Effect of GLP-1 on Postprandial Lipid Metabolism

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.

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.