Henningsson R, Alm P, Ekström P, Lundquist I
Department of Pharmacology, University of Lund, Sweden.
Diabetes. 1999 Jan;48(1):66-76. doi: 10.2337/diabetes.48.1.66.
Carbon monoxide (CO) has been suggested as a novel messenger molecule in the brain. We now report on the cellular localization and hormone secretory function of a CO-producing constitutive heme oxygenase (HO-2) in mouse islets. Islet homogenates produced large amounts of CO which were suppressed dose-dependently by the HO inhibitor zincprotoporphyrin-IX (ZnPP-IX). We also show, for the first time, that glucose markedly stimulates the HO activity (CO production) in intact islets. A further potentiation was induced by the HO substrate hemin. Western blot showed that islet tissue expressed HO-2, and confocal microscopy revealed that HO-2 resided in insulin, glucagon, somatostatin, and pancreatic polypeptide cells. ZnPP-IX dose-dependently inhibited, whereas hemin enhanced, both insulin and glucagon secretion from glucose-stimulated islets. Stimulation or inhibition of CO production was accompanied by corresponding changes in islet cGMP levels. Exogenously applied CO stimulated insulin and glucagon release from isolated islets, whereas exogenous nitric oxide (NO) inhibited insulin and stimulated glucagon release. Islets stimulated by glucose or L-arginine displayed a marked increase in their NO-synthase (NOS) activity. Such an increase was suppressed by hemin, conceivably because NOS activity was inhibited by hemin-derived CO. Consequently, hemin enhanced L-arginine-induced insulin secretion. Insulin release stimulated by either hemin-derived CO or exogenous CO was strongly inhibited by the guanylate cyclase inhibitor ODQ, but it was unaffected by ZnPP-IX. Glucagon release induced by CO (but not by hemin) was inhibited by ODQ and partly inhibited by ZnPP-IX. We propose that the islets of Langerhans are equipped with a heme oxygenase-carbon monoxide pathway, which constitutes a novel regulatory system of physiological importance for the stimulation of insulin and glucagon release. This pathway is stimulated by glucose, is at least partly dependent on the cGMP system, and displays interaction with islet NOS activity.
一氧化碳（CO）被认为是大脑中的一种新型信使分子。我们现在报告小鼠胰岛中一种组成型产CO的血红素加氧酶（HO-2）的细胞定位和激素分泌功能。胰岛匀浆产生大量CO，HO抑制剂锌原卟啉-IX（ZnPP-IX）可剂量依赖性地抑制其产生。我们还首次表明，葡萄糖能显著刺激完整胰岛中的HO活性（CO产生）。HO底物血红素可进一步增强这种作用。蛋白质印迹法显示胰岛组织表达HO-2，共聚焦显微镜检查显示HO-2存在于胰岛素、胰高血糖素、生长抑素和胰多肽细胞中。ZnPP-IX可剂量依赖性地抑制葡萄糖刺激的胰岛分泌胰岛素和胰高血糖素，而血红素则增强这种分泌。刺激或抑制CO产生伴随着胰岛cGMP水平的相应变化。外源性应用CO可刺激分离胰岛释放胰岛素和胰高血糖素，而外源性一氧化氮（NO）则抑制胰岛素释放并刺激胰高血糖素释放。葡萄糖或L-精氨酸刺激的胰岛其一氧化氮合酶（NOS）活性显著增加。这种增加被血红素抑制，推测是因为血红素衍生的CO抑制了NOS活性。因此，血红素增强了L-精氨酸诱导的胰岛素分泌。血红素衍生的CO或外源性CO刺激的胰岛素释放被鸟苷酸环化酶抑制剂ODQ强烈抑制，但不受ZnPP-IX影响。ODQ抑制CO（而非血红素）诱导的胰高血糖素释放，ZnPP-IX则部分抑制该释放。我们提出，胰岛配备了一条血红素加氧酶-一氧化碳途径，这构成了一个对刺激胰岛素和胰高血糖素释放具有重要生理意义的新型调节系统。该途径受葡萄糖刺激，至少部分依赖于cGMP系统，并与胰岛NOS活性相互作用。
