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Fatty Acid Oxidation Defects and Insulin Sensitivity

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02517307
Recruitment Status : Recruiting
First Posted : August 7, 2015
Last Update Posted : July 17, 2019
Sponsor:
Information provided by (Responsible Party):
Melanie B Gillingham, Oregon Health and Science University

Brief Summary:
The purpose of this study is to learn more about what causes insulin resistance. It has been suggested that proper breakdown of fat into energy (oxidation) in the body is important to allow insulin to keep blood sugar in the normal range. The investigators want to know if having one of the fatty acid oxidation disorders could have an influence on insulin action. Fatty acid oxidation disorders are genetic disorders that inhibit one of the enzymes that converts fat into energy. The investigators will study both normal healthy people and people with a long-chain fatty acid oxidation disorder.

Condition or disease Intervention/treatment Phase
Very Long-chain Acyl-CoA Dehydrogenase Deficiency Trifunctional Protein Deficiency Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency Medium-chain Acyl-CoA Dehydrogenase Deficiency Normal Volunteers Carnitine Palmitoyltransferase II Deficiency, Myopathic Drug: Intralipid/Heparin Drug: Glycerol/Saline Drug: Hyperinsulinemic euglycemic clamp Not Applicable

Detailed Description:

The overall goal of this proposal is to investigate the effects of disordered mitochondrial fatty acid oxidation on insulin resistance in humans. Mitochondrial dysfunction has been implicated in the development of insulin resistance and type 2 diabetes during excess dietary fat intake and from increased release of endogenous free fatty acids , such as occurs in obesity. Controversy exists, however, as to whether this insulin resistance results from intrinsic defects in mitochondrial energy utilization or from abnormalities resulting from excess free fatty acid flux, as well as the role that subsequent accumulation of cellular metabolic intermediates play in impaired insulin signaling.

To address these controversies, the investigators will study a unique population of patients with inherited defects in each of the three mitochondrial enzymes in the fatty acid oxidation pathway: 1) very long-chain acyl-CoA dehydrogenase (VLCAD); 2) trifunctional protein (TFP, which includes long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)); and 3) medium-chain acyl-CoA dehydrogenase (MCAD). These proteins are required for the oxidation of sequentially shorter fatty acids . The investigators will test the hypothesis that intrinsic defects in mitochondrial function involving oxidation of long-chain, but not medium-chain, fatty acids are sufficient to prevent intralipid-induced insulin resistance.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Role of Fatty Acid Oxidation Defects in Insulin Sensitivity
Study Start Date : February 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : April 2020


Arm Intervention/treatment
Experimental: glycerol/saline
Glycerol/Saline infusion
Drug: Glycerol/Saline
Co-infusion of a glycerol/saline solutions during a hyperinsulinemic euglycemic clamp

Drug: Hyperinsulinemic euglycemic clamp
Infusion of insulin at at 40 mU/m2/min for 5 hours. Blood glucose will be monitored every 5 min during the insulin infusion and euglycemia will be maintained throughout the clamp by infusing 20% dextrose at a variable rate.

Experimental: intralipid
Intralipid/Heparin infusion
Drug: Intralipid/Heparin
Co-infusion of intralipid and heparin solutions during a hyperinsulinemic euglycemic clamp

Drug: Hyperinsulinemic euglycemic clamp
Infusion of insulin at at 40 mU/m2/min for 5 hours. Blood glucose will be monitored every 5 min during the insulin infusion and euglycemia will be maintained throughout the clamp by infusing 20% dextrose at a variable rate.




Primary Outcome Measures :
  1. Glucose Disposal Rate (Rd)- the rate of glucose infusion to maintain euglycemia during steady state insulin infusion in ml/kg/hr [ Time Frame: 5 hours ]
    Amount of glucose disposal during hyperinsulinemic euglycemic clamp


Secondary Outcome Measures :
  1. Endogenous glucose production (Ra) - calculated by the equations of Steele during steady state in ml/kg/hr [ Time Frame: 5 hours ]
    Amount of glucose endogenously synthesized and secreted into circulation



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • confirmed diagnosis of VLCAD, LCHAD, TFP or MCAD deficiency or same gender, age and BMI as a subject with a fatty acid oxidation disorder
  • ability to travel to Oregon Health & Science University, Portland, Oregon
  • ability and willingness to complete the protocol

Exclusion Criteria:

  • hemoglobin <10g/dl, international normalized ratio (INR) >1.2 Prothrombin time (PTT) >36 sec, Platelets <150K/mm3
  • pregnant or lactating females
  • endocrine disorder such as diabetes or untreated thyroid disease
  • cardiovascular disease or elevated plasma lipids
  • regularly taking meds that strongly affect bleeding, bruising or platelets

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): NCT02517307


Contacts
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Contact: Julie Martin, MS 503-494-5313 martijul@ohsu.edu
Contact: Melanie B Gillingham, PhD 503-494-1682 gillingm@ohsu.edu

Locations
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United States, Oregon
Oregon Health & Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Julie Martin, MS    503-494-5313    martijul@ohsu.edu   
Contact: Melanie Gillingham, PhD    503-494-1682    gillingm@ohsu.edu   
Sponsors and Collaborators
Oregon Health and Science University

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Responsible Party: Melanie B Gillingham, Associate Professor, Oregon Health and Science University
ClinicalTrials.gov Identifier: NCT02517307    
Other Study ID Numbers: OHSU11258
First Posted: August 7, 2015    Key Record Dates
Last Update Posted: July 17, 2019
Last Verified: July 2019
Additional relevant MeSH terms:
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Insulin Resistance
Protein Deficiency
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Deficiency Diseases
Malnutrition
Nutrition Disorders
Insulin
Heparin
Calcium heparin
Soybean oil, phospholipid emulsion
Glycerol
Hypoglycemic Agents
Physiological Effects of Drugs
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Fat Emulsions, Intravenous
Parenteral Nutrition Solutions
Pharmaceutical Solutions
Cryoprotective Agents
Protective Agents