Insights into the pathogenesis and treatment of painful diabetic neuropathy

Greig, Marni; Tesfaye, Solomon; Selvarajah, Dinesh; Wilkinson, Iain D.

doi:10.1016/b978-0-444-53480-4.00037-0

Cited by 26 publications

(23 citation statements)

References 179 publications

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“…The patients often suffer from severe hyperalgesia and allodynia, which can be disabling and devastating (Didangelos et al, 2014). However, as the mechanism of painful diabetic neuropathy is incompletely understood, the treatment of painful diabetic neuropathy remains unsatisfactory (Greig et al, 2014). Therefore, it is imperative to look for effective drugs, especially with fewer side effects, for the management of painful diabetic neuropathy.…”

Section: Introductionmentioning

confidence: 99%

Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin

Liu

et al. 2015

European Journal of Pharmacology

107

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Section: Introductionmentioning

confidence: 99%

Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin

Liu

et al. 2015

European Journal of Pharmacology

107

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“…Pain is a manifestation of aberrant function of the nervous system in patients with diabetes (63,64). In this study, the expression and activity of PDK2/4 were found to be substantially increased at 1-6 weeks and peaking at 3 weeks in the DRG following diabetes induction.…”

Section: Discussionmentioning

confidence: 78%

Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy

Rahman

Jha

Kim

et al. 2016

Journal of Biological Chemistry

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The dorsal root ganglion (DRG) is a highly vulnerable site in diabetic neuropathy. Under diabetic conditions, the DRG is subjected to tissue ischemia or lower ambient oxygen tension that leads to aberrant metabolic functions. Metabolic dysfunctions have been documented to play a crucial role in the pathogenesis of diverse pain hypersensitivities. However, the contribution of diabetes-induced metabolic dysfunctions in the DRG to the pathogenesis of painful diabetic neuropathy remains ill-explored. In this study, we report that pyruvate dehydrogenase kinases (PDK2 and PDK4), key regulatory enzymes in glucose metabolism, mediate glycolytic metabolic shift in the DRG leading to painful diabetic neuropathy. Streptozotocin-induced diabetes substantially enhanced the expression and activity of the PDKs in the DRG, and the genetic ablation of Pdk2 and Pdk4 attenuated the hyperglycemia-induced pain hypersensitivity. Mechanistically, Pdk2/4 deficiency inhibited the diabetes-induced lactate surge, expression of pain-related ion channels, activation of satellite glial cells, and infiltration of macrophages in the DRG, in addition to reducing central sensitization and neuroinflammation hallmarks in the spinal cord, which probably accounts for the attenuated pain hypersensitivity. Pdk2/4-deficient mice were partly resistant to the diabetes-induced loss of peripheral nerve structure and function. Furthermore, in the experiments using DRG neuron cultures, lactic acid treatment enhanced the expression of the ion channels and compromised cell viability. Finally, the pharmacological inhibition of DRG PDKs or lactic acid production substantially attenuated diabetes-induced pain hypersensitivity. Taken together, PDK2/4 induction and the subsequent lactate surge induce the metabolic shift in the diabetic DRG, thereby contributing to the pathogenesis of painful diabetic neuropathy.Painful neuropathy is one of the most common complications of diabetes. Patients with diabetes frequently exhibit a variety of aberrant sensations, including pain hypersensitivity (1, 2). Interrelation and mutual perpetuation of distinct aberrations of specific metabolic pathways cause painful diabetic neuropathy. Furthermore, painful diabetic neuropathy probably results from a combination of metabolic and immune factors (3, 4). Metabolic aberrations are thought to be early events in painful diabetic neuropathy, leading to biochemical, structural, and functional changes in the dorsal root ganglion (DRG) 3 and its nerve trunk (5, 6). Likewise, hyperglycemia-induced immune activation creates an inflammatory microenvironment surrounding the influenced nerves (7).The DRG is pathologically important in diabetes presenting with painful neuropathic states, which patients with early polyneuropathy commonly experience (8). Ganglionic sensory neurons are devoid of any special protection by the blood-brain or blood-nerve barrier and have higher metabolic requirements than the nerve trunk, which makes the ganglion a vulnerable site in the pathogenesis of diabetic neurop...

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“…While there is no cure for diabetic peripheral neuropathy, symptoms are treatable and ameliorable through medications and frequent monitoring of patient symptoms and side effects to facilitate clinically appropriate treatment changes for maximum benefit. [5][6][7][8] Unfortunately, many patients may never achieve the maximum benefit from their medications due to the absence of routine monitoring of symptoms and treatment effects. 2,3 In this study, we use a cluster randomized trial design, endeavoring to reduce common threats to validity, 30 in order to evaluate the impact of an intervention to address this gap in care.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, all available treatments have significant side effects such as dizziness, somnolence, nausea and confusion that may be intolerable to some patients. 2,[5][6][7][8] Given the complexity of diabetic peripheral neuropathy medication management, new tools are needed to support more effective prescription and titration of available medicines.…”

Section: Introductionmentioning

confidence: 99%

The Diabetes Telephone Study: Design and challenges of a pragmatic cluster randomized trial to improve diabetic peripheral neuropathy treatment

et al. 2016

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Background-Challenges to effective pharmacologic management of symptomatic diabetic peripheral neuropathy include the limited effectiveness of available medicines, frequent side effects, and the need for ongoing symptom assessment and treatment titration for maximal effectiveness. We present here the rationale and implementation challenges of the Diabetes Telephone Study, a randomized trial designed to improve medication treatment, titration and quality of life among patients with symptomatic diabetic peripheral neuropathy.

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Insights into the pathogenesis and treatment of painful diabetic neuropathy

Cited by 26 publications

References 179 publications

Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin

Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin

Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy

The Diabetes Telephone Study: Design and challenges of a pragmatic cluster randomized trial to improve diabetic peripheral neuropathy treatment

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