Clinical trial NCT00330967: Mechanisms of Insulin Resistance in Humans
Official title: Mechanisms of Insulin Resistance in Humans
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Inflammation
Insulin Resistance
Keywords: Fat Emulsions, Intravenous
Free Fatty Acids
Glucose Clamp Technique
Inflammation
Insulin Resistance
Muscle, Skeletal
NF-Kappa B
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2006-05-29
Enrollment: 25
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: healthy subjects

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.

Eligibility criteria: 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

Primary outcomes:
measure: Insulin Signaling With Lipid Infusion
timeFrame: 4 h
measure: Phos-p38 MAPK Expression With Femoral Lipid and Insulin Infusions
timeFrame: 4 h
measure: p38 MAPK Expression With Femoral Lipid and Insulin Infusions
timeFrame: 4 h
measure: Phospho-ERK MAPK Expression With Femoral Lipid and Insulin Infusions
timeFrame: 4 h
measure: ERK MAPK Expression With Femoral Lipid and Insulin Infusions
timeFrame: 4 h
measure: Phospho-JNK MAPK Expression With Femoral Lipid and Insulin Infusions
timeFrame: 4 h
measure: JNK MAPK Expression With Femoral Lipid and Insulin Infusions
timeFrame: 4 h
Secondary outcomes:
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix VA Health Care System Carl T. Hayden VA Medical Center, Phoenix, AZ
state: Arizona
Study officials:
affiliation: Phoenix VA Health Care System Carl T. Hayden VA Medical Center, Phoenix, AZ
name: Charles C Oh, MD
role: PRINCIPAL_INVESTIGATOR
References: