INTERLEUKIN 1 REDUCES GLYCOLYTIC UTILIZATION OF GLUCOSE BY PANCREATIC ISLETS

白细胞介素1对大鼠胰岛细胞培养的影响 在诱导型一氧化氮合酶异构体上调中的作用 一氧化氮合酶(INOS)和一氧化氮(NO)生成过剩。这是关联的 可逆性抑制葡萄糖诱导的胰岛素分泌 和胰岛葡萄糖氧化，而这些影响是由 一氧化氮合酶抑制剂NG-单甲基精氨酸(NMMA)。IL-1还诱导 非酯化花生四烯酸在胰岛中的积累 NO依赖机制，如同位素稀释质量所证明的 光谱和对这种效应的一个可能的解释是 涉及IL-1诱导的胰岛糖酵解通量的增强。我们有 因此研究了IL-1对小鼠胰岛糖酵解利用的影响。 并发现胰岛在含有IL-1的培养液中培养 5.5 mM葡萄糖导致胰岛葡萄糖利用受到抑制 随后在葡萄糖浓度为6至18 mM时进行测量。 IL-1对胰岛葡萄糖利用的抑制作用 与胰岛葡萄糖激酶mRNA含量下降有关，因为 通过竞争性RT-PCR检测，并在葡糖激酶蛋白中 通过免疫沉淀实验确定的合成和所有 NMMA可以预防这些影响中的一部分。这些发现表明， IL-1可下调胰岛葡萄糖激酶的表达，而胰岛葡萄糖激酶是胰岛细胞的主要功能 胰岛葡萄糖传感器装置的组件，由非依赖的 机制。因为胰岛葡萄糖激酶水平的降低是已知的 导致一种形式的II型糖尿病，这些观察提出了 升高胰岛一氧化氮水平的因素可能 有助于糖耐量异常的发展。

Culture of rat pancreatic islets with interleukin-1 (IL-1) results in up-regulation of the inducible isoform of nitric oxide synthase (iNOS) and overproduction of nitric oxide (NO). This is associated with reversible inhibition of both glucose-induced insulin secretion and islet glucose oxidation, and these effects are prevented by the iNOS inhibitor NG-monomethyl-arginine (NMMA). IL-1 also induces accumulation of nonesterified arachidonic acid in islets by an NO-dependent mechanism, as demonstrated by isotope dilution mass spectrometry and one potential explanation for that effect would involve an IL-1-induced enhancement of islet glycolytic flux. We have therefore examined effects of IL-1 on islet glycolytic utilization of glucose and find that culture of islets with IL-1 in medium containing 5.5 mM glucose results in suppression of islet glucose utilization subsequently measured at glucose concentrations between 6 and 18 mM. The IL-1-induced suppression of islet gluc ose utilization is associated with a decline in islet glucokinase mRNA content, as determined by competitive RT-PCR, and in glucokinase protein synthesis, as determined by immuno-precipitation experiments, and all of these effects are prevented by NMMA. These findings suggest that IL-1 can down-regulate islet glucokinase, which is the primary component of the islet glucose-sensor apparatus, by an NO-dependent mechanism. Because reductions in islet glucokinase levels are known to cause a form of type II diabetes mellitus, these observations raise the possibility that factors which increase islet NO levels might contribute to development of glucose intolerance.