Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet
Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet
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DOI：
10.1007/s00125-009-1258-2
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发表时间：
2009-04-01
期刊：
影响因子：
8.2
通讯作者：
Nakao, K.
中科院分区：
文献类型：
--
作者：
Kusakabe, T.;Tanioka, H.;Nakao, K.
我们之前已经在小鼠模型中证明了瘦素在脂肪萎缩性糖尿病和胰岛素缺乏型糖尿病中的治疗作用，并且还可以证明其对人类脂肪萎缩性糖尿病的显着效果。本研究的目的是探索瘦素在肥胖增加的 2 型糖尿病小鼠模型中的治疗作用。 为了建立模拟肥胖增加的人类 2 型糖尿病的小鼠模型，我们结合使用了低剂量链脲佐菌素（STZ，120 μg/g 体重）和高脂肪饮食（HFD，45% 的能量为脂肪）。使用微型渗透泵长期输注重组小鼠瘦素（20 ng [g 体重](-1) h(-1)）14 天。研究了瘦素对食物摄入、体重、代谢变量、组织三酰甘油含量和 AMP 激活蛋白激酶 (AMPK) 活性的影响。低剂量 STZ 注射导致血浆胰岛素水平和高血糖大幅降低。随后的高脂饮食会增加肥胖并诱发胰岛素抵抗，并进一步加剧高血糖。在这个模仿人类 2 型糖尿病 (STZ/HFD) 的小鼠模型中，持续输注瘦素可减少食物摄入量和体重，并改善葡萄糖和脂质代谢，同时增强胰岛素敏感性。瘦素还降低肝脏和骨骼肌三酰甘油含量，同时骨骼肌中 α2 AMPK 活性增加。配对喂养实验表明，瘦素可独立于食物摄入量的减少而改善葡萄糖和脂质代谢。这项研究证明了瘦素对肥胖增加的 2 型糖尿病小鼠模型的血糖和脂质控制的有益作用，表明瘦素作为人类新型降糖药物的临床用途。
We have previously demonstrated the therapeutic usefulness of leptin in lipoatrophic diabetes and insulin-deficient diabetes in mouse models and could also demonstrate its dramatic effects on lipoatrophic diabetes in humans. The aim of the present study was to explore the therapeutic usefulness of leptin in a mouse model of type 2 diabetes with increased adiposity.To generate a mouse model mimicking human type 2 diabetes with increased adiposity, we used a combination of low-dose streptozotocin (STZ, 120 mu g/g body weight) and high-fat diet (HFD, 45% of energy as fat). Recombinant mouse leptin was infused chronically (20 ng [g body weight](-1) h(-1)) for 14 days using a mini-osmotic pump. The effects of leptin on food intake, body weight, metabolic variables, tissue triacylglycerol content and AMP-activated protein kinase (AMPK) activity were examined.Low-dose STZ injection led to a substantial reduction of plasma insulin levels and hyperglycaemia. Subsequent HFD feeding increased adiposity and induced insulin resistance and further augmentation of hyperglycaemia. In this model mouse mimicking human type 2 diabetes (STZ/HFD), continuous leptin infusion reduced food intake and body weight and improved glucose and lipid metabolism with enhancement of insulin sensitivity. Leptin also decreased liver and skeletal muscle triacylglycerol content accompanied by an increase of alpha 2 AMPK activity in skeletal muscle. Pair-feeding experiments demonstrated that leptin improved glucose and lipid metabolism independently of the food intake reduction.This study demonstrates the beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity, indicating the possible clinical usefulness of leptin as a new glucose-lowering drug in humans.