Insulin Resistance and Microvascular Blood Flow in Spinal Cord Injury

脊髓损伤中的胰岛素抵抗和微血管血流

• 批准号: 9030954
• 负责人: William A Bauman
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9030954
• 关键词: Acetylcholine; Address; Age; Biological Preservation; Blood Vessels; Blood flow; Contralateral; Control Groups; Cutaneous; Decubitus ulcer; Development; Diabetes Mellitus; Dilatation - action; Eligibility Determination; Endothelin-1; Endothelium; Gender; General Population; Glucose; Gold; Hand; Healed; Heating; High Prevalence; Hormones; Hyperinsulinism; Hypertension; Impairment; Individual; Injury; Insulin; Insulin Resistance; Intervention; Iontophoresis; Ipsilateral; Ischemia; Leg; Lesion; Limb structure; Lower Extremity; Matched Group; Measurement; Mediating; Metabolic Diseases; Microvascular Dysfunction; Motor; Muscle Cells; Nervous System Trauma; Neurologic; Nitric Oxide; Outcome; Paraplegia; Participant; Perfusion; Persons; Placebo Control; Placebos; Regulation; Relative (related person); Reporting; Residual state; Risk; Secondary to; Site; Skeletal Muscle; Skin; Spinal cord injury; Sympathetic Nervous System; Up-Regulation; Upper Extremity; Vascular Smooth Muscle; Vasoconstrictor Agents; Vasodilation; Visit; Withdrawal; Work; Wound Healing; arteriole; blood perfusion; demographics; endothelial dysfunction; glucose transport; group intervention; healing; hemodynamics; insight; insulin sensitivity; intravenous glucose tolerance test; medical complication; nerve supply; nervous system disorder; open label; peripheral blood; pressure; public health relevance; response; screening; vasoactive agent; vasoconstriction; vasomotion

Cutaneous microvascular blood flow is regulated by multiple mechanisms, including that by insulin and by the sympathetic nervous system (SNS). Insulin is the principal hormone responsible for the disposal and storage of glucose in skeletal muscle, in part by the re-direction of blood flow through the rhythmic dilatation or contraction of arterioles. In insulin-sensitive individuals, this "vasomotion" is thought to involve the activation of the vascular smooth muscle, with vasodilatation occurring through nitric oxide and vasoconstriction through the SNS and endothelin-1. A tonic upregulation of SNS activity and increased vasoconstrictor action of insulin may be a contributor to the development of hypertension, decreased peripheral blood flow, and endothelial dysfunction in the general population, especially in individuals with hyperinsulinemia and diabetes mellitus. In persons with spinal cord injury (SCI), a disproportionately high prevalence of insulin resistance and diabetes mellitus has been reported. We postulate that insulin resistance, in combination with the added consequence of SNS impairment below the neurological level of injury, contribute to hemodynamic dysregulation and a variety of medical complications, including pressure ulcer formation and decreased wound healing. Recently, our group demonstrated that the sub-lesional blood perfusion response to iontophoresis with insulin is blunted in euinsulinemic persons with motor-complete SCI compared to demographics-matched neurologically-intact control subjects. To confirm and extend our preliminary finding and to provide additional insight into its implications, we propose to perform an open-label, non-randomized, placebo-controlled, parallel-group intervention, observational trial to determine the hemodynamic actions of insulin in individuals with complete motor lower extremity paralysis due to SCI and either systemic insulin sensitivity or insulin resistance. Subjects will participate in a screening visit to determine their eligibility and insulin sensitivity (i.e., categorized as being insulin-sensitive or insulin-resistant). Eligible individuals will return for participation in our study to determine skin blood flow by iontophoresis with vasoactive agents or application of heat to the extremities. Measurements will be performed simultaneously with provocation (i.e., with either heat or insulin or acetylcholine iontophoresis) being performed on the ipsilateral extremity and no provocative intervention (i.e., either no heat or placebo iontophoresis) in parallel and simultaneously on the contralateral extremity. On a separate visit, all subjects will repeat the iontophoresis with acetylcholine, which is the gold-standard to induce endothelium-dependent vasodilatation of the microvasculature. The respective outcomes from iontophoresis with insulin will be compared and correlated to systemic insulin sensitivity (as determined by an intravenous glucose tolerance test with insulin administration) (Primary Aim). The peak microvascular perfusion responses to vasodilatation by iontophoresis with acetylcholine to that with insulin will be compared (Secondary Aim). In participants with SCI , the findings from the neurologically intact upper extremity will be compared to those of the neurologically impaired lower extremity (Tertiary Aim). A group of neurologically-intact subjects who are matched for group assignment (i.e., insulin-sensitive or insulin resistant) will serve as age- and gender-matched controls to the participants with SCI.

皮肤微血管血流受多种机制调节，包括 通过胰岛素和交感神经系统（SNS）。胰岛素是主要激素 负责在骨骼肌中处置和储存葡萄糖，部分是由 血液流过节奏扩张或小动脉的收缩。在胰岛素敏感的中 个人，这种“血管舒张”被认为涉及血管平滑的激活 肌肉，血管舒张通过一氧化氮和血管收缩通过 SNS和内皮素-1。 SNS活性的补品上调和增加血管收缩剂 胰岛素的作用可能是导致高血压发展，周围降低的贡献者 普通人群中的血流和内皮功能障碍，尤其是在个体中 与高胰岛素血症和糖尿病有关。在脊髓损伤的人（SCI）中 胰岛素抵抗和糖尿病的患病率过高 报告。我们假设胰岛素抵抗，结合 SNS损伤低于神经系统损伤水平，导致血流动力学 失调和各种医疗并发症，包括压力溃疡形成和 减少伤口愈合。最近，我们的小组证明了次级血液 胰岛素对离子噬菌体的灌注反应在Euinsulinemic患者中钝化 与人口统计学匹配的神经系统独立对照受试者相比，运动完整的SCI。 确认和扩展我们的初步发现，并提供更多的见解 含义，我们建议执行开放标签，非随机，安慰剂对照， 平行组干预，观察性试验，以确定 由于SCI而患有完全运动下肢瘫痪的个体的胰岛素，要么 全身性胰岛素敏感性或胰岛素抵抗。受试者将参加筛查 确定其资格和胰岛素敏感性（即归类为胰岛素敏感或 抗胰岛素）。符合条件的人将返回参加我们的研究以确定 通过血管活性剂或热量施用热量或将热量应用于 四肢。测量将与挑衅同时​​执行（即 在同侧肢体上进行热或胰岛素或乙酰胆碱离子噬菌体） 没有挑衅性干预（即没有热量或安慰剂离子噬菌体）并联，并且 同时在对侧肢体上。在另一次访问中，所有受试者都会重复 乙酰胆碱的离子噬菌体，这是诱导内皮依赖性的金标准 微脉管系统的血管扩张。 将比较带有胰岛素离子噬菌体的各自的结局，并将其比较 与全身胰岛素敏感性相关（如静脉葡萄糖耐受性确定 用胰岛素给药测试（主要目的）。峰值微血管灌注反应 将与乙酰胆碱与胰岛素进行离子噬菌体的血管舒张 （次要目标）。在SCI的参与者中，来自神经系统完整的鞋面的发现 将肢体与神经学障碍的下肢相比（第三级 目的）。一组与小组分配相匹配的神经独立受试者（即 胰岛素敏感或胰岛素耐药）将作为年龄和性别匹配的对照 SCI的参与者。