IR and Microvascular Blood Flow in 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.

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.

Inclusion Criteria:

1. Male or female, age 20 to 69;

2. Chronic (e.g., duration of injury at least 6 months), stable SCI (regardless of level
of neurological lesion);

3. American Spinal Injury Association Impairment Scale (AIS) designation of A or B
(reflects the level of somato-sensory impairment below the neurological level of
injury: AIS A being complete sensory and motor lesion; AIS B being incomplete sensory
and complete motor lesion);

4. Neurologically intact, age-matched control subjects

5. insulin-sensitive group: Si ≥ 2.5 min-1 ∙ mU-1 ∙ L x 104; and

6. insulin resistant group: Si < 2.5 min-1 ∙ mU-1 ∙ L x 104

Exclusion Criteria:

1. Diminished mental capacity;

2. Inability or unwillingness of subject to provide informed consent;

3. Acute illness or infection;

4. Current pharmacological treatment for diabetes mellitus or insulin resistance with
exogenous insulin (or its synthetic dialogues), insulin-sensitizing agents, or agents
that alter pancreatic secretion of insulin;

5. Current pharmacological treatment with sympathomimetic agents demonstrating direct
vascular actions or indirect implications (e.g., alpha-1 agonists, cholinesterase
inhibitors, norepinephrine, calcium channel blockers, angiotensin converting
enzymes);

6. Moderate to high dose glucocorticoid administrations (i.e., ≥ 40mg prednisone or
equivalent steroid dose) within the past 3 months;

7. Atherosclerosis, congestive heart failure, or history of myocardial infarction;

8. Previous diagnosis of diabetes mellitus or insulin resistance; and

9. AIS designation of C, D or E (for SCI subjects only).