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Small nerve fibre damage and sexual dysfunction in diabetes and obesity. A mechanistic assessment and effect of lipid modifying agents.


Project Description

Diabetes and its complications represent a growing global health burden, affecting an estimated 366 million people worldwide. The triad of retinopathy, nephropathy and neuropathy are well recognised microvascular complications, and are the leading causes of premature blindness, end-stage renal failure, foot ulceration and amputation, respectively. Once established, they have a major impact on the quality of life of patients with diabetes and are associated with adverse healthcare outcomes.

Diabetic retinopathy (DR) is strongly associated with nephropathy, and is one of the earliest microvascular complications. However, recent studies have shown that early neuronal abnormalities, such as altered multi-focal electroretinogram (mfERG) responses, retinal nerve fibre layer thinning and loss of central visual field sensitivity occur before the onset of overt vascular lesions in the retina, and may be of prognostic value. Krolewski et al. have previously found a strong association between cardiac autonomic neuropathy (CAN) and proliferative DR (PDR) in patients with type 1 diabetes suggesting an underlying etiologic link. Indeed, the Rochester Diabetic Neuropathy Study has shown that markers of microvessel damage such as DR and proteinuria or microalbuminuria (MA) are the strongest predictors for the severity of DPN.

Corneal nerve morphology assessed by IVCCM is an early surrogate marker for small nerve fibre damage in DPN. Furthermore, corneal nerve fibre length correlates with clinical and electrophysiological measures of diabetic peripheral neuropathy and long term glycaemic control [15, 16]. Recent studies have shown a stepwise deterioration in corneal nerve morphology in healthy subjects and patients with pre-proliferative and proliferative DR. Petropoulos et al. have shown that IVCCM detects early small fibre damage in the absence of retinopathy or microalbuminuria in patients with Type 1 diabetes. The exact temporal relationship between neuropathy and retinopathy or nephropathy however remains unclear. We have also shown that corneal nerve damage relates to the severity of erectile dysfunction in patients with T1DM and those with obesity.

We recently reported small nerve fibre structure abnormalities in type 1 diabetes patients who have erectile dysfunction and that obese patients with erectile dysfunction there is a significant small nerve structure damage but no difference in sex hormones compared to obese patients with no erectile dysfunction.

The objectives of this PhD project are:

1) In a cross sectional study establish the association between corneal small fibre and endothelial cell structure (IVCCM) and autonomic neuropathy (Cardiac autonomic function tests and pupilometry) with the presence and severity of erectile dysfunction (ED) (IEFF questionnaire), biochemical markers of endothelial damage and lipoprotein derangements in patients with type 1 and type 2 diabetes in relation to response to therapy with PDE5i’s.
2) In a longitudinal study assess the impact of lipid modifications therapy on small nerve fibre and endothelial cell structure, autonomic neuropathy (Cardiac autonomic function tests and pupilometry), severity of erectile dysfunction (ED) (IEFF questionnaire) and biochemical markers of endothelial damage and lipoprotein derangement.
3) The impact of weight loss in male patients on sexual function and if this correlates with sex hormone changes, improvements in small nerve fibre structure, autonomic nerve function or endothelial cell integrity/marker.

Methods & Techniques:
These studies have already gained approval by the local research ethics committee. The successful candidate will recruit patients, organise research visits, train to undertake IVCCM and neuropathy assessment, liaise with the research biochemists and coordinate sample transfer and laboratory analysis, interpret the results and write papers and their PhD thesis. The successful candidate will have the opportunity to visit collaborating centres in Europe and will be strongly encouraged to apply for visiting fellowships. The group has a good record of securing visiting fellowships to enable research fellows and PhD students to learn new skills.


Entry requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. This project is suitable for medically qualified candidates, optometrists, scientists or qualified nurses with an interest in diabetes, obesity or ophthalmology. BSc, MSc or equivalent and previous research experience is desired.

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Endocrinology and Diabetes.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

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