Clinical trial NCT02517307: Fatty Acid Oxidation Defects and Insulin Sensitivity
Official title: Role of Fatty Acid Oxidation Defects in Insulin Sensitivity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: 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
Lead sponsor: Oregon Health and Science University
Sponsor class: OTHER
First posted: 2015-08-07
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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

Primary outcomes:
measure: Glucose Disposal Rate (Rd)- the Rate of Glucose Infusion to Maintain Euglycemia During Steady State Insulin Infusion in mg/Min
timeFrame: Calculated during the last 30 minutes of a 300 minute clamp.
Secondary outcomes:
measure: Endogenous Glucose Production (Ra) - Calculated by the Equations of Steele During Steady State in mg/Min
timeFrame: Calculated during the last 30 minutes of a 300 minute clamp.
Other outcomes:
Locations:
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
Study officials:
References: