Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity -: Role in β-cell adaptation and failure in the etiology of diabetes
Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity -: Role in β-cell adaptation and failure in the etiology of diabetes
复制标题
DOI：
10.2337/diabetes.51.2007.s405
复制
发表时间：
2002-12-01
期刊：
影响因子：
7.7
通讯作者：
Roduit, R
中科院分区：
文献类型：
--
作者：
Prentki, M;Joly, E;Roduit, R
β细胞具有固有的机制来适应营养过剩和葡萄糖脂肪酸的普遍浓度，以及维持葡萄糖稳态的其他燃料。然而，这是由同样的营养物质的潜在有害作用来平衡的。葡萄糖和脂肪酸都可能对β细胞产生有益/适应性或有害/毒性作用，这取决于它们的浓度和它们升高的时间。慢性高糖通过底物利用率、糖脂代谢酶活性和表达的变化以及关键转录因子表达水平的改变，显著影响β细胞脂质代谢。我们在这里讨论一种新兴的观点，即β细胞的“糖毒性”部分是由“脂肪毒性”间接引起的，当葡萄糖和循环脂肪酸都很高时，β细胞的异常会变得特别明显。我们支持升高的葡萄糖和脂肪酸协同作用在胰岛和其他器官中引起毒性的概念，这一过程可能有助于与代谢综合征和1型和2型糖尿病相关的多效性缺陷。讨论了高血糖和高脂血症改变胰岛素分泌的机制和β细胞“糖脂毒性”模型，该模型涉及β细胞丙二酰辅酶a浓度的改变；过氧化物酶体增殖物活化受体和固醇调节元件结合蛋白1c表达；并提出脂质分配。
beta-Cells possess inherent mechanisms to adapt to overnutrition and the prevailing concentrations of glucose fatty acids, and other fuels to maintain glucose homeostasis. However, this is balanced by potentially harmful actions of the same nutrients. Both glucose and fatty acids may cause good/adaptive or evil/toxic actions on the beta-cell, depending on their concentrations and the time during which they are elevated. Chronic high glucose dramatically influences beta-cell lipid metabolism via substrate availability, changes in the activity and expression of enzymes of glucose and lipid metabolism, and modifications in the expression level of key transcription factors. We discuss here the emerging view that beta-cell "glucotoxicity" is in part indirectly caused by "lipotoxicity," and that beta-cell abnormalities will become particularly apparent when both glucose and circulating fatty acids are high. We support the concept that elevated glucose and fatty acids synergize in causing toxicity in islets and other organs, a process that may be instrumental in the pleiotropic defects associated with the metabolic syndrome and type 1 and type 2 diabetes. The mechanisms by which hyperglycemia, and hyperlipidemia alter insulin secretion are discussed and a model of beta-cell "glucolipotoxicity" that implicates alterations in beta-cell malonyl-CoA concentrations; peroxisome proliferator-activated receptor-alpha and -gamma and sterol regulatory element binding protein-1c expression; and lipid partitioning is proposed.