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

项目摘要 糖尿病前期是一种年龄相关的疾病，血糖水平不够高，无法诊断 作为糖尿病，是发展为2型糖尿病(T2D)、心血管疾病的重要危险因素 疾病、肾脏疾病和中风。令人信服的证据支持氧化应激和线粒体 功能障碍在胰岛素抵抗(IR)的发生发展中起重要作用。肾素的激活- 血管紧张素系统(RAS)导致IR和T2D的部分原因是通过增加线粒体的生成 自由基氧物种(MtROS)可能选择性地损伤线粒体DNA(MtDNA)并增加 线粒体功能障碍。因此，线粒体功能障碍可能在糖尿病前期的发病中起作用。在……里面 抑制RAS可改善线粒体功能障碍。然而，RAS的分子机制 血管紧张素受体(AT1)阻滞剂对人类糖尿病前期的抑制作用尚不清楚。我们 结果表明，氯沙坦显著降低糖尿病前期恒河猴的胰岛素水平和血糖水平 治疗12个月后，健康/非糖尿病猴子。因此，氯沙坦在这两种情况下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，我们的结果表明，健康的中年人 与幼年动物相比，猴子表现出更高的nDNA损伤水平，而用 氯沙坦显著减少病变数量，达到与幼年动物相似的水平。这些发现表明， 氯沙坦逆转衰老对核DNA损伤的影响。我们将检验这样一种假设，即抑制 RAS通过刺激胰岛素信号通路和阻止线粒体逆转糖尿病前期 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)。这项研究可能会揭示延迟的机制 或预防IR/T2D，并将重点放在当前RAS临床应用的潜在典型性变化上 在T2D的前驱阶段早期阻断。

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.