Colca J R, Wolf B A, McDaniel M L
Diabetes and Gl Diseases Research, Upjohn Company, Kalamazoo, Michigan.
Prog Clin Biol Res. 1988;265:117-32.
Figure 8 summarizes some of the processes that may impact on the secretion of insulin by regulating Ca2+ handling by the beta-cell endoplasmic reticulum. A role for calmodulin in controlling the rate of Ca2+ efflux is indicated by both the ability of the calmodulin antagonist, W7 to stimulate Ca2+ efflux and by the ability of exogenous calmodulin to antagonize Ca2+ efflux in response to inositol trisphosphate (IP3). The impact of calmodulin on this system may be to serve as link in the feedback control of cellular Ca2+. In addition to IP3, a second messenger that may link signal transduction to the release of Ca2+ is the guanine nucleotide, GTP. GTP stimulates the efflux of Ca2+ from the endoplasmic reticulum through a mechanism distinct from IP3. It will be important to determine whether extracellular glucose concentration, or other modifiers of secretion, acutely regulate the GTP concentrations in the beta-cell and to assess if this function may be altered with a decrease in beta-cell function. A variety of evidence indicates that metabolism of glucose by the beta-cell somehow plays a major role in the cellular control of insulin secretion (Hedeskov, 1980). An important link in this process may be the direct effects of glucose 6-phosphate on the handling of Ca2+ by the endoplasmic reticulum. Glucose 6-phosphate is able to increase the active uptake of Ca2+ by these membranes and also to specifically inhibit Ca2+ efflux produced by the IP3. Concentrations of glucose 6-phosphate needed to achieve these effects are likely achieved under physiological conditions (Aschroft et al., 1970). It is also easy to imagine that in diabetes when the islets are chronically exposed to high glucose that, as a result of the content of the high Km glucokinase in the islet (Meglasson and Matschinsky, 1986), higher concentrations of glucose 6-phosphate may be achieved. Under these conditions glucose 6-phosphate may contribute to the islet-cell pathology by interfering with the acute control of Ca2+ handling by the endoplasmic reticulum.
图8总结了一些可能通过调节β细胞内质网对Ca2+的处理来影响胰岛素分泌的过程。钙调蛋白拮抗剂W7刺激Ca2+外流的能力以及外源性钙调蛋白拮抗由肌醇三磷酸（IP3）引起的Ca2+外流的能力，均表明钙调蛋白在控制Ca2+外流速率中发挥作用。钙调蛋白对该系统的影响可能是作为细胞内Ca2+反馈控制的一个环节。除了IP3外，另一种可能将信号转导与Ca2+释放联系起来的第二信使是鸟嘌呤核苷酸GTP。GTP通过一种不同于IP3的机制刺激Ca2+从内质网外流。确定细胞外葡萄糖浓度或其他分泌调节因子是否能急性调节β细胞中的GTP浓度，以及评估随着β细胞功能下降该功能是否会改变，将是很重要的。各种证据表明，β细胞对葡萄糖的代谢在胰岛素分泌的细胞控制中以某种方式起着主要作用（赫德斯科夫，1980年）。这一过程中的一个重要环节可能是6-磷酸葡萄糖对内质网处理Ca2+的直接影响。6-磷酸葡萄糖能够增加这些膜对Ca2+的主动摄取，还能特异性抑制由IP3产生的Ca2+外流。在生理条件下可能会达到实现这些作用所需的6-磷酸葡萄糖浓度（阿什克罗夫特等人，1970年）。也很容易想象，在糖尿病中，当胰岛长期暴露于高血糖时，由于胰岛中高Km葡萄糖激酶的含量（梅格拉斯森和马奇辛斯基，1986年），可能会达到更高浓度的6-磷酸葡萄糖。在这些条件下，6-磷酸葡萄糖可能通过干扰内质网对Ca2+处理的急性控制而导致胰岛细胞病变。
