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

• Age 40-75 years old
• Body mass index (BMI) from 22 to 35 kg/m2
• Normal glucose tolerance as determined by fasting blood glucose (< 100 mg/dl) and 75 gm glucose load (2 hr glucose <140 mg/dl)
• Fasting triglyceride levels ≥ 75 mg/dl and <500 mg/dl

Exclusion criteria

• Type 1 or 2 diabetes mellitus or a hemoglobin A1c value >6.5 mg/dl
• Any diabetes medications in the past month, thiazolidinedione medications in the prior 3 months or prior regular use of insulin
• Lactose intolerance or avoidance of dairy products
• 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)
• Known 'Nonalcoholic Fatty Liver Disease'
• Malabsorption of fat or other nutrients, severe lactose intolerance or other significant gastrointestinal or pancreatic problems (including history of acute or chronic pancreatitis).
• Recent history of nausea or vomiting
• Acute bacterial or viral illness or evidence of other active infection in the past 4 weeks
• Prior cardiovascular event, stable or unstable angina or other major illness in the past 6 months
• 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)
• Subjects receiving a lipid lowering medication must be on a stable dose for at least 6 weeks prior to participation.
• Personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia 2
• Ethanol consumption more than 4 oz day
• Pregnancy, or lack of appropriate contraceptive use in premenopausal women (extremely rare in our older predominately male population)
• 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.
• BMI <22 and >35 kg/m2