Antidiabetic Effects of IGFBP2, a Leptin-Regulated Gene
Antidiabetic Effects of IGFBP2, a Leptin-Regulated Gene
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DOI：
10.1016/j.cmet.2009.11.007
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发表时间：
2010-01-06
期刊：
影响因子：
29
通讯作者：
Friedman, Jeffrey M.
中科院分区：
文献类型：
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作者：
Hedbacker, Kristina;Birsoy, Kivanc;Friedman, Jeffrey M.
我们通过确定瘦素治疗ob/ob小鼠降低血糖和胰岛素浓度的最低剂量来测试瘦素是否可以独立于体重减轻而改善糖尿病。我们发现，12.5 ng/hr的瘦素剂量显著降低血糖，25 ng/hr的瘦素使血糖和胰岛素正常化，而不显著降低体重，从而确定瘦素对葡萄糖代谢发挥其最有效的作用。为了找到这种效应的可能介质，我们使用微阵列分析了肝脏mRNA，并确定了IGF结合蛋白2（IGFBP 2）受瘦素的调节，具有类似的高效力。在胰岛素抵抗的ob/ob、Ay/a和饮食诱导的肥胖小鼠以及胰岛素缺乏的链脲佐菌素治疗的小鼠中，腺病毒过表达IGFBP 2可逆转糖尿病。高胰岛素钳夹研究显示，ob/ob小鼠接受IGFBP 2治疗后，肝脏胰岛素敏感性提高了3倍。这些结果表明IGFBP 2可以调节葡萄糖代谢，这一发现对糖尿病的发病机制和治疗具有潜在意义。
We tested whether leptin can ameliorate diabetes independent of weight loss by defining the lowest dose at which leptin treatment of ob/ob mice reduces plasma glucose and insulin concentration. We found that a leptin dose of 12.5 ng/hr significantly lowers blood glucose and that 25 ng/hr of leptin normalizes plasma glucose and insulin without significantly reducing body weight, establishing that leptin exerts its most potent effects on glucose metabolism. To find possible mediators of this effect, we profiled liver mRNA using microarrays and identified IGF Binding Protein 2 (IGFBP2) as being regulated by leptin with a similarly high potency. Overexpression of IGFBP2 by an adenovirus reversed diabetes in insulin-resistant ob/ob, Ay/a, and diet-induced obese mice, as well as insulin-deficient streptozotocin-treated mice. Hyperinsulinemic clamp studies showed a 3-fold improvement in hepatic insulin sensitivity following IGFBP2 treatment of ob/ob mice. These results show that IGFBP2 can regulate glucose metabolism, a finding with potential implications for the pathogenesis and treatment of diabetes.