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首页> 外文期刊>Islets >Monomethylated-adenines potentiate glucose-induced insulin production and secretion via inhibition of phosphodiesterase activity in rat pancreatic islets
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Monomethylated-adenines potentiate glucose-induced insulin production and secretion via inhibition of phosphodiesterase activity in rat pancreatic islets

机译：单甲基化的腺嘌呤通过抑制大鼠胰岛中的磷酸二酯酶活性来增强葡萄糖诱导的胰岛素产生和分泌

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Monomethyladenines have effects on DNA repair, G-protein-coupled receptor antagonism and autophagy. In islet ss-cells, 3-methyladenine (3-MA) has been implicated in DNA-repair and autophagy, but its mechanism of action is unclear. Here, the effect of monomethylated adenines was examined in rat islets. 3-MA, N6-methyladenine (N6-MA) and 9-methyladenine (9-MA), but not 1- or 7-monomethylated adenines, specifically potentiated glucose-induced insulin secretion (3-4 fold; p 0.05) and proinsulin biosynthesis (approximate to 2-fold; p 0.05). Using 3-MA as a model' monomethyladenine, it was found that 3-MA augmented [cAMP](i) accumulation (2-3 fold; p 0.05) in islets within 5 minutes. The 3-, N6- and 9-MA also enhanced glucose-induced phosphorylation of the cAMP/protein kinase-A (PKA) substrate cAMP-response element binding protein (CREB). Treatment of islets with pertussis or cholera toxin indicated 3-MA mediated elevation of [cAMP](i) was not mediated via G-protein-coupled receptors. Also, 3-MA did not compete with 9-cyclopentyladenine (9-CPA) for adenylate cyclase inhibition, but did for the pan-inhibitor of phosphodiesterase (PDE), 3-isobutyl-1-methylxanthine (IBMX). Competitive inhibition experiments with PDE-isoform specific inhibitors suggested 3-MA to have a preference for PDE4 in islet ss-cells, but this was likely reflective of PDE4 being the most abundant PDE isoform in ss-cells. In vitro enzyme assays indicated that 3-, N6- and 9-MA were capable of inhibiting most PDE isoforms found in ss-cells. Thus, in addition to known inhibition of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/m Target of Rapamycin (mTOR) signaling, 3-MA also acts as a pan-phosphodiesterase inhibitor in pancreatic ss-cells to elevate [cAMP](i) and then potentiate glucose-induced insulin secretion and production in parallel.
机译：单甲基ade烯对DNA修复，G蛋白偶联受体拮抗作用和自噬具有影响。在胰岛ss细胞中，3-甲基腺嘌呤（3-MA）与DNA修复和自噬有关，但其作用机理尚不清楚。在这里，检查了大鼠胰岛中单甲基化腺嘌呤的作用。 3-MA，N6-甲基腺嘌呤（N6-MA）和9-甲基腺嘌呤（9-MA），而不是1-或7-单甲基腺嘌呤，特别是增强葡萄糖诱导的胰岛素分泌（3-4倍; p 0.05）和胰岛素原生物合成（约2倍; p 0.05）。使用3-MA作为模型的单甲基腺嘌呤，发现3-MA在5分钟内增加了[cAMP]（i）在胰岛中的积累（2-3倍; p 0.05）。 3-，N6-和9-MA还可增强葡萄糖诱导的cAMP /蛋白激酶-A（PKA）底物cAMP反应元件结合蛋白（CREB）的磷酸化。用百日咳或霍乱毒素治疗胰岛表明3-MA介导的[cAMP]（i）升高不是通过G蛋白偶联受体介导的。而且，3-MA不能与9-环戊基腺嘌呤（9-CPA）竞争腺苷酸环化酶抑制作用，但可以与磷酸二酯酶（PDE）的泛抑制剂3-异丁基-1-甲基黄嘌呤（IBMX）竞争。用PDE异构体特异性抑制剂进行的竞争性抑制实验表明3-MA在胰岛ss细胞中偏爱PDE4，但这很可能反映了PDE4是ss细胞中最丰富的PDE异构体。体外酶分析表明3-，N6-和9-MA能够抑制在ss细胞中发现的大多数PDE亚型。因此，除了已知抑制磷脂酰肌醇-4,5-双磷酸3-激酶（PI3K）/ m雷帕霉素（mTOR）信号的靶标外，3-MA还充当胰腺ss细胞中的泛磷酸二酯酶抑制剂，以提高[ cAMP]（i），然后平行增强葡萄糖诱导的胰岛素分泌和产生。

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