Dept. of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, NY 14214, USA.
Am J Physiol Endocrinol Metab. 2011 Mar;300(3):E435-44. doi: 10.1152/ajpendo.00398.2010. Epub 2010 Oct 19.
Atrial natriuretic peptide (ANP) levels correlate with hyperglycemia in diabetes mellitus, but ANP effects on pancreatic islet β-cell insulin secretion are controversial. ANP was investigated for short- and long-term effects on insulin secretion and mechanisms regulating secretion in isolated rat pancreatic islets. A 3-h incubation with ANP did not affect basal or glucose-stimulated islet insulin secretion. However, 7-day culture of islets with 5.5 mM glucose and ANP (1 nM - 1 μM) markedly inhibited subsequent glucose (11 mM)-stimulated insulin secretion; total islet insulin content was not affected. Following ANP removal for 24 h, the islet insulin-secretory response to glucose was restored. The insulin-secretory response to other insulin secretagogues, including α-ketoisocaproic acid, forskolin, potassium chloride, and ionomycin were also markedly inhibited by chronic exposure to ANP. However, the combination of potassium chloride and α-ketoisocaproic acid was sufficient to overcome the inhibitory effects of ANP on insulin secretion. The glucose-stimulated increases in islet ATP levels and the ATP/ADP ratio were completely inhibited in ANP 7-day-treated islets vs. control; removal of ANP for 24 h partially restored the glucose response. ANP did not affect islet glycolysis. ANP significantly increased levels of islet activated hormone-sensitive lipase and the expression of uncoupling protein-2 and peroxisome proliferator-activated receptor-δ and -α. Although islet ANP-binding natriuretic peptide receptor-A levels were reduced to 60% of control after 7-day culture with ANP, the ANP-stimulated cGMP levels remained similar to control islet levels. Thus, long-term exposure to ANP inhibits glucose-stimulated insulin secretion and ATP generation in isolated islets.
心房利钠肽（ANP）水平与糖尿病中的高血糖相关，但 ANP 对胰岛β细胞胰岛素分泌的影响仍存在争议。本研究旨在探讨 ANP 对分离的大鼠胰岛胰岛素分泌的短期和长期作用及其调节机制。3 小时的 ANP 孵育并不影响基础或葡萄糖刺激的胰岛胰岛素分泌。然而，7 天用 5.5 mM 葡萄糖和 ANP（1 nM - 1 μM）培养胰岛会显著抑制随后的葡萄糖（11 mM）刺激的胰岛素分泌；胰岛总胰岛素含量不受影响。ANP 去除 24 h 后，胰岛对葡萄糖的胰岛素分泌反应得到恢复。慢性暴露于 ANP 还显著抑制了其他胰岛素分泌激动剂（包括 α-酮异己酸、福司可林、氯化钾和离子霉素）对胰岛素分泌的作用。然而，氯化钾和 α-酮异己酸的组合足以克服 ANP 对胰岛素分泌的抑制作用。与对照组相比，ANP 处理 7 天的胰岛中葡萄糖刺激的胰岛 ATP 水平和 ATP/ADP 比值的增加完全受到抑制；ANP 去除 24 h 后部分恢复了葡萄糖反应。ANP 不影响胰岛糖酵解。ANP 显著增加胰岛激活的激素敏感脂肪酶的水平以及解偶联蛋白-2 和过氧化物酶体增殖物激活受体-δ和-α的表达。尽管 ANP 处理 7 天后胰岛 ANP 结合型利钠肽受体-A 水平降至对照组的 60%，但 ANP 刺激的 cGMP 水平仍与对照组胰岛水平相似。因此，长期暴露于 ANP 会抑制分离胰岛中葡萄糖刺激的胰岛素分泌和 ATP 生成。
