Fatty Acid Oxidation Defects and Insulin Sensitivity

Oregon Health & Science University (OHSU)

Status: Completed

Conditions: Medium-chain Acyl-CoA Dehydrogenase Deficiency; Trifunctional Protein Deficiency; Carnitine Palmitoyltransferase II Deficiency, Myopathic; Normal Volunteers; Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency; Very Long-chain Acyl-CoA Dehydrogenase Deficiency

Treatments: Drug: Intralipid/Heparin; Drug: Glycerol/Saline; Drug: Hyperinsulinemic euglycemic clamp

Study type: Interventional

Funder types: Other

Identifiers

NCT02517307

OHSU11258

Details and patient eligibility

About

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.

Full 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.

Enrollment: 41 patients

Sex: All

Ages: 18+ years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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41 participants in 4 patient groups

glycerol/saline FAOD

Experimental group

Description:

Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD)

Treatment:

Drug: Glycerol/Saline

Drug: Hyperinsulinemic euglycemic clamp

intralipid FAOD

Experimental group

Description:

Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD)

Treatment:

Drug: Intralipid/Heparin

Drug: Hyperinsulinemic euglycemic clamp

glycerol/saline Control

Experimental group

Description:

Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control)

Treatment:

Drug: Glycerol/Saline

Drug: Hyperinsulinemic euglycemic clamp

intralipid Control

Experimental group

Description:

Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control)

Treatment:

Drug: Intralipid/Heparin

Drug: Hyperinsulinemic euglycemic clamp