Exenatide (Byetta ®) Regulation of Intestinal and Hepatic Lipoprotein Particle Production in Humans
Condition: Hyperlipidemia
MeSH terms: Hyperlipidemias
Study type: Interventional

Summary: 
      Exenatide acutely inhibits intestinal lipoprotein particle production. We are unable to
      speculate whether exenatide affects hepatic lipoprotein production in humans since there is
      currently no evidence from animal models or in vitro studies that have demonstrated an effect
    

Detailed description: 
      Subjects will receive an infusion of stable isotope enriched acetate, leucine and a bolus of
      glycerol in order to measure the rates of fatty acid synthesis, apolipoprotein and
      triglyceride turnover respectively. This in vivo stable isotope enrichment methodology has
      been widely established and used by investigators around the world for more than 30 years to
      examine the metabolism of various metabolites in humans.

      Following an overnight fast, at approximately 9am on day 1 of the study the subject will be
      admitted to hospital and will have a 30ml fasting blood sample drawn for analysis of plasma
      glucose, total plasma cholesterol, LDL-cholesterol, HDL cholesterol, triglycerides (TG), free
      fatty acids (FFA), insulin, GLP-1, growth hormone, glucagon, stable isotope enrichment and a
      more detailed analysis of triglyceride rich lipoprotein (TRL) composition (lipid and
      apolipoprotein content). A radio-opaque polyvinyl feeding tube (Entriflex NG Tube 55''
      [140cm] 10fr Item # 8884721055, Kendall Products, Tyco Healthcare, Toronto, ON) will be
      inserted through the nose into the stomach, with enough length provided for migration of the
      tip into the duodenum. The subject will be administered 10 mg metoclopramide orally to
      facilitate transport of the tip of the tube into the duodenum. The subject will be allowed to
      eat regular meals during the day but will fast overnight after 7pm and will remain fasting
      for the duration of the study. Water ad lib will be allowed. At approximately 3pm on day 1 an
      abdominal X-Ray will confirm the position of the tube in the duodenum. At 4pm 2 iv's will be
      inserted into a superficial vein in each forearm, one for infusion and one for sampling. An
      infusion of 1-13C acetate (15 gm in a bag of ½ N saline at 32ml/hr) will begin after the iv's
      have been inserted and will be infused for the remainder of the study, which is 27 hours.

      Starting at 4am a synthetic triglyceride emulsion, Intralipid (20% solution, Baxter Canada) ,
      will be infused through the feeding tube into the duodenum at a rate of 40 ml/hr for the
      duration of the experiment (ie until 7pm that evening). This will provide a steady state fed
      state for the subsequent assessment of lipoprotein turnover kinetics.

      The subjects will receive, in random order, either exenatide 10 mg or equivalent volume of
      saline subcutaneously at 7am on day 2 of the hospitalization (i.e. at -2hr) during the first
      of the two studies. The pancreatic clamp will begin at 7am (-2hr), immediately following
      administration of either exenatide or saline and continue throughout the subsequent 12 hours
      (until 7pm). . During the pancreatic clamp the subjects will receive an iv infusion of
      glucagon (0.65ng/kg/min), growth hormone (Humatrope, 3.0 ng/kg/min), somatostatin
      (sandostatin, 25 µg/hr) and insulin (Novolin R, 0.05 mU/kg/min).

      At 9 am (we will refer to this time point as 0hr of the lipoprotein turnover study), the
      lipoprotein turnover study will begin. An iv bolus of deuterated-glycerol (d5-glycerol, 75
      mmol/kg) will be administered, followed by a primed-constant infusion of deuterated leucine;
      d3-leucine, (10 mmol/kg bolus followed by 10 mmol/kg/hr for 10 hours). Blood samples will be
      collected prior to and at regular time intervals for 10 hours after the iv bolus of
      d3-glycerol and start of the constant infusion of d3-leucine (for assessment of lipoprotein
      kinetics). Blood samples will be collected prior to (30ml at -2hr, 10ml at -1hr and 30ml at
      0hr) and 5min and 15min (10ml each) and then 30ml each at 30min, 1hr, 2hr, 3hr, 4hr, 5hr, 6hr
      (only 10ml),7hr, 8hr, 9hr and 10hr after administration of d5-glycerol and start of
      d3-leucine infusion.
    

Intervention name(s): exenatide
Intervention type(s): Drug
Intervention description(s): In each study, the subjects will receive s.c. injection of either exenatide or matched placebo, in the Metabolic Testing Center and 2 hours prior to the start of the lipoprotein turnover study. Subjects will be blinded with regard to the treatments.
Other intervention name(s): Byetta
Intervention MeSH terms: Exenatide
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Intestinal lipoprotein; Apo B48 and apoB100; Pancreatic clamp; GLP-1 agonist