Rockefeller University, New York, NY 10065, USA.
Cell Metab. 2010 Jan;11(1):11-22. doi: 10.1016/j.cmet.2009.11.007.
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.
我们通过定义瘦素治疗 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来改善糖尿病。我们发现，12.5ng/hr 的瘦素剂量可显著降低血糖，而 25ng/hr 的瘦素可使血糖和胰岛素正常化，而体重无明显减轻，这表明瘦素对葡萄糖代谢发挥了最有效的作用。为了寻找这种作用的可能介导物，我们使用微阵列对肝脏 mRNA 进行了分析，发现 IGF 结合蛋白 2 (IGFBP2) 受到瘦素的调节，其作用强度相似。腺病毒过表达 IGFBP2 可逆转胰岛素抵抗的 ob/ob、Ay/a 和饮食诱导肥胖的小鼠以及胰岛素缺乏的链脲佐菌素治疗的小鼠的糖尿病。高胰岛素钳夹研究表明，IGFBP2 治疗 ob/ob 小鼠后，肝胰岛素敏感性提高了 3 倍。这些结果表明，IGFBP2 可以调节葡萄糖代谢，这一发现可能对糖尿病的发病机制和治疗具有重要意义。
