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

预防糖尿病进展中的胰腺β细胞功能障碍是该病长期治疗的重要课题。采用C57BL/KSJ db+/db小鼠(db+/db+小鼠)肥胖糖尿病动物模型，观察二氮卓和吡格列酮对胰腺β细胞损伤的预防作用。长期(db+/db+小鼠6-18周龄)给予二氮嗪(100 mg/kg，每日灌胃)。或吡格列酮(100 mg/kg，每天灌胃)可显著降低18周龄大鼠的空腹血糖水平(P&lt；0.05，与未处理的对照组相比)。经二氮卓和吡格列酮处理的小鼠胰岛面积百分比均大于未经处理的对照db+/db+小鼠(p&lt；0.001)。吡格列酮治疗组小鼠的β细胞比率也显著高于对照组小鼠(p&lt；0.01)。短期试验中(10-12周龄)，二氮嗪或吡格列酮可显著降低血糖、甘油三酯和游离脂肪酸水平。在接受二氮卓和吡格列酮治疗的小鼠中，血浆脂联素水平显著升高。二氮嗪和吡格列酮联合治疗后，这一水平进一步升高(与对照组相比P&lt；0.001)。吡格列酮而不是二氮嗪显著增加胰岛素敏感性(p&lt；0.01)。对照组小鼠胰岛甘油三酯含量经吡格列酮处理后显著降低，但用二氮嗪处理后未见显著降低(p&lt；0.05)。二氮卓酮或吡格列酮可恢复正常小鼠胰岛葡萄糖刺激的胰岛素分泌(p&lt；0.05)。提示二氮嗪可直接减轻db+/db+小鼠胰腺β细胞过度工作，改善葡萄糖毒性，从而控制β细胞损伤。另一方面，吡格列酮通过增加胰岛素敏感性和减少db+/db+小鼠胰岛脂肪蓄积来改善糖脂毒性。

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