a leptin-deficient congenic mouse line. The animals developed a disease pattern of hyperglycemia, reduced gonadal fat mass, and increased plasma and liver triglycerides, resembling a potential defect in triglyceride storage . In order to elucidate the impact of the human ortholog of Zfp69 in the development of type 2 diabetes, we tested its mRNA expression in human white adipose tissue. Consistent with the mouse data, mRNA-expression was significantly higher in diabetic subjects than in unaffected controls.
The product of the intronless single copy gene RSC1A1, named RS1, is an intracellular 617-amino-acid protein that is involved in the regulation of the Na super(+)-D-glucose cotransporter SGLT1. We ...generated and characterized RS1 knockout (RS1 super(-) super(/) super(-)) mice. In the small intestines of RS1 super(-) super(/) super(- ) mice, the SGLT1 protein was up-regulated sevenfold compared to that of wild- type mice but was not changed in the kidneys. The up-regulation of SGLT1 was posttranscriptional. Small intestinal D-glucose uptake measured in jointly perfused small bowel and liver was increased twofold compared to that of the wild-type, with increased peak concentrations of D-glucose in the portal vein. At birth, the weights of RS1 super(-) super(/) super(-) and wild-type mice were similar. At the age of 3 months, male RS1 super(-) super(/) super(-) mice had 5% higher weights and 15% higher food intakes, whereas their energy expenditures and serum leptin concentrations were similar to those of wild-type mice. At the age of 5 months, male and female RS1 super(-) super(/) super(-) mice were obese, with 30% increased body weight, 80% increased total fat, and 30% increased serum cholesterol. At this age, serum leptin was increased, whereas food intake was the same as for wild- type mice. The data suggest that the removal of RS1 leads to leptin-independent up-regulation of food intake, which causes obesity.
Inactivation of the transcription factor AP-2 beta in a genetically mixed C57BL/6/129S1 mouse strain resulted in perinatal lethality as a consequence of massively enhanced apoptotic death of renal ...epithelial cells (Genes Dev 1997;11:1938-1948). Recently, we observed that the phenotype is modulated by genetic background because AP-2 beta mutant mice, backcrossed onto 129P2 background, survive approximately 2 weeks after birth, allowing for a detailed analysis of kidney function. Here we show that kidneys reveal varying amounts of cysts derived from all tubular structures (proximal and distal tubuli, collecting ducts). However, all mice died irrespective of the degree of cyst formation. Serum analysis of AP-2 beta mutant animals revealed defective tubular secretory function and ion homeostasis including severe hypocalcemia, hyperphosphatemia, and hyperuremia. Because hormonal calcium regulation was not impaired, the mice developed secondary renal hyperparathyroidism as typically observed in patients with terminal renal failure. We further demonstrate that molecular defects in the collecting duct system lead to insufficient water retention and urinary concentration. In summary, our studies reveal essential, nonredundant roles of AP-2 beta in renal tubular functions.
In this report we describe the development of two rabbit strains, HAR (high atherosclerotic response) and LAR (low atherosclerotic response), and their propensities to develop atherosclerosis in the ...aorta despite similar levels of diet-induced hypercholesterolemia. Sixty-two randomly selected male New Zealand White rabbits were fed a cholesterol-enriched diet (0.5%) for 84 days and developed 57 plus/minus 25% sudanophilic lesions of the aortic surface; 12 rabbits showed a low atherosclerotic response (0% to 30% surface involvement), and 22 rabbits showed a high atherosclerotic response (70% to 100% surface involvement). The offspring of rabbits with low atherosclerotic response were used for breeding the strain of rabbits resistant to atherosclerosis (LAR strain), while the offspring of rabbits with high atherosclerotic response were used for breeding the HAR strain. Controlled breeding was started after the 4th generation and performed for the subsequent 6 generations. Thus, in the LAR rabbits the lipid-stainable surface area of aorta amounted to only 27 plus/minus 17% after 112 days of cholesterol feeding. On the other hand, in HAR rabbits, aortic surface involvement reached 85 plus/minus 25% after 112 days on the cholesterol-enriched diet. The measurements of surface area involvement were corroborated also by a significantly lower, chemically determined cholesterol content of the aorta in LAR rabbits. Plasma lipids and lipoproteins were determined at baseline, after 21 and 42 days of cholesterol feeding, and at the time the animals were killed. The plasma cholesterol concentrations of cholesterol-fed HAR and LAR rabbits showed a 13-fold increase after 21 days and a 21-fold increase after 84 days on the cholesterol diet. The development of hypercholesterolemia was similar in both rabbit strains. At the time the animals were killed, the plasma concentrations in the HAR and LAR rabbits were 1241 plus/minus 489 mg/dL and 1370 plus/minus 473 mg/dL, respectively. There was a comparable effect of cholesterol feeding on the plasma VLDL, IDL, and LDL levels, but no significant differences were observed in plasma HDL cholesterol levels. The degree of genetic diversity between the two rabbit strains was studied in inherited protein polymorphism of plasma and erythrocytes. The alleles of six protein markers segregated in both rabbit strains, with significant differences at the Es-1 and the Pgd loci. The outbred strain of LAR rabbits appears to represent a model of inherited resistance to the development of atherosclerosis. (Arterioscler Thromb Vasc Biol. 1995;15:1181-1188.)
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