Toyoshima Yuka, Gavrilova Oksana, Yakar Shoshana, Jou William, Pack Stephanie, Asghar Zeenat, Wheeler Michael B, LeRoith Derek
Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Room 8D12, Building 10, MSC 1758, National Institutes of Health, Bethesda, Maryland 20892-1758, USA.
Endocrinology. 2005 Sep;146(9):4024-35. doi: 10.1210/en.2005-0087. Epub 2005 Jun 9.
Leptin has metabolic effects on peripheral tissues including muscle, liver, and pancreas, and it has been successfully used to treat lipodystrophic diabetes, a leptin-deficient state. To study whether leptin therapy can be used for treatment of more common cases of type 2 diabetes, we used a mouse model of type 2 diabetes (MKR mice) that show normal leptin levels and are diabetic due to a primary defect in both IGF-I and insulin receptors signaling in skeletal muscle. Here we show that leptin administration to the MKR mice resulted in improvement of diabetes, an effect that was independent of the reduced food intake. The main effect of leptin therapy was enhanced hepatic insulin responsiveness possibly through decreasing gluconeogenesis. In addition, the reduction of lipid stores in liver and muscle induced by enhancing fatty acid oxidation and inhibiting lipogenesis led to an improvement of the lipotoxic condition. Our data suggest that leptin could be a potent antidiabetic drug in cases of type 2 diabetes that are not leptin resistant.
瘦素对包括肌肉、肝脏和胰腺在内的外周组织具有代谢作用，并且已成功用于治疗脂肪营养不良性糖尿病，这是一种瘦素缺乏状态。为了研究瘦素疗法是否可用于治疗更常见的2型糖尿病病例，我们使用了2型糖尿病小鼠模型（MKR小鼠），该模型瘦素水平正常，由于骨骼肌中IGF-I和胰岛素受体信号传导的原发性缺陷而患有糖尿病。在此我们表明，给MKR小鼠施用瘦素可改善糖尿病，这种作用与食物摄入量减少无关。瘦素疗法的主要作用可能是通过减少糖异生来增强肝脏对胰岛素的反应性。此外，通过增强脂肪酸氧化和抑制脂肪生成诱导的肝脏和肌肉中脂质储存的减少导致脂毒性状况的改善。我们的数据表明，在非瘦素抵抗的2型糖尿病病例中，瘦素可能是一种有效的抗糖尿病药物。
