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

Overview

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.

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.