Glucagon-like Peptide 1 (GLP-1) and Endothelial Dysfunction in Metabolic Syndrome
Condition: Metabolic Syndrome
MeSH terms: Metabolic Syndrome; Syndrome
Study type: Interventional

Summary: 
      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.
    

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.
    

Intervention name(s): GLP-1 infusion
Intervention type(s): Drug
Intervention description(s): Participants will receive intraarterial infusion of GLP-1 (20 pmol/ml solution) for 100 min.
Other intervention name(s): Incretins
Intervention MeSH terms: Incretins
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Keywords: GLP-1; Endothelial Function; Metabolic Syndrome