Ebihara K, Ogawa Y, Masuzaki H, Shintani M, Miyanaga F, Aizawa-Abe M, Hayashi T, Hosoda K, Inoue G, Yoshimasa Y, Gavrilova O, Reitman M L, Nakao K
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Diabetes. 2001 Jun;50(6):1440-8. doi: 10.2337/diabetes.50.6.1440.
Lipoatrophic diabetes is caused by a deficiency of adipose tissue and is characterized by severe insulin resistance, hypoleptinemia, and hyperphagia. The A-ZIP/F-1 mouse (A-ZIPTg/+) is a model of severe lipoatrophic diabetes and is insulin resistant, hypoleptinemic, hyperphagic, and shows severe hepatic steatosis. We have also produced transgenic "skinny" mice that have hepatic overexpression of leptin (LepTg/+) and no adipocyte triglyceride stores, and are hypophagic and show increased insulin sensitivity. To explore the pathophysiological and therapeutic roles of leptin in lipoatrophic diabetes, we crossed LepTg/+ and A-ZIPTg/+ mice, producing doubly transgenic mice (LepTg/+:A-ZIPTg/+) virtually lacking adipose tissue but having greatly elevated leptin levels. The LepTg/+:A-ZIPTg/+ mice were hypophagic and showed improved hepatic steatosis. Glucose and insulin tolerance tests revealed increased insulin sensitivity, comparable to LepTg/+ mice. These effects were stable over at least 6 months of age. Pair-feeding the A-ZIPTg/+ mice to the amount of food consumed by LepTg/+:A-ZIPTg/+ mice did not improve their insulin resistance, diabetes, or hepatic steatosis, demonstrating that the beneficial effects of leptin were not due to the decreased food intake. Continuous leptin administration that elevates plasma leptin concentrations to those of LepTg/+:A-ZIPTg/+ mice also effectively improved hepatic steatosis and the disorder of glucose and lipid metabolism in A-ZIP/F-1 mice. These data demonstrate that leptin can improve the insulin resistance and diabetes of a mouse model of severe lipoatrophic diabetes, suggesting that leptin may be therapeutically useful in the long-term treatment of lipoatrophic diabetes.
脂肪萎缩性糖尿病由脂肪组织缺乏引起，其特征为严重的胰岛素抵抗、低瘦素血症和食欲亢进。A-ZIP/F-1小鼠（A-ZIPTg/+）是严重脂肪萎缩性糖尿病的模型，具有胰岛素抵抗、低瘦素血症、食欲亢进，并表现出严重的肝脏脂肪变性。我们还培育了转基因“瘦”小鼠，其肝脏中瘦素过表达（LepTg/+），没有脂肪细胞甘油三酯储存，食欲减退且胰岛素敏感性增加。为了探究瘦素在脂肪萎缩性糖尿病中的病理生理和治疗作用，我们将LepTg/+和A-ZIPTg/+小鼠进行杂交，产生了几乎缺乏脂肪组织但瘦素水平大幅升高的双转基因小鼠（LepTg/+:A-ZIPTg/+）。LepTg/+:A-ZIPTg/+小鼠食欲减退，肝脏脂肪变性得到改善。葡萄糖和胰岛素耐量试验显示胰岛素敏感性增加，与LepTg/+小鼠相当。这些作用在至少6个月龄时保持稳定。将A-ZIPTg/+小鼠的食物摄入量配对调整至LepTg/+:A-ZIPTg/+小鼠的摄入量，并未改善它们的胰岛素抵抗、糖尿病或肝脏脂肪变性，这表明瘦素的有益作用并非由于食物摄入量减少。持续给予瘦素使血浆瘦素浓度升高至LepTg/+:A-ZIPTg/+小鼠的水平，也有效改善了A-ZIP/F-1小鼠的肝脏脂肪变性以及葡萄糖和脂质代谢紊乱。这些数据表明，瘦素可以改善严重脂肪萎缩性糖尿病小鼠模型的胰岛素抵抗和糖尿病，提示瘦素可能对脂肪萎缩性糖尿病的长期治疗具有治疗作用。
