Effect of GLP-1 on Postprandial Lipid Metabolism
Primary Purpose
Heart Disease
Status
Unknown status
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Exendin-9
GLP-1
saline
Sponsored by

About this trial
This is an interventional basic science trial for Heart Disease focused on measuring heart disease, GLP-1, Exendin-9, postprandial lipids
Eligibility 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.
Sites / Locations
- Veteran's Affairs Clinical Research Unit
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Placebo Comparator
Experimental
Experimental
Arm Label
Saline
Exendin-9 (Ex-9)
GLP-1
Arm Description
0.9% saline
Bolus of Ex-9 (7,500 pmol/kg) followed by a continuous infusion at 750 pmol/kg/min
GLP-1 infusion at 0.3 pmol/kg/min
Outcomes
Primary Outcome Measures
Postprandial Lipids Levels and Apolipoprotein B (ApoB) Levels in plasma
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
Plasma insulin and glucagon in the fasting and postprandial periods
Plasma free fatty acid (FFA) and glucose levels
Plasma FFA and glucose levels during the fasting and postprandial state
Plasma d-xylose and acetaminophen levels
Plasma d-xylose and acetaminophen levels as indices of gastric emptying
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01760772
Brief Title
Effect of GLP-1 on Postprandial Lipid Metabolism
Official Title
The Role of GLP-1 in Lipid Metabolism in Healthy Subjects and in Subjects After Bariatric Surgery
Study Type
Interventional
2. Study Status
Record Verification Date
November 2012
Overall Recruitment Status
Unknown status
Study Start Date
February 2013 (undefined)
Primary Completion Date
February 2015 (Anticipated)
Study Completion Date
February 2015 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
David Dalessio
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Disease
Keywords
heart disease, GLP-1, Exendin-9, postprandial lipids
7. Study Design
Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Factorial Assignment
Masking
Participant
Allocation
Randomized
Enrollment
42 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Saline
Arm Type
Placebo Comparator
Arm Description
0.9% saline
Arm Title
Exendin-9 (Ex-9)
Arm Type
Experimental
Arm Description
Bolus of Ex-9 (7,500 pmol/kg) followed by a continuous infusion at 750 pmol/kg/min
Arm Title
GLP-1
Arm Type
Experimental
Arm Description
GLP-1 infusion at 0.3 pmol/kg/min
Intervention Type
Drug
Intervention Name(s)
Exendin-9
Other Intervention Name(s)
Synthetic exendin (9-39) injection
Intervention Description
Bolus of Ex-9 (7500 pmol/kg) over 1 minute followed by continuous infusion at 750 pmol/kg/min
Intervention Type
Drug
Intervention Name(s)
GLP-1
Other Intervention Name(s)
7-36 amide
Intervention Description
Constant infusion of GLP-1 at 0.3 pmol/kg/min
Intervention Type
Other
Intervention Name(s)
saline
Intervention Description
Constant infusion
Primary Outcome Measure Information:
Title
Postprandial Lipids Levels and Apolipoprotein B (ApoB) Levels in plasma
Description
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.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Plasma insulin and glucagon
Description
Plasma insulin and glucagon in the fasting and postprandial periods
Time Frame
2 years
Title
Plasma free fatty acid (FFA) and glucose levels
Description
Plasma FFA and glucose levels during the fasting and postprandial state
Time Frame
2 years
Title
Plasma d-xylose and acetaminophen levels
Description
Plasma d-xylose and acetaminophen levels as indices of gastric emptying
Time Frame
2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michelle R Adams, PhD
Phone
513-558-6920
Email
michelle.adams@uc.edu
First Name & Middle Initial & Last Name or Official Title & Degree
David D'Alessio, MD
Phone
513-558-6689
Email
DALESSD@UCMAIL.UC.EDU
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michelle R Adams, PhD
Organizational Affiliation
University of Cincinnati
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
David D'Alessio, MD
Organizational Affiliation
University of Cincinnati
Official's Role
Principal Investigator
Facility Information:
Facility Name
Veteran's Affairs Clinical Research Unit
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45220
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michelle R Adams, PhD
Phone
513-558-6920
Email
michelle.adams@uc.edu
First Name & Middle Initial & Last Name & Degree
Michelle R Adams, PhD
First Name & Middle Initial & Last Name & Degree
David D'Alessio, MD
12. IPD Sharing Statement
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Effect of GLP-1 on Postprandial Lipid Metabolism
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