Expired Study
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Philadelphia, Pennsylvania 19140


Purpose:

The overall objective of the current proposal is to strengthen the putative link between FFA induced insulin resistance and atherosclerotic vascular disease (ASVD). To this end, the investigators will test the following hypotheses: 1) that FFA induced activation of protein kinase C βII (PKC β II) and δ and other serine kinases such as IκB kinase (IKK) in human muscle is associated with a decrease in insulin stimulated tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1) and of IRS-1 associated phosphatidylinositol 3 (PI3) kinase; 2) that these changes precede the development of insulin resistance; 3) that the decrease in IκB-α results in activation of nuclear factor κB (NFκB) and the expression of adhesion molecules and cytokines; 4) that PKC and IKK are involved in producing insulin resistance and activation of the IκB/ NFκB pathway and lastly 5) that the same mechanisms operative in healthy volunteers are also operative in patients with T2DM.The investigators will test these hypotheses in normal (current) and diabetic volunteers (previously completed) . Euglycemic-hyperinsulinemic clamps will be performed with and without co-infusion of lipid plus heparin (to raise FFAs) and by obtaining serial muscle and fat biopsies and blood samples will be obtained for measurement of substrates, hormones, enzymes and metabolites.


Study summary:

All subjects will be admitted to the GCRC in the afternoon before the tests (Day 1) and will undergo a thorough physical examination. Routine admission lab tests (including a 2-h 75g OGTT) and body composition measurements will be obtained. A standardized dinner will be served at ~ 6PM. The next (Day 2) after an overnight fast, IV lines will be placed (arms will be wrapped with a heating blanket and kept at 70ºF to arterialize venous blood). The following studies will be performed. Thirty-two healthy volunteers will undergo euglycemic - hyperinsulinemic clamping without radioactive isotopes and with (n=16) and without (n=16) lipid/heparin co-infusion for 8 hours. Serial (at 0, 1, 2 and 4 h) muscle and fat biopsies and serial blood samples (q' 1 h) will be obtained. The following measurements will be obtained in muscle biopsies and T-cell extracts: PKC-βI and II and PKC-δ, IKK, IκB-α, NFκB, IRS-1 tyrosine phosphorylation, IRS-1 associated PI3- kinase, ICAM, VCAM and e-selectin mRNAs.


Criteria:

Inclusion Criteria: - The investigators plan to study 32 healthy normal subjects. - These volunteers will be male and female, between the ages of 30 and 75 years and of all races. - None of these volunteers will have a family history of diabetes or any other endocrine disorder and none will be taking any medications. Exclusion Criteria: - Patients with chronic health problems including cardiovascular, pulmonary, hematologic (*Hb< 9 g/dl), renal (serum creatinine > 1.8 mg/dl), hepatic disease, AIDS or other chronic infectious disease will be excluded. - Pregnant women will be excluded. Non-pregnant women will be studied during the follicular phase of their menstrual cycle. If needed, a pregnancy test will be performed to exclude pregnancy.


Study is Available At:


Original ID:

4148


NCT ID:

NCT02348190


Secondary ID:


Study Acronym:


Brief Title:

Fat Induced Insulin Resistance and Atherosclerosis


Official Title:

Fat Induced Insulin Resistance and Atherosclerosis


Overall Status:

Completed


Study Phase:

N/A


Genders:

Both


Minimum Age:

18 Years


Maximum Age:

75 Years


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

Temple University


Oversight Authority:

United States: Institutional Review Board


Reasons Why Stopped:


Study Type:

Interventional


Study Design:

Allocation: Non-Randomized, Intervention Model: Pa


Number of Arms:

2


Number of Groups:

0


Total Enrollment:

86


Enrollment Type:

Actual


Overall Contact Information

Official Name:Guenther Boden, MD
Principal Investigator
Temple University

Study Dates

Start Date:June 2003
Completion Date:June 2015
Completion Type:Actual
Primary Completion Date:December 2014
Primary Completion Type:Actual
Verification Date:November 2015
Last Changed Date:November 23, 2015
First Received Date:January 22, 2015

Study Outcomes

Outcome Type:Secondary Outcome
Measure:protein kinase C enzyme activity in T cells
Time Frame:0, 1, 2, 3, 4, 5, 6, 7, 8 hours
Safety Issues:False
Description:T cell extracts will be used to assay PKC, IKK, IκB-α, NFκB and VCAM, ICAM and e-selectin mRNA.
Outcome Type:Secondary Outcome
Measure:Free fatty acids
Time Frame:0, 1 2, 3, 4, 5, 6, 7 ,8 hours
Safety Issues:False
Description:Free fatty acid levels will be measured by standard methods in the investigator's laboratory
Outcome Type:Secondary Outcome
Measure:Insulin sensitivity
Time Frame:0, 1, 2, 3, 4, 5, 6, 7, 8 hours
Safety Issues:False
Description:Glucose infusion rates during the 8 hour euglycemic-hyperinsulemic clamp will be calculated.
Outcome Type:Primary Outcome
Measure:protein kinase C enzyme activity in tissue samples
Time Frame:baseline, 1 hour, 2 hour, 4 hours
Safety Issues:False
Description:The following measurements will be obtained in muscle biopsies: PKC-βI and II and PKC-δ, IKK, IκB-α, NFκB, IRS-1 tyrosine phosphorylation, IRS-1 associated PI3- kinase, ICAM, VCAM and e-selectin mRNAs.

Study Interventions

Intervention Type:Other
Name:Lipid/heparin
Description:32 healthy volunteers will undergo euglycemic - hyperinsulinemic clamping without radioactive isotopes and with (n=16) and without (n=16) lipid/heparin co-infusion for 8 hours. Serial (at 0, 1, 2 and 4 h) muscle and fat biopsies and serial blood samples (q' 1 h) will be obtained. The following measurements will be obtained in muscle biopsies and T-cell extracts: PKC-βI and II and PKC-δ, IKK, IκB-α, NFκB, IRS-1 tyrosine phosphorylation, IRS-1 associated PI3- kinase, ICAM, VCAM and e-selectin mRN
Arm Name:Lipid/heparin

Study Arms

Study Arm Type:Placebo Comparator
Arm Name:Control
Description:16 healthy volunteers will undergo euglycemic - hyperinsulinemic clamping without radioactive isotopes and without (n=16) lipid/heparin co-infusion for 8 hours.
Study Arm Type:Active Comparator
Arm Name:Lipid/heparin
Description:16 healthy volunteers will undergo euglycemic - hyperinsulinemic clamping without radioactive isotopes and with (n=16) lipid/heparin co-infusion for 8 hours.

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:Temple University

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: January 21, 2020

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