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

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ClinicalTrials.gov Identifier: NCT02403284
Recruitment Status : Active, not recruiting
First Posted : March 31, 2015
Last Update Posted : August 1, 2019
Sponsor:
Collaborator:
Novo Nordisk A/S
Information provided by (Responsible Party):
Phoenix VA Health Care System

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.

Condition or disease Intervention/treatment Phase
Insulin Resistance Drug: Liraglutide Drug: Sugar Pill Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: The Effect of Liraglutide on Dietary Lipid Induced Insulin Resistance in Humans
Study Start Date : March 2013
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : May 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Dietary Fats

Arm Intervention/treatment
Experimental: Liraglutide
Liraglutide titration up to 1.8 mg/d over approximately 3 weeks
Drug: Liraglutide
Subcutaneous injection by patient
Other Name: Victoza

Placebo Comparator: Sugar pill
matching placebo and titration
Drug: Sugar Pill
Subcutaneous injection daily
Other Name: Placebo




Primary Outcome Measures :
  1. Whole Body Insulin Sensitivity (insulin suppression test) [ Time Frame: 3 weeks ]
    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


Secondary Outcome Measures :
  1. Postprandial lipid changes (area under the curve difference in triglyceride,total apolipoprotein B100, apolipoprotein B48, and apolipoprotein C3. [ Time Frame: 3 weeks ]
    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.

  2. Postprandial changes in glucose metabolism (total and incremental area under the curve differences in glucose, insulin and glucagon) [ Time Frame: 3 weeks ]
    total and incremental area under the curve differences in glucose, insulin and glucagon between treatment arms

  3. Changes in adipose tissue insulin signaling pathway activation (compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation) [ Time Frame: 3 weeks ]
    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.

  4. subcutaneous adipose tissue lipid intermediates (e.g., ceramide, diacylglycerol, acylcarnitine concentrations) [ Time Frame: 3 weeks ]
    Adipose tissue biopsy samples will be used to compare lipid intermediates in placebo and liraglutide treatment phases.

  5. skeletal muscle tissue lipid intermediates (e.g., ceramide, diacylglycerol, acylcarnitine concentrations) [ Time Frame: 3 weeks ]
    skeletal muscle tissue samples will be used to compare lipid intermediates in placebo and liraglutide treatment phases.

  6. Adipose tissue inflammation measures (e.g., interleukin (IL)-6, and -8, adiponectin, TNF-alpha, nuclear factor-kappa b, gene and protein expression) [ Time Frame: 3 weeks ]
    Adipose tissue biopsy samples will be used to compare inflammation measures in placebo and liraglutide treatment phases.

  7. Skeletal muscle inflammation measures (e.g., IL-6,8, TNF-alpha, nuclear factor-kappa b gene and protein expression) [ Time Frame: 3 weeks ]
    skeletal muscle tissue samples will be used to compare inflammation measures in placebo and liraglutide treatment phases

  8. Adipose tissue arteriole function (vasodilation measurement) [ Time Frame: 3 weeks ]
    Adipose tissue biopsy samples will be used to isolate arterioles and measure ex vivo vascular function in placebo and liraglutide treatment phases.

  9. Changes in skeletal muscle insulin signaling pathway [ Time Frame: 3 weeks ]
    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.



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Ages Eligible for Study:   40 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02403284


Locations
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United States, Arizona
Carl T. Hayden VA Medical Hospital
Phoenix, Arizona, United States, 85012
Sponsors and Collaborators
Phoenix VA Health Care System
Novo Nordisk A/S
Investigators
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Principal Investigator: Peter D Reaven, MD Carl T. Hayden Medical Research Foundation

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Responsible Party: Phoenix VA Health Care System
ClinicalTrials.gov Identifier: NCT02403284     History of Changes
Other Study ID Numbers: 028
First Posted: March 31, 2015    Key Record Dates
Last Update Posted: August 1, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Subject to VA regulation.
Keywords provided by Phoenix VA Health Care System:
insulin resistance
lipid metabolism
glucose metabolism
high fat diets
Additional relevant MeSH terms:
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Liraglutide
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists