Prentki Marc, Joly Erik, El-Assaad Wissal, Roduit Raphaël
Molecular Nutrition Unit, Department of Nutrition, University of Montreal, the Centre de Recherche du CHUM, Montreal, Quebec, Canada.
Diabetes. 2002 Dec;51 Suppl 3:S405-13. doi: 10.2337/diabetes.51.2007.s405.
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.
β细胞具有内在机制以适应营养过剩以及葡萄糖、脂肪酸和其他燃料的现有浓度，从而维持葡萄糖稳态。然而，同样这些营养素的潜在有害作用会对此形成平衡。葡萄糖和脂肪酸对β细胞都可能产生有益/适应性或有害/毒性作用，这取决于它们的浓度以及浓度升高的持续时间。慢性高血糖通过底物可用性、葡萄糖和脂质代谢酶活性及表达的变化以及关键转录因子表达水平的改变，极大地影响β细胞脂质代谢。我们在此讨论一种新出现的观点，即β细胞的“糖毒性”部分是由“脂毒性”间接引起的，并且当葡萄糖和循环脂肪酸都处于高水平时，β细胞异常将变得尤为明显。我们支持这样一种观点，即升高的葡萄糖和脂肪酸在导致胰岛及其他器官毒性方面具有协同作用，这一过程可能在与代谢综合征以及1型和2型糖尿病相关的多效性缺陷中起作用。文中讨论了高血糖和高血脂改变胰岛素分泌的机制，并提出了一种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激活受体α和γ以及固醇调节元件结合蛋白1c的表达；以及脂质分配。
