Department of Cell Physiology and Metabolism & Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland.
Department of Cell Physiology and Metabolism & Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland.
Atherosclerosis. 2024 Nov;398:118623. doi: 10.1016/j.atherosclerosis.2024.118623. Epub 2024 Oct 4.
Pancreatic ß-cells are glucose sensors in charge of regulated insulin delivery to the organism, achieving glucose homeostasis and overall energy storage. The latter function promotes obesity when nutrient intake chronically exceeds daily expenditure. In case of ß-cell failure, such weight gain may pave the way for the development of Type-2 diabetes. However, the causal link between excessive body fat mass and potential degradation of ß-cells remains largely unknown and debated. Over the last decades, intensive research has been conducted on the role of lipids in the pathogenesis of ß-cells, also referred to as lipotoxicity. Among various lipid species, the usual suspects are essentially the non-esterified fatty acids (NEFA), in particular the saturated ones such as palmitate. This review describes the fundamentals and the latest advances of research on the role of fatty acids in ß-cells. This includes intracellular pathways and receptor-mediated signaling, both participating in regulated glucose-stimulated insulin secretion as well as being implicated in ß-cell dysfunction. The discussion extends to the contribution of high glucose exposure, or glucotoxicity, to ß-cell defects. Combining glucotoxicity and lipotoxicity results in the synergistic and more deleterious glucolipotoxicity effect. In recent years, alternative roles for intracellular lipids have been uncovered, pointing to a protective function in case of nutrient overload. This requires dynamic storage of NEFA as neutral lipid droplets within the ß-cell, along with active glycerolipid/NEFA cycle allowing subsequent recruitment of lipid species supporting glucose-stimulated insulin secretion. Overall, the latest studies have revealed the two faces of the same coin.
胰岛 β 细胞是负责调节胰岛素向机体输送的葡萄糖传感器，从而实现葡萄糖的体内平衡和整体能量储存。当营养摄入长期超过日常支出时，后者的功能会导致肥胖。在 β 细胞功能衰竭的情况下，这种体重增加可能为 2 型糖尿病的发展铺平道路。然而，过量的体脂肪量和潜在的 β 细胞退化之间的因果关系在很大程度上仍然未知和存在争议。在过去的几十年中，人们对脂质在 β 细胞发病机制中的作用进行了深入研究，也称为脂毒性。在各种脂质中，常见的罪魁祸首主要是非酯化脂肪酸 (NEFA)，特别是饱和脂肪酸，如棕榈酸。本文描述了脂肪酸在 β 细胞中的作用的基础和最新研究进展。这包括细胞内途径和受体介导的信号转导，它们都参与调节葡萄糖刺激的胰岛素分泌，并与 β 细胞功能障碍有关。讨论还扩展到高葡萄糖暴露或糖毒性对 β 细胞缺陷的贡献。将糖毒性和脂毒性结合起来会产生协同的、更具危害性的糖脂毒性作用。近年来，细胞内脂质的替代作用已经被揭示出来，表明在营养超负荷的情况下具有保护功能。这需要将 NEFA 作为中性脂滴动态储存在 β 细胞内，并进行活跃的甘油磷脂/NEFA 循环，以便随后募集支持葡萄糖刺激的胰岛素分泌的脂质。总的来说，最新的研究揭示了同一枚硬币的两面。
