Mechanisms of Axonal Pathophysiology in Diabetes and Chronic Kidney Disease

Mechanisms of Axonal Pathophysiology in Diabetes and Chronic Kidney Disease Tushar Issar A thesis submitted in fulfilment of the requirement for the degree of Doctor of Philosophy Prince of Wales Clinical School University of New South Wales July 2020 Thesis/Dissertation Sheet Australia's Global University Surname/Family Name lssar Given Name/s Tushar Abbreviation for degree as give in the University calendar PhD Faculty Medicine School Prince of Wales Clinical School Thesis Title Mechanisms of axonal pathophysiology in diabetes and chronic kidney disease Abstract 350 words maximum: (PLEASE TYPE) Peripheral neuropathy is a common and debilitating complication of diabetes and chronic kidney disease (CKD). The pathophysiological mechanisms contributing to peripheral neuropathy in these conditions remain unclear. In this thesis, axonal excitability studies and nerve ultrasonography were utilised to assess peripheral nerve structure and function in human subjects with either diabetes, CKD, or both to investigate the mechanisms underlying peripheral nerve dysfunction in each condition. To commence, it was essential that an instrument to assess the severity of neuropathy in patients CKD with and without type 2 diabetes (T2DM) was formally validated. Having validated The Total Neuropathy Score in Chapter 1, axon al excitability studies were then utilised to determine the relative contributions of T2DM and CKD underlying nerve dysfunction in diabetic kidney disease in Chapter 2. It was established that CKD, and not diabetes, underlies axonal pathophysiology in patients with diabetic kidney disease. Studies were then conducted in autoimmune diabetes. In type 1 diabetes (TlDM), despite good glycaemic control as measured by HbA1c, development of peripheral neuropathy frequently occurs. In search of an explanation, the association between acute glucose control and nerve structure and function was explored in Chapter 3. Greater acute glucose variability and longer time spent in hyperglycaemia were associated with worse nerve excitability measures, altered corneal nerve morphology, and a higher number of corneal micro-neuromas. In Chapter 4, the mechanisms underlying axonal dysfunction in a recently recognised form of autoimmune diabetes known as latent autoimmune diabetes in adults (LADA) were then investigated. The basis of nerve dysfunction in LADA was different to TlDM and T2DM, and LADA patients exhibited more severe changes in nerve excitability and ultrasound measures. Investigations were then undertaken in T2DM. There is a strong association between the metabolic syndrome (Mets) and the development of peripheral neuropathy. To explain this relationship, the effect of the metabolic syndrome (MetS) in T2DM was examined in Chapter 5. A reduction in the function of the Na+/K+ pump was found to explain the more severe changes in nerve structure and function in T2DM patients with Mets compared to patients with T2DM alone. Finally, in exploration of potential neuroprotective options for peripheral neuropathy, the effect of anti-diabetic medication on nerve function was then investigated in Chapter 6. Exenatide treatment was associated with better nerve function in cross-sectional and prospective studies. Prominent abnormalities remained in patients receiving SGLT2 inhibitor or DPP-4 inhibitor therapy. Declaration relating to disposition of project thesis/dissertation I hereby grant to lhe University of New South Wales or its agents a non-exclusive licence to archive and lo make available (including to members of the public) my thesis or disserlation in whole or in part in lhe University libraries in all forms of media, now or here after known. I acknowledge that I retain all intellectual property rights which subsist in my thesis or dissertation. such as copyright and patent rights, subject to applicable law. I also retain the right to use all or part of my thesis or dissertation in future works (such as articles or books). .. , , , . .. ,44, .. (•., ..... ,,,,,, ... ,.... , .... ,,,, .. ........ §/-?:(:.::��( .......... , .. Si nature Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years can be made when submitting the final copies of your thesis to the UNSW Library. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….............. COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents a non-exclusive licence to archive and to make available (including to members of the public) my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known. I acknowledge that I retain all intellectual property rights which subsist in my thesis or dissertation, such as copyright and patent rights, subject to applicable law. I also retain the right to use all or part of my thesis or dissertation in future works (such as articles or books).’ ‘For any substantial portions of copyright material used in this thesis, written permission for use has been obtained, or the copyright material is removed from the final public version of the thesis.’ Signed ……………………………………………........................... Date …………………………………………….............................. AUTHENTICITY STATEMENT ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis.’ Signed ……………………………………………........................... Date …………………………………………….............................. ( .......� � INCLUSION OF PUBLICATIONS STATEMENT ; Austral1a·s Global Ut:��yv University UNSW is supportive of candidates publishing their research results during their candidature as detailed in the UNSW Thesis Examination Procedure. Publications can be used in their thesis in lieu of a Chapter if: • The candidate contributed greater than 50% of the content in the publication and is the "primary author", ie. the candidate was responsible primarily for the planning, execution and preparation of the work for publication • The candidate has approval to include the publication in their thesis in lieu of a Chapter from their supervisor and Postgraduate Coordinator. • The publication is not subject to any obligations or contractual agreements with a third party that would constrain its inclusion in the thesis Please indicate whether this thesis contains published material or not: This thesis contains no publications, either published or submitted for publication □ (if this box is checked, you may delete all the material on page 2) Some of the work described in this thesis has been published and it has been documented in the relevant Chapters with acknowledgement □ (if this box is checked, you may delete all the material on page 2) This thesis has publications (either published or submitted for publication) incorporated into it in lieu of a chapter and the details are presented below CANDIDATE'S DECLARATION I declare that: • I have complied with the UNSW Thesis Examination Procedure • where I have used a publication in lieu of a Chapter, the listed publication(s) below meet(s) the requirements to be included in the thesis. Candidate's Name Date (dd/mm/yy) Tushar lssar S/t/::2.i?zr POSTGRADUATE COORDINATOR'S DECLARATION To only be filled in where publications are used in lieu of Chapters I declare that: G the information below is accurate G where listed publication(s) have been used in lieu of Chapter(s), their use complies with the UNSW Thesis Examination Procedure G the minimum requirements for the format of the thesis have been met. PGC's Name PGC's Signature Date (dd/mm/yy) For each publication incorporated into the thesis in lieu of a Chapter, provide all of the requested details and signatures required Details of publication #1: Full title: The utility of the Total Neuropathy Score as an instrument to assess neuropathy severity in chronic kidney disease: A validation study Authors: lssar T, Arnold R, Kwai, NCG, Pussell, BA, Endre, ZH, Poynten, AM, Kiernan, MC, Krishnan, AV Journal or book name: Clinical Neurophysiology Volume/page numbers: Volume 129, Issue 5, Pages 889-894 Date accepted/ published: Accepted 4th February 2018 Status Published X Accepted and In ress The Candidate's Contribution to the Work Tushar lssar was responsible for the study design, recruitment, data collection, data interpretation, and the manuscript composition. Location of the work in the thesis and/or how the work is incorporated in the thesis: Chapter 1. Validates the Total Neuropathy Score as a means to assess peripheral neuropathy in chronic kidney

Load more