Mechanism of pancreatic β-cell dusfunction in db/db mice and approach for protection of the cell function

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Prevention of the pancreatic β- cell dysfunction progressed in diabetes mellitus is important subject in the long- tern management of this disease. Preventive effects of diazoxide and pioglitazone on the pancreatic β- cell damage were evaluated using C57BL/KsJ db + /db mice (db + /db + mice), obese diadetic animal model. Long- term trearment (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 of the fasting blood glucose level (p< 0.05 vs untreated control, at 18 weeks of age). The % islet area was larger in both diazoxide- and pioglitazone- treated mice than in untreated control db + /db + mice (p< 0.001). The β- cell ratio was also significantly larger in pioglitazone- treated mice than in the control mice (p< 0.01). In short- term experiment (10- 12 weeks of age), plasma levels of glucose, tiglyceride, and free fatty acid were significantly decreased by the treatment with diazoxide or pioglitazone. Plasma adiponectin level was increased significantly in both 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 with diazoxide (p< 0.05). Imparied 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 the pancreatic β- cell overwork and improves the glucose toxicity in db + /db + mice, resulting in the control of β-cell damage. On the other hand, pioglitazone improves the glucolipotoxicity by increasing insulin sensitivity and reducing fat accumulation in the islets in db + /db + mice