Mechanisms of Insulin Resistance in Humans

Overview

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.

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: January 2012

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

  • Drug: 20% Intralipid
    • lipid infusion

Arms, Groups and Cohorts

  • Group 1
    • healthy subjects
  • Group 2
    • healthy subjects different from group 1

Clinical Trial Outcome Measures

Primary Measures

  • Insulin Signaling With Lipid Infusion
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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.

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 21 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • US Department of Veterans Affairs
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Charles C Oh, MD, Principal Investigator, Phoenix VA Health Care System Carl T. Hayden VA Medical Center, Phoenix, AZ

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