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Completed

NCT Number: NCT02348190

Fat Induced Insulin Resistance and Atherosclerosis

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.

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Key information

Conditions

Other Fatty Acid Oxidation Disorders Diabetes Mellitus Endocrine System Diseases Glucose Metabolism Disorders Hyperinsulinism Insulin Resistance Metabolic Diseases Nutritional and Metabolic Diseases

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Temple University Hospital

Philadelphia, Pennsylvania, 19140, United States

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Lipid/heparin

Other

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 outcomes

  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 outcomes

  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.

Sponsors and collaborators

Lead sponsor

Temple University

Other

Registry information

Important dates

Study start
2003
Primary completion
2014
Study completion
2015
First posted
Jan 28, 2015
Registry last updated
Nov 25, 2015

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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