Metformin for Preventing Frailty in High Risk Older Adults

二甲双胍预防高危老年人的衰弱

• 批准号: 10598726
• 负责人: Sara Elyse Espinoza
• 金额: $ 38.7万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598726
• 关键词: Acceleration; Adult; Aging; Anti-Inflammatory Agents; Antidiabetic Drugs; Applications Grants; Cessation of life; Chronic; Clinical; Communities; Data; Defect; Development; Diabetes Mellitus; Economics; Elderly; Etiology; Glucose Intolerance; Goals; Growth; Health; Health Care Costs; Healthcare; Hospitalization; Incidence; Inflammation; Institutionalization; Insulin Resistance; Intervention; Link; Metformin; Molecular; Older Population; Outcome; Pathogenesis; Patients; Pharmacology; Physiological; Plasma; Play; Population; Prediabetes syndrome; Prevention; Property; Research; Risk; Risk Factors; Signal Transduction; Societies; Sterility; Sulfonylurea Compounds; Syndrome; Testing; Veterans; adverse outcome; aging population; base; cost; disability; falls; frailty; high risk; inflammatory marker; insulin sensitizing drugs; insulin signaling; novel; prevent

ABSTRACT Frailty is a geriatric syndrome which leads to poor health outcomes in older adults, such as falls, disability, hospitalization, institutionalization, and death. Due to the dramatic growth in the U.S. aging population and the health care costs associated with frailty (estimated at more than $18 billion per year), frailty is a major health care problem. There has been little research into potential pharmacologic interventions that would delay or reduce the incidence of frailty. Thus, the major goal of this study is to test metformin as a novel intervention for the prevention of frailty. We propose that diabetes/insulin resistance and inflammation are major contributors to frailty, and that the use of metformin to modulate diabetes/insulin resistance and inflammation will prevent and/or ameliorate the progression of frailty. The rationale for testing metformin for frailty prevention is based on the following: 1) Insulin resistance has been linked to the pathogenesis of frailty and our own research shows that diabetes is a significant predictor of frailty onset or worsening in community-dwelling older adults; 2) Several studies have shown that frail older subjects (compared with non-frail) are under a state of chronic low grade “sterile” inflammation, as evidenced by increase plasma concentration of inflammatory markers; 3) In addition to frailty, inflammation also plays a key role in the pathogenesis of insulin resistance; 4) Metformin has both insulin sensitizing and anti-inflammatory properties, and; 5) Our analyzed clinical administrative data from 2,415 adult veterans with diabetes shows that those who were taking metformin as monotherapy were at 34% reduced risk of becoming frail compared to patients taking sulfonylureas. We hypothesize that metformin will lead to reduced inflammation and insulin resistance present in older glucose-intolerant subjects and that these changes will consequently prevent the onset and/or progression of frailty in this sub-population of older adults. We propose to study glucose intolerant subjects, a population which encompasses approximately one-third of older adults, and is most likely to benefit from metformin. To our knowledge, this research will be the first to study a potential intervention targeted toward a central mechanism involved in the etiology of frailty. We will also assess potential molecular mechanisms (insulin signaling, AMPK signaling, etc.) as potential cellular defects in frailty that are alleviated by metformin. Because of the enormous costs associated with frailty (both personal and economic), a treatment that prevents or delays frailty, even in a sub-population of older adults, would have a major positive impact in our society.

抽象的 衰弱是一种老年综合症，会导致老年人健康状况不佳，例如跌倒、残疾、 由于美国人口老龄化和死亡人数急剧增长。 与虚弱相关的医疗保健费用（估计每年超过 180 亿美元），虚弱是一个主要的健康问题 对于可能延迟或延迟的潜在药物干预措施的研究很少。 因此，本研究的主要目标是测试二甲双胍作为一种新的干预措施。 我们认为糖尿病/胰岛素抵抗和炎症是导致虚弱的主要原因。 虚弱，并且使用二甲双胍来调节糖尿病/胰岛素抵抗和炎症将预防 和/或改善虚弱的进展。 测试二甲双胍预防衰弱的基本原理如下： 1) 胰岛素抵抗与虚弱的发病机制有关，我们自己的研究表明 糖尿病是社区老年人衰弱发作或恶化的重要预测因素； 2）多项研究表明，体弱的老年受试者（与非体弱者相比）处于慢性状态 低度“无菌”炎症，如炎症血浆浓度增加所证明 标记； 3）除了体弱，炎症在胰岛素抵抗的发病机制中也起着关键作用； 4) 二甲双胍具有胰岛素增敏和抗炎特性； 5) 我们分析了 2,415 名患有糖尿病的成年退伍军人的临床管理数据，结果显示， 服用二甲双胍作为单一疗法的患者与患者相比，变得虚弱的风险降低了 34% 服用磺脲类药物。 我们认为二甲双胍将导致减少炎症和胰岛素抵抗 老年葡萄糖不耐受受试者，这些变化将因此预防其发作和/或 这一老年人亚群的衰弱进展。 我们建议研究葡萄糖不耐症受试者，该人群约占三分之一 据我们所知，这项研究将是第一个针对老年人的研究。 我们将研究针对与虚弱病因有关的中心机制的潜在干预措施。 还评估潜在的分子机制（胰岛素信号、AMPK 信号等）作为潜在的细胞 由于与虚弱相关的巨大成本（两者），二甲双胍可以缓解虚弱的缺陷。 个人和经济），一种可以预防或延缓衰弱的治疗方法，即使是在老年人的亚人群中， 将对我们的社会产生重大的积极影响。