Insulin resistance in obesity and its molecular control.
The Wistar fatty rat is a model of obese non-insulin-dependent diabetes mellitus. Males, but not females, develop hyperglycemia, glucouria and polyuria within 8 weeks of age. The regulation of gene expression by insulin has been shown to be differentially impaired in the liver of the fatty rats. The genes resistant to insulin include glucokinase gene and phosphoenolpyruvate carboxykinase gene. In contrast, L-type pyruvate kinase gene responds to insulin normally, raising the possibility that the signaling pathway from the insulin receptor to the insulin-resistant genes, but not to the insulin-sensitive genes, is defective at a point beyond the receptor kinase in the fatty rats. On the other hand, female fatty rats develop hyperglycemia only when they are given sucrose for several weeks. This treatment causes a decrease in gucokinase while enzymes involved in gluconeogenesis are increased. Chronic feeding of sucrose also leads to hypertriglycemia and visceral fat accumulation, which is more frequently associated with abnormalities in glucose and lipid metabolisms. Fructose is believed to be the responsible component of sucrose for these effects. Hypertriglyceridemic effect of fructose is mainly due to an increase in hepatic production of VLDL. Most enzymes related to lipogenesis in the liver are induced by dietary fructose even in diabetes. L-type pyruvate kinase is one of such enzymes. Cis-acting element named PKL-III in the 5'-flanking region of this gene is shown to be responsive to dietary fructose as well as to dietary glucose. Thus, identification and characterization of a protein bound to this element could help in the further understanding of the molecular mechanism of the fructose actions.
Noguchi
T
T
Department of Nutrition and Physiological Chemistry, Osaka University Medical School, Japan.
Tanaka
T
T
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D005941:Glucokinase / Q000235:genetics / Q000502:physiology; D005943:Gluconeogenesis / Q000502:physiology; D007328:Insulin / Q000235:genetics; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D009765:Obesity / Q000235:genetics / Q000503:physiopathology*; D011770:Pyruvate Kinase / Q000235:genetics / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics
D007328:Insulin; D005941:Glucokinase; D011770:Pyruvate Kinase