Type 2 Diabetes Mellitus
Conditions
Keywords
insulin resistance, insulin signaling, endothelium-dependent vasodilation
Brief summary
This study will test the hypothesis that reduction in release of free fatty acids from adipocytes will restore insulin-mediated endothelium-dependent vasodilation and skeletal muscle glucose metabolism in subject with type 2 diabetes.
Detailed description
During the past two decades, there has been a steady increase in the incidence of diabetes mellitus, such that nearly 17 million people are now afflicted. The vast majority of these have type 2 diabetes. Over the next 40 years, the type 2 diabetic population in the United States is expected to increase to nearly 30 million. Diabetes substantially increases the risk of atherosclerosis, and thereby, cardiovascular morbidity and mortality. Indeed, cardiovascular disease causes more than 50% of the mortality in patients with diabetes. People with type 2 diabetes manifest two cardinal signs of dysmetabolism: hyperglycemia and insulin resistance. Insulin resistance is a progressive phenomenon that occurs well before the onset of frank diabetes, and results in alterations in insulin signaling. Experimental studies suggest that insulin signaling is required for vascular homeostasis, and its impairment is associated with endothelial dysfunction. In the clinical setting, insulin resistance is associated with atherosclerosis and predicts cardiovascular events independent of hyperglycemia. Therefore, we will study the importance of insulin signaling in endothelial biology in humans and the effects of free fatty acids on endothelial function in people with type 2 diabetes.
Interventions
DRUGacipimox
subjects will receive acipimox 250 mg orally every 6 hours (or matching placebo) for 7 days, including a dose at 6am on the morning of the study testing visit
DRUGplacebo
matching placebo
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* type 2 diabetes mellitus (as defined by the National Diabetes Data Group) * normal cardiovascular exam * non smoker (for 1 year prior to entry) * Healthy volunteers * no known medical problems * normal cardiovascular exam * fasting glucose \< 110 mg/dL * non-smoker (for 1 year prior to entry)
Exclusion criteria
Type 2 Diabetics * untreated hypertension (\>140/90 mmHg) * untreated hypercholesterolemia (LDL \> 75th percentile for age) * cigarette smoking within 1 year * neuropathy requiring medication * nephropathy (\> 300mg/24 hour urinary albumin, or serum creatinine \> 1.4 mg/dL * abnormal cardiovascular exam * treatment with thiazolidinedione within 1 year * post-menopausal women taking hormone replacement therapy (Note: subjects taking angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) must stop these medications for 2 weeks prior to taking study drug. If blood pressure rises to \>140/90, subjects will be prescribed an alternative medication or be withdrawn from the study. Healthy Volunteers * abnormal cardiovascular exam * use of prescription medications * fasting glucose \> 110mg/dL * cigarette smoking within 1 year
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Flow-mediated Dilation After Placebo or Acipimox Treatment Between Healthy Controls and Those With Metabolic Syndrome | 7 days | Flow mediated dilation is calculated as follows: A resting arterial diameter measurement is obtained using the average of 10 EKG-gated ultrasound images. Next, an occlusive pressure is applied (using a blood pressure cuff inflated to a suprasystolic pressure)for a period of 5 minutes. After 5 minutes, the cuff is rapidly deflated. This produces a reactive hyperemic response which is captured via ultrasound at 1 minute post cuff deflation (also 10 EKG-gated images averaged). The diameter of the artery following reactive hyperemia is calculated and compared to the resting diameter to obtain a percent dilation. This is flow-mediated dilation. |
| Difference in Insulin-mediated Skeletal Muscle Glucose Utilization Between Test Agent and Placebo | baseline, 7 days | Insulin sensitivity (M) is measured by using a hyperinsulinaemic-euglycaemic clamp. Insulin sensitivity (M) was calculated as the average glucose infusion rate (mg/kg of body weight per min) over the last 30 min of the clamp. Higher values indicate better outcomes (more insulin sensitive), while lower values indicate more insulin resistance. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Controls | 18 |
| Metabolic Syndrome | 22 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Study Visit Day 2 | Withdrawal by Subject | 1 | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | Metabolic Syndrome | Healthy Controls | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 18 Participants | 40 Participants |
| Age, Continuous | 58.6 years STANDARD_DEVIATION 8.1 | 52.1 years STANDARD_DEVIATION 5.6 | 55.6 years STANDARD_DEVIATION 8.05 |
| Region of Enrollment United States | 22 participants | 18 participants | 40 participants |
| Sex: Female, Male Female | 15 Participants | 12 Participants | 27 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 22 |
| other Total, other adverse events | 0 / 18 | 0 / 22 |
| serious Total, serious adverse events | 0 / 18 | 0 / 22 |
Outcome results
Primary
Difference in Insulin-mediated Skeletal Muscle Glucose Utilization Between Test Agent and Placebo
Insulin sensitivity (M) is measured by using a hyperinsulinaemic-euglycaemic clamp. Insulin sensitivity (M) was calculated as the average glucose infusion rate (mg/kg of body weight per min) over the last 30 min of the clamp. Higher values indicate better outcomes (more insulin sensitive), while lower values indicate more insulin resistance.
Time frame: baseline, 7 days
Population: The data for this outcome measure was lost when the investigator left the institution, so the measure was not analyzed.
Primary
Flow-mediated Dilation After Placebo or Acipimox Treatment Between Healthy Controls and Those With Metabolic Syndrome
Flow mediated dilation is calculated as follows: A resting arterial diameter measurement is obtained using the average of 10 EKG-gated ultrasound images. Next, an occlusive pressure is applied (using a blood pressure cuff inflated to a suprasystolic pressure)for a period of 5 minutes. After 5 minutes, the cuff is rapidly deflated. This produces a reactive hyperemic response which is captured via ultrasound at 1 minute post cuff deflation (also 10 EKG-gated images averaged). The diameter of the artery following reactive hyperemia is calculated and compared to the resting diameter to obtain a percent dilation. This is flow-mediated dilation.
Time frame: 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls, Placebo Treatment | Flow-mediated Dilation After Placebo or Acipimox Treatment Between Healthy Controls and Those With Metabolic Syndrome | 10.65 Flow mediated dilation | Standard Deviation 4.73 |
| Healthy Controls, Acipimox Treatment | Flow-mediated Dilation After Placebo or Acipimox Treatment Between Healthy Controls and Those With Metabolic Syndrome | 11.57 Flow mediated dilation | Standard Deviation 5.72 |
| Metabolic Syndrome, Placebo Treatment | Flow-mediated Dilation After Placebo or Acipimox Treatment Between Healthy Controls and Those With Metabolic Syndrome | 8.79 Flow mediated dilation | Standard Deviation 6.9 |
| Metabolic Syndrome, Acipimox Treatment | Flow-mediated Dilation After Placebo or Acipimox Treatment Between Healthy Controls and Those With Metabolic Syndrome | 9.52 Flow mediated dilation | Standard Deviation 6.38 |