Access Type

Open Access Dissertation

Date of Award

January 2022

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmaceutical Sciences

First Advisor

Zhengping Yi

Abstract

Skeletal muscle insulin resistance is one of the main contributors to Type 2 Diabetes (T2D), which is a chronic disease affecting 37.3 million people in United States (US), with an estimated annual cost exceeding $300 billion in the US. T2D is being treated with a variety of medications, including Pioglitazone (PIO), a potent insulin sensitizer for skeletal muscle. PIO is a synthetic ligand for the peroxisome proliferator-activated receptor (PPAR-γ), nuclear receptors regulating the expression of many genes involved in lipid and glucose metabolism. To date, the molecular action of PIO that sensitizes muscle to insulin is incompletely understood. Protein phosphorylation events and protein-protein interactions are important in regulating variuos signaling pathways including insulin signaling. Abnormalities in these processes are a main cause in the development of skeletal muscle insulin resistance. Most research on regulation of these events has been focused on kinases, however phosphatases such as Protein phosphatase 2A (PP2A) also play a pivotal role. PP2A is a major serine/threonine phosphatase modulating various signaling pathways such as insulin signaling. It is been known that PP2A is hyperactivated in various cell and animal models of diabetes and obesity. Whether or not PP2A plays a role in PIO induced insulin sensitivity improvement in human skeletal muscles remains to be elucidated. We hypothesized that PIO increases insulin sensitivity through improving phosphorylation of insulin signaling proteins (Aim 1), and/or improving PP2Ac protein-protein interactions (Aim 2) in human skeletal muscle cells (HSKM) derived from obese insulin resistant participants. In this project we are performing a quantitative phosphoproteomics approach to assess phosphorylation changes in primary HSKM cells treated with PIO (Aim 1), and co-immunoprecipitation experiments followed by our proteomics approach for PP2Ac protein-protein interactions (Aim 2). The goal of this project is to invistigate the molecular mechanisms for insulin sensitizing effect of pioglitazone in human skeletal muscle cells. It will be an important step forward in the development of novel drug for treating and preventing insulin resistance and T2D.

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