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SHETTI-DISSERTATION-2023.pdf (112.77 MB)

The Role of Caveolin-1 in Insulin Impairements in Type-II Diabetes; Implications for Alzheimer's Disease

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posted on 2023-08-01, 00:00 authored by Aashutosh Uday Shetti
Severe impairments in insulin signaling in the brain of type-II diabetes patients increases their risk of developing Alzheimer’s disease by five times. However, the cause of these impairments has not been fully understood. Our study focused on the db/db (Lepr db/db) mouse model of type-II diabetes and found that protein levels of Cav-1 in brain endothelial cells were reduced, which was associated with changes in insulin receptor expression and signaling in brain microvessels and parenchyma. These findings were consistent with those in endothelial cell-specific Cav-1 knock-out (Tie2Cre; Cav-1fl/fl) mice. We used primary brain endothelial cells to demonstrate that lack of Cav-1 in these cells reduced response to insulin and insulin uptake. Our results also indicate that Cav-1 is necessary for insulin receptor-b stabilization within lipid rafts, as it interacts with this receptor. We observed that the insulin receptor interacts with other proteins such as insulin-degrading enzyme and tight junction protein Zonula Occludence-1. Pathway analysis of the insulin receptor interactome further showed its association with proteins involved in type-2 diabetes, Alzheimer’s disease, endothelial and central nervous system function, and golgi-endosome function. The restoration of Cav-1 in Cav-1 knock out brain endothelial cells improved insulin receptor expression, signaling, and localization. Overall, these findings indicate that Cav-1 regulates insulin signaling and uptake by brain endothelial cells through regulating IR-a and IR-b localization and function in lipid rafts. The depletion of endothelial cell-specific Cav-1 and impairment in insulin transport result in alterations in insulin signaling in the brain parenchyma of type-II diabetes.

History

Advisor

Lazarov, Orly

Chair

Tseng, Kuei

Department

Anatomy and Cell Biology

Degree Grantor

University of Illinois at Chicago

Degree Level

  • Doctoral

Degree name

PhD, Doctor of Philosophy

Committee Member

Lutz, Sarah Minshall, Richard Cologna, Stephanie

Submitted date

August 2023

Thesis type

application/pdf

Language

  • en

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