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Effect of GLP-1 on Postprandial Lipid Metabolism

This study is not yet open for participant recruitment.
Verified November 2012 by University of Cincinnati
Sponsor:
Information provided by (Responsible Party):
David Dalessio, University of Cincinnati
ClinicalTrials.gov Identifier:
NCT01760772
First received: November 17, 2012
Last updated: January 2, 2013
Last verified: November 2012
History of Changes
  Purpose

Individuals with obesity have an increased risk for heart disease and diabetes. There are current drugs on the market that target the hormone, Glucagon like peptide-1 (GLP-1) to treat diabetes. The investigators want to determine if targeting this hormone will also help people with high cholesterol and triglycerides. In this study, the investigators are looking at the role of GLP-1 in healthy subjects and subjects that have had bariatric surgery.


Condition Intervention
Heart Disease
 Drug: Exendin-9
Drug: GLP-1
Other: saline

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Factorial Assignment
Masking: Single Blind (Subject)
Primary Purpose: Basic Science
Official Title: The Role of GLP-1 in Lipid Metabolism in Healthy Subjects and in Subjects After Bariatric Surgery

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by University of Cincinnati:

Primary Outcome Measures:
  • Postprandial Lipids Levels and Apolipoprotein B (ApoB) Levels in plasma [ Time Frame: 2 years ] [ Designated as safety issue: No ]

    Total and lipoprotein-associated triglyceride and cholesterol levels in baseline and postprandial plasma.

    Total apolipoprotein B48 (ApoB48) and apolipoprotein B100 (ApoB100) levels in baseline and postprandial plasma.



Secondary Outcome Measures:
  • Plasma insulin and glucagon [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Plasma insulin and glucagon in the fasting and postprandial periods

  • Plasma free fatty acid (FFA) and glucose levels [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Plasma FFA and glucose levels during the fasting and postprandial state

  • Plasma d-xylose and acetaminophen levels [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Plasma d-xylose and acetaminophen levels as indices of gastric emptying


Estimated Enrollment: 42
Study Start Date: February 2013
Estimated Study Completion Date: February 2015
Estimated Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Saline
0.9% saline
 Other: saline
Constant infusion
Experimental: Exendin-9 (Ex-9)
Bolus of Ex-9 (7,500 pmol/kg) followed by a continuous infusion at 750 pmol/kg/min
 Drug: Exendin-9
Bolus of Ex-9 (7500 pmol/kg) over 1 minute followed by continuous infusion at 750 pmol/kg/min
Other Name: Synthetic exendin (9-39) injection
Experimental: GLP-1
GLP-1 infusion at 0.3 pmol/kg/min
 Drug: GLP-1
Constant infusion of GLP-1 at 0.3 pmol/kg/min
Other Name: 7-36 amide

Detailed Description:

Major consequences of the global pandemic of obesity include cardiovascular disease, type 2 diabetes and dyslipidemia. The dyslipidemia of obesity commonly consists of fasting hypertriglyceridemia with increased plasma very low-density lipoprotein (VLDL), reduced high-density lipoprotein (HDL) and the presence of small, dense low-density lipoprotein (LDL). However, more recently, increased secretion of intestinally derived lipoproteins (LPs) has been recognized as contributing to this dyslipidemic profile and postprandial lipemia has been linked to adverse health outcomes. Glucagon-like peptide-1 (GLP-1), a hormone secreted during meal absorption that plays a key role in the control of plasma glucose has been implicated as a candidate hormone for regulating intestinal lipid metabolism. Studies in rodents demonstrate that treatment with the GLP-1R agonist; exendin-4 (Ex-4) reduced postprandial chylomicron (CM) production and CM-associated cholesterol and triglyceride (TG). Similar results were found in Type 2 diabetes (T2D) subjects treated with Ex-4; in these reports there was a reduction in both intestinally derived LP production and total plasma TG. The objective of this study is to determine whether GLP-1 is involved in the physiologic regulation of postprandial lipid metabolism in healthy women, and to test the hypothesis that the improved lipid parameters found in overweight women who have had bariatric surgery are mediated by GLP-1. The specific aims for this project will 1) determine if either pharmacologic treatment with GLP-1 and/or antagonism of endogenous GLP-1 activity improves postprandial lipid metabolism in healthy subjects and 2) determine the role of elevated postprandial GLP-1 levels on lipid metabolism in obese subjects who have had a sleeve gastrectomy. The investigators will use infusions of synthetic GLP-1 with the native hormone to confirm the lipid-lowering results that have been published using pharmacologic GLP-1 receptor (GLP-1R) agonists. The investigators will also use the GLP-1R antagonist exendin-(9-39) to determine the role of endogenous GLP-1 on lipemia after a test meal. A demonstration that this is a physiologic action would expand the current understanding of lipid metabolism, provide new insight into the effects of bariatric surgery, and allow the design of more refined, mechanistic studies of this process. In addition, the potential for GLP-1R signaling to promote lipid metabolism has direct translational importance in that therapies already exist that could capitalize on this mechanism. Understanding the role of GLP-1R regulation of lipid absorption and clearance could lead to more appropriate targeting of GLP-1 based drugs to specific diabetic patients, i.e. ones with problematic dyslipidemia and higher risk for cardiovascular disease. Moreover, understanding the effects of GLP-1 on plasma lipids could eventually lead to new approaches for treating nondiabetic dyslipidemic persons.

  Eligibility

Ages Eligible for Study:   40 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Aim 1: Healthy, normolipemic men and postmenopausal women; aged 40-60 years; BMI between 25-35
  • Aim 2: Men and postmenopausal women after successful vertical sleeve gastrectomy (VSG) surgery and age- and weight-matched non-surgical control men and postmenopausal women; ages between 40-6- years; BMI between 28-35; steady weight for at least 3 months prior to study

Exclusion Criteria:

Exclusion Criteria for Aim 1:

  • History or clinical evidence of impaired fasting glucose or diabetes mellitus, myocardial infarction or symptoms of congestive heart failure, history or active liver or renal disease, calculated glomerular filtration rate < 60 mL/min).
  • History of extreme dyslipidemia (i.e. familial hypercholesterolemia) or Cardiovascular disease (CVD).
  • Fasting plasma total cholesterol > 200 mg/dL and fasting plasma TGs > 150 mg/dL.
  • Surgery within 6 months.
  • Pregnancy or lactation.
  • Anemia defined as hematocrit < 33%.
  • History of cancer or anorexia nervosa or GI disorders.
  • Use of medications that alter insulin sensitivity (i.e. niacin, glucocorticoids, metformin) or lipid metabolism (i.e. statin, niacin, fibrate, ezetimibe).
  • Plasma HbA1c > 6.0.
  • Fasting glucose > 110 mg/dL
  • Electrocardiogram (ECG) abnormalities: evidence of ischemia or arrhythmia.

Exclusion Criteria for Aim 2:

  • History of CVD.
  • Fasting plasma total cholesterol > 250 mg/dL and fasting plasma TGs > 300 mg/dL.
  • Surgical intervention within 6 months.
  • Anemia defined as hematocrit < 33%.
  • History of cancer or anorexia nervosa or other major GI disease or surgery.
  • Use of medications that alter insulin sensitivity (i.e. niacin, glucocorticoids, metformin) or lipid metabolism (i.e. statin, ezetimibe).
  • HbA1c > 6.0.
  • Fasting glucose > 110 mg/dL
  • Electrocardiogram (ECG) abnormalities: evidence of ischemia or arrhythmia.
  • Significant renal, hepatic or pulmonary disease.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01760772

Contacts
Contact: Michelle R Adams, PhD 513-558-6920 michelle.adams@uc.edu
Contact: David D'Alessio, MD 513-558-6689 DALESSD@UCMAIL.UC.EDU

Locations
United States, Ohio
Veteran's Affairs Clinical Research Unit Not yet recruiting
Cincinnati, Ohio, United States, 45220
Contact: Michelle R Adams, PhD     513-558-6920     michelle.adams@uc.edu    
Principal Investigator: Michelle R Adams, PhD            
Principal Investigator: David D'Alessio, MD            
Sponsors and Collaborators
David Dalessio
Investigators
Principal Investigator: Michelle R Adams, PhD University of Cincinnati
Principal Investigator: David D'Alessio, MD University of Cincinnati
  More Information

No publications provided

Responsible Party: David Dalessio, Professor, University of Cincinnati
ClinicalTrials.gov Identifier: NCT01760772     History of Changes
Other Study ID Numbers: 12-09-20-01
Study First Received: November 17, 2012
Last Updated: January 2, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of Cincinnati:
heart disease
GLP-1
Exendin-9
postprandial lipids

Additional relevant MeSH terms:
Heart Diseases
Cardiovascular Diseases
Glucagon-Like Peptide 1
Incretins
 Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 19, 2013