Diazoxide prevents abdominal adiposity and fatty liver in obese OLETF rats at prediabetic stage

Epidemiological studies in both humans and experimental animals have shown an association between visceral obesity and cardiovascular risk factors such as dyslipidemia, hyperinsulinemia, and type 2 diabetes mellitus. The objective of this study was to evaluate the effects of diazoxide, an inhibitor of glucose-stimulated insulin secretion, on the prevention of fat deposition in the liver and in the abdominal cavity of prediabetic rats. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are a well-established animal model of human obesity, were used. Diazoxide (25 mg/kg/day) was administered from 8 to 30 weeks of age. Various fat distribution parameters, including computerized tomography imaging, histopathological examination, lipid metabolism, and insulin resistance, were determined in prediabetic OLETF rats. Occurrences of abdominal adiposity and fatty liver were markedly reduced by diazoxide treatment. Diazoxide significantly lowered hyperinsulinemia, triglycerides, free fatty acid levels, insulin resistance, weight gain, and food intake. In addition, it inhibited the development of diabetes in these animals. Linear regression assay demonstrated a close correlation between decreasing hyperinsulinemia and the protective effects of diazoxide. The present study demonstrates that diazoxide treatment in obese OLETF rats at prediabetic stage prevents abdominal obesity and fat deposition in the liver. These metabolic changes may occur through a direct effect on beta-cells through reduction of their workload and suppression of insulin secretion.