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Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy

Abstract

Diabetic sensorimotor peripheral neuropathy (DSPN) is a serious complication of diabetes mellitus and is associated with increased mortality, lower-limb amputations and distressing painful neuropathic symptoms (painful DSPN). Our understanding of the pathophysiology of the disease has largely been derived from animal models, which have identified key potential mechanisms. However, effective therapies in preclinical models have not translated into clinical trials and we have no universally accepted disease-modifying treatments. Moreover, the condition is generally diagnosed late when irreversible nerve damage has already taken place. Innovative point-of-care devices have great potential to enable the early diagnosis of DSPN when the condition might be more amenable to treatment. The management of painful DSPN remains less than optimal; however, studies suggest that a mechanism-based approach might offer an enhanced benefit in certain pain phenotypes. The management of patients with DSPN involves the control of individualized cardiometabolic targets, a multidisciplinary approach aimed at the prevention and management of foot complications, and the timely diagnosis and management of neuropathic pain. Here, we discuss the latest advances in the mechanisms of DSPN and painful DSPN, originating both from the periphery and the central nervous system, as well as the emerging diagnostics and treatments.

Key points

  • Diabetic sensorimotor peripheral neuropathy (DSPN) is a common complication of diabetes mellitus that is associated with increased mortality, neuropathic pain, foot ulceration and lower-limb amputation.

  • The mechanisms of DSPN are not fully understood but involve downstream injurious pathways associated with hyperglycaemia, dyslipidaemia and microvascular disease leading to neuronal inflammation, oxidative stress, mitochondrial dysfunction and cell death.

  • There are no universally accepted disease-modifying treatments for DSPN; management is focused on optimizing glycaemic control, the achievement of cardiometabolic targets, and the prevention and/or treatment of diabetic foot complications.

  • The reasons why some patients develop painless rather than painful DSPN are unknown; however, alterations in the peripheral and central nervous system have emerged as potential explanations.

  • New compounds for the treatment of painful DSPN are being developed and the concept of stratifying patients according to various pain characteristics to improve analgesic response is being explored.

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Fig. 1: The pathways to foot ulceration and amputation.
Fig. 2: Peripheral and central nervous system structural and functional abnormalities in DSPN.
Fig. 3: Mechanisms of neuronal cell death in DSPN.
Fig. 4: Mechanisms of painful DSPN.
Fig. 5: Management of DSPN.

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Acknowledgements

The authors thank M. Yorek (University of Iowa, USA) for his advice on the manuscript.

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Correspondence to Solomon Tesfaye.

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S.T. has received honoraria (speaker fees) from Abbott, Astellas Pharma, AstraZeneca, Eva Pharma, Grunenthal, Hikma, Impeto Medical, Merk, Novo Nordisk and Pfizer. S.T. is on, or has been on, the Advisory Board of Angelini, Bayer, Mitsubushi Tanabe Pharma, Nervo, Trigocare International and Worwag Pharma. G.S. and D.S. declare no competing interests.

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Sloan, G., Selvarajah, D. & Tesfaye, S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nat Rev Endocrinol 17, 400–420 (2021). https://doi.org/10.1038/s41574-021-00496-z

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