Document Type

Thesis

Publication Date

4-29-2022

Disciplines

Chemistry

Advisor

Lisa Gentile

Abstract

Type two diabetes mellitus is a highly prevalent disease for which the mechanism of insulin signaling to initiate glucose uptake in cleaving TUG-UBL1 by the protease Usp25m is currently not well understood. As increased insulin resistance can lead to the development of type one insulin deficient diabetes, the knowledge of this pathway may uncover underlying causes of insulin resistance. This research aims to understand the effect and stoichiometry of Usp25m binding to TUG-UBL1 in relationship to the cleavage of TUG-UBL1 initiating translocation of GLUT4 glucose transporter. The action of protease effector PIST will be investigated to understand the importance of order in protein presence to initiate TUG-UBL1 cleavage. The mechanism of PIST action on TUG-UBL1 Usp25m protease will be elucidated to understand the cascade of insulin signaling effects on glucose uptake. The understanding of this mechanism will allow for investigation of this mechanism in relationship to a novel therapeutic pathway in insulin resistant diabetes treatment. Current diabetes medications do not directly impact the cellular uptake of glucose but negate the negative symptoms of insulin resistance, while a therapeutic targeting this cleavage pathway can bypass insulin stimulation to reduce increased insulin resistance. The specific description of this mechanism allows for therapeutic small molecule investigations to stimulate or replace PIST action on Usp25m to artificially trigger glucose uptake for diabetes treatment.

Comments

A poster related to this research is available at https://digitalcommons.csbsju.edu/ur_cscday/206/.

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