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The Objectives of the study are to: (1)compare the inflammatory response and insulin resistance in skeletal muscles during a systemic infusion of lipid with that during a local infusion of lipid into the femoral artery. which would cause minimal or no systemic hyperlipidemia but local plasma free fatty acid (FFA) concentrations similar to those during the systemic lipid infusion, and (2) determine the inflammatory response and insulin resistance in skeletal muscle during an infusion of lipid into the femoral artery as described above after NF-KB inhibition by high dose salicylate treatment in humans.
Insulin resistance in skeletal muscle is a characteristic abnormality in obesity and the metabolic syndrome and a major factor responsible for the development of type 2 diabetes. Although the mechanisms responsible for muscle insulin resistance are largely unclear, lipid oversupply is an important factor. Among numerous potential mechanisms whereby lipid oversupply may cause muscle insulin resistance, current evidence points towards inflammation as being critical. Recent studies in animals, however, indicate that the inflammatory response in skeletal muscles may require the presence of circulating pro-inflammatory factors suggesting that the inflammation induced insulin resistance in skeletal muscles may be a secondary event. More specifically, activation of Nuclear Factor-Kappa B(NF-kB), and inflammatory master switch that drives the production of numerous pro-inflammatory cytokines in fat and liver, has been implicated in causing insulin resistance in skeletal muscles by increasing circulating pro-inflammatory cytokines. In contrast, animal studies have found that activation of NF-KB directly in skeletal muscles has no or little effect on its insulin sensitivity but does produce other abnormalities such as increased proteasome activity. The study shall therefore be undertaken to determine to what extent lipid-induced inflammation and insulin resistance in skeletal muscles requires the presence of circulating proinflammatory factors in humans.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group 1 | healthy subjects |
| |
| Group 2 | healthy subjects different from group 1 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 20% Intralipid | Drug | lipid infusion |
|
| Measure | Description | Time Frame |
|---|---|---|
| Insulin Signaling With Lipid Infusion | IRS-1 expression in response to femoral lipid infusion in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blot bands, normalized to a housekeeping protein, GAPDH, in control and treated groups. | 4 h |
| Phos-p38 MAPK Expression With Femoral Lipid and Insulin Infusions | Phosphorylation of p38 MAPK in response to femoral lipid and insulin infusions. phospho-p38 MAPK expression in response to femoral lipid infusion in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups. | 4 h |
| p38 MAPK Expression With Femoral Lipid and Insulin Infusions | p38 MAPK expression in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups. | 4 h |
| Phospho-ERK MAPK Expression With Femoral Lipid and Insulin Infusions | Phosphorylation of ERK MAPK in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups. | 4 h |
| ERK MAPK Expression With Femoral Lipid and Insulin Infusions | ERK MAPK expression in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups. | 4 h |
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Inclusion Criteria:
Exclusion Criteria:
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healthy subjects
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| Name | Affiliation | Role |
|---|---|---|
| Charles C Oh, MD | Phoenix VA Health Care System Carl T. Hayden VA Medical Center, Phoenix, AZ | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Phoenix VA Health Care System Carl T. Hayden VA Medical Center, Phoenix, AZ | Phoenix | Arizona | 85012 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Group 1 | Systemic Intralipid infusion subjects 20% Intralipid: lipid infusion |
| FG001 | Group 2 | Femoral arterial Intralipid infusion subjects 20% Intralipid: lipid infusion |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Group 1 | Systemic Intralipid infusion subjects 20% Intralipid: lipid infusion |
| BG001 | Group 2 | Femoral Intralipid infusion subjects 20% Intralipid: lipid infusion |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Number |
| 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 | Insulin Signaling With Lipid Infusion | IRS-1 expression in response to femoral lipid infusion in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blot bands, normalized to a housekeeping protein, GAPDH, in control and treated groups. | Posted | Mean | Standard Deviation | ratio | 4 h |
|
|
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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 | Group 1 | Systemic Intralipid infusion group 20% Intralipid: lipid infusion |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Edema | Surgical and medical procedures | Non-systematic Assessment | Right lower extremity edema following muscle biopsy. |
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The study's original Principal Investigator left the VA prior to the completion of data acquisition and no further subjects were enrolled. The data entered were analyzed based solely on study files in the system.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Charles Oh | Phoenix VA Health Care System | 602-277-5551 | 1-5127 | charles.oh@va.gov |
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| ID | Term |
|---|---|
| D007249 | Inflammation |
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
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| ID | Term |
|---|---|
| C545823 | soybean oil, phospholipid emulsion |
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Blood samples, muscle biopsies
| Phospho-JNK MAPK Expression With Femoral Lipid and Insulin Infusions | Phosphorylation of JNK MAPK in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups. | 4 h |
| JNK MAPK Expression With Femoral Lipid and Insulin Infusions | JNK MAPK expression in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups. | 4 h |
| BG002 | Total | Total of all reporting groups |
| participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Gender | Number | participants |
|
| Region of Enrollment | Number | participants |
|
|
| Primary | Phos-p38 MAPK Expression With Femoral Lipid and Insulin Infusions | Phosphorylation of p38 MAPK in response to femoral lipid and insulin infusions. phospho-p38 MAPK expression in response to femoral lipid infusion in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups. | Posted | Mean | Standard Deviation | ratio | 4 h |
|
|
|
| Primary | p38 MAPK Expression With Femoral Lipid and Insulin Infusions | p38 MAPK expression in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups. | Posted | Mean | Standard Deviation | ratio | 4 h |
|
|
|
| Primary | Phospho-ERK MAPK Expression With Femoral Lipid and Insulin Infusions | Phosphorylation of ERK MAPK in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups. | Posted | Mean | Standard Deviation | ratio | 4 h |
|
|
|
| Primary | ERK MAPK Expression With Femoral Lipid and Insulin Infusions | ERK MAPK expression in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups. | Posted | Mean | Standard Deviation | ratio | 4 h |
|
|
|
| Primary | Phospho-JNK MAPK Expression With Femoral Lipid and Insulin Infusions | Phosphorylation of JNK MAPK in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups. | Posted | Mean | Standard Deviation | ratio | 4 h |
|
|
|
| Primary | JNK MAPK Expression With Femoral Lipid and Insulin Infusions | JNK MAPK expression in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups. | Posted | Mean | Standard Deviation | ratio | 4 h |
|
|
|
| 0 |
| 0 |
| 0 |
| 0 |
| EG001 | Group 2 | Femoral Intralipid infusion group 20% Intralipid: lipid infusion | 1 | 25 | 0 | 25 |
|
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| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| Title | Measurements |
|---|---|
|
| Phos-p38 MAPK Insulin Lipid |
|
|
| p38 MAPK Insulin Lipid |
|
|
| Phos-ERK MAPK Insulin Lipid |
|
|
| ERK MAPK Insulin Lipid |
|
|
| Phos-JNK MAPK Insulin Lipid |
|
|
| JNK MAPK Insulin Lipid |
|