Impact of Type 1 diabetes on basal and insulin-responsive pan-arterial function

1 型糖尿病对基础和胰岛素反应性全动脉功能的影响

• 批准号: 8714249
• 负责人: Amanda Russell-Kleiner
• 金额: $ 6.19万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-11 至 2016-07-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714249
• 关键词: Adult; Age; Arteries; Atherosclerosis; Biological Markers; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Clinical; Development; Disease; Disease Outcome; Early Intervention; Evaluation; Event; Figs - dietary; Future; Gender; General Population; Goals; Health; Hormones; Hour; Hyperglycemia; Incidence; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Knowledge; Laboratories; Measurement; Measures; Mediating; Metabolic; Modeling; Morbidity - disease rate; Myocardial; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Outcome Study; Pathogenesis; Pathology; Patients; Peripheral Vascular Diseases; Persons; Physiologic pulse; Population; Prevention; Research; Resistance; Risk; Risk Factors; Skeletal Muscle; Stratification; Testing; Therapeutic; Trees; Ultrasonography; Vascular Diseases; Weight; Work; aged; arteriole; basal insulin; base; cardiovascular disorder risk; cardiovascular risk factor; early onset; endothelial dysfunction; experience; glycemic control; improved; indexing; insight; mortality; non-diabetic; public health relevance; skeletal; vascular inflammation; young adult

DESCRIPTION (provided by applicant): Vascular disease is the major cause of morbidity and mortality in persons with Type 1 Diabetes Mellitus (T1DM). T1DM patients experience earlier onset of cardiovascular disease (CVD) by several decades and have a greater CVD mortality rate compared to the general population. Tight glycemic control modestly improves CVD outcomes in this population, but the pathogenesis of accelerated atherosclerosis in T1DM cannot be fully explained by hyperglycemia or typical cardiovascular risk factors. Given the markedly increased CVD risk in T1DM, a greater understanding of vascular dysfunction in T1DM is urgently needed. Metabolic insulin resistance increases CVD risk, and T1DM patients are insulin resistant compared to matched controls. Insulin is a vasoactive hormone and vascular insulin resistance, manifest as impaired vasodilatory effects of insulin on the arterial vasculature, accompanies metabolic insulin resistance in Type 2 Diabetes (T2DM) and obesity. It is unclear whether this similarly occurs in T1DM. Endothelial dysfunction and increased vascular stiffness occur early in the genesis of atherosclerosis and predict CVD risk in obesity, T2DM and peripheral vascular disease. Neither baseline nor post-insulin vascular function has ever been systematically studied across the entirety of the arterial tree (i.e. in conduit arteries resistance arterioles, and arteriolar micro vascular vessels) in T1DM. We hypothesize that baseline and insulin-responsive pan-arterial vascular function is impaired in young adults with T1DM compared to healthy controls. Young adults are targeted as vascular inflammation and abnormal vascular function which contribute to CVD pathogenesis begin early, long before the development of clinical disease. Early intervention may significantly improve outcomes through the identification, prevention, stabilization or reversal of such pathology. This hypothesis will b tested by measurement of conduit artery, resistance arteriolar, skeletal and myocardial micro vascular function in both the basal state and under conditions of a euglycemic insulin clamp in T1DM and aged matched healthy controls. Results from this study will increase our understanding of vascular function in T1DM by determining whether: 1) baseline vascular function is impaired; 2) vascular insulin resistance accompanies metabolic insulin resistance in T1DM (as is found in obesity and T2DM) and is present throughout the arterial tree in young persons with T1DM. The results of this work may facilitate development of a non-invasive "biomarker" of vascular health which can then be used in T1DM to: 1) investigate potential therapies targeting vascular dysfunction; 2) improve cardiovascular risk stratification; and 3) better identify those persons likely to respond to treatment, thereby enabling personalization of therapeutic strategies. These insights are critical steps toward our ultimate goal of improving cardiovascular outcomes in T1DM.

描述(申请人提供)：血管疾病是1型糖尿病(T1 DM)患者发病和死亡的主要原因。与普通人群相比，T1 DM患者心血管疾病(CVD)的发病时间提前了几十年，并且心血管疾病的死亡率更高。严格的血糖控制适度改善了这一人群的心血管疾病预后，但T1 DM动脉粥样硬化加速的发病机制不能完全用高血糖或典型的心血管危险因素解释。鉴于T1 DM患者心血管风险显著增加，迫切需要对T1 DM患者的血管功能障碍有更深入的了解。代谢性胰岛素抵抗会增加心血管疾病的风险，与匹配的对照组相比，T1 DM患者存在胰岛素抵抗。胰岛素是一种血管活性激素和血管胰岛素抵抗，表现为胰岛素对动脉血管的扩张作用受损，在2型糖尿病(T2 DM)和肥胖症中伴随着代谢性胰岛素抵抗。目前还不清楚这种情况是否类似地发生在T1 DM患者中。内皮功能障碍和血管僵硬增加发生在动脉粥样硬化的早期，并预测肥胖、T2 DM和外周血管疾病的心血管风险。在T1 DM患者的整个动脉树(即导管动脉、阻力小动脉和小动脉微血管)中，无论是基线还是胰岛素后的血管功能都没有得到系统的研究。我们假设，与健康对照组相比，患有T1 DM的年轻人的基线和胰岛素反应性泛动脉血管功能受损。年轻人被认为是血管炎症和血管功能异常的靶点，这些因素导致CVD的发病机制早在临床疾病发展之前就开始了。早期干预可以通过识别、预防、稳定或逆转这种病理来显著改善预后。这一假说将通过测量T1 DM和老年匹配的健康对照组在基础状态和正常血糖胰岛素钳夹条件下的导管动脉、阻力微动脉、骨骼和心肌微血管功能来验证。这项研究的结果将增加我们对T1 DM患者血管功能的了解，确定：1)基线血管功能受损；2)血管胰岛素抵抗伴随着T1 DM患者的代谢性胰岛素抵抗(如肥胖和T2 DM患者)，并存在于青年T1 DM患者的整个动脉树中。这项工作的结果可能有助于开发一种非侵入性的血管健康“生物标记物”，然后可用于T1糖尿病：1)研究针对血管功能障碍的潜在疗法；2)改善心血管风险分层；以及3)更好地识别那些可能对治疗有反应的人，从而实现治疗策略的个性化。这些见解是我们朝着改善T1 DM患者心血管结局的最终目标迈出的关键一步。