Mechanism of pancreatic β cell dysfunction in obese diabetes model db/db mice

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It is well known that deranged pancreatic b cell function is an important phathophysiology in type 2 diabetes. In order to clarify the mechanism of β cell dysfunction, structural and functional analyses of the pancreatic islet of C57BL/KsJ db/db mice were carried out, and effects of pioglitazone on islet morphology and function were also examined. In addition, gene expression profiles of pancreatic islet was analyzed by using Laser Capture microdissection method and real time RT-PCR method. Pioglitazone has been demonstrated to have potency not only on peripheral tissues but also pancreatic β cells. To evaluate preventive effects of pioglitazone on pancreatic β-cell damage in db/db mice, an obese diabetic animal model, and to elucidate their mechanisms, we administered pioglitazone on db/db mice, and investigated the pancreas histologically, and compared pancreatic islets biochemically and physiologically with those obtained from untreated mice and db/+ non-diabetic mice. Twelve weeks' … More treatment (6-18 weeks of age) in db/db mice with pioglitazone (100 mg/kg or 30 mg/kg daily p.o.) induced a significant reduction in the fasting blood glucose level (260±12 vs 554±62 mg/dl in untreated control at 18 weeks of age, p<0.05). The % islet area in the pancreas was significantly larger in pioglitazone-treated mice than in the untreated control db/db mice (2.54±0.28 vs 1.16±0.06%, p<0.001). The ratio of β-cells determined by immunohistochemistry to total cells in a pancreatic islet was also greater in the pioglitazone-treated mice (80.6±12.0 vs 73.4±2.2 % in untreated control, p<0.01). After six weeks' treatment with pioglitazone (100 mg/kg daily p.o.), the plasma levels of glucose, triglyceride, and free fatty acid were significantly decreased, while the plasma adiponectin level increased significantly (65.2±18.0 vs 18.3±1.3 μg/ml in untreated control, p<0.05). Insulin tolerance tests revealed that pioglitazone increased insulin sensitivity. The triglyceride content in pancreatic islets was significantly reduced by pioglitazone (43.3±3.6 vs 65.6±7.6 ng/islet in untreated control, p<0.05). Impaired glucose-stimulated insulin secretion from pancreatic islets in the control mice was restored by the treatment with pioglitazone. In the db/db mice, gene expression for pancreatic hormones such as glucagons and somatostatin was observed in the core area of islet, indicating deranged islet architecture. In addition, apoptotic gene expression was accerelated in db/db mice. A compensatory up-regulation of insulin gene expression was suggested in the db/+ mice. The present results demonstrate a molecular mechanism of deranged β cell function in db/db mice, and suggest that pioglitazone improves glucolipotoxicity by increasing insulin sensitivity and reducing fat accumulation in the islets in db/db mice. Less