Insulin Resistance and Microvascular Blood Flow in Spinal Cord Injury

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）。胰岛素是主要的激素 负责处理和储存骨骼肌中的葡萄糖，部分由重定向 指血流通过小动脉有节奏的扩张或收缩。胰岛素敏感性 在个体中，这种“血管舒缩”被认为涉及血管平滑肌的激活， 肌肉，血管舒张通过一氧化氮发生，血管收缩通过 SNS和内皮素-1。紧张性上调SNS活性和增加血管收缩剂 胰岛素的作用可能是导致高血压、外周血白细胞减少、 血流和内皮功能障碍，尤其是在个体中 患有高胰岛素血症和糖尿病脊髓损伤（SCI）患者， 胰岛素抵抗和糖尿病的发病率高得不成比例， 报道我们假设，胰岛素抵抗，结合额外的后果， SNS损伤低于神经水平损伤，有助于血流动力学 失调和各种医学并发症，包括压力性溃疡的形成， 减少伤口愈合。最近，我们的研究小组证明， 在正常胰岛素血症患者中， 与人口统计学匹配的神经系统完整的对照受试者相比，运动完全性SCI。 为了证实和扩展我们的初步发现，并提供更多的见解， 影响，我们建议进行一项开放标签、非随机、安慰剂对照， 平行组干预，观察性试验，以确定 胰岛素在SCI所致下肢运动性完全瘫痪患者中的作用， 全身胰岛素敏感性或胰岛素抵抗。受试者将参加筛选访视， 确定他们的资格和胰岛素敏感性（即，被归类为胰岛素敏感或 胰岛素抗性）。符合条件的个人将返回参与我们的研究，以确定 通过用血管活性剂的离子电渗疗法或对皮肤施加热来促进皮肤血流 四肢测量将与激发同时进行（即，用 热或胰岛素或乙酰胆碱离子电渗疗法）， 没有挑衅性干预（即，无加热或安慰剂离子电渗疗法）， 同时在对侧肢体上。在单独访视时，所有受试者将重复 用乙酰胆碱进行离子电渗，这是诱导内皮依赖性 微血管的血管舒张。 将比较使用胰岛素的离子电渗疗法的相应结果， 与全身胰岛素敏感性相关（通过静脉内葡萄糖耐量测定 胰岛素试验）（主要目的）。微血管灌注反应峰值 将比较乙酰胆碱离子电渗与胰岛素离子电渗对血管舒张的影响 （次要目标）。在SCI参与者中，来自神经系统完整的上皮层的发现， 肢体将与神经功能受损的下肢（第三下肢）进行比较 Aim）。一组神经系统完整的受试者，他们在分组时匹配（即， 胰岛素敏感或胰岛素抵抗）将作为年龄和性别匹配的对照， 参加SCI。

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.