a Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia , Philadelphia, PA , USA.
b Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA.
Islets. 2019;11(4):77-88. doi: 10.1080/19382014.2019.1566683. Epub 2019 Mar 8.
A potentiating effect of medium-chain triglycerides on glucose-stimulated insulin secretion (GSIS) has been observed since the 1960s. Subsequent observations identified octanoic acid (OA), the main component of medium-chain triglyceride, as the potentiator of GSIS, but the mechanism was unclear. We used wild-type (WT), short-chain 3-hydroxyacyl-CoA dehydrogenase knockout (), and sulfonylurea receptor 1 knockout () mouse islets to define the mechanism of OA potentiation of insulin secretion. Application of OA alone induced a 2- to 3- fold increase of insulin secretion with an apparent threshold of 3 mM in WT mouse islets, suggesting that OA itself is a weak insulin secretagogue. However, OA at 1 mM strongly potentiated fuel-stimulated insulin secretion, especially GSIS. The potentiating effect on fuel-stimulated insulin secretion by OA did not require fatty acid β-oxidation because OA also potentiated amino acid-stimulated insulin secretion in islets isolated from mice, which cannot fully oxidize OA. Measurements using islets indicated that the potentiating effect of OA on fuel-stimulated insulin secretion is Ca dependent and is often accompanied by β-cell membrane potential depolarization, and may also involve the Ca/calmodulin complex. Experiments using DCPIB, an ethacrynic acid derivative, to inhibit volume-sensitive anion channels (VSACs) in islets demonstrated that the potentiation effects of OA on insulin secretion are in part medicated by activation of VSAC. In addition, inhibition of IP3 receptor also abolishes the OA-induced intracellular Ca increase in islets.
自 20 世纪 60 年代以来，人们就观察到中链甘油三酯（MCT）对葡萄糖刺激的胰岛素分泌（GSIS）具有增强作用。随后的观察结果确定了辛酸（OA），即中链甘油三酯的主要成分，是 GSIS 的增强剂，但作用机制尚不清楚。我们使用野生型（WT）、短链 3-羟酰基辅酶 A 脱氢酶敲除（）和磺酰脲受体 1 敲除（）小鼠胰岛来定义 OA 增强胰岛素分泌的机制。单独应用 OA 可在 WT 小鼠胰岛中诱导 2-3 倍的胰岛素分泌增加，其明显的阈值为 3 mM，表明 OA 本身是一种较弱的胰岛素分泌激动剂。然而，1 mM 的 OA 强烈增强了燃料刺激的胰岛素分泌，特别是 GSIS。OA 对燃料刺激的胰岛素分泌的增强作用不需要脂肪酸β氧化，因为 OA 还增强了不能完全氧化 OA 的小鼠胰岛中的氨基酸刺激的胰岛素分泌。使用 胰岛进行的测量表明，OA 对燃料刺激的胰岛素分泌的增强作用是 Ca 依赖性的，通常伴随着β细胞膜电位去极化，并且可能还涉及 Ca/钙调蛋白复合物。使用 DCPIB（一种丙烯酸盐衍生物）抑制 胰岛中的体积敏感性阴离子通道（VSAC）的实验表明，OA 对胰岛素分泌的增强作用部分是通过激活 VSAC 介导的。此外，抑制 IP3 受体也可消除 OA 诱导的 胰岛中的细胞内 Ca 增加。
