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

肥胖糖尿病模型db/db小鼠胰腺β细胞功能障碍的机制

基本信息

批准号：
15590962
负责人：
KAKU Kohei
金额：
$ 2.18万
依托单位：
Kawasaki Medical School, Faculty of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590962/
关键词：
db db mice β cell function Laser Capture Microdissection islet gene expression pioglitazone 膵ラ氏島糖・脂肪毒性遺伝子発現プロファイリング diazoxide %膵ラ氏島面積 β細胞比率アディポネクチン膵ラ島内中性脂肪含量

项目摘要

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

众所周知，胰腺b细胞功能紊乱是2型糖尿病的重要病理生理机制。为了阐明β细胞功能障碍的机制，我们对C57BL/KsJ db/db小鼠胰岛进行了结构和功能分析，并观察了吡格列酮对胰岛形态和功能的影响。此外，采用激光捕获显微解剖法和实时RT-PCR法分析胰岛基因表达谱。吡格列酮已被证明不仅对外周组织而且对胰腺β细胞有效力。为了评估吡格列酮对肥胖糖尿病动物模型db/db小鼠胰腺β细胞损伤的预防作用，并阐明其机制，我们给药db/db小鼠，研究胰腺组织学，并与未治疗小鼠和db/+非糖尿病小鼠的胰岛进行生化和生理比较。给db/db小鼠服用吡格列酮（100mg /kg或30mg /kg每日p.o） 12周后（6-18周龄），其空腹血糖水平显著降低（18周龄对照组为554±62 mg/dl， p<0.05）。吡格列酮组小鼠胰岛面积明显大于对照组（2.54±0.28 vs 1.16±0.06%,p<0.001）。吡格列酮组小鼠胰岛β细胞占总细胞的比例（80.6±12.0 vs 73.4±2.2%,p<0.01）也高于吡格列酮组小鼠。吡格列酮（100mg /kg每日p.o）治疗6周后，血浆葡萄糖、甘油三酯和游离脂肪酸水平显著降低，血浆脂联素水平显著升高（对照组为65.2±18.0 vs对照组为18.3±1.3 μg/ml, p<0.05）。胰岛素耐量试验显示吡格列酮增加胰岛素敏感性。吡格列酮组胰岛甘油三酯含量（43.3±3.6 ng/胰岛vs 65.6±7.6 ng/胰岛）显著降低（p<0.05）。经吡格列酮治疗后，对照组小鼠的胰岛胰岛素分泌功能恢复正常。在db/db小鼠中，胰岛核心区观察到胰高血糖素和生长抑素等胰腺激素的基因表达，表明胰岛结构紊乱。此外，db/db小鼠的凋亡基因表达加速。db/+小鼠的胰岛素基因表达出现代偿性上调。本研究结果揭示了db/db小鼠β细胞功能紊乱的分子机制，并提示吡格列酮通过增加db/db小鼠胰岛的胰岛素敏感性和减少脂肪积累来改善糖脂毒性。少