Hefetz Simona, Ziv Ehud, Jörns Anne, Lenzen Sigurd, Shafrir Eleazar
Diabetes Center, Hadassah University Hospital, Jerusalem, Israel.
Diabetes Metab Res Rev. 2006 Mar-Apr;22(2):139-45. doi: 10.1002/dmrr.583.
Psammomys obesus is a desert gerbil developing hyperglycaemia, hyperinsulinaemia and insulin resistance when placed for 2 weeks on a high-energy (HE) diet. The mechanism underlying the antidiabetic effect of rosiglitazone (RG) treatment (20 mg/kg per day for 2 weeks) was studied.
The antidiabetogenic effect of RG treatment on serum insulin and metabolic parameters in serum and target tissues of insulin action was investigated in vivo and compared with the pancreatic beta cell protective effects of RG.
Almost all RG-treated animals remained normoglycaemic compared to controls, but, at the same time, they were hyperinsulinaemic. RG had no effect on serum free fatty acid and serum and muscle triglyceride concentrations and did not appreciably affect body weight and fat depots. RG prevented a HE diet-induced reduction of GLUT 4 glucose transporter content in epididymal adipose tissue, but not in gastrocnemius muscle. The normoglycaemic effect was not associated with a suppression of liver PEPCK activity. Muscle PKCepsilon expression, known to be elevated in diabetic Psammomys and to inhibit insulin signalling, was only marginally decreased. However, RG treatment prevented the marked decrease in insulin immunostaining as well as the vacuolization of the beta cells and accelerated beta cell proliferation.
These data indicate that the skeletal muscle is not the primary target of RG action, whereas the preservation of the insulin secretory capacity and the prevention of degenerative beta cell vacuolization in spite of persisting insulin resistance appear to be the basis for the anti-hyperglycaemic effect of RG in Psammomys.
肥胖沙鼠是一种沙漠沙鼠，在给予高能（HE）饮食2周后会出现高血糖、高胰岛素血症和胰岛素抵抗。本研究探讨了罗格列酮（RG）治疗（每天20mg/kg，持续2周）的抗糖尿病作用机制。
在体内研究RG治疗对血清胰岛素以及胰岛素作用的血清和靶组织中代谢参数的抗糖尿病作用，并与RG对胰腺β细胞的保护作用进行比较。
与对照组相比，几乎所有接受RG治疗的动物血糖均保持正常，但同时它们存在高胰岛素血症。RG对血清游离脂肪酸、血清和肌肉甘油三酯浓度无影响，对体重和脂肪储存也无明显影响。RG可防止HE饮食诱导的附睾脂肪组织中GLUT 4葡萄糖转运蛋白含量降低，但对腓肠肌无此作用。血糖正常的作用与肝脏磷酸烯醇式丙酮酸羧激酶（PEPCK）活性的抑制无关。已知糖尿病肥胖沙鼠中肌肉蛋白激酶Cε（PKCε）表达升高并抑制胰岛素信号传导，而RG治疗仅使其略有降低。然而，RG治疗可防止胰岛素免疫染色的显著降低以及β细胞的空泡化，并加速β细胞增殖。
这些数据表明骨骼肌不是RG作用的主要靶点，尽管存在持续的胰岛素抵抗，但保留胰岛素分泌能力以及防止β细胞发生退行性空泡化似乎是RG对肥胖沙鼠抗高血糖作用的基础。
