Mechanisms of Insulin Resistance in Humans

Completed

• Conditions: Inflammation; Insulin Resistance
• Interventions: Drug: 20% Intralipid

• Registration Number: NCT00330967
• Lead Sponsor: US Department of Veterans Affairs

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2006-04
• Study First Submitted: 2006-05-26
• Study First Submitted QC: 2006-05-26
• Study First Posted: 2006-05-29
• Primary Completion: 2012-01
• Study Completion: 2014-08
• Results First Submitted: 2015-01-22
• Status Verified: 2015-03
• Results First Submitted QC: 2015-03-04
• Results First Posted: 2015-03-17
• Last Update Submitted: 2015-03-17
• Last Update Posted: 2015-04-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

• two groups of 16 healthy subjects

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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

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Group 1	20% Intralipid	healthy subjects
Group 2	20% Intralipid	healthy subjects different from group 1

Primary Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (1)

Phoenix VA Health Care System Carl T. Hayden VA Medical Center, Phoenix, AZ; 🇺🇸 Phoenix, Arizona, United States