TEMPOL and Insulin Resistance: A study of the underlying mechanisms behind changes in glucose metabolism, lipid accumulation and cellular stress

Manodara, Gihani

TEMPOL and Insulin Resistance: A study of the underlying mechanisms behind changes in glucose metabolism, lipid accumulation and cellular stress

Manodara, Gihani

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Publication Type:: Thesis
Issue Date:: 2024

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Field	Value	Language
dc.contributor.author	Manodara, Gihani
dc.date.accessioned	2024-06-18T04:23:26Z
dc.date.available	2024-06-18T04:23:26Z
dc.date.issued	2024
dc.identifier.uri	http://hdl.handle.net/10453/179549
dc.description	University of Technology Sydney. Faculty of Science.	en_US.UTF-8
dc.description.abstract	Environmental factors are major contributors to obesity. Overnutrition-induced obesity drives oxidative stress and inflammation, leading to insulin resistance. There are currently no successful treatments to treat insulin resistance or its downstream clinical sequelae. It was hypothesized that TEMPOL, a nitroxide, could suppress diet-induced insulin resistance through its anti-inflammatory and antioxidant properties. To explore this hypothesis, C57BL/6 mice were treated with a high-fat diet to induce obesity-associated insulin resistance, followed by an 8-week administration of TEMPOL to determine if systemic insulin resistance was reversed, in association with suppressed oxidative and inflammatory stress. Results show that TEMPOL treatment reduced body mass, improved lipid metabolism, decreased adipogenesis, reduced inflammation and oxidative stress, and improved insulin sensitivity in high-fat diet-fed mice. In vitro studies delineated underlying cellular mechanisms showing TEMPOL protected against lipotoxicity-induced pancreatic β-cell dysfunction, hyperlipidaemia, mitochondrial and endoplasmic reticulum stress, and insulin secretion. In summary, TEMPOL was shown to attenuate oxidative stress and inflammation in all three key tissue types that underpin insulin resistance. The findings provide a strong impetus to follow up with a pre-clinical study. TEMPOL is used currently for other medical issues and thus re-purposing the drug for insulin resistance could be realized upon further studies.	en_US.UTF-8
dc.format	Thesis (PhD)
dc.language.iso	en_US	en_US.UTF-8
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/179549/1/thesis.pdf
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	© 2024 Gihani Manodara
dc.rights	au.edu.uts.lib/cph
dc.title	TEMPOL and Insulin Resistance: A study of the underlying mechanisms behind changes in glucose metabolism, lipid accumulation and cellular stress	en_US.UTF-8
dc.type	Thesis
utslib.copyright.status	open_access	*

Abstract:

Environmental factors are major contributors to obesity. Overnutrition-induced obesity drives oxidative stress and inflammation, leading to insulin resistance. There are currently no successful treatments to treat insulin resistance or its downstream clinical sequelae. It was hypothesized that TEMPOL, a nitroxide, could suppress diet-induced insulin resistance through its anti-inflammatory and antioxidant properties. To explore this hypothesis, C57BL/6 mice were treated with a high-fat diet to induce obesity-associated insulin resistance, followed by an 8-week administration of TEMPOL to determine if systemic insulin resistance was reversed, in association with suppressed oxidative and inflammatory stress. Results show that TEMPOL treatment reduced body mass, improved lipid metabolism, decreased adipogenesis, reduced inflammation and oxidative stress, and improved insulin sensitivity in high-fat diet-fed mice. In vitro studies delineated underlying cellular mechanisms showing TEMPOL protected against lipotoxicity-induced pancreatic β-cell dysfunction, hyperlipidaemia, mitochondrial and endoplasmic reticulum stress, and insulin secretion. In summary, TEMPOL was shown to attenuate oxidative stress and inflammation in all three key tissue types that underpin insulin resistance. The findings provide a strong impetus to follow up with a pre-clinical study. TEMPOL is used currently for other medical issues and thus re-purposing the drug for insulin resistance could be realized upon further studies.

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http://hdl.handle.net/10453/179549