Ishiyama Nobuyoshi, Ravier Magalie A, Henquin Jean-Claude
Unité d'Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, Brussels, Belgium.
Am J Physiol Endocrinol Metab. 2006 Mar;290(3):E540-9. doi: 10.1152/ajpendo.00032.2005. Epub 2005 Oct 25.
Glucose induces insulin secretion (IS) and also potentiates the insulin-releasing action of secretagogues such as arginine and sulfonylureas. This potentiating effect is known to be impaired in type 2 diabetic patients, but its cellular mechanisms are unclear. IS and cytosolic Ca(2+) concentration (Ca(2+)) were measured in mouse islets during perifusion with 3-15 mmol/l glucose (G3-G15, respectively) and pulse or stepwise stimulation with 1-10 mmol/l arginine or 5-250 micromol/l tolbutamide. In G3, arginine induced small increases in Ca(2+) but no IS. G7 alone only slightly increased Ca(2+) and IS but markedly potentiated arginine effects on Ca(2+), which resulted in significant IS (already at 1 mmol/l). For each arginine concentration, both responses further increased at G10 and G15, but the relative change was distinctly larger for IS than Ca(2+). At all glucose concentrations, tolbutamide dose dependently increased Ca(2+) and IS with thresholds of 25 micromol/l for Ca(2+) and 100 micromol/l for IS at G3 and of 5 micromol/l for both at G7 and above. Between G7 and G15, the effect of tolbutamide on Ca(2+) increased only slightly, whereas that on IS was strongly potentiated. The linear relationship between IS and Ca(2+) at increasing arginine or tolbutamide concentrations became steeper as the glucose concentration was raised. Thus glucose augmented more the effect of each agent on IS than that on Ca(2+). In conclusion, glucose potentiation of arginine- or tolbutamide-induced IS involves increases in both the rise of Ca(2+) and the action of Ca(2+) on exocytosis. This dual mechanism must be borne in mind to interpret the alterations of the potentiating action of glucose in type 2 diabetic patients.
葡萄糖可诱导胰岛素分泌（IS），还能增强诸如精氨酸和磺脲类等促分泌剂的胰岛素释放作用。已知这种增强作用在2型糖尿病患者中受损，但其细胞机制尚不清楚。在小鼠胰岛用3 - 15 mmol/l葡萄糖（分别为G3 - G15）进行灌流期间，以及用1 - 10 mmol/l精氨酸或5 - 250 μmol/l甲苯磺丁脲进行脉冲或逐步刺激时，测量了IS和胞质Ca(2+)浓度（Ca(2+)）。在G3时，精氨酸使Ca(2+)略有增加，但未引起IS。单独的G7仅使Ca(2+)和IS略有增加，但显著增强了精氨酸对Ca(2+)的作用，这导致在1 mmol/l时就有显著的IS。对于每个精氨酸浓度，在G10和G15时两种反应进一步增加，但IS的相对变化明显大于Ca(2+)。在所有葡萄糖浓度下，甲苯磺丁脲剂量依赖性地增加Ca(2+)和IS，在G3时Ca(2+)的阈值为25 μmol/l，IS为100 μmol/l，在G7及以上两者的阈值均为5 μmol/l。在G7和G15之间，甲苯磺丁脲对Ca(2+)的作用仅略有增加，而对IS的作用则被强烈增强。随着精氨酸或甲苯磺丁脲浓度增加，IS与Ca(2+)之间的线性关系随着葡萄糖浓度升高而变得更陡峭。因此，葡萄糖对每种药物诱导的IS的增强作用比对Ca(2+)的增强作用更大。总之，葡萄糖对精氨酸或甲苯磺丁脲诱导的IS的增强作用涉及Ca(2+)升高和Ca(2+)对胞吐作用的作用两者的增加。在解释2型糖尿病患者中葡萄糖增强作用的改变时必须牢记这种双重机制。
