Effects of losartan on mitochondria and prediabetes in rhesus monkeys (Macaca mulatta)

项目摘要 前驱糖尿病是一种与年龄相关的疾病，其中葡萄糖水平不足以诊断 糖尿病是2型糖尿病（T2 D）、心血管疾病和糖尿病并发症的重要危险因素。 疾病、肾病和中风。令人信服的证据支持氧化应激和线粒体 胰岛素抵抗（IR）的发生与胰岛素抵抗（IR）的发生密切相关。激活肾素- 血管紧张素系统（RAS）导致IR和T2 D，部分是通过增加线粒体血管紧张素的产生。 自由基氧（mtROS），可能选择性地损伤线粒体DNA（mtDNA）， 线粒体功能障碍因此，线粒体功能障碍可能在前驱糖尿病的发病中起作用。在 啮齿类动物对RAS的抑制改善了线粒体功能障碍。然而，RAS的分子机制 血管紧张素受体（AT 1）阻断剂对预防人类前驱糖尿病的抑制作用仍然未知。我们 显示氯沙坦显著降低了糖尿病前期恒河猴的胰岛素水平和糖尿病前期小鼠的葡萄糖水平， 健康/非糖尿病猴治疗12个月后。因此，氯沙坦在这两个方面都发挥了有益的作用。 糖尿病前期和健康的中年恒河猴。此外，我们的研究结果表明，健康的中年人 与年轻动物相比，猴子表现出增加的nDNA损伤水平，并且用 洛沙坦显著地将病变数目减少到与年轻动物相似的水平。这些发现表明 氯沙坦逆转衰老对核DNA损伤的影响。我们将检验这一假设， RAS通过刺激胰岛素信号通路和阻止线粒体膜电位的变化来逆转糖尿病前期 损伤和线粒体功能障碍。为了验证我们的假设，我们将使用骨骼肌和脂肪组织 来自中年糖尿病前期恒河猴（Macaca mulatta）。这项研究可能揭示延迟的机制， 或预防IR/T2 D，并将重点关注RAS当前临床应用的潜在范式变化 在T2 D的前驱期早期阻断。

Project Summary Prediabetes is an age-associated condition where glucose levels are not high enough to be diagnosed as diabetes and is an important risk factor for the development of type 2 diabetes (T2D), cardiovascular disease, kidney disease and stroke. Compelling evidence supports that oxidative stress and mitochondrial dysfunction contribute significantly to the development of insulin resistance (IR). Activation of the renin- angiotensin system (RAS) results in IR and T2D in part through the increased production of mitochondrial radical oxygen species (mtROS) that may selectively damage mitochondrial DNA (mtDNA) and increase mitochondrial dysfunction. Thus, mitochondrial dysfunction may play a role in the onset of prediabetes. In rodents inhibition of RAS ameliorates mitochondrial dysfunction. However, the molecular mechanisms of RAS inhibition by angiotensin receptor (AT1) blockers on precluding prediabetes in humans remain unknown. We show that losartan significantly decreases insulin levels in prediabetic rhesus monkeys and glucose levels in healthy/non-diabetic monkeys after 12 months of treatment. Thus, losartan is exerting beneficial effects in both prediabetic and healthy middle-aged rhesus monkeys. In addition, our results show that healthy middle-age monkeys exhibit increased levels of nDNA damage compared with young animals, and that treatment with losartan significantly reduces lesion numbers to levels similar to young animals. These findings suggest that losartan reverses the effects of aging on nuclear DNA damage. We will test the hypothesis that inhibition of RAS reverses prediabetes by stimulating the insulin signaling pathway and by preventing mitochondrial damage and mitochondrial dysfunction. To test our hypothesis we will use skeletal muscle and adipose tissue from middle-age prediabetic rhesus monkeys (Macaca mulatta). This study may uncover mechanisms to delay or prevent IR/T2D and will focus on a potential paradigmatic change in the current clinical application of RAS blockade early in the prodromal phase of T2D.