Glucagon-like Peptide 1 (GLP-1) and Endothelial Dysfunction in Metabolic Syndrome

This study has been completed.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Manfredi Tesauro, University of Rome Tor Vergata
ClinicalTrials.gov Identifier:
NCT00856700
First received: March 5, 2009
Last updated: December 10, 2013
Last verified: December 2013
  Purpose

Glucagon-like peptide 1 (GLP-1) is an intestinal peptide hormone secreted in a nutrient-dependent manner that stimulates the pancreatic beta cells to secrete more insulin in response to the same amount of blood glucose. In patients with Type 2 diabetes, GLP-1 secretion is lower than normal, thus suggesting that the hormone may contribute to the pathogenesis of the disease. Whether infusion of GLP-1 affects endothelial function and glucose uptake in humans has never been investigated. In the current proposal, the investigators hypothesize that GLP-1 administration might ameliorate endothelial dysfunction in patients with metabolic syndrome. To test this hypothesis, the investigators will evaluate the acute effects of GLP-1 in the forearm circulation of patients with metabolic syndrome during local hyperinsulinemia by use of the forearm perfusion technique.


Condition Intervention
Metabolic Syndrome
Drug: GLP-1 infusion

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Official Title: Effect of GLP-1 on Endothelial Function and Glucose Uptake in Patients With Metabolic Syndrome

Resource links provided by NLM:


Further study details as provided by University of Rome Tor Vergata:

Primary Outcome Measures:
  • Endothelium-dependent vasodilation capacity [ Time Frame: 60 minutes ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Insulin-mediated glucose uptake [ Time Frame: 100 minutes ] [ Designated as safety issue: Yes ]

Enrollment: 20
Study Start Date: November 2008
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GLP-1 infusion
Patients with metabolic syndrome
Drug: GLP-1 infusion
Participants will receive intraarterial infusion of GLP-1 (20 pmol/ml solution) for 100 min.
Other Name: Incretins

Detailed Description:

Subjects meeting the entrance criteria will be studied in a quiet room with a temperature of approximately 22°C. While the participants are supine, a 20-gauge Teflon catheter will be inserted into the brachial artery of the nondominant arm under local anesthesia. This arm will be slightly elevated above the level of the heart, and a mercury-filled Silastic strain gauge will be placed on the widest part of the forearm. The strain gauge will be connected to a plethysmography calibrated to measure the percent change in volume; the plethysmograph in turn will be connected to a chart recorder to record the forearm flow measurements. For each measurement, a cuff placed on the upper arm will be inflated to 40 mmHg with a rapid cuff inflator to occlude venous outflow from the extremity. A wrist cuff will be inflated to suprasystolic pressures l min before each measurement to exclude the hand circulation. Flow measurements will be recorded for approximately 7 seconds every 15 seconds; 7 readings will be obtained for each value.

The intraarterial catheter will be connected by a 3-way stopcock to both a pressure transducer (to measure intraarterial blood pressure) and an infusion pump. Saline or drugs then will be infused at the rate of 0.5-1ml per minute. Another 20-gauge Teflon catheter will be inserted in a homolateral antecubital vein for blood sampling.

To assess the effects of GLP-1 on insulin stimulated vasodilation, after the forearm will be instrumented, patients with metabolic syndrome will receive intraarterial infusion of saline for 15 minutes; blood samples will be collected and baseline flow will be measured. Then infusion of regular insulin (Humulin, Eli Lilly, Indianapolis, IN; 0.1 mU per kg of body weight per minute) will be started. Next, forearm blood flow will be measured after infusion of Ach, a vasodilator whose effect is predominantly related to nitric oxide (NO), and sodium nitroprusside (SNP), an exogenous NO donor.

After 20 min of insulin infusion, another baseline measurement will be obtained and continuous intraarterial infusion of GLP-1 will be started at 20 pmol/min infusion rate. This dose has been chosen in order to achieve intravascular GLP-1 concentrations within the infused forearm in a range (approximately 0.50 pmol/mL) previously shown effective to improve insulin sensitivity. GLP-1 infusion will be continued for 60 minutes, and forearm blood flow will be measured every 30 minutes; venous blood samples will be obtained at the end of this infusion period. Then, while maintaining GLP-1 infusion unchanged, dose-response curves to ACh and SNP will be repeated, at the same doses and following the same protocol as before.

  Eligibility

Ages Eligible for Study:   20 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Otherwise healthy individuals aged between 20 and 60 years
  • Must satisfy 3 out of the 5 listed criteria for the diagnosis of the metabolic syndrome (ATP III) will be included

Exclusion Criteria:

  • Pregnancy
  • Liver disease
  • Pulmonary disease
  • Renal insufficiency
  • Coronary heart disease
  • Heart failure
  • Peripheral vascular disease
  • Coagulopathy
  • Any disease predisposing to vasculitis or Raynaud's phenomenon
  • Bleeding disorders
  • Kidney stones
  • Platelet count < 150,000/ml blood
  • Prothrombin time/partial thromboplastin time (PT/PTT) > 1 second above the normal range, and positive tests for HIV, or hepatitis B or C
  • Subjects who are taking any kind of medication will not be included in this study; therefore, antihypertensive and/or lipid-lowering drugs will be discontinued at least 2 weeks before enrollment into this study
  • All subjects will be told to refrain from alcohol, beverages containing caffeine, or smoking for at least 24 hours before the study is performed
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00856700

Locations
Italy
Tor Vergata University
Rome, Italy, 90100
Sponsors and Collaborators
University of Rome Tor Vergata
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Manfredi Tesauro, MD Internal Medicine Department, Tor Vergata University, Rome
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Manfredi Tesauro, Associate Professor of Internal Medicine, University of Rome Tor Vergata
ClinicalTrials.gov Identifier: NCT00856700     History of Changes
Other Study ID Numbers: 144/08
Study First Received: March 5, 2009
Last Updated: December 10, 2013
Health Authority: Italy: Ethics Committee

Keywords provided by University of Rome Tor Vergata:
GLP-1
Endothelial Function
Metabolic Syndrome

Additional relevant MeSH terms:
Metabolic Syndrome X
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Glucagon-Like Peptide 1
Glucagon
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Gastrointestinal Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 14, 2014