This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.In normoglycemic individuals, insulin resistance is a key risk factor for the future development of type 2 diabetes and is also associated with the Insulin Resistance Syndrome: hypertension, glucose intolerance, upper body fat distriubtion, dyslipidemia, and dysfibrinolysis that predisposes ASHD, and cardiovascular disease. Estimated to affect 20-25% of individuals in Western Societies, it is therefore important to elucidate the molecular mechanisms causing this phenomena. This must involve skeletal muscle since this tissue accounts for the major portion of insulin-mediated glucose uptake in-vivo. This proposal will study 20 insulin sensitive and 20 insulin resistant subjects with normal glucose tolerance as well as a group of 20 untreated type 2 diabetics. Subjects will be admitted to GCRC and evaluated with an oral glucose tolerance test, DEXA scan to ascess body composition, and waist-hip-ratio. Insulin sensitivity will be assessed with a hyperinsulinemic euglycemic clamp and percutaneous biopsies of the vastus lateralis and adipose tissue biopsies will be performed under basal and insulin stimulated conditions. A second series of studies will be performed on 10 insulin resistant subjects who will be re-studied after treatment with a TZD (Rosiglitazone/or Pioglitazone for 2 months), thus serving as their own control. Proteomic studies will be conducted on the tissue to identify differential protein expresson or modification associated with insulin resistance (IR). The study design focuses the search for proteins that directly influence insulin sensitivity (IS). Then the proteomic database will be combine with cDNA microarray to identify differentially expressed genes at both the mRNA and protein levels. This will increase the confidence that these genes are truly induced or suppressed by insulin. Then, the study subgroup will enhance the ability to identify relevant proteins that are acutely insulin responsive, altered in stated of chronic IR, and normalized by TZD theapy. In selecting genes for physiological and molecular studies, proteins will be further analyzed using an array of bioinformatic databases.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
General Clinical Research Centers Program (M01)
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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