IR and Microvascular Blood Flow in SCI
Condition: Spinal Cord Injury; Insulin Resistance
MeSH terms: Spinal Cord Injuries; Insulin Resistance
Study type: Interventional

Summary: 
      Persons with spinal cord injury (SCI) are at an increased risk for metabolic disorders,
      including that of insulin resistance. As a result of neurological injury, they often have
      impaired mechanisms that regulate blood vessel function below the level of injury. Insulin,
      which facilitates the transport of glucose into muscle cells, is also capable of regulating
      skin blood flow, with insulin resistance reducing perfusion. Although beyond the scope of
      this proposal, the possibility exists that impaired microvascular skin blood flow responses
      due to insulin may further predispose to ischemia of the skin at pressure points of bony
      prominence. This perturbed cutaneous vascular response may place persons with SCI at risk for
      the development and poor healing of pressure ulcers due to microvascular dysfunction
      secondary to neurologic and metabolic disorders.

      Primary Aim: To determine the association between systemic insulin sensitivity and
      insulin-mediated vasodilatation below the neurological level of injury.

      We hypothesize that individuals with systemic insulin sensitivity compared to those with
      insulin resistance will have greater insulin-mediated vasodilatation and an associated
      proportional increase in cutaneous blood perfusion. Thus, intact and appropriate
      endothelial-mediated regulation by insulin will be operative despite sub-lesional
      neurological impairment in insulin sensitive individuals with SCI. However, because of the
      absence of the SNS-mediated insulin action on the microvasculature (i.e., insulin-mediated
      sympathetic withdrawal), it is being hypothesized that the vasodilatory response to
      iontophoresis with insulin in insulin sensitive subjects with SCI will be less than that
      observed in neurologically intact controls with insulin sensitivity.

      Secondary Aim: To compare peak microvascular perfusion responses to endothelial-dependent
      vasodilatation by iontophoresis with acetylcholine to insulin.

      We hypothesize that the peak blood perfusion responses to iontophoresis with insulin will be
      comparable in magnitude to that of acetylcholine in individuals with greater systemic insulin
      sensitivity. This will be in contrast to individuals with systemic insulin resistance who
      will demonstrate a diminished response to iontophoresis with insulin when compared to that of
      acetylcholine. Because of SNS impairment, the peak vasodilatory response observed to these
      interventions will be lower in the group with SCI.
    

Detailed description: 
      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.

      After screening, subjects will participate in 2 study visits where the iontophoresis (i.e.,
      placebo, insulin, and acetylcholine) and heat provocation will be performed one time on the
      upper and one time on the lower extremity. Each study visit will take no more than 4 hours.
      The expected enrollment time for a participant to complete the study should be no more than 3
      weeks.

      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.
    

Intervention name(s): Insulin iontophoresis; Placebo Iontophoresis; Acetylcholine Iontophoresis; Heat application
Intervention type(s): Drug; Drug; Drug; Other
Intervention description(s): For insulin iontophoresis, the cathode electrode will contain 0.2 ml of liquid insulin. For preparation and instrumentation, the arms will be uncovered below the elbow; the participant's lower extremities will be uncovered below knee for leg evaluations. The laser Doppler flowmetry (LDF) lead will be placed bilaterally, 2 inches proximal to the lateral malleolus over the peroneus longus muscle. For arm evaluations, a lead will be placed (and secured with dual-sided transparent tape) bilaterally, 2 inches distal to the lateral epicondyle over the flexor carpi ulnaris muscle along the midline with the ulnar process. Baseline and peak cutaneous blood flow responses to application of insulin iontophoresis will be determined for each LDF lead during the evaluation.; For placebo iontophoresis, the cathode electrode will contain 0.2 ml of preservative-free normal saline; the anode electrode will contain a medical grade adhesive for skin placement and last 20 minutes. Preparation, instrumentation and data collection for this intervention are the same as the insulin iontophoresis.; For acetylcholine iontophoresis, the anode electrode will contain 0.2 ml of 1% acetylcholine chloride; the cathode electrode will contain a medical grade adhesive for skin placement and last 20 minutes. Preparation, instrumentation and data collection for this intervention are the same as the insulin iontophoresis.; For the provocation with heat, an insulated thermal heat pack (~106°F) will be applied to the exposed arm or leg for 18 minutes. The thermal heat pack is comparable to what is routinely used as a heat therapy in conventional rehabilitation settings. LDF leads and temperature sensors will be placed in the previously specified locations to evaluate the changes.
Intervention MeSH terms: Acetylcholine
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Insulin Sensitivity; Microvascular permeability; Sympathetic nervous system