Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Fat Induced Insulin Resistance and Atherosclerosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02348190
Recruitment Status : Completed
First Posted : January 28, 2015
Last Update Posted : November 25, 2015
Sponsor:
Information provided by (Responsible Party):
Temple University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Other Fatty Acid Oxidation Disorders Diabetes Mellitus Insulin Resistance Other: Lipid/heparin Not Applicable

Detailed Description:

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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 86 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Official Title: Fat Induced Insulin Resistance and Atherosclerosis
Study Start Date : June 2003
Actual Primary Completion Date : December 2014
Actual Study Completion Date : June 2015

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Lipid/heparin
16 healthy volunteers will undergo euglycemic - hyperinsulinemic clamping without radioactive isotopes and with (n=16) lipid/heparin co-infusion for 8 hours.
Other: Lipid/heparin

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 mRNAs.


Placebo Comparator: Control
16 healthy volunteers will undergo euglycemic - hyperinsulinemic clamping without radioactive isotopes and without (n=16) lipid/heparin co-infusion for 8 hours.
Other: Lipid/heparin

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 mRNAs.





Primary Outcome Measures :
  1. protein kinase C enzyme activity in tissue samples [ Time Frame: baseline, 1 hour, 2 hour, 4 hours ]
    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.


Secondary Outcome Measures :
  1. Insulin sensitivity [ Time Frame: 0, 1, 2, 3, 4, 5, 6, 7, 8 hours ]
    Glucose infusion rates during the 8 hour euglycemic-hyperinsulemic clamp will be calculated.

  2. Free fatty acids [ Time Frame: 0, 1 2, 3, 4, 5, 6, 7 ,8 hours ]
    Free fatty acid levels will be measured by standard methods in the investigator's laboratory

  3. protein kinase C enzyme activity in T cells [ Time Frame: 0, 1, 2, 3, 4, 5, 6, 7, 8 hours ]
    T cell extracts will be used to assay PKC, IKK, IκB-α, NFκB and VCAM, ICAM and e-selectin mRNA.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02348190


Locations
Layout table for location information
United States, Pennsylvania
Temple University Hospital
Philadelphia, Pennsylvania, United States, 19140
Sponsors and Collaborators
Temple University
Investigators
Layout table for investigator information
Principal Investigator: Guenther Boden, MD Temple University

Layout table for additonal information
Responsible Party: Temple University
ClinicalTrials.gov Identifier: NCT02348190     History of Changes
Other Study ID Numbers: 4148
First Posted: January 28, 2015    Key Record Dates
Last Update Posted: November 25, 2015
Last Verified: November 2015

Additional relevant MeSH terms:
Layout table for MeSH terms
Diabetes Mellitus
Insulin Resistance
Atherosclerosis
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Hyperinsulinism
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Heparin
Calcium heparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action