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Antiobesity effect of diazoxide in obese Zucker rats
R Alemzadeh1, W Jacobs, P Pitukcheewanont
1Department of Pediatrics, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA.
Abstract:
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.
Insights
Diazoxide (DZ) reduced weight gain and improved glucose tolerance in obese rats by increasing insulin receptor binding and glucose transport, despite decreasing insulin levels. This suggests potential therapeutic benefits for obesity.
Area of Science:
- Metabolic disorders
- Endocrinology
- Pharmacology
Background:
- Obesity is characterized by hyperinsulinism and insulin resistance.
- Obesity is linked to reduced insulin receptors and impaired glucose disposal.
- Insulin's antilipolytic action sensitivity remains unaltered in obesity.
Purpose of the Study:
- To investigate the anti-obesity effects of diazoxide (DZ), a glucose-stimulated insulin release inhibitor.
- To evaluate DZ's impact on insulin metabolism and glucose homeostasis in obese rats.
Main Methods:
- Zucker obese and lean rats were treated with diazoxide (150 mg/kg/d) or a control.
- Body weight, calorie consumption, plasma lipids, glucose, and insulin levels were measured.
- Insulin receptor binding and glucose transport in adipocytes were assessed.
Main Results:
- Diazoxide-treated obese rats showed reduced weight gain despite similar calorie intake.
- DZ treatment lowered plasma triglycerides and improved glucose tolerance in obese rats.
- Insulin receptor binding and glucose transport increased in DZ-treated obese and lean rats.
Conclusions:
- Diazoxide enhances insulin receptor binding and glucose transport.
- DZ treatment ameliorates hyperinsulinemia and improves glucose tolerance in obese rats.
- Pharmacological modulation of insulin metabolism may offer therapeutic strategies for obesity.