Malaisse W J, Rasschaert J, Villanueva-Penacarrillo M L, Valverde I
Laboratorie of Experimental Medicine, Brussels Free University, Belgium.
Am J Physiol. 1993 Mar;264(3 Pt 1):E428-33. doi: 10.1152/ajpendo.1993.264.3.E428.
The methyl esters of succinic acid were introduced a few years ago as new potent insulin secretagogues. In the present study, they were found to increase O2 uptake by rat islets incubated in the absence or presence of D-glucose; to decrease 86Rb outflow from prelabeled islets; to stimulate biosynthetic activity in the islets, with a preferential effect on the synthesis of proinsulin; to inhibit 45Ca efflux from prelabeled islets perifused in the absence of extracellular Ca2+ but to augment 45Ca net uptake and to cause a biphasic stimulation of 45Ca outflow in islets incubated or perifused in the presence of extracellular Ca2+; and to evoke a biphasic stimulation of insulin release. The insulinotropic action of these methyl esters coincided with a shift to the left of the sigmoidal relationship between insulin output and D-glucose concentration, was concentration related in the 2-10 mM range, failed to be duplicated by succinic acid, displayed both Ca2+ dependency and resistance to a lowering of extracellular pH, and was operative in the absence of D-glucose whether or not the islets were stimulated by non-nutrient secretagogues. It is concluded that the respiratory, cationic, biosynthetic, and secretory responses of the islets to succinate methyl esters display the characteristic features usually encountered in the process of nutrient-stimulated insulin release.
琥珀酸甲酯作为新型强效胰岛素促分泌剂于几年前被引入。在本研究中，发现它们可增加在有无D - 葡萄糖情况下孵育的大鼠胰岛的氧气摄取；减少预先标记的胰岛中86Rb的流出；刺激胰岛中的生物合成活性，对胰岛素原的合成有优先作用；在无细胞外Ca2+的情况下，抑制预先标记的胰岛中45Ca的流出，但增加45Ca的净摄取，并在有细胞外Ca2+存在的情况下孵育或灌流的胰岛中引起45Ca流出的双相刺激；并引起胰岛素释放的双相刺激。这些甲酯的促胰岛素作用与胰岛素分泌量和D - 葡萄糖浓度之间的S形关系向左移动相一致，在2 - 10 mM范围内与浓度相关，琥珀酸无法复制这种作用，显示出对细胞外pH降低的Ca2+依赖性和抗性，并且无论胰岛是否受到非营养性促分泌剂的刺激，在无D - 葡萄糖的情况下均起作用。得出的结论是，胰岛对琥珀酸甲酯的呼吸、阳离子、生物合成和分泌反应表现出营养刺激胰岛素释放过程中通常遇到的特征。
