Microvascular Dysfunction in Diabetic Peripheral Neuropathy

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Diabetic Peripheral Neuropathy; Painful Diabetic Neuropathy
• Intervention / Treatment: Other: This is a non-interventional study

Detailed Description

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

• Study Type: Observational
• Enrollment (Anticipated): 72

Contacts and Locations

• Study Contact: Name: Calvin Howorth, BSc (Hons); Phone Number: 07508993412; Email: calvin.howorth@plymouth.ac.uk
• Study Contact Backup: Name: Leanne Smewing, PhD; Phone Number: 01752 587 541; Email: leanne.smewing@plymouth.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Individuals with Type 2 Diabetes and Diabetic Peripheral Neuropathy

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Clinical DPN without pain; Score above 2.5 on the Michigan Neuropathy Screening Instrument; Score below 4 on the DN4	Other: This is a non-interventional study; This is a non-interventional study
Painful DPN; Score above 2.5 on the MNSI; Score above 4 on the DN4	Other: This is a non-interventional study; This is a non-interventional study

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Plymouth
• Investigators: Principal Investigator: Calvin Howorth, BSc (Hons), University of Plymouth

Study record dates

Study Major Dates

• Study Start (Anticipated): November 18, 2021
• Primary Completion (Anticipated): April 30, 2022
• Study Completion (Anticipated): April 30, 2022

Study Registration Dates

• First Submitted: October 12, 2020
• First Submitted That Met QC Criteria: November 10, 2021
• First Posted (Actual): November 11, 2021

Study Record Updates

• Last Update Posted (Actual): November 11, 2021
• Last Update Submitted That Met QC Criteria: November 10, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: endothelial dysfunction; microvascular dysfunction
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Neuromuscular Diseases; Peripheral Nervous System Diseases; Pain; Diabetic Neuropathies
• Other Study ID Numbers: IRAS: 261329

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: The Chief Investigator will have access to the final dataset. Any study data arising from the conduction of the study will be owned by the Sponsor (University of Plymouth). At the end of trial, anonymised participant level data may be shared with other researchers under an appropriate data sharing agreement. Data shared in this manner will ensure that the identity of all participants are obscured, and anonymity is enshrined in its presentation.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No