Defining the underlying defect in insulin action in type 2 diabetes.
Defining the underlying defect in insulin action in type 2 diabetes.
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DOI：
10.1007/s00125-021-05415-5
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发表时间：
2021-05
期刊：
影响因子：
8.2
通讯作者：
Kahn CR
中科院分区：
文献类型：
--
作者：
Batista TM;Haider N;Kahn CR
胰岛素抵抗是2型糖尿病发病机制中最早的缺陷之一。在过去的50年里，胰岛素信号网络的阐明提供了重要的机制洞察葡萄糖，脂质和蛋白质代谢异常的基础胰岛素抵抗。在经典靶组织（肝脏、肌肉和脂肪组织）中，胰岛素与其受体结合启动了广泛的信号级联反应，该信号级联反应由磷酸化、基因表达和囊泡运输的变化介导，导致营养利用和储存增加，并抑制分解代谢过程。胰岛素受体也在非经典靶点中表达，如脑和内皮细胞，它有助于调节食欲，能量消耗，生殖激素，情绪/行为和血管功能。细胞生物学和无偏分子谱质谱和DNA/RNA测序的最新进展提供了一个独特的机会，剖析2型糖尿病和代谢综合征的胰岛素抵抗的决定因素;最好的研究是外在因素，如循环脂质，氨基酸和其他代谢物和外泌体microRNA。更具有挑战性的是定义由遗传学和表观遗传学编程的细胞内在因子，这些因子是胰岛素抵抗的基础。在这方面，使用人类诱导多能干细胞和组织的研究指出了信号传导超级网络中的细胞自主改变，涉及经典胰岛素信号传导途径内外的磷酸化和基因表达的变化。了解这些多层分子网络如何调节胰岛素在不同组织中的作用和代谢，将为2型糖尿病及其相关病理的治疗和预防开辟新的途径。
Insulin resistance is one of the earliest defects in the pathogenesis of type 2 diabetes. Over the past 50 years, elucidation of the insulin signalling network has provided important mechanistic insights into the abnormalities of glucose, lipid and protein metabolism that underlie insulin resistance. In classical target tissues (liver, muscle and adipose tissue), insulin binding to its receptor initiates a broad signalling cascade mediated by changes in phosphorylation, gene expression and vesicular trafficking that result in increased nutrient utilisation and storage, and suppression of catabolic processes. Insulin receptors are also expressed in non-classical targets, such as the brain and endothelial cells, where it helps regulate appetite, energy expenditure, reproductive hormones, mood/behaviour and vascular function. Recent progress in cell biology and unbiased molecular profiling by mass spectrometry and DNA/RNA-sequencing has provided a unique opportunity to dissect the determinants of insulin resistance in type 2 diabetes and the metabolic syndrome; best studied are extrinsic factors, such as circulating lipids, amino acids and other metabolites and exosomal microRNAs. More challenging has been defining the cell-intrinsic factors programmed by genetics and epigenetics that underlie insulin resistance. In this regard, studies using human induced pluripotent stem cells and tissues point to cell-autonomous alterations in signalling super-networks, involving changes in phosphorylation and gene expression both inside and outside the canonical insulin signalling pathway. Understanding how these multi-layered molecular networks modulate insulin action and metabolism in different tissues will open new avenues for therapy and prevention of type 2 diabetes and its associated pathologies.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1073/pnas.68.8.1833
发表时间：
1971-01-01
影响因子：
11.1
作者：
FREYCHET, P;ROTH, J;NEVILLE, DM
通讯作者：
NEVILLE, DM
影响因子：
158.5
作者：
Cline, GW;Petersen, KF;Shulman, GI
通讯作者：
Shulman, GI
DOI：
10.1016/j.bbacli.2015.09.001
发表时间：
2015-12
期刊：
BBA clinical
影响因子：
--
作者：
Carter G;Miladinovic B;Patel AA;Deland L;Mastorides S;Patel NA
通讯作者：
Patel NA
影响因子：
29
作者：
Batista TM;Jayavelu AK;Wewer Albrechtsen NJ;Iovino S;Lebastchi J;Pan H;Dreyfuss JM;Krook A;Zierath JR;Mann M;Kahn CR
通讯作者：
Kahn CR