Increased responsiveness to the hyperglycemic, hyperglucagonemic and hyperinsulinemic effects of circulating norepinephrine in ob/ob mice
Increased responsiveness to the hyperglycemic, hyperglucagonemic and hyperinsulinemic effects of circulating norepinephrine in ob/ob mice
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DOI：
10.1038/sj.ijo.0801614
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发表时间：
2001-05-01
影响因子：
4.9
通讯作者：
Cincotta, AH
中科院分区：
文献类型：
--
作者：
Liang, Y;Cincotta, AH
目的：多项研究表明交感神经张力增加是 ob/ob 小鼠高血糖和高胰高血糖素血症的一个促成因素。然而，与正常瘦小鼠相比，ob/ob 小鼠血浆葡萄糖、胰岛素和胰高血糖素对循环去甲肾上腺素 (NE) 的反应性从未被描述过。因此，本研究调查了 15 分钟静脉内 NE 输注 (1 pmol/min/g) 对麻醉瘦小鼠、ob/ob、ob/ob 并发育亨宾（α (2) 拮抗剂）治疗和 ob/ob 慢性交感神经多巴胺激动剂治疗（输注前 14 天）小鼠的血浆葡萄糖、胰岛素和胰高血糖素的影响。为了深入了解 ob/ob 小鼠去甲肾上腺素、高胰高血糖素血症和高胰岛素血症之间可能的关系，本研究还检查了瘦小鼠、ob/ob 和 ob/ob 交感神经多巴胺激动剂治疗小鼠中分离的胰岛对 NE 和胰高血糖素的反应。 结果：与瘦小鼠相比，ob/ob 的葡萄糖、胰岛素和胰高血糖素基础体液值均升高（分别升高 63、1900 和分别为 63%，P < 0.01）。然而，NE输注进一步增加了ob/ob中的葡萄糖、胰岛素和胰高血糖素水平（分别增加80%、90%和60%，P<0.05），但在瘦小鼠中则没有（所有参数的组间差异P<0.05）。急性同时育亨宾治疗以及慢性先前的交感多巴胺激动剂治疗（溴隐亭加SKF38393）同时强烈地消除或消除了ob/ob小鼠中对静脉注射NE的所有这些体液超敏反应（P <0.05）。将未经治疗的 ob/ob 小鼠的血浆葡萄糖水平限制在通过 NE 输注建立的高水平 (30 mM) 并没有显着改变血浆胰岛素水平，这表明 NE 的其他一些影响是造成这种胰岛素效应的原因。向瘦小鼠和 ob/ob 小鼠的胰岛直接施用 1 μM NE 可以抑制两组中 15 mM 葡萄糖刺激的胰岛素分泌，但 0.1 μM 的 NE 仅在 ob/ob 小鼠的胰岛中具有抑制作用。然而，胰高血糖素 (10 nM) 增加了 ob/ob 小鼠中 15 mM 葡萄糖刺激的胰岛素分泌（增加 170%，P < 0.05），但对瘦小鼠没有增加（组间差异 P < 0.05）。结论：这些发现表明，对循环 NE 的过敏可能会加剧 ob/ob 小鼠的高血糖和高胰高血糖素血症，以及随后的高胰高血糖素血症与胰岛 β 细胞胰岛素分泌增加相结合。 ob/ob 小鼠对胰高血糖素的反应可能支持高胰岛素血症，从而解释了这些动物对静脉注射 NE 的血浆胰岛素水平反应增加。这些发现进一步支持外周去甲肾上腺素能活性增加在高血糖、高胰高血糖素和高胰岛素状态（2型糖尿病的特征）的发展和维持中的作用。
OBJECTIVE: Several studies have implicated increased sympathetic tone as a contributing factor to the hyperglycemia and hyperglucagonemia of ob/ob mice. However, the responsiveness of plasma glucose, insulin and glucagon to circulating norepinephrine (NE) in ob/ob vs normal lean mice has never been described. Therefore, the present study investigated the effect of a 15 min intravenous NE infusion (1 pmol/min/g) on plasma glucose, insulin and glucagon in anesthetized lean, ob/ob, ob/ob-concurrent yohimbine (alpha (2) antagonist) treated, and ob/ob-chronically sympatholytic dopamine agonist treated (for 14 days prior to infusion) mice. In an effort to gain insight into a possible relation between norepinephrine, hyperglucagonemia and hyperinsulinemia in ob/ob mice, this study also examined the isolated islet responses to NE and glucagon in lean, ob/ob and ob/ob-sympatholytic dopamine agonist treated mice.RESULTS: Basal humoral values of glucose, insulin and glucagon were all elevated in ob/ob vs lean mice (by 63, 1900 and 63%, respectively, P < 0.01). However, NE infusion further increased levels of glucose, insulin and glucagon in ob/ob (by 80, 90 and 60%, respectively, P < 0.05) but not in lean mice (between group difference for all parameters P < 0.05). Acute concurrent yohimbine treatment as well as chronic prior sympatholytic dopamine agonist treatment (bromocriptine plus SKF38393) simultaneously strongly aborgated or abolished all these humoral hypersensitivity responses to intravenous NE in ob/ob mice (P < 0.05). Clamping the plasma glucose level in untreated ob/ob mice at a high level (30 mM) established by NE infusion did not significantly alter the plasma insulin level, suggesting that some other influence of NE was responsible for this insulin effect. Direct NE administration at 1 muM to islets from lean and ob/ob mice inhibited 15 mM glucose-stimulated insulin secretion in both groups, but at 0.1 muM it was inhibitory only in islets from ob/ob mice. However, glucagon (10 nM) increased 15 mM glucose-stimulated insulin secretion in ob/ob (by 170%, P < 0.05) but not lean mice (between group difference P < 0.05).CONCLUSION: These findings suggest that hypersensitivity to circulating NE may potentiate hyperglycemia and hyperglucagonemia in ob/ob mice, and the subsequent hyperglucagonemia coupled with increased islet beta -cell insulin secretory responsiveness to glucagon in ob/ob mice may support hyperinsulinemia, thus explaining the increased plasma insulin level response to intravenous NE in these animals. These findings further support a role for increased peripheral noradrenergic activities in the development and maintenance of the hyperglycemic, hyperglucagonemic and hyperinsulinemic state, characteristic of type 2 diabetes.