Free Fatty Acids and Vascular Function in Subjects With Diabetes

The Impact of Free Fatty Acid Reduction on Vascular Function and Skeletal Muscle Glucose Utilization in Type 2 Diabetes Mellitus

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: acipimox; Drug: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; Acipimox treatment for 7 days	Drug: acipimox; 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; Other Names: Olbetam
Placebo Comparator: 2; placebo treatment for 7 days	Drug: placebo; matching placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	7 days
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.	baseline, 7 days

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Mark Creager, M.D., Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: September 8, 2005
• First Submitted That Met QC Criteria: September 8, 2005
• First Posted (Estimate): September 12, 2005

Study Record Updates

• Last Update Posted (Actual): September 25, 2018
• Last Update Submitted That Met QC Criteria: August 26, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: insulin resistance; insulin signaling; endothelium-dependent vasodilation
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Acipimox
• Other Study ID Numbers: 2005P-000088

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No