Fatty Acid Oxidation Defects and Insulin Sensitivity

NCT ID: NCT02517307

Last Updated: 2024-01-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 41 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-02-29
• Study Completion Date: 2021-03-31

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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

glycerol/saline FAOD

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

Group Type: EXPERIMENTAL

Glycerol/Saline

Intervention Type: DRUG

Co-infusion of a glycerol/saline solutions during a hyperinsulinemic euglycemic clamp

Hyperinsulinemic euglycemic clamp

Intervention Type: DRUG

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.

intralipid FAOD

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

Group Type: EXPERIMENTAL

Intralipid/Heparin

Intervention Type: DRUG

Co-infusion of intralipid and heparin solutions during a hyperinsulinemic euglycemic clamp

Hyperinsulinemic euglycemic clamp

Intervention Type: DRUG

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.

glycerol/saline Control

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

Group Type: EXPERIMENTAL

Glycerol/Saline

Intervention Type: DRUG

Co-infusion of a glycerol/saline solutions during a hyperinsulinemic euglycemic clamp

Hyperinsulinemic euglycemic clamp

Intervention Type: DRUG

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.

intralipid Control

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

Group Type: EXPERIMENTAL

Intralipid/Heparin

Intervention Type: DRUG

Co-infusion of intralipid and heparin solutions during a hyperinsulinemic euglycemic clamp

Hyperinsulinemic euglycemic clamp

Intervention Type: DRUG

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.

Interventions

Intralipid/Heparin

Co-infusion of intralipid and heparin solutions during a hyperinsulinemic euglycemic clamp

Intervention Type: DRUG

Glycerol/Saline

Co-infusion of a glycerol/saline solutions during a hyperinsulinemic euglycemic clamp

Intervention Type: 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.

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Oregon Health and Science University

OTHER

Sponsor Role: lead

Responsible Party

Melanie B Gillingham

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Oregon Health & Science University

Portland, Oregon, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

OHSU11258

Identifier Type: -

Identifier Source: org_study_id