Fat Induced Insulin Resistance and Atherosclerosis
Condition: Other Fatty Acid Oxidation Disorders; Diabetes Mellitus; Insulin Resistance
MeSH terms: Atherosclerosis; Insulin Resistance
Study type: Interventional

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.
    

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.
    

Intervention name(s): Lipid/heparin
Intervention type(s): Other
Intervention description(s): 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.
Intervention MeSH terms: Heparin
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)