Prevention of pancreatic β-cell damage by pharmacological intervention with diazoxide and pioglitazone in obese diabetic mice *
Prevention of the progression of pancreatic /?-cell dysfunction in diabetes mellitus is an important subject in the long-term management of this disease. The preventive effects of diazoxide and pioglitazone on pancreatic /?-cell damage were evaluated using C57BL/KsJ db+/db+ mice {db+/db+ mice) with an obese diabetic animal model. Long-term treatment (6 ~ 18 weeks of age in db+/db+ mice) with diazoxide (100 mg/kg daily p.o.) or pioglitazone (100 mg/kg daily p.o.) induced a significant reduction in the fasting blood glucose level (p<0.05 vs the untreated control, at 18 weeks of age). The % islet area was larger in both diazoxide- and pioglitazone-treated mice than in the untreated control db+/db+ mice (p<0.001). The /? -cell ratio was also significantly larger in the pioglitazone-treated mice than in the control mice (p< 0.01). In a short-term experiment (10 - 12 weeks of age) , the plasma levels of glucose, triglyceride, and free fatty acid were significantly decreased by the treatment with diazoxide or pioglitazone. The plasma adiponectin level increased significantly in both the diazoxide- and pioglitazone-treated mice. This level was further increased by combined treatment with diazoxide and pioglitazone (p< 0-001 vs control). Pioglitazone, but not diazoxide, significantly increased insulin sensitivity (p< 0.01). Triglyceride content in pancreatic islets from the control mice was significantly reduced by the treatment with pioglitazone, but not by that with diazoxide (p<0.05). Impaired glucose-stimulated insulin secretion from pancreatic islets in the control mice was restored by the treatment with dizoxide or pioglitazone (p<0.05). The present results suggest that diazoxide directly reduces pancreatic /?-cell overwork and improves the glucose toxicity in db+/db+ mice, resulting in control of /?-ceIl damage. Pioglitazone, on the other hand, improves glucolipotoxicity by increasing insulin sensitivity and reducing fat accumulation in the islets in db+/db+ mice. (Accepted onJune 9 , 2003)
