Hypothalamic pathogenesis of type 2 diabetes
Hypothalamic pathogenesis of type 2 diabetes
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DOI：
10.1016/j.mehy.2006.02.033
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发表时间：
2006-01-01
影响因子：
4.7
通讯作者：
Ikeda, Hiroki
中科院分区：
文献类型：
--
作者：
Koshiyama, Hiroyuki;Hamamoto, Yoshiyuki;Ikeda, Hiroki
最近越来越多的实验和临床证据表明下丘脑失调可能是糖代谢异常的潜在机制之一。首先，无法控制的过度压力导致下丘脑-垂体-肾上腺轴活性增加，可能导致糖尿病以及内脏血脂异常。肥胖和骨质疏松症与库欣病有些相似。其次，已知有几种分子在胰腺和下丘脑中表达；三磷酸腺苷敏感钾通道、丙二酰辅酶A、葡萄糖激酶和 AMP 激活蛋白激酶。这些分子似乎形成了一个完整的下丘脑系统，可以感知下丘脑的燃料状态，特别是葡萄糖水平，并抑制胰岛素对肝脏糖异生的作用，从而形成脑-肝回路。第三，下丘脑对胰岛素的抵抗作为肥胖信号可能参与外周胰岛素抵抗的发病机制。胰岛素受体基因神经元特异性破坏的小鼠或下丘脑中胰岛素受体底物 2 的小鼠的结果支持了这种可能性。最后，最近有人提出，下丘脑时钟基因的失调可能导致葡萄糖代谢异常。总而言之，某些下丘脑异常可能是人类 2 型糖尿病或胰岛素抵抗的至少一部分的基础，这种 2 型糖尿病下丘脑发病机制的观点可能会导致 2 型糖尿病新药的开发。 (c) 2006 Elsevier Ltd. 保留所有权利。
There have recently been increasing experimental and clinical evidences suggesting that hypothalamic dysregulation may be one of the underlying mechanisms of abnormal glucose metabolism. First, increased hypothalamic-pituitary-adrenal axis activity induced by uncontrollable excess stress may cause diabetes mellitus as well as dyslipidemia, visceral. obesity, and osteoporosis with some resemblance to Cushing's disease. Second, several molecules are known to be expressed both in pancreas and hypothalamus; adenosine triphosphate-sensitive potassium channels, malonyl-CoA, glucokinase, and AMP-activated protein kinase. Those molecules appear to form an integrated hypothalamic system, which may sense hypothalamic fuel status, especially glucose level, and inhibit action of insulin on hepatic gluconeogenesis, thereby forming a brain-liver circuit. Third, hypothalamic resistance to insulin as an adiposity signal may be involved in pathogenesis of peripheral insulin resistance. The results with mice with a neuron-specific disruption of the insulin receptor gene or those tacking insulin receptor substrate 2 in hypothalamus supported this possibility. Finally, it has very recently been suggested that dysregulation of clock genes in hypothalamus may cause abnormal glucose metabolism. Taken together, it is plausible that some hypothalamic abnormality may underlie at least some portion of type 2 diabetes or insulin resistance in humans, and this viewpoint of hypothalamic pathogenesis of type 2 diabetes may lead to the development of new drugs for type 2 diabetes. (c) 2006 Elsevier Ltd. All rights reserved.