Clinical trial NCT02403284: The Effect of Liraglutide on Dietary Lipid Induced Insulin Resistance in Humans
Official title: The Effect of Liraglutide on Dietary Lipid Induced Insulin Resistance in Humans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Insulin Resistance
Keywords: insulin resistance
lipid metabolism
glucose metabolism
high fat diets
Lead sponsor: Phoenix VA Health Care System
Sponsor class: FED
Collaborators: name: Novo Nordisk A/S
First posted: 2015-03-31
Enrollment: 97
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: In this research study, investigators will test the effects of an approved medication for diabetes,Liraglutide, to reduce insulin resistance that develops from eating a diet high in saturated fats.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Whole Body Insulin Sensitivity (insulin suppression test)
timeFrame: 3 weeks
Secondary outcomes:
measure: Postprandial lipid changes (area under the curve difference in triglyceride,total apolipoprotein B100, apolipoprotein B48, and apolipoprotein C3.
timeFrame: 3 weeks
measure: Postprandial changes in glucose metabolism (total and incremental area under the curve differences in glucose, insulin and glucagon)
timeFrame: 3 weeks
measure: Changes in adipose tissue insulin signaling pathway activation (compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation)
timeFrame: 3 weeks
measure: subcutaneous adipose tissue lipid intermediates (e.g., ceramide, diacylglycerol, acylcarnitine concentrations)
timeFrame: 3 weeks
measure: skeletal muscle tissue lipid intermediates (e.g., ceramide, diacylglycerol, acylcarnitine concentrations)
timeFrame: 3 weeks
measure: Adipose tissue inflammation measures (e.g., interleukin (IL)-6, and -8, adiponectin, TNF-alpha, nuclear factor-kappa b, gene and protein expression)
timeFrame: 3 weeks
measure: Skeletal muscle inflammation measures (e.g., IL-6,8, TNF-alpha, nuclear factor-kappa b gene and protein expression)
timeFrame: 3 weeks
measure: Adipose tissue arteriole function (vasodilation measurement)
timeFrame: 3 weeks
measure: Changes in skeletal muscle insulin signaling pathway
timeFrame: 3 weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Carl T. Hayden VA Medical Hospital
state: Arizona
Study officials:
affiliation: Carl T. Hayden Medical Research Foundation
name: Peter D Reaven, MD
role: PRINCIPAL_INVESTIGATOR
References: