The Effect of Liraglutide on Dietary Lipid Induced Insulin Resistance in Humans

The specific aim of this study is to determine the ability of subacute liraglutide
administration to protect against dietary lipid induced peripheral insulin resistance in
non-diabetic subjects who have normal glucose tolerance. Recent data from our laboratory and
others suggest that high fat meals, enriched with saturated fatty acids (SFA) in particular,
have a unique and profound ability to induce rapid (in ≤ 24 hr) and profound onset of insulin
resistance in humans. This is presumably mediated in part through delivery of lipids and
lipid products generated during postprandial lipolysis into non-adipose tissue. This unique
model therefore provides an excellent platform to test agents for their ability to inhibit
dietary induced insulin resistance. As we and others have demonstrated the ability of GLP-1
receptor agonists to markedly suppress postprandial lipid elevations and to modify lipid
metabolism, we hypothesize that liraglutide may be an effective agent to inhibit development
of dietary induced insulin resistance.

Inclusion Criteria:

1. Age 40-75 years old

2. Body mass index (BMI) from 22 to 35 kg/m2

3. Normal glucose tolerance as determined by fasting blood glucose (< 100 mg/dl) and 75
gm glucose load (2 hr glucose <140 mg/dl)

4. Fasting triglyceride levels ≥ 75 mg/dl and <500 mg/dl

Exclusion Criteria:

1. Type 1 or 2 diabetes mellitus or a hemoglobin A1c value >6.5 mg/dl

2. Any diabetes medications in the past month, thiazolidinedione medications in the prior
3 months or prior regular use of insulin

3. Lactose intolerance or avoidance of dairy products

4. Creatinine > 2.0 mg/dl or other laboratory evidence of active disease, including
hepatic enzyme elevation (AST or ALT) > 2.5 x normal and anemia (Hct < 35)

5. Known 'Nonalcoholic Fatty Liver Disease'

6. Malabsorption of fat or other nutrients, severe lactose intolerance or other
significant gastrointestinal or pancreatic problems (including history of acute or
chronic pancreatitis).

7. Recent history of nausea or vomiting

8. Acute bacterial or viral illness or evidence of other active infection in the past 4
weeks

9. Prior cardiovascular event, stable or unstable angina or other major illness in the
past 6 months

10. Current regular use of anti-inflammatory medications or antioxidants in excess of a
standard daily multi-vitamin, including over- the-counter medications and high dose
salicylates (> 1 gm/ day)

11. Subjects receiving a lipid lowering medication must be on a stable dose for at least 6
weeks prior to participation.

12. Personal or family history of medullary thyroid carcinoma or in patients with multiple
endocrine neoplasia 2

13. Ethanol consumption more than 4 oz day

14. Pregnancy, or lack of appropriate contraceptive use in premenopausal women (extremely
rare in our older predominately male population)

15. Poorly controlled hypertension, systolic blood pressure (SBP) > 150 or diastolic blood
pressure (DBP) > 90 on 2 or more occasions during screening visits. Subjects receiving
blood pressure medication will be on a stable dosing for at least 6 weeks prior to
participation.

16. BMI <22 and >35 kg/m2