Fatty Acid Oxidation Defects and Insulin Sensitivity

Role of Fatty Acid Oxidation Defects in Insulin Sensitivity

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.

Study Overview

• Status: Completed
• Conditions: Normal Volunteers; Trifunctional Protein Deficiency; Very Long-chain Acyl-CoA Dehydrogenase Deficiency; Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency; Medium-chain Acyl-CoA Dehydrogenase Deficiency; Carnitine Palmitoyltransferase II Deficiency, Myopathic
• Intervention / Treatment: Drug: Glycerol/Saline; Drug: Hyperinsulinemic euglycemic clamp; Drug: Intralipid/Heparin

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.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: glycerol/saline FAOD; Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD)	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 FAOD; Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD)	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.; Drug: Intralipid/Heparin; Co-infusion of intralipid and heparin solutions during a hyperinsulinemic euglycemic clamp
Experimental: glycerol/saline Control; Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control)	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 Control; Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control)	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.; Drug: Intralipid/Heparin; Co-infusion of intralipid and heparin solutions during a hyperinsulinemic euglycemic clamp

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose Disposal Rate (Rd)- the Rate of Glucose Infusion to Maintain Euglycemia During Steady State Insulin Infusion in mg/Min	Insulin infusion induces glucose disposal into muscle and adipose tissue in insulin sensitive participants. During the glycerol co-infusion, glucose disposal will be high. Intralipid co-infusion can induce a temporary insulin resistant state. During the intralipid co-infusion, glucose disposal will be decreased. We are comparing how intralipid dampens glucose disposal between participants with a FAOD and matched control participants. Glucose disposal is measured by measuring the ratio of deuterated glucose to unlabeled glucose at the beginning and end of the clamp. The calculated glucose disposal rate or RD is mg of glucose taken into muscle and adipose tissue per minute.	Calculated during the last 30 minutes of a 300 minute clamp.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endogenous Glucose Production (Ra) - Calculated by the Equations of Steele During Steady State in mg/Min	Infusion of insulin will suppress endogenous glucose production from the liver in insulin sensitive people. Insulin infusion with glycerol should suppress the endogenous glucose production in the liver but intralipid induces a temporary state of insulin resistance and the decrease in endogenous glucose production or Ra will be blunted with intralipid co-infusion. We are looking at the difference in Ra with intralipid between participants with a FAOD and matched control participants. Ra or endogenous glucose production during high insulin is measured in mg new glucose synthesized per minute.	Calculated during the last 30 minutes of a 300 minute clamp.

Collaborators and Investigators

• Sponsor: Oregon Health and Science University

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): January 1, 2021
• Study Completion (Actual): March 1, 2021

Study Registration Dates

• First Submitted: July 2, 2015
• First Submitted That Met QC Criteria: August 6, 2015
• First Posted (Estimated): August 7, 2015

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 8, 2024
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Nutrition Disorders; Hyperinsulinism; Deficiency Diseases; Malnutrition; Insulin Resistance; Protein Deficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Protective Agents; Anticoagulants; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Fat Emulsions, Intravenous; Cryoprotective Agents; Heparin; Soybean oil, phospholipid emulsion; Glycerol
• Other Study ID Numbers: OHSU11258