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

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.

Study Overview

• Status: Unknown
• Conditions: Insulin Resistance
• Intervention / Treatment: Drug: Liraglutide; Drug: Sugar Pill

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.

• Study Type: Interventional
• Enrollment (Anticipated): 35
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85012
      • Carl T. Hayden VA Medical Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 38 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Liraglutide; Liraglutide titration up to 1.8 mg/d over approximately 3 weeks	Drug: Liraglutide; Subcutaneous injection by patient; Other Names: Victoza
Placebo Comparator: Sugar pill; matching placebo and titration	Drug: Sugar Pill; Subcutaneous injection daily; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Whole Body Insulin Sensitivity (insulin suppression test)	An insulin suppression test will be measured before and approximately 3 weeks after each treatment phase. Key time frames for assessing steady state plasma glucose will be between 150 and 180 minutes during the insulin suppression test	3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postprandial lipid changes (area under the curve difference in triglyceride,total apolipoprotein B100, apolipoprotein B48, and apolipoprotein C3.	The major endpoints will be the area under the curve difference in triglyceride and free fatty acids between treatment arms on test day 1 and 2 following a standard meal. Other postprandial lipids will include total apolipoprotein B100, apolipoprotein B48, and apolipoprotein C3.	3 weeks
Postprandial changes in glucose metabolism (total and incremental area under the curve differences in glucose, insulin and glucagon)	total and incremental area under the curve differences in glucose, insulin and glucagon between treatment arms	3 weeks
Changes in adipose tissue insulin signaling pathway activation (compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation)	Adipose tissue biopsy samples will be used to compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation) in placebo and liraglutide treatment phases.	3 weeks
subcutaneous adipose tissue lipid intermediates (e.g., ceramide, diacylglycerol, acylcarnitine concentrations)	Adipose tissue biopsy samples will be used to compare lipid intermediates in placebo and liraglutide treatment phases.	3 weeks
skeletal muscle tissue lipid intermediates (e.g., ceramide, diacylglycerol, acylcarnitine concentrations)	skeletal muscle tissue samples will be used to compare lipid intermediates in placebo and liraglutide treatment phases.	3 weeks
Adipose tissue inflammation measures (e.g., interleukin (IL)-6, and -8, adiponectin, TNF-alpha, nuclear factor-kappa b, gene and protein expression)	Adipose tissue biopsy samples will be used to compare inflammation measures in placebo and liraglutide treatment phases.	3 weeks
Skeletal muscle inflammation measures (e.g., IL-6,8, TNF-alpha, nuclear factor-kappa b gene and protein expression)	skeletal muscle tissue samples will be used to compare inflammation measures in placebo and liraglutide treatment phases	3 weeks
Adipose tissue arteriole function (vasodilation measurement)	Adipose tissue biopsy samples will be used to isolate arterioles and measure ex vivo vascular function in placebo and liraglutide treatment phases.	3 weeks
Changes in skeletal muscle insulin signaling pathway	skeletal muscle biopsy samples will be used to compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation) in placebo and liraglutide treatment phases.	3 weeks

Collaborators and Investigators

• Sponsor: Phoenix VA Health Care System
• Collaborators: Novo Nordisk A/S
• Investigators: Principal Investigator: Peter D Reaven, MD, Carl T. Hayden Medical Research Foundation

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (Anticipated): December 1, 2020
• Study Completion (Anticipated): May 1, 2021

Study Registration Dates

• First Submitted: November 3, 2014
• First Submitted That Met QC Criteria: March 25, 2015
• First Posted (Estimate): March 31, 2015

Study Record Updates

• Last Update Posted (Actual): March 13, 2020
• Last Update Submitted That Met QC Criteria: March 11, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: lipid metabolism; insulin resistance; glucose metabolism; high fat diets
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: 028

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Subject to VA regulation.