Nutrient-Induced Metabolic Stress, Adaptation, Detoxification, and Toxicity in the Pancreatic β-Cell
Nutrient-Induced Metabolic Stress, Adaptation, Detoxification, and Toxicity in the Pancreatic β-Cell
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DOI：
10.2337/dbi19-0014
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发表时间：
2020-03-01
期刊：
影响因子：
7.7
通讯作者：
Madiraju, S. R. Murthy
中科院分区：
文献类型：
--
作者：
Prentki, Marc;Peyot, Marie-Line;Madiraju, S. R. Murthy
用瑞士医生、毒理学之父帕拉塞尔苏斯（Paracelsus，1493-1541年）关于用作治疗剂的化学药剂的话来说，“剂量决定毒药”，现在人们意识到这一点非常适用于产热营养素。这里的情况是胰岛β细胞呈现出过量的营养物质，如葡萄糖、脂质和氨基酸。这些营养素对β细胞的短期影响是增强胰岛素的生物合成和分泌以及葡萄糖敏感性的变化。然而，慢性燃料过量触发β细胞的额外补偿和适应机制，以科普增加的胰岛素需求或保护自身。当这些机制失败时，由于营养过剩引起的毒性增强，导致β细胞功能障碍、去分化和凋亡。术语糖毒性、脂毒性和糖脂毒性已被广泛使用，但对于它们的确切含义以及哪种最适合特定情况存在一些混淆。在这里，我们通过评估支持和反对每一个的证据来解决β细胞中的葡萄糖，脂肪和糖脂毒性。我们还讨论了潜在的机制和捍卫的观点，许多已确定的“有毒”的营养过剩的影响，其中也可能包括氨基酸，实际上是有益的适应过程。此外，候选燃料过量解毒途径进行了评估。最后，我们建议，超重相关的2型糖尿病的体内情况应该使用一个更一般的术语，反映了对混合生热营养素过量的适应性和毒性过程：“营养素诱导的代谢应激”，或简称“营养应激”。"
Paraphrasing the Swiss physician and father of toxicology Paracelsus (1493-1541) on chemical agents used as therapeutics, "the dose makes the poison," it is now realized that this aptly applies to the calorigenic nutrients. The case here is the pancreatic islet beta-cell presented with excessive levels of nutrients such as glucose, lipids, and amino acids. The short-term effects these nutrients exert on the beta-cell are enhanced insulin biosynthesis and secretion and changes in glucose sensitivity. However, chronic fuel surfeit triggers additional compensatory and adaptive mechanisms by beta-cells to cope with the increased insulin demand or to protect itself. When these mechanisms fail, toxicity due to the nutrient surplus ensues, leading to beta-cell dysfunction, dedifferentiation, and apoptosis. The terms glucotoxicity, lipotoxicity, and glucolipotoxicity have been widely used, but there is some confusion as to what they mean precisely and which is most appropriate for a given situation. Here we address the gluco-, lipo-, and glucolipo-toxicities in beta-cells by assessing the evidence both for and against each of them. We also discuss potential mechanisms and defend the view that many of the identified "toxic" effects of nutrient excess, which may also include amino acids, are in fact beneficial adaptive processes. In addition, candidate fuel-excess detoxification pathways are evaluated. Finally, we propose that a more general term should be used for the in vivo situation of overweight-associated type 2 diabetes reflecting both the adaptive and toxic processes to mixed calorigenic nutrients excess: "nutrient-induced metabolic stress" or, in brief, "nutri-stress."