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首页> 外文期刊>Endocrinology >Up-regulating the heme oxygenase system with hemin improves insulin sensitivity and glucose metabolism in adult spontaneously hypertensive rats.
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Up-regulating the heme oxygenase system with hemin improves insulin sensitivity and glucose metabolism in adult spontaneously hypertensive rats.

机译：用血红素上调血红素加氧酶系统可改善成年自发性高血压大鼠的胰岛素敏感性和葡萄糖代谢。

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摘要

Accumulating clinical evidence indicates that impaired glucose tolerance is a common phenomenon in essential hypertension. Although recent evidence underscores the role of heme-oxygenase (HO) in diabetes, its effects on insulin sensitivity and glucose metabolism in spontaneously hypertensive rat (SHR), a model of essential hypertension with characteristics of metabolic syndrome including insulin resistance/impaired glucose metabolism remains largely unclear. Here we report the effects of the HO inducer, hemin, and the HO blocker, chromium-mesoporphyrin on insulin sensitivity and glucose metabolism in SHRs. Adult SHRs were severely hypertensive but normoglycemic. Hemin therapy lowered blood pressure, increased plasma insulin, decreased glycemia, and enhanced insulin sensitivity by improving glucose tolerance (ip glucose tolerance test) and insulin tolerance (ip insulin tolerance test) but reduced insulin resistance (homeostasis model assessment index). These effects were accompanied by increased gastrocnemius muscle HO-1, HO activity, cGMP, cAMP alongside antioxidants including bilirubin, ferritin, superoxide dismutase, catalase, and the total antioxidant capacity, whereas oxidative/inflammatory mediators like 8-isoprostane, nuclear-factor-kappaB, activating-protein-1, activating-protein-2, c-Jun-NH2-terminal-kinase, and heme were abated. Furthermore, hemin reduced proteinuria/albuminuria and enhanced the depressed levels of adiponectin, AMP-activated protein-kinase, and glucose transporter-4 in SHRs, suggesting that although SHRs are normoglycemic, insulin signaling and renal function may be impaired. Contrarily, the HO inhibitor chromium-mesoporphyrin exacerbated oxidative stress, aggravated insulin resistance, glucose tolerance, insulin tolerance and nephropathy. Hemin also enhanced HO signaling in Wistar Kyoto and Sprague Dawley rats and increased insulin sensitivity albeit less intensely than in SHRs, suggesting greater selectivity of HO in SHRs with dysfunctional insulin signaling. These results suggest that perturbations of insulin signaling may be a forerunner to hyperglycemia in essential hypertension. By concomitantly potentiating insulin-sensitizing agents, suppressing insulin/glucose intolerance, and abating oxidative stress, HO inducers may prevent metabolic and cardiovascular complications in essential hypertension.
机译：越来越多的临床证据表明，糖耐量降低是原发性高血压的常见现象。尽管最近的证据强调了血红素加氧酶（HO）在糖尿病中的作用，但它对自发性高血压大鼠（SHR）的胰岛素敏感性和葡萄糖代谢的影响，这是一种具有包括胰岛素抵抗/受损的糖代谢在内的代谢综合征特征的原发性高血压模型在很大程度上不清楚。在这里，我们报告了HO诱导剂，血红素和HO阻断剂铬-中卟啉对SHR中胰岛素敏感性和葡萄糖代谢的影响。成人SHR严重高血压，但血糖正常。 Hemin治疗通过改善葡萄糖耐量（ip葡萄糖耐量试验）和胰岛素耐受性（ip胰岛素耐量试验）来降低血压，增加血浆胰岛素，降低血糖并增强胰岛素敏感性，但降低了胰岛素抵抗（体内稳态模型评估指标）。这些影响伴随着腓肠肌HO-1，HO活性，cGMP，cAMP的增加以及抗氧化剂包括胆红素，铁蛋白，超氧化物歧化酶，过氧化氢酶和总抗氧化剂的能力，而氧化/炎症介质如8-异前列腺素，核因子-减少了kappaB，活化蛋白1，活化蛋白2，c-Jun-NH2-末端激酶和血红素。此外，血红素降低了SHR中的蛋白尿/白蛋白尿并增加了脂联素，AMP激活的蛋白激酶和葡萄糖转运蛋白4的降低水平，这表明尽管SHR是正常血糖的，但胰岛素信号传导和肾功能可能受损。相反，HO抑制剂铬-美卟啉加重了氧化应激，加剧了胰岛素抵抗，葡萄糖耐量，胰岛素抵抗和肾病。与SHRs相比，Hemin还增强了Wistar Kyoto和Sprague Dawley大鼠的HO信号传导，并增加了胰岛素敏感性，但提示胰岛素在功能异常的SHRs中HO选择性更高。这些结果表明，胰岛素信号的微扰可能是原发性高血压中高血糖的先兆。通过同时增强胰岛素增敏剂，抑制胰岛素/葡萄糖耐受不良和减轻氧化应激，HO诱导剂可预防原发性高血压的代谢和心血管并发症。

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