Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery.
Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery.
复制标题
非胰岛素决定通路在代谢手术后维持葡萄糖稳态
DOI：
10.1038/s41421-018-0062-x
复制
发表时间：
2018
期刊：
影响因子：
33.5
通讯作者：
Zhu Z
中科院分区：
文献类型：
--
作者：
Lu Z;Wei X;Sun F;Zhang H;Gao P;Pu Y;Wang A;Chen J;Tong W;Li Q;Zhou X;Yan Z;Zheng H;Yang G;Huang Y;Liu D;Zhu Z
胰岛素对于葡萄糖稳态是至关重要的，并且胰岛素缺乏或抵抗导致糖尿病的发展。最近的证据表明，糖尿病可以独立于胰岛素而缓解。然而，基本机制在很大程度上仍然难以捉摸。在这项研究中，我们利用代谢手术作为一种工具，以确定非胰岛素决定簇的机制。在这里，我们报告说，最常见的代谢手术，Roux-en-Y胃旁路术（RYGB），减少胰岛素的生产，但持续保持健康的SD大鼠和C57小鼠的血糖正常。胰岛素产生的减少与RYGB介导的胰腺前胰岛素原和多聚嘧啶片段结合蛋白1的抑制有关。此外，RYGB还降低了胰岛素敏感性，这是通过高胰岛素-正葡萄糖钳夹试验和下调胰岛素敏感组织中的信号通路来评估的。机制证据表明，RYGB主要通过减少肠道能量摄取，将代谢模式从葡萄糖利用转变为脂肪酸氧化，增加能量消耗并激活多种代谢途径。重要的是，RYGB的独特作用扩展到胰岛破坏的大鼠和2型糖尿病患者。这些结果表明，胃肠道的强制性重排可以启动非胰岛素决定簇途径，以维持葡萄糖稳态。基于RYGB作用的原理，开发胃肠道的非侵入性干预是一种有前途的治疗途径，以对抗以能量代谢失调为特征的疾病。
Insulin is critical for glucose homeostasis, and insulin deficiency or resistance leads to the development of diabetes. Recent evidence suggests that diabetes can be remitted independent of insulin. However, the underlying mechanism remains largely elusive. In this study, we utilized metabolic surgery as a tool to identify the non-insulin determinant mechanism. Here, we report that the most common metabolic surgery, Roux-en-Y gastric bypass (RYGB), reduced insulin production but persistently maintained euglycemia in healthy Sprague-Dawley (SD) rats and C57 mice. This reduction in insulin production was associated with RYGB-mediated inhibition of pancreatic preproinsulin and polypyrimidine tract-binding protein 1. In addition, RYGB also weakened insulin sensitivity that was evaluated by hyperinsulinemic-euglycemic clamp test and downregulated signaling pathways in insulin-sensitive tissues. The mechanistic evidence suggests that RYGB predominately shifted the metabolic profile from glucose utilization to fatty acid oxidation, enhanced the energy expenditure and activated multiple metabolic pathways through reducing gut energy uptake. Importantly, the unique effect of RYGB was extended to rats with islet disruption and patients with type 2 diabetes. These results demonstrate that compulsory rearrangement of the gastrointestinal tract can initiate non-insulin determinant pathways to maintain glucose homeostasis. Based on the principle of RYGB action, the development of a noninvasive intervention of the gastrointestinal tract is a promising therapeutic route to combat disorders characterized by energy metabolism dysregulation.
登录
查看更多内容
影响因子：
7.7
作者：
Edgerton DS;Ramnanan CJ;Grueter CA;Johnson KM;Lautz M;Neal DW;Williams PE;Cherrington AD
通讯作者：
Cherrington AD
影响因子：
29
作者：
Fan W;Waizenegger W;Lin CS;Sorrentino V;He MX;Wall CE;Li H;Liddle C;Yu RT;Atkins AR;Auwerx J;Downes M;Evans RM
通讯作者：
Evans RM
影响因子：
21.3
作者：
Knoch, KP;Bergert, H;Solimena, M
通讯作者：
Solimena, M
影响因子：
5.8
作者：
Laferrere, Blandine;Teixeira, Julio;Olivan, Blanca
通讯作者：
Olivan, Blanca
影响因子：
7.7
作者：
Juhl, C;Grofte, T;Porksen, N
通讯作者：
Porksen, N