Yaney G C, Civelek V N, Richard A M, Dillon J S, Deeney J T, Hamilton J A, Korchak H M, Tornheim K, Corkey B E, Boyd A E
Evans Department of Medicine, Boston Medical Center, Massachusetts 02118, USA.
Diabetes. 2001 Jan;50(1):56-62. doi: 10.2337/diabetes.50.1.56.
Glucagon-like peptide 1 (GLP-1) is the most potent physiological incretin for insulin secretion from the pancreatic beta-cell, but its mechanism of action has not been established. It interacts with specific cell-surface receptors, generates cAMP, and thereby activates protein kinase A (PKA). Many changes in pancreatic beta-cell function have been attributed to PKA activation, but the contribution of each one to the secretory response is unknown. We show here for the first time that GLP-1 rapidly released free fatty acids (FFAs) from cellular stores, thereby lowering intracellular pH (pHi) and stimulating FFA oxidation in clonal beta-cells (HIT). Similar changes were observed with forskolin, suggesting that stimulation of lipolysis was a function of PKA activation in beta-cells. Triacsin C, which inhibits the conversion of FFAs to long-chain acyl CoA (LC-CoA), enhanced basal FFA efflux as well as GLP-1-induced acidification and efflux of FFAs from the cell. Increasing the concentration of the lipase inhibitor orlistat progressively and largely diminished the increment in secretion caused by forskolin. However, glucose-stimulated secretion was less inhibited by orlistat and only at the highest concentration tested. Because the acute addition of FFAs also increases glucose-stimulated insulin secretion, these data suggest that the incretin function of GLP-1 may involve a major role for lipolysis in cAMP-mediated potentiation of secretion.
胰高血糖素样肽1（GLP-1）是促进胰腺β细胞分泌胰岛素的最有效的生理性肠促胰岛素，但其作用机制尚未明确。它与特定的细胞表面受体相互作用，生成环磷酸腺苷（cAMP），从而激活蛋白激酶A（PKA）。胰腺β细胞功能的许多变化都归因于PKA的激活，但其中每一项对分泌反应的贡献尚不清楚。我们在此首次表明，GLP-1能迅速从细胞储存中释放游离脂肪酸（FFA），从而降低细胞内pH值（pHi），并刺激克隆β细胞（HIT）中的FFA氧化。用福司可林也观察到了类似的变化，这表明脂解作用的刺激是β细胞中PKA激活的一个功能。抑制FFA转化为长链酰基辅酶A（LC-CoA）的三辛素C增强了基础FFA外流以及GLP-1诱导的FFA从细胞中的酸化和外流。增加脂肪酶抑制剂奥利司他的浓度会逐渐并在很大程度上减少福司可林引起的分泌增加。然而，奥利司他对葡萄糖刺激的分泌抑制作用较小，且仅在测试的最高浓度下有抑制作用。由于急性添加FFA也会增加葡萄糖刺激的胰岛素分泌，这些数据表明，GLP-1的肠促胰岛素功能可能在cAMP介导的分泌增强中涉及脂解作用的主要作用。
