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Diabetic Neuropathy: Mechanisms, Emerging Treatments, and Subtypes

  • Nerve and Muscle (LH Weimer, Section Editor)
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Abstract

Diabetic neuropathies (DNs) differ in clinical course, distribution, fiber involvement (type and size), and pathophysiology, the most typical type being a length-dependent distal symmetric polyneuropathy (DSP) with differing degrees of autonomic involvement. The pathogenesis of diabetic DSP is multifactorial, including increased mitochondrial production of free radicals due to hyperglycemia-induced oxidative stress. Mechanisms that impact neuronal activity, mitochondrial function, membrane permeability, and endothelial function include formation of advanced glycosylation end products, activation of polyol aldose reductase signaling, activation of poly(ADP ribose) polymerase, and altered function of the Na+/K+-ATPase pump. Hyperglycemia-induced endoplasmic reticulum stress triggers several neuronal apoptotic processes. Additional mechanisms include impaired nerve perfusion, dyslipidemia, altered redox status, low-grade inflammation, and perturbation of calcium balance. Successful therapies require an integrated approach targeting these mechanisms. Intensive glycemic control is essential but is insufficient to prevent onset or progression of DSP, and disease-modifying treatments for DSP have been disappointing. Atypical forms of DN include subacute-onset sensory (symmetric) or motor (asymmetric) predominant conditions that are frequently painful but generally self-limited. DNs are a major cause of disability, associated with reduced quality of life and increased mortality.

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Conflict of Interest

Within the past 36 months, James W. Albers’ institution has received support from Eli Lilly and Company/Amylin Pharmaceuticals for his participation as a clinical investigator in a diabetes drug trial. He has also received personal compensation from Eli Lilly and Company (NZ), an affiliate of Eli Lilly and Company, Alnylam Pharmaceuticals/Veristat, Dow Chemical Company, Dow AgroSciences, and PeriphaGen (formerly Diamyd), and from firms representing these companies. These activities have been as a consultant, data monitoring committee member, advisory board member, or expert witness.

Rodica Pop-Busui’s institution has received grant support from Eli Lilly and Company/Amylin Pharmaceuticals (now Bristol-Myers Squibb) for an investigator-initiated trial testing the effects of exenatide on measures of diabetic neuropathy in which she is the principal investigator, and she receives grant support from the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and the American Diabetes Association. She has also received personal compensation from Acorda Therapeutics, Astra Zeneca, and Janssen Pharmaceuticals as a consultant.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. Neuromuscular Section, Department of Neurology, University of Michigan Health System, 1C325 University Hospital, 1500 East Medical Center Drive, Ann Arbor, MI, 48109-0032, USA

    James W. Albers

  2. Division of Metabolism, Endocrinology and Diabetes, University of Michigan, 5329 Brehm Tower, 1000 Wall Street, Ann Arbor, MI, 48105, USA

    Rodica Pop-Busui

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Correspondence to James W. Albers.

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Albers, J.W., Pop-Busui, R. Diabetic Neuropathy: Mechanisms, Emerging Treatments, and Subtypes. Curr Neurol Neurosci Rep 14, 473 (2014). https://doi.org/10.1007/s11910-014-0473-5

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