Understanding PPARg-Ligand Interactions to Treat Type 2 Diabetes
Files
(Thesis)
Date
2021
Authors
Frkic, Rebecca Louise
Editors
Advisors
Bruning, John
Whitelaw, Murray
Richter, Katharina
Whitelaw, Murray
Richter, Katharina
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Thesis
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Abstract
The incidence of type 2 diabetes mellitus (T2DM) is increasing, caused by our growingly obese population among other predisposing factors. In fact, the World Health Organisation has predicted that diabetes will be the 7th leading cause of death by 2030. Despite this, there is a shortage of practical treatments effective at restoring a patient’s sensitivity to insulin. Current treatments of T2DM typically require the combination of multiple therapeutics in highly regulated doses, together with insulin injections. The rising occurrence of T2DM highlights the necessity for an effective treatment to increase insulin sensitivity in T2DM sufferers. The most promising class of antidiabetic compounds are the thiazolidinediones (TZDs), which have an impressive capacity to effectively restore insulin sensitivity. They work by modulating PPARγ, a nuclear receptor central to many roles, including metabolism, inflammation, and the regulation of glucose homeostasis. However, TZDs have been restricted from clinical use due to unfavourable side effects, such as congestive heart failure, loss of bone density, kidney damage, and oedema. The effectiveness of TZDs as insulin sensitisers merits their development to achieve an improved antidiabetic treatment that does not exhibit harmful side effects. It has been established that the side effects associated with TZDs correlate to their transactivation of PPARγ, and their insulin-sensitising properties are attributed to blocking the phosphorylation of Ser273 of PPARγ, a mechanism distinct from classical transactivation. This phenomenon is the basis for current research of T2DM therapies, where the focus is on new and improved compounds which exhibit low transactivation of PPARγ while still blocking phosphorylation of Ser273. This thesis presents a number of peer-reviewed publications which shed light on knowledge gaps in the field of PPARγ research, namely the structural mechanism of an improved partial agonist SR1988, as well as critical developments in understanding the mode of action of non-activating ligands SR10171, SR11023, and SR10221. In addition, the thesis includes publications highlighting the merit of repurposing TZD-like compounds and developing the PPARγ inverse agonist SR1903 for treating inflammation.
School/Discipline
School of Biological Sciences : Molecular and Biomedical Science
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 2021
Provenance
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