Fatty Acid Oxidation Defects and Insulin Sensitivity

Not Applicable

Completed

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

Interventions: Drug: Glycerol/Saline
Drug: Intralipid/Heparin
Drug: Hyperinsulinemic euglycemic clamp

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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
glycerol/saline FAOD	Glycerol/Saline	Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD)
glycerol/saline FAOD	Hyperinsulinemic euglycemic clamp	Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD)
intralipid FAOD	Intralipid/Heparin	Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD)
intralipid FAOD	Hyperinsulinemic euglycemic clamp	Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD)
glycerol/saline Control	Glycerol/Saline	Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control)
glycerol/saline Control	Hyperinsulinemic euglycemic clamp	Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control)
intralipid Control	Intralipid/Heparin	Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control)
intralipid Control	Hyperinsulinemic euglycemic clamp	Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control)

Primary Outcome Measures

Name	Time	Method
Glucose Disposal Rate (Rd)- the Rate of Glucose Infusion to Maintain Euglycemia During Steady State Insulin Infusion in mg/Min	Calculated during the last 30 minutes of a 300 minute clamp.	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.

Secondary Outcome Measures

Name	Time	Method
Endogenous Glucose Production (Ra) - Calculated by the Equations of Steele During Steady State in mg/Min	Calculated during the last 30 minutes of a 300 minute clamp.	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.

Locations (1): Oregon Health & Science University
🇺🇸
Portland, Oregon, United States