Microvascular Dysfunction in Diabetic Peripheral Neuropathy

Study Overview
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Brief Summary
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This study primarily seeks to evaluate dysfunction of small blood vessels and their linkage to dysfunction of nerves in people with Type 2 Diabetes. The purpose of this research is to explore some of the underlying pathophysiology of diabetic peripheral neuropathy, particularly painful diabetic peripheral neuropathy. The pain experienced by individuals with painful diabetic peripheral neuropathy is severe and associated with low quality of life. The pain does not typically respond well to pharmacological management. The processes underpinning the sources of pain are poorly understood, consequently only around a third of patients benefit from existing treatments. Some historic research on the sources of pain suggest the retention of the ability to reduce blood flow in small vessels may underpin these pain pathways. This research aims to explore this possibility, looking at the nerve-linked response in small vessels with a flickering light within the eye. Participants will complete three or four questionnaires: one demographic, two to aid with stratifying participants into groups concerning symptoms of neuropathy and an additional questionnaire if participants are stratified to the painful DPN group. A basic neurological examination of the feet will follow. Basic measurements of height, weight and blood pressure will be recorded for each participant. The primary sites of measurement of this small vessel dysfunction will be the eye and the foot investigated in a non-invasive manner. A bright flickering light will be shone into participants eyes, with the reaction of small vessels recorded. Sensors will also be placed on the feet and chest of participants and warmed to  44C. An image will be taken of participants eyes to measure nerve layer thickness and an area of skin on the forearm will be illuminated to measure for levels of a metabolic marker. A picture of the eye will also be taken to determine nerve layer thickness.

Detailed Description
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This cross-sectional observational study will take place between November 2021 and May 2022 and will recruit individuals with Type 2 Diabetes alongside painful or non-painful peripheral neuropathy. The study aims to determine the relationship between microvascular and metabolic markers and i) clinical neuropathy, ii) of painful neuropathy and iii) severity of neuropathic pain within a Type 2 Diabetic cohort. This will be done through achieving the following objectives: i) determination of whether retinal vasodilation in response to flicker-light stimulus is associated with i) the severity of neuropathy, ii) the presence of painful neuropathy and iii) severity of neuropathic pain within a T2DM cohort. ii) determination of whether levels of tissue-bound advanced glycation endproducts (AGEs) measured by skin autofluorescence are associated with i) the severity of neuropathy, ii) the presence of painful neuropathy and iii) severity of neuropathic pain within a T2DM cohort. iii) determination of whether pedal skin transcutaneous oxygen tension (TcPO2) measured by transcutaneous oximetry is associated with i) the severity of neuropathy, ii) the presence of painful neuropathy and iii) severity of neuropathic pain within a T2DM cohort. iv)determination of whether retinal nerve layer thickness is associated with the severity of neuropathy, the presence of painful neuropathy and severity of neuropathic pain within a T2DM cohort v)determination of whether the following factors are associated with the severity of neuropathy, the presence of painful neuropathy and severity of neuropathic pain within a T2DM cohort HbA1c Lipid profile Body Mass Index Blood Pressure

Official Title
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Retinal Microvascular Dysfunction in Non-Painful and Painful Diabetic Peripheral Neuropathy in Type 2 Diabetes Mellitus

Conditions
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Diabetic Peripheral Neuropathy, Painful Diabetic Neuropathy

Intervention / Treatment
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* Other: This is a non-interventional study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is willing and able to give informed consent for participation in the study Male or Female, aged 18 years or above. Diagnosed with Type 2 Diabetes Mellitus (confirmed on clinical notes) History of an abnormal neurovascular testing result (typically, 10g monofilament test) Able (in the Investigators opinion) and willing to comply with all study requirements. Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the study. Must be willing to refrain from caffeine and tobacco consumption 24hrs before procedures are undertaken. Participants must be willing and able (in the Investigator's opinion) to undertake DN4, Brief Pain Inventory-DPN and Michigan Neuropathy Screening Instrument questionnaires. Able to lie flat Exclusion Criteria: The participant may not enter the study if ANY of the following apply: Patients with neuropathy due to other aetiological causes, such as hereditary, metabolic, inflammatory, cervical and lumbar spine diseases; cerebrovascular diseases; uremia; alcohol use; or toxic factors. All patients with Type 1 diabetes. A positive history of malignancy; connective tissue or infectious disease; Deficiency of vitamin B12 or folate; Chronic renal failure; Liver failure; Glaucoma; Age-related macular degeneration Epilepsy; Severely sight-impaired Presence of a neurological disorder; Inflammatory arthropathies Pregnancy. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Clinical DPN without pain<br>Score above 2.5 on the Michigan Neuropathy Screening Instrument Score below 4 on the DN4 | Other: This is a non-interventional study<br>* This is a non-interventional study<br>|
| Painful DPN<br>Score above 2.5 on the MNSI Score above 4 on the DN4 | Other: This is a non-interventional study<br>* This is a non-interventional study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dynamic Vessel Analysis | Retinal vasodilation in response to flicker light stimulus - Response will be recorded as baseline corrected flicker response (bFR). Baseline will be recorded as the period from -30 to -5 seconds prior to flicker light stimulation. bFR will be calculated as the difference between peak dilation after provocation (dil%) and the minimum of the subsequent reactive constriction (constr%) and the width of the baseline amplitude (width BL%). | during the procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Static Vessel Analysis | The standard parameters for Static Retinal Vessel Function observed will be as follows: Diameter of the central retinal artery equivalent (CRAE) Diameter of the central retinal vein equivalent (CRVE) The ratio of CRAE-CRVE expressed as the arterio-venous ratio (AVR) Outcome Measure: AVR | during the procedure | 
| Retinal Nerve Layer Thickness | A measure of central retinal nerve fibre layer (RNFL) thickness will be obtained using the Heidelberg Spectralis OCT. This is a commercially available, non-invasive device that provides a high resolution scan of the retinal layers. Outcome Measure: Retinal Nerve Layer Thickness | during the procedure | 
| Skin Autofluorescence | Outcome Measure: Skin Autofluorescence (AU) | during the procedure | 
| Transcutaneous Oximetry | TcPO₂ (mmHg) | during the procedure | 
| Blood pressure | mmHg | during the procedure | 
| Lipid Profile | HDL and LDL lipid levels - obtained from participants general practitioner with consent | pre-procedure | 
| HbA1c | As standard - obtained from participants general practitioner with consent | pre-procedure | 
| Body Mass Index | Body Mass Index | during the procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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microvascular dysfunction, endothelial dysfunction