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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| glycerol/saline FAOD | Experimental | Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD) |
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| intralipid FAOD | Experimental | Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD) |
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| glycerol/saline Control | Experimental | Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control) |
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| intralipid Control | Experimental | Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intralipid/Heparin | Drug | Co-infusion of intralipid and heparin solutions during a hyperinsulinemic euglycemic clamp |
|
| 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. |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Oregon Health & Science University | Portland | Oregon | 97239 | United States |
2 initial control participants who did not have a comparable FAO matched participant completed the protocol procedures to establish the final protocol; the data was not included in the final analysis. 23 participants with a FAOD were randomized. Of those randomized, 2 did not meet inclusion criteria, and 2 declined to participate. 27 control participants were randomized. Of those randomized, 2 did not meet inclusion criteria and 3 declined to participate.
2 control participants were recruited between February 2016 and June 2016 to complete testing of the protocol procedures. Adjustments to clamp, MRS and biopsy protocols were made and a final manual of operating procedures developed. These 2 participants were not included in the final data analysis. Then, 23 participants with a FAOD were screened for eligibility from June 2016 to August 2019. 27 control participants were screened for eligibility from July 2016 to February 2020.
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| ID | Title | Description |
|---|---|---|
| FG000 | FAOD Glycerol Then Intralipid | Participants with a FAOD first complete a hyperinsulinemic euglycemic clamp with a co-infusion of glycerol. After a wash-out of 4 months, they then complete a a hyperinsulinemic euglycemic clamp with a co-infusion of intralipid. |
| FG001 | FAOD Intralipid Then Glycerol |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 23, 2020 |
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| Glycerol/Saline | Drug | Co-infusion of a glycerol/saline solutions during a hyperinsulinemic euglycemic clamp |
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| Hyperinsulinemic euglycemic clamp | 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. |
|
| Calculated during the last 30 minutes of a 300 minute clamp. |
Participants with a FAOD first complete a hyperinsulinemic euglycemic clamp with a co-infusion of intralipid. After a wash-out of 4 months, they then complete a a hyperinsulinemic euglycemic clamp with a co-infusion of glycerol. |
| FG002 | Control Glycerol Then Intralipid | Matched normal control participants first complete a hyperinsulinemic euglycemic clamp with a co-infusion of glycerol. After a wash-out of 4 months, they then complete a a hyperinsulinemic euglycemic clamp with a co-infusion of intralipid. |
| FG003 | Control Intralipid Then Glycerol | Matched normal control participants first complete a hyperinsulinemic euglycemic clamp with a co-infusion of intralipid. After a wash-out of 4 months, they then complete a a hyperinsulinemic euglycemic clamp with a co-infusion of glycerol. |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | FAOD Glycerol Then Intralipid | Participants with a FAOD first complete a hyperinsulinemic euglycemic clamp with a co-infusion of glycerol. After a wash-out of 4 months, they then complete a a hyperinsulinemic euglycemic clamp with a co-infusion of intralipid. |
| BG001 | FAOD Intralipid Then Glycerol | Participants with a FAOD first complete a hyperinsulinemic euglycemic clamp with a co-infusion of intralipid. After a wash-out of 4 months, they then complete a a hyperinsulinemic euglycemic clamp with a co-infusion of glycerol. |
| BG002 | Control Glycerol Then Intralipid | Matched control participants first complete a hyperinsulinemic euglycemic clamp with a co-infusion of glycerol. After a wash-out of 4 months, they then complete a a hyperinsulinemic euglycemic clamp with a co-infusion of intralipid. |
| BG003 | Control Intralipid Then Glycerol | Matched control participants first complete a hyperinsulinemic euglycemic clamp with a co-infusion of intralipid. After a wash-out of 4 months, they then complete a a hyperinsulinemic euglycemic clamp with a co-infusion of glycerol. |
| BG004 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | 1 participant with a FAOD withdrew after completing the glycerol clamp . 2 control participants completed the protocol to establish the study procedures, but are not included in the statistical analysis. 1 control participants withdrew and 1 was discontinued leaving 18 participants data for the intralipid clamp. In addition, 1 other control was discontinued and 1 control had technical challenges during the glycerol clamp leaving 16 control participants data for glycerol clamp. | Posted | Mean | Standard Deviation | mg/min | Calculated during the last 30 minutes of a 300 minute clamp. |
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| Secondary | 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. | 1 participant with a FAOD withdrew after completing the glycerol clamp . 2 control participants completed the protocol to establish the study procedures, but are not included in the statistical analysis. 1 control withdrew and 1 was discontinued leaving 18 participants data for the intralipid clamp. In addition, 1 other control was discontinued and 1 control had technical challenges during the glycerol clamp leaving 16 control participants data for the glycerol clamp. | Posted | Mean | Standard Deviation | mg/min | Calculated during the last 30 minutes of a 300 minute clamp. |
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3 months for each intervention
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Glycerol/Saline FAOD | Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD) Glycerol/Saline: Co-infusion of a glycerol/saline solutions during a hyperinsulinemic euglycemic clamp 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. | 0 | 19 | 1 | 19 | 13 | 19 |
| EG001 | Intralipid FAOD | Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD) Intralipid/Heparin: Co-infusion of intralipid and heparin solutions during a hyperinsulinemic euglycemic clamp 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. | 0 | 18 | 2 | 18 | 12 | 18 |
| EG002 | Glycerol/Saline Control | Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control) Glycerol/Saline: Co-infusion of a glycerol/saline solutions during a hyperinsulinemic euglycemic clamp 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. | 0 | 20 | 0 | 20 | 11 | 20 |
| EG003 | Intralipid Control | Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control) Intralipid/Heparin: Co-infusion of intralipid and heparin solutions during a hyperinsulinemic euglycemic clamp 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. | 0 | 21 | 1 | 21 | 13 | 21 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Rhabdomyolysis | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Urinary Tract Infection/Kidney Infection | Infections and infestations | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | General disorders | Systematic Assessment |
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| Pain at muscle biopsy site | Surgical and medical procedures | Systematic Assessment |
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| Pain at fat biopsy site | Surgical and medical procedures | Systematic Assessment |
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| Upper respiratory infection/colds | Infections and infestations | Systematic Assessment |
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| UTI | Infections and infestations | Systematic Assessment |
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| allergic reaction | General disorders | Systematic Assessment |
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| Emesis, Diarrhea, GI upset, Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Hematoma at fat biopsy site | Surgical and medical procedures | Systematic Assessment |
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| Bleeding or bruising at biopsy sites | Surgical and medical procedures | Systematic Assessment |
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| Tooth pain | General disorders | Systematic Assessment |
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| Syncopal episode | Nervous system disorders | Systematic Assessment |
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| general pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| hypoglycemia during clamp | Endocrine disorders | Systematic Assessment |
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| IV infiltration or phlebitis | Surgical and medical procedures | Systematic Assessment |
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| heavy menstrual cycles | Reproductive system and breast disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Melanie Gillingham, PhD | Oregon Health & Science University | 503-494-1682 | gillingm@ohsu.edu |
| Feb 8, 2023 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| C536353 | VLCAD deficiency |
| C566945 | Trifunctional Protein Deficiency With Myopathy And Neuropathy |
| C536038 | Medium chain acyl CoA dehydrogenase deficiency |
| C563461 | Carnitine Palmitoyltransferase II Deficiency, Late-Onset |
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| ID | Term |
|---|---|
| C545823 | soybean oil, phospholipid emulsion |
| D006493 | Heparin |
| D005990 | Glycerol |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |
| D002241 | Carbohydrates |
| D000073999 | Triose Sugar Alcohols |
| D013402 | Sugar Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
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| Between 18 and 65 years |
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| >=65 years |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
|
| Unknown or Not Reported |
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| OG001 | Intralipid FAOD | Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD) Intralipid/Heparin: Co-infusion of intralipid and heparin solutions during a hyperinsulinemic euglycemic clamp 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. |
| OG002 | Glycerol/Saline Control | Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control) Glycerol/Saline: Co-infusion of a glycerol/saline solutions during a hyperinsulinemic euglycemic clamp 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. |
| OG003 | Intralipid Control | Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control) Intralipid/Heparin: Co-infusion of intralipid and heparin solutions during a hyperinsulinemic euglycemic clamp 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. |
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