Zawalich W S, Zawalich K C
Yale University School of Nursing, New Haven, Connecticut 06536-0740, USA.
Am J Physiol. 1996 Sep;271(3 Pt 1):E409-16. doi: 10.1152/ajpendo.1996.271.3.E409.
Biphasic insulin secretion in response to a sustained glucose stimulus occurs when rat or human islets are exposed to high levels of the hexose. A transient burst of hormone secretion is followed by a rising and sustained secretory response that, in the perfused rat pancreas, is 25- to 75-fold greater than prestimulatory insulin release rates. This insulin secretory response is paralleled by a significant five- to sixfold increase in the phospholipase C (PLC)-mediated hydrolysis of islet phosphoinositide (PI) pools by high glucose. In contrast, mouse islets, when stimulated under comparable conditions with high glucose, display a second-phase response that is flat and only slightly (two- to threefold) greater than prestimulatory release rates. The minimal second-phase insulin secretory response to high glucose is accompanied by the minimal activation of PLC in mouse islets as well. However, stimulation of mouse islets with the protein kinase C (PKC) activator tetradecanoyl phorbol acetate (TPA) or the muscarinic agonist carbachol, which significantly activates an isozyme of PLC distinct from that activated by high glucose, induces a rising and sustained second-phase insulin secretory response. When previously exposed to high glucose, both rat and human islets respond to subsequent restimulation with an amplified insulin secretory response. They display priming, sensitization, or time-dependent potentiation. In contrast, mouse islets primed under similar conditions with high glucose fail to display this amplified insulin secretory response on restimulation. Mouse islets can, however, be primed by brief exposure to either TPA or carbachol. Finally, whereas rat islets are desensitized by chronic exposure to high glucose, mouse islet insulin secretory responses are relatively immune to this adverse effect of the hexose. These and other findings are discussed in relationship to the role being played by agonist-induced increases in the PLC-mediated hydrolysis of islet phosphoinositide pools and the activation of PKC in these species-specific insulin secretory response patterns.
当大鼠或人类胰岛暴露于高水平的己糖时，会出现对持续葡萄糖刺激的双相胰岛素分泌。激素分泌的短暂爆发之后是分泌反应的上升和持续，在灌注的大鼠胰腺中，这种分泌反应比刺激前的胰岛素释放速率高25至75倍。这种胰岛素分泌反应与高葡萄糖引起的磷脂酶C（PLC）介导的胰岛磷酸肌醇（PI）池水解显著增加五至六倍平行。相比之下，小鼠胰岛在与高葡萄糖相当的条件下受到刺激时，显示出的第二阶段反应是平稳的，仅比刺激前的释放速率略高（两至三倍）。对高葡萄糖的最小第二阶段胰岛素分泌反应也伴随着小鼠胰岛中PLC的最小激活。然而，用蛋白激酶C（PKC）激活剂十四酰佛波醇乙酸酯（TPA）或毒蕈碱激动剂卡巴胆碱刺激小鼠胰岛，可显著激活一种与高葡萄糖激活的PLC不同的同工酶，从而诱导胰岛素分泌反应的上升和持续的第二阶段。当先前暴露于高葡萄糖时，大鼠和人类胰岛对随后的再刺激都会产生放大的胰岛素分泌反应。它们表现出启动、致敏或时间依赖性增强。相比之下，在类似条件下用高葡萄糖启动的小鼠胰岛在再刺激时未能显示出这种放大的胰岛素分泌反应。然而，小鼠胰岛可以通过短暂暴露于TPA或卡巴胆碱来启动。最后，虽然大鼠胰岛会因长期暴露于高葡萄糖而脱敏，但小鼠胰岛的胰岛素分泌反应对己糖的这种不利影响相对免疫。这些以及其他发现将结合激动剂诱导的胰岛磷酸肌醇池PLC介导水解增加和PKC激活在这些物种特异性胰岛素分泌反应模式中所起的作用进行讨论。
