Division of Endocrinology, Diabetes, Nutrition and Patient Education, Department of Medicine, University Hospitals of Geneva and University of Geneva, Geneva, Switzerland.
Unit of Toxicology, University Centre of Legal Medicine, Lausanne-Geneva, Switzerland.
Physiol Rep. 2021 Mar;9(6):e14786. doi: 10.14814/phy2.14786.
Beta cell failure is one of the most important features of type 2 diabetes mellitus (T2DM). High-density lipoprotein (HDL) has been proposed to improve β-cell function. However, the mechanisms involved in this process are still poorly understood. The aim of this study was to investigate the contribution of sphingosine-1-phosphate (S1P) in the impact of HDL treatment on insulin secretion by pancreatic β-cells and to determine its mechanisms. Primary cultures of β-cells isolated from rat were treated with or without HDL in the presence or absence of S1P pathway inhibitors and insulin secretion response was analyzed. The S1P content of HDL (HDL-S1P) isolated from T2DM patients was analyzed and correlated to the HDL-induced insulin secretion. The expression of genes involved in the biosynthesis of the insulin was also evaluated. HDL as well as S1P treatment enhanced glucose-stimulated insulin secretion (GSIS). In HDL isolated from T2DM patients, while HDL-S1P was strongly correlated to its pro-secretory capacity (r = 0.633, p = 0.005), HDL-cholesterol and apolipoprotein AI levels were not. HDL-induced GSIS was blocked by the S1P1/3 antagonist but not by the S1P2 antagonist, and was also accompanied by increased intracellular S1P in β-cells. We also observed that HDL improved GSIS without significant changes in expression levels of insulin biosynthesis genes. Our present study highlights the importance HDL-S1P in GSIS in T2DM patients and demonstrates that HDL induces insulin secretion by a process involving both intra- and extra-cellular sources of S1P independently of an effect on insulin biosynthesis genes.
β细胞衰竭是 2 型糖尿病（T2DM）的最重要特征之一。高密度脂蛋白（HDL）被认为可以改善β细胞功能。然而，这一过程中涉及的机制仍知之甚少。本研究旨在研究鞘氨醇-1-磷酸（S1P）在 HDL 处理对胰岛β细胞胰岛素分泌的影响中的作用，并确定其机制。用或不用 HDL 处理分离自大鼠的原代β细胞，在存在或不存在 S1P 途径抑制剂的情况下分析胰岛素分泌反应。分析来自 T2DM 患者的 HDL（HDL-S1P）中的 S1P 含量，并将其与 HDL 诱导的胰岛素分泌相关联。还评估了参与胰岛素生物合成的基因的表达。HDL 以及 S1P 处理增强了葡萄糖刺激的胰岛素分泌（GSIS）。在来自 T2DM 患者的 HDL 中，虽然 HDL-S1P 与它的促分泌能力强烈相关（r=0.633，p=0.005），但 HDL-胆固醇和载脂蛋白 AI 水平没有。HDL 诱导的 GSIS 被 S1P1/3 拮抗剂阻断，但不被 S1P2 拮抗剂阻断，并且还伴有β细胞内 S1P 的增加。我们还观察到 HDL 改善 GSIS，而胰岛素生物合成基因的表达水平没有显著变化。本研究强调了 HDL-S1P 在 T2DM 患者 GSIS 中的重要性，并表明 HDL 通过涉及细胞内外 S1P 来源的独立于对胰岛素生物合成基因的作用的过程诱导胰岛素分泌。
