Remote ischaemic conditioning in the context of type 2 diabetes and neuropathy: the case for repeat application as a novel therapy for lower extremity ulceration.

J A Epps,N A Smart

doi:10.1186/s12933-016-0444-z

Abstract

An emerging treatment modality for reducing damage caused by ischaemia–reperfusion injury is ischaemic conditioning. This technique induces short periods of ischaemia that have been found to protect against a more significant ischaemic insult. Remote ischaemic conditioning (RIC) can be administered more conveniently and safely, by inflation of a pneumatic blood pressure cuff to a suprasystolic pressure on a limb. Protection is then transferred to a remote organ via humoral and neural pathways. The diabetic state is particularly vulnerable to ischaemia–reperfusion injury, and ischaemia is a significant cause of many diabetic complications, including the diabetic foot. Despite this, studies utilising ischaemic conditioning and RIC in type 2 diabetes have often been disappointing. A newer strategy, repeat RIC, involves the repeated application of short periods of limb ischaemia over days or weeks. It has been demonstrated that this improves endothelial function, skin microcirculation, and modulates the systemic inflammatory response. Repeat RIC was recently shown to be beneficial for healing in lower extremity diabetic ulcers. This article summarises the mechanisms of RIC, and the impact that type 2 diabetes may have upon these, with the role of neural mechanisms in the context of diabetic neuropathy a focus. Repeat RIC may show more promise than RIC in type 2 diabetes, and its potential mechanisms and applications will also be explored. Considering the high costs, rates of chronicity and serious complications resulting from diabetic lower extremity ulceration, repeat RIC has the potential to be an effective novel advanced therapy for this condition.

Highlights

Diabetes-related foot disease is a frequent complication of type 2 diabetes mellitus (T2DM), with up to 25 % of diabetic patients eventually developing foot ulceration [1,2,3]
Pathogenesis of lower extremity ulceration in diabetes Sustained hyperglycaemia and associated abnormal metabolic pathways in T2DM lead to peripheral neuropathy, micro- and macro- vascular peripheral arterial disease, mechanical changes and subsequent foot trauma (e.g. Charcot neuroarthropathy), high plantar pressure, increased susceptibility to infection, skin changes resulting from autonomic neuropathy, increased pro-inflammatory cytokines, decreased neovascularisation and tissue regeneration, decreased neuropeptides involved in angiogenesis, and an altered extracellular matrix [2, 10, 19,20,21,22]
Neural pathways may frequently be affected in diabetic cohorts with known or undiagnosed peripheral sensory neuropathy, cardiovascular autonomic neuropathy (CAN) and/or gastrointestinal autonomic neuropathy (GAN)

Summary

Introduction

Diabetes-related foot disease is a frequent complication of type 2 diabetes mellitus (T2DM), with up to 25 % of diabetic patients eventually developing foot ulceration [1,2,3]. Rates have improved in some higher income countries by 40 to 60 % [12], data from countries of lower income and poorer access to health care (yet a higher prevalence of diabetes) are notably lacking [8, 12]. The benefits of improved access to primary health foot care, in addition to multidisciplinary foot clinics, cannot be overemphasised. They are highlighted by the impressive 72 % reduction, following adjustment of variables, in lower extremity amputation rates identified in a 15 year longitudinal observational study of a West Australian city [16]. The need to improve statistics worldwide for diabetic ulcer prevalence, complication rate and cost is undeniable, and new therapeutic options must be considered. This article will assess the potential for repeat remote ischaemic conditioning (RRIC) as a novel adjuvant treatment in diabetic lower extremity ulceration

Methods

Background

Findings

Conclusions