Mechanisms of Insulin Resistance in Humans

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Mechanisms of Insulin Resistance in Humans

Conditions
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Inflammation, Insulin Resistance

Intervention / Treatment
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* Drug: 20% Intralipid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1<br>healthy subjects | Drug: 20% Intralipid<br>* lipid infusion<br>|
| Group 2<br>healthy subjects different from group 1 | Drug: 20% Intralipid<br>* lipid infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fat Emulsions, Intravenous, Free Fatty Acids, Glucose Clamp Technique, Inflammation, Insulin Resistance, Muscle, Skeletal, NF-Kappa B