Inflammation, Insulin Resistance
Conditions
Keywords
Fat Emulsions, Intravenous, Free Fatty Acids, Glucose Clamp Technique, Inflammation, Insulin Resistance, Muscle, Skeletal, NF-Kappa B
Brief summary
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.
Detailed description
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.
Interventions
DRUG20% Intralipid
lipid infusion
Sponsors
US Department of Veterans Affairs
Study design
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* two groups of 16 healthy subjects
Exclusion criteria
* diabetes or impaired glucose tolerance * peripheral vascular disease * pulmonary disease * clinically significant hepatic or renal disease * triglycerides \>200mg/dl * anemia * abnormal PT, PTT or INR * pregnancy or lactation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Signaling With Lipid Infusion | 4 h | 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. |
| Phos-p38 MAPK Expression With Femoral Lipid and Insulin Infusions | 4 h | 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. |
| p38 MAPK Expression With Femoral Lipid and Insulin Infusions | 4 h | 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. |
| Phospho-ERK MAPK Expression With Femoral Lipid and Insulin Infusions | 4 h | 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. |
| ERK MAPK Expression With Femoral Lipid and Insulin Infusions | 4 h | 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. |
| Phospho-JNK MAPK Expression With Femoral Lipid and Insulin Infusions | 4 h | 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. |
| JNK MAPK Expression With Femoral Lipid and Insulin Infusions | 4 h | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Systemic Intralipid infusion subjects
20% Intralipid: lipid infusion | 0 |
| Group 2 Femoral Intralipid infusion subjects
20% Intralipid: lipid infusion | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 9 |
| Overall Study | Withdrawal by Subject | 0 | 5 |
Baseline characteristics
| Characteristic | Total | Group 2 |
|---|---|---|
| Age, Categorical <=18 years | 0 participants | 0 participants |
| Age, Categorical >=65 years | 0 participants | 0 participants |
| Age, Categorical Between 18 and 65 years | 25 participants | 25 participants |
| Age, Continuous | 47.65 years STANDARD_DEVIATION 11.43 | 47.65 years STANDARD_DEVIATION 11.43 |
| Gender Female | 4 participants | 4 participants |
| Gender Male | 21 participants | 21 participants |
| Region of Enrollment United States | 25 participants | 25 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 25 |
| serious Total, serious adverse events | 0 / 0 | 1 / 25 |
Outcome results
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.
Time frame: 4 h
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 2 | ERK MAPK Expression With Femoral Lipid and Insulin Infusions | ERK MAPK Basal | 0.000103 ratio | Standard Deviation 0.0000722 |
| Group 2 | ERK MAPK Expression With Femoral Lipid and Insulin Infusions | ERK MAPK Basal Lipid | 0.000158 ratio | Standard Deviation 0.0000826 |
| Group 2 | ERK MAPK Expression With Femoral Lipid and Insulin Infusions | ERK MAPK Insulin | 0.000124 ratio | Standard Deviation 0.0000237 |
| Group 2 | ERK MAPK Expression With Femoral Lipid and Insulin Infusions | ERK MAPK Insulin Lipid | 0.000114 ratio | Standard Deviation 0.0000017 |
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.
Time frame: 4 h
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 2 | Insulin Signaling With Lipid Infusion | IRS-1 Basal | 0.4334 ratio | Standard Deviation 0.2199 |
| Group 2 | Insulin Signaling With Lipid Infusion | IRS-1 Basal Lipid | 0.7276 ratio | Standard Deviation 0.0173 |
| Group 2 | Insulin Signaling With Lipid Infusion | IRS-1 Insulin | 0.5264 ratio | Standard Deviation 0.381 |
| Group 2 | Insulin Signaling With Lipid Infusion | IRS-1 Insulin Lipid | 0.3534 ratio | Standard Deviation 0.1391 |
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.
Time frame: 4 h
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 2 | JNK MAPK Expression With Femoral Lipid and Insulin Infusions | JNK MAPK Basal | 0.001364 ratio | Standard Deviation 0.00594 |
| Group 2 | JNK MAPK Expression With Femoral Lipid and Insulin Infusions | JNK MAPK Basal Lipid | 0.002996 ratio | Standard Deviation 0.002837 |
| Group 2 | JNK MAPK Expression With Femoral Lipid and Insulin Infusions | JNK MAPK Insulin | 0.002151 ratio | Standard Deviation 0.002032 |
| Group 2 | JNK MAPK Expression With Femoral Lipid and Insulin Infusions | JNK MAPK Insulin Lipid | 0.001783 ratio | Standard Deviation 0.001883 |
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.
Time frame: 4 h
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 2 | p38 MAPK Expression With Femoral Lipid and Insulin Infusions | p38 MAPK Basal | 0.000455 ratio | Standard Deviation 0.0000088 |
| Group 2 | p38 MAPK Expression With Femoral Lipid and Insulin Infusions | p38 MAPK Basal Lipid | 0.001291 ratio | Standard Deviation 0.0008 |
| Group 2 | p38 MAPK Expression With Femoral Lipid and Insulin Infusions | p38 MAPK Insulin | 0.000502 ratio | Standard Deviation 0.000337 |
| Group 2 | p38 MAPK Expression With Femoral Lipid and Insulin Infusions | p38 MAPK Insulin Lipid | 0.000377 ratio | Standard Deviation 0.0000903 |
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.
Time frame: 4 h
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 2 | Phos-p38 MAPK Expression With Femoral Lipid and Insulin Infusions | Phos-p38 MAPK Basal | 0.000394 ratio | Standard Deviation 0.000164 |
| Group 2 | Phos-p38 MAPK Expression With Femoral Lipid and Insulin Infusions | Phos-p38 MAPK Basal Lipid | 0.001271 ratio | Standard Deviation 0.001013 |
| Group 2 | Phos-p38 MAPK Expression With Femoral Lipid and Insulin Infusions | Phos-p38 MAPK Insulin | 0.000337 ratio | Standard Deviation 0.00014 |
| Group 2 | Phos-p38 MAPK Expression With Femoral Lipid and Insulin Infusions | Phos-p38 MAPK Insulin Lipid | 0.000270 ratio | Standard Deviation 0.000049 |
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.
Time frame: 4 h
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 2 | Phospho-ERK MAPK Expression With Femoral Lipid and Insulin Infusions | Phos-ERK MAPK Basal | 0.000091 ratio | Standard Deviation 0.0000378 |
| Group 2 | Phospho-ERK MAPK Expression With Femoral Lipid and Insulin Infusions | Phos-ERK MAPK Basal Lipid | 0.000108 ratio | Standard Deviation 0.0000366 |
| Group 2 | Phospho-ERK MAPK Expression With Femoral Lipid and Insulin Infusions | Phos-ERK MAPK Insulin | 0.000096 ratio | Standard Deviation 0.0000103 |
| Group 2 | Phospho-ERK MAPK Expression With Femoral Lipid and Insulin Infusions | Phos-ERK MAPK Insulin Lipid | 0.000092 ratio | Standard Deviation 0.000007 |
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.
Time frame: 4 h
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 2 | Phospho-JNK MAPK Expression With Femoral Lipid and Insulin Infusions | Phos-JNK MAPK Basal | 0.00401 ratio | Standard Deviation 0.002967 |
| Group 2 | Phospho-JNK MAPK Expression With Femoral Lipid and Insulin Infusions | Phos-JNK MAPK Basal Lipid | 0.005888 ratio | Standard Deviation 0.004952 |
| Group 2 | Phospho-JNK MAPK Expression With Femoral Lipid and Insulin Infusions | Phos-JNK MAPK Insulin | 0.003756 ratio | Standard Deviation 0.002537 |
| Group 2 | Phospho-JNK MAPK Expression With Femoral Lipid and Insulin Infusions | Phos-JNK MAPK Insulin Lipid | 0.00224 ratio | Standard Deviation 0.001161 |