Fat Induced Insulin Resistance and Atherosclerosis

NCT ID: NCT02348190

Last Updated: 2015-11-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 86 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-06-30
• Study Completion Date: 2015-06-30

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.

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.

Conditions

Other Fatty Acid Oxidation Disorders; Diabetes Mellitus; Insulin Resistance

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Blinding Strategy: NONE

Study Groups

Lipid/heparin

16 healthy volunteers will undergo euglycemic - hyperinsulinemic clamping without radioactive isotopes and with (n=16) lipid/heparin co-infusion for 8 hours.

Group Type: ACTIVE_COMPARATOR

Lipid/heparin

Intervention Type: 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.

Control

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

Group Type: PLACEBO_COMPARATOR

Lipid/heparin

Intervention Type: 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.

Interventions

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.

Intervention Type: OTHER

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Temple University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Guenther Boden, MD

Role: PRINCIPAL_INVESTIGATOR

Temple University

Locations

Temple University Hospital

Philadelphia, Pennsylvania, United States

Countries

United States

Other Identifiers

4148

Identifier Type: -

Identifier Source: org_study_id