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首页> 外文期刊>Diabetes >Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice
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Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

机译：硬脂酰辅酶A去饱和酶1的损失改善了瘦小鼠的胰岛素敏感性，但在缺乏瘦素的肥胖小鼠中糖尿病更严重

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The lipogenic gene stearoyl-CoA desaturase (SCD)1 appears to be a promising new target for obesity-related diabetes, as mice deficient in this enzyme are resistant to diet- and leptin deficiency-induced obesity. The BTBR mouse strain replicates many features of insulin resistance found in humans with excess visceral adiposity. Using the hyperinsulinemic-euglycemic clamp technique, we determined that insulin sensitivity was improved in heart, soleus muscle, adipose tissue, and liver of BTBR SCD1-deficient mice. We next determined whether SCD1 deficiency could prevent diabetes in leptin-deficient BTBR mice. Loss of SCD1 in leptin~(ob/ob) mice unexpectedly accelerated the progression to severe diabetes; 6-week fasting glucose increased ～70%. In response to a glucose challenge, Scd1~(-/-) leptin~(ob/ob) mice had insufficient insulin secretion, resulting in glucose intolerance. A morphologically distinct class of islets isolated from the Scd1~(-/-) leptin~(ob/ob) mice had reduced insulin content and increased triglycerides, free fatty acids, esterified cholesterol, and free cholesterol and also a much higher content of saturated fatty acids. We believe the accumulation of lipid is due to an upregulation of lipoprotein lipase (20-fold) and Cd36 (167-fold) and downregulation of lipid oxidation genes in this class of islets. Therefore, although loss of Scd1 has beneficial effects on adiposity, this benefit may come at the expense of β-cells, resulting in an increased risk of diabetes.
机译：脂肪生成基因硬脂酰辅酶A去饱和酶（SCD）1似乎是肥胖相关糖尿病的有希望的新靶标，因为缺乏这种酶的小鼠对饮食和瘦素缺乏引起的肥胖具有抵抗力。 BTBR小鼠品系复制了内脏脂肪过多的人体内发现的许多胰岛素抵抗特征。使用高胰岛素-正常血糖钳夹技术，我们确定BTBR SCD1缺陷小鼠的心脏，比目鱼肌，脂肪组织和肝脏的胰岛素敏感性得到改善。接下来，我们确定SCD1缺乏症是否可以预防瘦素缺乏症BTBR小鼠的糖尿病。瘦素〜（ob / ob）小鼠中SCD1的丢失出乎意料地加速了严重糖尿病的发展。空腹6周血糖升高〜70％。响应葡萄糖挑战，Scd1〜（-/-）瘦素〜（ob / ob）小鼠的胰岛素分泌不足，导致葡萄糖耐受不良。从Scd1〜（-/-）瘦素〜（ob / ob）小鼠分离出的形态不同的胰岛具有降低的胰岛素含量和增加的甘油三酸酯，游离脂肪酸，酯化胆固醇和游离胆固醇，并且饱和脂肪酸的含量也高得多脂肪酸。我们认为脂质的积累是由于此类胰岛中脂蛋白脂肪酶（20倍）和Cd36（167倍）的上调以及脂质氧化基因的下调。因此，尽管Scd1的丢失对肥胖有有益的作用，但这种好处可能是以β细胞为代价的，从而导致患糖尿病的风险增加。

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