Remote Ischaemic Conditioning and Type 2 Diabetes Mellitus: Role of Neuropathy in Translational Difficulties

Abstract

<p><b>Background</b></p> <p>Remote ischaemic conditioning (RIC) is a promising therapy for minimising ischaemia reperfusion injury. Despite initial success in animal studies, translational and clinical studies have had mixed results, and type 2 diabetes mellitus (T2DM) is a likely confounder. Key research has demonstrated diabetic sensorimotor peripheral neuropathy (DSPN) in people with T2DM inhibits acute RIC cardioprotection, although no further studies have investigated the mechanisms involved. This thesis aimed to investigate how forms of neuropathy in T2DM may impact upon the neurohumoral mechanisms of RIC and contribute to translational difficulties. It was hypothesised that DSPN may alter the release of calcitonin gene-related peptide (CGRP) in response to acute RIC, adding to reduced RIC efficacy in DSPN. A further aim was to make a series of recommendations for future research regarding the effects of DSPN on RIC studies.</p> <p><b>Methods</b></p> <p>A systematic review assessing the efficacy of chronic RIC was undertaken. A literature review outlining the differing effects of, and mechanisms involved in acute vs chronic RIC was published, exploring the hypothesis that chronic RIC may be more efficacious than acute RIC in T2DM. A small randomised controlled pilot study of acute RIC in people with T2DM was conducted, measuring change in circulating blood CGRP and VEGF in response to a single dose of RIC, aiming to assess if changes correlated with severity of DSPN. The results of the reviews and study lead to publishing a narrative review of the prevalence, subtypes of, and diagnostic methods used for DSPN and its precursors, and implications for past and future RIC research.</p> <p><b>Results and Discussion</b></p> <p>Chronic RIC appears a better candidate for therapeutic benefit in vascular complications of T2DM. There are several likely mechanisms for inhibitory effects of diabetic neuropathy on RIC protection, for DSPN and potentially cardiac autonomic neuropathy. Although underpowered, the T2DM pilot study found that the difference in median plasma CGRP values from 60 min post intervention compared to baseline was significant (p=0.03) in the RIC vs Sham group, with less of a decrease in CGRP for the RIC group. There was no significant change in VEGF. Decreased CGRP levels in RIC participants compared to baseline was in direct contrast to previous studies in animals, where circulating CGRP rose significantly after RIC. The study was limited because a high proportion of participants had DSPN. The final narrative review discussed the potential that DSPN and its precursors may be missed in the initial screening of participants for RIC studies, and the need to consider the impact of DSPN and its precursors more adequately in RIC study design.</p> <p><b>Conclusion</b></p> <p>This novel human study suggests that CGRP release in response to RIC may be inhibited in participants with T2DM and/or DSPN. This could be one underlying reason why DSPN appears to inhibit protective benefits of RIC. Larger studies are warranted, including comparing groups both with and without T2DM and DSPN. A series of recommendations were made for future RIC studies involving participants with T2DM, DSPN and its precursors with the aim of improving translational success.</p>