Diabetes mellitus, or simply “diabetes”, is a syndrome with a heterogeneous and multifactorial substrate. It is characterized by a disorder of carbohydrates, fat, and protein metabolism due to insulin deficiency. This deficiency may be complete, partial, or relative. Relative insulin deficiency is when, despite elevated levels in the blood, insulin is not sufficient to meet metabolic needs due to inhibition of its action in peripheral tissues (insulin resistance). The main expression of metabolic disturbance in diabetes is an increase in blood glucose levels. ¹ Diabetes and its complications are now a major public health issue globally, with the number of people diagnosed increasing. ^{2, 3} According to the International Diabetes Federation (IDF), the number of individuals diagnosed with diabetes in 2013 was estimated to be 381.3 million. Projections indicate that this figure will rise to 519.9 million by 2035, representing a 55% increase. ²

In patients diagnosed with diabetes, inadequate glycemic control can lead to microvascular complications, including peripheral diabetic neuropathy (DPN) (encompassing sensory, motor, and autonomic nerve fibers, and thus multiple organ systems) nephropathy, and retinopathy. ^{4, 5} The microvascular alterations in retinal blood vessels resulting from diabetes constitute the disease entity called “diabetic retinopathy” (DR), which occurs worldwide in 30-40% of people with type 2 diabetes and is considered one of the main causes of partial vision loss and the leading cause of blindness in the working-age population (20-60 years) in developed countries (DR currently accounts for 4.8% of all cases of blindness). ^{6, 7} Among people with diabetes, an overall prevalence analysis ⁸ showed that 35% had any type of diabetic retinopathy, 7% had proliferative retinopathy, 7% had macular edema, and 10% had sight-threatening retinopathy. Although all prevalences, which increased with duration of diabetes, poor glycemic control, and poor blood pressure control, were observed to be higher in patients with type 1 diabetes than in those with type 2 diabetes ⁹ the number of patients with type 2 diabetes far exceeds that of patients with type 1 diabetes. Therefore, patients with type 2 diabetes represent a larger proportion of patients with DR. ¹⁰ Nearly 50% of people with diabetes develop diabetic neuropathy, a disabling condition that can affect any part of the nervous system. The prevalence of diabetic neuropathy with pain can be as high as 15-30% but approaches 60% in some populations of persons with diabetes. It is a late finding in type 1 diabetes but can be found early in type 2 diabetes. ¹¹ The motor and sensory nerves of the peripheral nervous system, since they are outside the central nervous system (CNS) and far from the protection of the blood-brain barrier, are particularly sensitive to harmful/toxic substances, such as substances resulting from diabetes and e.g. chemotherapeutic agents, as well as being a conduit to the CNS for the transport of viruses and neurotoxins. ¹² Protein glycation and the polyol pathway are the main causes of peripheral neuropathy in people with diabetes. ¹¹ The diagnosis of DPN is based on exclusion, where the presence or absence of symptoms and signs of nerve dysfunction, the duration of the disease, and the degree of glycaemic control are considered. ¹³ It should be highlighted that for patients with diabetes, it is not enough to determine whether they have peripheral neuropathy, the severity of neuropathy must also be determined. The more severe the DPN, the more severe the impairment of activities of daily living. ¹⁴ Often, there are differences between diagnostic criteria in clinical care and in clinical research. ⁵ In clinical practice, the diagnosis of DPN, and the determination of its severity, is made after careful clinical examination with the application of at least two neurological tests. ¹⁵ According to Boulton et al., ¹⁶ these two tests would include the Semmes-Weinstein 10g monofilament and a second test. The wide measurement range and excellent reliability make the biothesiometer a valuable, after the 10g monofilament, research and clinical tool for quantifying sensory loss. ^{17, 18} In cases where the clinical features are atypical, electrophysiological tests (nerve conduction tests and electromyography -EMG-), as well as specialized neurological evaluation are necessary for the diagnosis of diabetic neuropathy. ⁵ Recent advances in elucidating the pathogenetic mechanisms of diabetic neuropathy and improvements in clinical trial design have reinvigorated the potential for agents developed in preclinical studies to be translated into new therapeutic agents, as well as highlighting the need for improved and effective means of measuring neuropathy in preclinical and clinical research. ¹⁹ The systematic investigation of the literature regarding the methods of measuring the severity of DPN and the association of the results of each method with diabetic retinopathy would contribute positively to the efforts to improve the methods/means of measuring neuropathy and predicting retinopathy, as well as, consequently, other microvascular complications of diabetes.

A preliminary search for existing systematic or scoping reviews in the literature on the association between DPN and retinopathy (in Scopus, Web of Science, ²⁰ and PubMed), as well as for registered in registers, as listed by Pieper and Rombey, ²¹ on such linking protocols of systematic or scoping reviews, in April 2024, was conducted. The search terms, in the databases, were for the records’ title (“retinopathy” OR “eye disease” OR “maculopathy” OR “retinal” OR “macular”) AND “neuropathy” and for the title/abstract or abstract only “severity” AND (“diabetes” OR “diabetic”), while in the registers the same terms in a single sequence, all or part of them together -in particular, consecutively the terms of the first Boolean sequence up to the first ‘AND’- if the register did not provide the possibility to search with a Boolean sequence, without distinction between search by title or by title/abstract or abstract only. The team of researchers who undertook the searches considered that the above sequence of terms and Boolean operators was sufficient/satisfactory quantitatively and qualitatively and that it prevented the generation of results noise. ²² Figure 1 shows the search/screening process, in the registers PROSPERO (Specific to systematic reviews), Research Registry, INPLASY, OSF Registries (Generic), and protocols.io, ²¹ of protocols (possibly) relevant to the association between diabetic peripheral neuropathy and diabetic retinopathy. A screening of the found protocols was performed by two researchers, AK and PP, to determine whether they were relevant to the proposed literature review. Table 1 presents the results of the above search/screening process. In particular, one protocol was found, by Wang et al., ²³ whose although its topic “oversees” ²⁴ the proposed literature review the protocol does not mention anything about including how to measure the severity of peripheral neuropathy, as well as mentioned only two databases (PubMed and Embase) to be searched for articles. Based on the above, it was concluded that is limited, if any, evidence regarding already existing scoping reviews on ways of measuring peripheral neuropathy severity and its association with retinopathy in patients with diabetes.

After reporting the results narratively and in a table, a discussion of the results will follow. The different ways of measuring the severity of peripheral neuropathy identified, based on previous literature, will be discussed, as well as the association of neuropathy and/or its severity with retinopathy, in patients with diabetes. The main objective of the discussion will be to elucidate the role of different ways of measuring the severity of peripheral neuropathy with its association with retinopathy.

Conclusions will be drawn in line with the objective(s) of the proposed scoping review and will be based on the results. Following the conclusions, recommendations for future research will be made, which will include suggestions for conducting systematic reviews, with more specific questions to be explored, ²⁸ with or without meta-analysis, based on the knowledge gaps identified from the results. ^{27, 28}

Aristomenis Kossioris wrote the introduction section of the topic under examination, part of the methodology, as well as did a preliminary search of databases and protocol registers for existing publications on the topic under examination.

Stylianos Kandarakis wrote part of the methods section, helped sorting the protocols found, wrote part of the discussion, and made editorial and grammatical corrections.

Spyridon Doumazos helped sorting the protocols found, wrote the limitations section, as well as made editorial and grammatical corrections.

Petros Petrou contributed to the search strategy planning, wrote part of the methodology, as well as had overall supervision of the project.

Ethical approval and consent were not required.