Fat Induced Insulin Resistance and Atherosclerosis
| Status: | Completed |
|---|---|
| Conditions: | Cardiology, Endocrine, Diabetes |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Endocrinology |
| Healthy: | No |
| Age Range: | 18 - 75 |
| Updated: | 4/21/2016 |
| Start Date: | June 2003 |
| End Date: | June 2015 |
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.
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.
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.
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.
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.
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Temple University Hospital On January 18, 1892 a three-story house at 3403 North Broad Street...
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