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Access Type
WSU Access
Date of Award
January 2024
Degree Type
Thesis
Degree Name
M.S.
Department
Pharmaceutical Sciences
First Advisor
Zhengping Yi
Second Advisor
Kyle Burghardt
Abstract
Diabetes affects approximately 37 million individuals in the United States, constituting approximately 11.3% of the population, primarily through Type 2 Diabetes (T2D) characterized by insulin resistance. Individuals with schizophrenia face an elevated risk of developing T2D, exacerbated by treatment with second-generation antipsychotics (SGAs). Understanding the metabolic disturbances induced by SGAs in schizophrenia necessitates investigations into their acute effects in healthy volunteers to delineate primary metabolic impacts from those secondary to chronic conditions like obesity or T2D. Studies on skeletal muscle have demonstrated that SGAs impair insulin signaling, glycogen content, and glucose transport. Olanzapine, a prominent SGA, is associated with significant metabolic liabilities, including insulin resistance independent of weight gain but underlying molecular mechanisms are still unknown. This study employs advanced proteomics methodologies to elucidate the molecular mechanisms by which olanzapine modulates insulin sensitivity in skeletal muscle. Proteomics profiling of lean, healthy skeletal muscle exposed to olanzapine identified substantial alterations in protein abundance and pathways pertinent to metabolism, glycosaminoglycan metabolism, muscular function, and diverse metabolic processes. Our analysis identified a total of 2127 proteins using TMT 29 plex. Among these, 23 proteins exhibited significant differences in abundance between pre and post Olanzapine treatment groups. Identified proteins are known to be involved in important pathways like muscle contraction, synthesis of pyrophosphates, inositol phosphate metabolism, diseases associated with glycosaminoglycan metabolism and glycosylation. These findings illuminate the molecular pathways through which olanzapine may instigate insulin resistance, irrespective of its effects on weight gain or adiposity. This research contributes novel insights into the proteomic disparities induced by olanzapine in skeletal muscle and provides a foundational basis for future investigations targeting the precise proteins implicated in insulin resistance pathways.
Recommended Citation
Jaiswal, Ruchi, "Olanzapine-Induced Molecular Alterations In Skeletal Muscle Of Lean, Healthy Human Participants" (2024). Wayne State University Theses. 959.
https://digitalcommons.wayne.edu/oa_theses/959