Effect of the antiobesity agent sibutramine in obese-diabetic ob/ob mice

BACKGROUND: Sibutramine is a reuptake inhibitor of 5-hydroxytryptamine and noradrenaline, being developed as a treatment for obesity. OBJECTIVE: To investigate the effect of sibutramine on glucose homeostasis in obese-hyperglycaemic insulin-resistant ob/ob mice. DESIGN: Sibutramine 5 mg/kg once daily was administered orally to ob/ob mice for six weeks. RESULTS: Sibutramine treatment decreased body weight gain by 12% without a significant overall change in daily food intake. Sibutramine reduced the hyperinsulinaemia by 31%, and lowered plasma non-esterified fatty acids (NEFA) by 17%, Basal plasma glucose concentrations were not significantly altered by sibutramine, but glucose concentrations fell more rapidly after an i.p, glucose challenge, despite lower insulin concentrations. The rate of insulin-induced glucose disappearance was increased by 10% during sibutramine treatment. First administration of sibutramine, 5 mg/kg, did not acutely alter basal plasma glucose, insulin or NEFA concentrations in ob/ob mice, although NEFA concentrations were raised after 24 h. CONCLUSION: The results indicate that chronic administration of sibutramine can reduce weight gain, lower NEFA concentrations, decrease hyperinsulinaemia and ameliorate the insulin resistance of ob/ob mice.