Access Type

Open Access Thesis

Date of Award

January 2015

Degree Type

Thesis

Degree Name

M.S.

Department

Pharmaceutical Sciences

First Advisor

Zhengping yi

Abstract

Type 2 Diabetes is a metabolic disorder associated with insulin resistance and consequent high blood glucose levels. Maximum glucose disposal takes place in skeletal muscle and studying skeletal muscle insulin resistance is crucial. Protein Phosphatase 2A (PP2A) is one of the major serine/threonine phosphatases belonging to PhosphoProteinPhosphatase (PPP) family. It constitutes about 80% of all serine/threonine phosphatases. It is regulated by numerous regulatory subunits as well as other substrate molecules and post translational modifications. This alters their localization, activity and also its target molecules. Many evidences show the effect of insulin on PP2Ac and its abnormal regulation in conditions of glucolipotoxicity. Thus, studying PP2Ac interaction partners in respect to type 2 diabetes will give insight into its role in insulin resistance.

Here, we studied interaction partners of PP2Ac in obese insulin resistant human subjects. Two skeletal muscle biopsies, basal and insulin stimulated are obtained from each individual using hyperinsulenemic euglycemic clamp technique. Using ESI-HPLC-MS/MS, we identified 186 interaction partners. Out of which 14 partners were previously identified by other groups which leaves 172 novel partners. This is the largest PP2Ac interaction network found till date. We also identified 17 insulin responsive PP2Ac partners. Several important PP2Ac interaction partners molecules were identified, for the 1st time, in skeletal muscle from humans. Among them,, some are known to affect PP2Ac activity and others are significantly associated with insulin signaling. Further validation of these partners will help with a better understanding of the role and regulation of PP2Ac in terms of insulin resistance in obese individuals.

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