Diabetic polyneuropathy: Progress in diagnostic strategy and novel target discovery, but stagnation in drug development

Abstract

Diagnostic strategy of diabetic polyneuropathy has progressed. In particular, Baba's classification on the severity of diabetic polyneuropathy using nerve conduction study and a point‐of‐care device of nerve conduction study will realize the objective quantitative evaluation of diabetic polyneuropathy.

Diabetic polyneuropathy (DPN), one of the most prevalent diabetic complications, asymptomatically progresses in the early stages of the disease. Although early diagnosis is critical, as therapeutic intervention is often delayed, no consensus has been established for early diagnosis. However, fortunately, the recent development of objective quantitative tests that contribute to the diagnosis of DPN has been remarkable. The nerve conduction study (NCS) has long been known as the gold standard test for DPN diagnosis. In an attempt to further develop the possibilities of NCS, Baba et al.1 proposed an NCS‐based diagnosis and severity classification of DPN (Figure 1). Using this classification, it was reported that the cardiovascular prognosis deteriorated significantly after 5 years in the moderate‐to‐severe DPN groups2. Given this result, the reliability of this classification was validated; at the same time, the severity of DPN was recognized as an important factor to define the prognosis of diabetes patients. As NCS requires expensive equipment and well‐trained examiners, it is difficult to clinically popularize the use of NCS. However, the usefulness of the simple NCS device, NC‐stat/DPNCheck™ (Neurometrix, Inc., Waltham, MA, USA), which can reproduce a part of NCS, has been proven. Among studies considering the Asian population, Hirayasu et al.3 evaluated the difference in normal thresholds of the device between people of Japanese and Caucasian descent. Furthermore, the authors showed the reproducibility of the device for the Japanese population and the strong correlation with conventional NCS4. In the future, researchers should establish further effectiveness of this device in the diagnosis and severity assessment of DPN. Another aspect that can be used for diagnosis and evaluation of DPN is autonomic nervous dysfunction. R‐R interval variability in the electrocardiogram has mainly been used for the diagnosis of cardiovascular autonomic neuropathy, which is a major diabetic autonomic neuropathy5. However, a recent study reported that orthostatic hypotension, one of the symptoms of cardiovascular autonomic neuropathy, was found in the so‐called non‐dippers whose blood pressure does not show a normal fall during sleep, in which the cardiovascular prognosis was poor6. It would be necessary to verify the usefulness of the night‐time blood pressure variability as a new parameter of diabetic autonomic neuropathy.

Figure 1.

Baba's classification: a diagnostic and staging algorithm for diabetic polyneuropathy based on nerve conduction study. CMAP, compound muscle action potential; MCV, motor nerve conduction velocity; SCV, sensory nerve conduction velocity; SNAP, sensory nerve action potential. Adapted/translated from Baba et al. 2, Japanese Journal of Clinical Neurophysiology, 2018, by permission of Japanese Society of Clinical Neurophysiology. This image/content is not covered by the terms of the Creative Commons license of this publication. For permission to reuse, please contact the rights holder.

The relationship of DPN to newly‐highlighted diabetic complications has been illuminated by recent findings. Among musculoskeletal complications of diabetes, Charcot neuroarthropathy, also called diabetic neuropathic arthropathy, which is one of the conditions contributing to diabetic foot, has been identified for a long time, although its pathology has not been fully elucidated. One of the most popularly supported hypotheses is that the disease develops in patients with DPN and abnormal bone metabolism, when their condition is compounded by trauma or vascular disorders. It has been suggested that local inflammation, rather than DPN, is a critical factor in its pathogenesis7, 8. However, using a corneal confocal microscope, Khan et al.9 showed that severe impairment of small nerve fibers was associated with the disease. Although it is still difficult to explain the overall pathology of the disease, it was reconfirmed that the coexistence of DPN is an important factor in the underlying pathology.

Sarcopenia has recently attracted attention in older adults with diabetes. Especially in advanced countries with an aging population, sarcopenia and subsequent frailty are becoming a major social issue that needs to be addressed10, 11. It has been reported that the prevalence of sarcopenia increases in diabetes patients12, and the prevalence further increases in patients with DPN13. Furthermore, it has been reported that the same functional deterioration of the musculoskeletal system is remarkable not only in the lower limbs, but also in the upper limbs14. We professionals should attend to the importance of DPN in upper limb dysfunction. Considering these new findings, in addition to the prevention and treatment of diabetic foot associated with severe DPN, countermeasure strategies against sarcopenia and frailty associated with mild DPN should be fully considered. In other words, the importance of early diagnosis and treatment of DPN must be recognized.

However, there is no well‐established worldwide treatment protocol for DPN, although preferred regional treatments exist. For example, an aldose reductase inhibitor, epalrestat, is widely used in Japan. Epalrestat is highly effective in mild DPN, but has limited effectiveness in advanced DPN15. Although it is important to diagnose DPN at the early stage when epalrestat can be effective, early diagnosis and intervention are rarely achieved due to the limited availability of medical resources. Fortunately, a more effective aldose reductase inhibitor, ranirestat, has been developed in recent years. As ranirestat has been shown to ameliorate the parameters of NCS16, 17, it might improve the treatment of advanced DPN. In addition, preclinical studies are actively developing new treatments for DPN. Based on the reports that chronic inflammation associated with metabolic abnormalities also partially comprise the pathology in DPN18, the effect of omega‐3 polyunsaturated fatty acids that have anti‐inflammatory/anti‐oxidative effects was investigated19. The report showed that omega‐3 polyunsaturated fatty acids exerted neuroprotective effects through Nrf‐2 signaling19.

Furthermore, it should be noted that attempts to elucidate new pathologies of DPN are steadily underway. As male sex has been shown as a risk factor for DPN in humans20, male rodents have been conventionally used as animal models for DPN. Paradoxically focusing on the current convention, one preclinical study attending to the insusceptibility of females to DPN has reported that DPN was less frequently induced in female rats, similarly to human females21. It is expected that the detailed mechanisms of their insusceptibility to DPN will be elucidated in the future. Additionally, there are prospective attempts to elucidate the pathophysiology of DPN; for example studies focusing on microribonucleic acids22, studies using metabolomics23 and studies focusing on sphingolipids24. We should carefully observe the future developments of DPN research.

Disclosure

The authors declare no conflict of interest.