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

氯沙坦对恒河猴（Macaca mulatta）线粒体和糖尿病前期的影响

基本信息

批准号：
10084237
负责人：
Janice Griselle Lozada Delgado
金额：
$ 4.53万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-15 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084237
关键词：
Adipose tissue Age Aging Angiotensin II Type 1 Receptor Blockers Angiotensin Receptor Attenuated Biogenesis Cardiovascular Diseases Cell membrane DNA Damage DNA copy number Development Diabetes Mellitus Diagnosis Disease Electron Transport Exhibits Functional disorder Genus Hippocampus Glucose Goals Human Impaired fasting glycaemia Insulin Insulin Receptor Insulin Resistance Insulin Signaling Pathway Intervention Kidney Diseases Lesion Longevity Losartan Macaca mulatta Maintenance Measures Membrane Metabolic Diseases Mitochondria Mitochondrial DNA Modeling Molecular Monkeys Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Outcome Oxidative Stress Oxygen Consumption Pathology Pharmacology Phase Phosphorylation Play Prediabetes syndrome Process Production Reactive Oxygen Species Receptor Inhibition Renin-Angiotensin System Risk Factors Rodent Role SLC2A1 gene Serine Skeletal Muscle Stroke Testing Tyrosine Phosphorylation Western Blotting age effect age related clinical application fasting glucose glucose tolerance improved indexing inhibitor/antagonist insulin receptor substrate 1 protein insulin sensitivity insulin signaling intravenous glucose tolerance test juvenile animal middle age mitochondrial dysfunction non-diabetic nonhuman primate novel parkin gene/protein prevent receptor response

项目摘要

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.

项目总结