Fat Induced Insulin Resistance and Atherosclerosis

Diabetes Mellitus Clinical Trial

Official title:

Fat Induced Insulin Resistance and Atherosclerosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02348190
• Other study ID #: 4148
• Status: Completed
• Phase: N/A
• First received: January 22, 2015
• Last updated: November 23, 2015
• Start date: June 2003
• Est. completion date: June 2015

Study information

• Verified date: November 2015
• Source: Temple University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 86
• Est. completion date: June 2015
• Est. primary completion date: December 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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.

Study Design

Allocation: Non-Randomized, Intervention Model: Parallel Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Atherosclerosis
• Diabetes Mellitus
• Insulin Resistance
• Other Fatty Acid Oxidation Disorders

Intervention

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-ßI and II and PKC-d, IKK, I?B-a, NF?B, IRS-1 tyrosine phosphorylation, IRS-1 associated PI3- kinase, ICAM, VCAM and e-selectin mRNAs.

Locations

Country	Name	City	State
United States	Temple University Hospital	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Temple University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	protein kinase C enzyme activity in tissue samples	The following measurements will be obtained in muscle biopsies: PKC-ßI and II and PKC-d, IKK, I?B-a, NF?B, IRS-1 tyrosine phosphorylation, IRS-1 associated PI3- kinase, ICAM, VCAM and e-selectin mRNAs.	baseline, 1 hour, 2 hour, 4 hours	No
Secondary	Insulin sensitivity	Glucose infusion rates during the 8 hour euglycemic-hyperinsulemic clamp will be calculated.	0, 1, 2, 3, 4, 5, 6, 7, 8 hours	No
Secondary	Free fatty acids	Free fatty acid levels will be measured by standard methods in the investigator's laboratory	0, 1 2, 3, 4, 5, 6, 7 ,8 hours	No
Secondary	protein kinase C enzyme activity in T cells	T cell extracts will be used to assay PKC, IKK, I?B-a, NF?B and VCAM, ICAM and e-selectin mRNA.	0, 1, 2, 3, 4, 5, 6, 7, 8 hours	No