Antiobesity effect of diazoxide in obese Zucker rats.
Hyperinsulinism and insulin resistance are characteristic findings in obese subjects. Obesity in both humans and experimental animals is associated with a reduced number of insulin receptors and a decreased insulin-mediated glucose disposal, whereas sensitivity to insulin's antilipolytic action is unaltered. To evaluate the antiobesity effect of diazoxide (DZ), an inhibitor of glucose-stimulated insulin release, 7-week-old Zucker obese and lean rats were studied. Obese and lean rats were grouped into DZ-treated (150 mg/kg/d) and control (C) groups. DZ-treated obese rats consumed similar amounts of calories per kilogram body weight (BW) compared with C obese animals, but gained less weight (P<.01). Postabsorptive plasma free fatty acids (FFA), cholesterol, and triglycerides were significantly higher in obese versus lean animals (P<.01). DZ treatment reduced plasma triglyceride levels in obese animals (P<.001), but had no significant effect on FFA or cholesterol concentrations. Plasma glucose concentrations in the postabsorptive state and during glucose tolerance tests (GTTs) were significantly lower in DZ obese versus C obese rats (P<.01) despite a decrease in plasma insulin concentrations in DZ-treated animals (P<.01). In contrast, DZ lean rats developed glucose intolerance (P<.05). Sensitivity and responsiveness to the antilipolytic effect of insulin in isolated adipocytes were significantly decreased in DZ obese as compared with C obese rats (P<.01). Moreover, adipocyte specific insulin receptor binding was increased in both DZ lean and DZ obese animals (P<.01). This was accompanied by increased basal and insulin-stimulated glucose transport in both genotypes (P<.01). In conclusion, DZ increased insulin receptor binding and glucose transport while decreasing hyperinsulinemia and insulin sensitivity to the antilipolytic action of insulin. This combined effect resulted in improved glucose tolerance and a decrease in weight gain in obese rats, implying that pharmacologic modification of the disturbed insulin metabolism of obesity may be therapeutically beneficial.
Alemzadeh
R
R
Department of Pediatrics, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA.
Jacobs
W
W
Pitukcheewanont
P
P
D017667:Adipocytes / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003981:Diazoxide / Q000627:therapeutic use*; D002149:Energy Intake; D005260:Female; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D008066:Lipolysis / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D011972:Receptor, Insulin / Q000032:analysis
D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D011972:Receptor, Insulin; D005947:Glucose; D003981:Diazoxide