Glucolipotoxicity of the pancreatic beta cell.
Glucolipotoxicity of the pancreatic beta cell.
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DOI：
10.1016/j.bbalip.2009.08.006
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发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
Fontés G
中科院分区：
文献类型：
--
作者：
Poitout V;Amyot J;Semache M;Zarrouki B;Hagman D;Fontés G
糖脂毒性的概念是指升高的葡萄糖和脂肪酸水平对胰腺β细胞功能和存活的组合有害作用。近年来，在更好地理解β细胞中糖脂毒性的细胞和分子基础方面取得了重大进展。升高的葡萄糖对脂肪酸的有害作用的容许效应源于葡萄糖对细胞内脂肪酸代谢的影响，促进细胞脂质的合成。因此，过量的脂肪酸和葡萄糖水平的组合导致胰岛素分泌减少、胰岛素基因表达受损和细胞凋亡导致的β细胞死亡，所有这些可能具有不同的潜在机制。我们实验室最近的研究已经确定了脂肪酸抑制胰岛素基因表达的几种途径，包括细胞外调节激酶（ERK 1/2）途径;代谢传感器Per-Arnt-Sim激酶（PASK）;和未折叠蛋白反应的ATF 6分支。我们还在大鼠体内证实，胰岛素基因表达的减少是胰岛素分泌任何可检测异常之前的早期缺陷。虽然人体中的糖脂毒性作用仍有争议，但长期升高的脂肪酸水平的抑制作用已在几项研究中得到明确证明，至少在遗传上易患2型糖尿病的个体中。因此，很可能是葡萄糖脂毒性导致2型糖尿病中的β细胞衰竭以及疾病发作后观察到的β细胞功能下降。
The concept of glucolipotoxicity refers to the combined, deleterious effects of elevated glucose and fatty acid levels on pancreatic beta-cell function and survival. Significant progress has been made in recent years towards a better understanding of the cellular and molecular basis of glucolipotoxicity in the beta cell. The permissive effect of elevated glucose on the detrimental actions of fatty acids stems from the influence of glucose on intracellular fatty-acid metabolism, promoting the synthesis of cellular lipids. The combination of excessive levels of fatty acids and glucose therefore leads to decreased insulin secretion, impaired insulin gene expression, and beta-cell death by apoptosis, all of which probably have distinct underlying mechanisms. Recent studies from our laboratory have identified several pathways implicated in fatty-acid inhibition of insulin gene expression, including the extracellular-regulated kinase (ERK1/2) pathway; the metabolic sensor Per-Arnt-Sim kinase (PASK); and the ATF6 branch of the unfolded protein response. We have also confirmed in vivo in rats that the decrease in insulin gene expression is an early defect which precedes any detectable abnormality in insulin secretion. While the role of glucolipotoxicity in humans is still debated, the inhibitory effects of chronically elevated fatty acid levels has been clearly demonstrated in several studies, at least in individuals genetically predisposed to developing type 2 diabetes. It is therefore likely that glucolipotoxicity contributes to beta-cell failure in type 2 diabetes as well as to the decline in beta-cell function observed after the onset of the disease.
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影响因子：
3.9
作者：
Cnop, Miriam;Igoillo-Esteve, Mariana;Eizirik, Decio L.
通讯作者：
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7.7
作者：
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通讯作者：
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5.7
作者：
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通讯作者：
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