Fraenkel Merav, Ketzinel-Gilad Mali, Ariav Yafa, Pappo Orit, Karaca Melis, Castel Julien, Berthault Marie-France, Magnan Christophe, Cerasi Erol, Kaiser Nurit, Leibowitz Gil
Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem, Israel.
Diabetes. 2008 Apr;57(4):945-57. doi: 10.2337/db07-0922. Epub 2008 Jan 3.
Mammalian target of rapamycin (mTOR) and its downstream target S6 kinase 1 (S6K1) mediate nutrient-induced insulin resistance by downregulating insulin receptor substrate proteins with subsequent reduced Akt phosphorylation. Therefore, mTOR/S6K1 inhibition could become a therapeutic strategy in insulin-resistant states, including type 2 diabetes. We tested this hypothesis in the Psammomys obesus (P. obesus) model of nutrition-dependent type 2 diabetes, using the mTOR inhibitor rapamycin.
Normoglycemic and diabetic P. obesus were treated with 0.2 mg x kg(-1) x day(-1) i.p. rapamycin or vehicle, and the effects on insulin signaling in muscle, liver and islets, and on different metabolic parameters were analyzed.
Unexpectedly, rapamycin worsened hyperglycemia in diabetic P. obesus without affecting glycemia in normoglycemic controls. There was a 10-fold increase of serum insulin in diabetic P. obesus compared with controls; rapamycin completely abolished this increase. This was accompanied by weight loss and a robust increase of serum lipids and ketone bodies. Rapamycin decreased muscle insulin sensitivity paralleled by increased glycogen synthase kinase 3beta activity. In diabetic animals, rapamycin reduced beta-cell mass by 50% through increased apoptosis. Rapamycin increased the stress-responsive c-Jun NH(2)-terminal kinase pathway in muscle and islets, which could account for its effect on insulin resistance and beta-cell apoptosis. Moreover, glucose-stimulated insulin secretion and biosynthesis were impaired in islets treated with rapamycin.
Rapamycin induces fulminant diabetes by increasing insulin resistance and reducing beta-cell function and mass. These findings emphasize the essential role of mTOR/S6K1 in orchestrating beta-cell adaptation to hyperglycemia in type 2 diabetes. It is likely that treatments based on mTOR inhibition will cause exacerbation of diabetes.
雷帕霉素的哺乳动物靶点（mTOR）及其下游靶点S6激酶1（S6K1）通过下调胰岛素受体底物蛋白，进而降低Akt磷酸化水平，介导营养物质诱导的胰岛素抵抗。因此，抑制mTOR/S6K1可能成为包括2型糖尿病在内的胰岛素抵抗状态的一种治疗策略。我们使用mTOR抑制剂雷帕霉素，在营养依赖型2型糖尿病的肥胖沙鼠（P. obesus）模型中验证了这一假设。
对血糖正常和患糖尿病的肥胖沙鼠分别腹腔注射0.2 mg·kg⁻¹·d⁻¹的雷帕霉素或赋形剂，并分析其对肌肉、肝脏和胰岛中胰岛素信号传导以及不同代谢参数的影响。
出乎意料的是，雷帕霉素使患糖尿病的肥胖沙鼠的高血糖症恶化，而对血糖正常的对照组的血糖水平没有影响。与对照组相比，患糖尿病的肥胖沙鼠血清胰岛素增加了10倍；雷帕霉素完全消除了这种增加。这伴随着体重减轻以及血清脂质和酮体的显著增加。雷帕霉素降低了肌肉胰岛素敏感性，同时糖原合酶激酶3β活性增加。在糖尿病动物中，雷帕霉素通过增加细胞凋亡使β细胞量减少了50%。雷帕霉素增加了肌肉和胰岛中应激反应性c-Jun氨基末端激酶途径，这可能解释了其对胰岛素抵抗和β细胞凋亡的影响。此外，用雷帕霉素处理的胰岛中葡萄糖刺激的胰岛素分泌和生物合成受损。
雷帕霉素通过增加胰岛素抵抗以及降低β细胞功能和数量，诱发暴发性糖尿病。这些发现强调了mTOR/S6K1在2型糖尿病中协调β细胞适应高血糖方面的重要作用。基于mTOR抑制的治疗方法可能会导致糖尿病恶化。
