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

预防糖尿病患者胰岛β细胞功能障碍进展是糖尿病长期治疗的重要课题。采用肥胖型糖尿病动物模型C57BL/KsJ db + /db小鼠（db + /db +小鼠），观察二氮氧化合物和吡格列酮对胰腺β-细胞损伤的预防作用。长期给药（db + /db +小鼠6 ~ 18周龄），用二氮氧化合物（100 mg/kg每日p o）或吡格列酮（100 mg/kg每日p o）可显著降低18周龄时的空腹血糖水平（与未处理对照组相比，p< 0.05）。二氮氧化合物组和吡格列酮组小鼠的胰岛面积均大于未治疗的对照组（db + /db +） （p< 0.001）。吡格列酮组β细胞比例显著高于对照组（p< 0.01）。在短期实验中（10- 12周龄），用二氮氧化合物或吡格列酮治疗可显著降低血浆中葡萄糖、替甘油酯和游离脂肪酸的水平。两组小鼠血浆脂联素水平均显著升高。二氮氧化物和吡格列酮联合治疗进一步增加了这一水平（与对照组相比p< 0.001）。吡格列酮显著提高胰岛素敏感性（p< 0.01），而二氮氧化物不显著提高胰岛素敏感性（p< 0.01）。吡格列酮组显著降低对照组小鼠胰岛甘油三酯含量（p< 0.05），二氮氧化合物组无显著差异（p< 0.05）。吡格列酮和二氮卓组均能恢复正常的胰岛胰岛素分泌（p< 0.05）。本研究结果提示，二氮氧化合物可直接减轻db + /db +小鼠胰腺β-细胞的过度劳累，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db + /db +小鼠的胰岛素敏感性和减少胰岛脂肪积累来改善糖脂毒性

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