To evaluate the roles of hyperglycemia and increased plasma FFA level in the development of insulin resistance, we examined the effects of phlorizin and acipimox treatments on tissue sensitivity to insulin in streptozotocin(STZ)-diabetic rats. Insulin sensitivity was assessed with the glucose-insulin clamp technique. Blood glucose concentration was clamped at basal levels of control and diabetic states, and plasma insulin concentrations were clamped at the levels of basal, approximately 60 and approximately 1500 microU/ml. In diabetic rats, the basal blood glucose and plasma FFA levels in the fasting state were elevated, while the plasma insulin concentration was lower than in normal controls. Moreover, diabetic rats became glucose intolerant after intravenous injection of glucose. The metabolic clearance rate(MCR) of glucose showed a decrease of basal and insulin stimulated response in diabetic rats. As results of the glucose-insulin clamp study and intravenous glucose tolerance test, insulin resistance was developed in STZ-diabetic rats. Phlorizin treatment of diabetic rats recovered insulin sensitivity to nearly normal levels and improved glucose tolerance, but had no effect on insulin action in controls. Insulin sensitivity was also improved by acipimox treatment in diabetic rats, but did not reach normal levels. These results show that hyperglycemia is an obvious causative factor of insulin resistance, and increased FFA level may also act on the development of insulin resistance in STZ-diabetic rats.
Animal ; Antilipemic Agents/*pharmacology ; Blood Glucose/analysis ; Diabetes Mellitus, Experimental/*metabolism ; Fatty Acids, Nonesterified/blood ; Female ; *Insulin Resistance ; Phlorhizin/*pharmacology ; Pyrazines/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Streptozocin

Fenofibrate is a drug that has been suggested to inhibit weight gain by increasing the catabolism of fatty acid in the hepatic mitochondria. We hypothesized that fenofibrate induces an increase in energy expenditure in the hepatic mitochondria, which results in the reduction of adipose tissue. In this study we measured hepatic uncoupling protein (UCP)-2, -3, core temperatures and abdominal fat composition with MRI in Otsuka Long-Evans Tokushima Fatty rats. The fenofibrate group (n=7) was fed fenofibrate (320 mg/kg) mixed chow. The control group (n=7) was fed chow only. The body weight (531.6+/-7.6 g) of the fenofibrate group was significantly lower than that (744.3+/-14.9 g) of the control group (p<0.005). The areas of visceral and subcutaneous fat in the fenofibrate group (11.0+/-0.9 cm2, 4.2+/-0.3 cm2) were significantly less than those in the control group (21.0+/-0.7 cm2, 7.4+/-0.4 cm2) (p=0.046, respectively). The esophageal and rectal temperatures of the fenofibrate group (37.7+/-0.1 degrees C, 33.1+/-0.2 degrees C) were significantly higher than those of the control group (37.3+/-0.1 degrees C, 32.2+/-0.1 degrees C) (p=0.025, p=0.005). There was de novo expression of UCP-3 in the liver of the fenofibrate group. These data suggest that increased energy dissipation, via hepatic UCP-3 by fenofibrate, contribute to decreased weight gain in obese rats.
Rats, Inbred OLETF ; Rats ; Procetofen/*pharmacology ; Obesity/*physiopathology ; Muscle, Skeletal/drug effects/physiopathology ; Liver/drug effects/*physiopathology ; Energy Metabolism/*drug effects ; Body Weight/*drug effects ; Body Temperature/*drug effects ; Antilipemic Agents/administration & dosage ; Animals ; Adipose Tissue/*drug effects

Peroxisome proliferator-activated receptor alpha (PPARalpha) activation in rodents is thought to improve insulin sensitivity by decreasing ectopic lipids in non-adipose tissues. Fenofibrate, a lipid-modifying agent that acts as a PPARalpha agonist, may prevent adipocyte hypertrophy and insulin resistance by increasing intracellular lipolysis from adipose tissue. Consistent with this hypothesis, fenofibrate decreased visceral fat mass and adipocyte size in high fat diet-fed obese mice, and concomitantly increased the expression of PPARalpha target genes involved in fatty acid beta-oxidation in both epididymal adipose tissue and differentiated 3T3-L1 adipocytes. However, mRNA levels of adipose marker genes, such as leptin and TNFalpha, were decreased in epididymal adipose tissue by fenofibrate treatment. Fenofibrate not only reduced circulating levels of free fatty acids and triglycerides, but also normalized hyperinsulinemia and hyperglycemia in obese mice. Blood glucose levels of fenofibrate-treated mice were significantly reduced during intraperitoneal glucose tolerance test compared with obese controls. These results suggest that fenofibrate-induced fatty acid beta-oxidation in visceral adipose tissue may be one of the major factors leading to decreased adipocyte size and improved insulin sensitivity.
3T3 Cells ; Adipocytes/cytology/*drug effects ; Animals ; Antilipemic Agents/*pharmacology ; Blood Glucose ; Body Weight ; Cell Enlargement/*drug effects ; Dietary Fats ; Gene Expression Regulation/drug effects ; Glucose Tolerance Test ; Insulin/blood ; *Insulin Resistance ; Leptin/genetics ; Lipids/blood ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; PPAR alpha/*metabolism ; Procetofen/*pharmacology ; Tumor Necrosis Factor-alpha/genetics