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Biology and Pathophysiology of Painful Diabetic Neuropathy

Chapter

Abstract

Painful neuropathy is a common but inconsistent feature of chronic diabetes. Clinical studies have yet to offer robust clues to the pathogenesis of pain in diabetic patients, so there are no targeted prophylactic therapies. Interventions against established pain are restricted to drugs developed for other conditions that are frequently ineffective and can have prohibitive side effect profiles. Studies in diabetic rodents have identified a number of molecular and cellular disorders that may underlie the behavioral indices of pain seen in these models of diabetic neuropathy. Plausible mechanisms include over-expression of sensory receptors and ion channels in primary afferents that exaggerate or modify sensory input from the periphery and also amplification of sensory processing at the spinal cord level via sensitization and disinhibition mechanisms. There is also an emerging appreciation that the higher nervous system is not spared in diabetes, so that amplifier or generator sites for pain may be located within the brain and project pain sensations to the periphery. The developing appreciation of the pathogenesis of pain in animal models of diabetes has offered mechanistic validations for some therapies in current clinical use such as gabapentinoids, low-dose lidocaine, and alpha-lipoic acid while also highlighting new sites for intervention that may offer greater specificity and a reduced side effect profile.

Keywords

Neuropathic Pain Diabetic Neuropathy Aldose Reductase Painful Diabetic Neuropathy Tactile Allodynia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements 

Supported by NIH grant DK057629 (NAC) and a UC MEXUS-CONACYT Fellowship (TM-Z)

References

  1. 1.
    Pop-Busui R, et al. DCCT and EDIC studies in type 1 diabetes: lessons for diabetic neuropathy regarding metabolic memory and natural history. Curr Diab Rep. 2010;10:276–82.PubMedCrossRefGoogle Scholar
  2. 2.
    Tesfaye S, Selvarajah D. The Eurodiab study: what has this taught us about diabetic peripheral neuropathy? Curr Diab Rep. 2009;9:432–4.PubMedCrossRefGoogle Scholar
  3. 3.
    Gibbons CH, Freeman R, Veves A. Diabetic neuropathy: a cross sectional study of the relationships among tests of neurophysiology. Diabetes Care. 2010;33(12):2629–34.PubMedCrossRefGoogle Scholar
  4. 4.
    Abbott CA, Malik RA, van Ross ERE, Kulkarni J, Boulton AJM. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K. Diabetes Care. 2011;34:2220–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Britland ST, Young RJ, Sharma AK, Clarke BF. Acute and remitting painful diabetic polyneuropathy: a comparison of peripheral nerve fibre pathology. Pain. 1992;48:361–70.PubMedCrossRefGoogle Scholar
  6. 6.
    Llewelyn JG, et al. Sural nerve morphometry in diabetic autonomic and painful sensory ­neuropathy. A clinicopathological study. Brain. 1991;114(Pt 2):867–92.PubMedCrossRefGoogle Scholar
  7. 7.
    Malik RA, et al. Sural nerve fibre pathology in diabetic patients with mild neuropathy: relationship to pain, quantitative sensory testing and peripheral nerve electrophysiology. Acta Neuropathol. 2001;101:367–74.PubMedGoogle Scholar
  8. 8.
    Quattrini C, et al. Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes. 2007;56:2148–54.PubMedCrossRefGoogle Scholar
  9. 9.
    Smith AG, et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care. 2006;29: 1294–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Bursova S, et al. Expression of growth-associated protein 43 in the skin nerve fibers of patients with type 2 diabetes mellitus. J Neurol Sci. 2012;315:60–3.PubMedCrossRefGoogle Scholar
  11. 11.
    Morley GK, Mooradian AD, Levine AS, Morley JE. Mechanism of pain in diabetic peripheral neuropathy. Effect of glucose on pain perception in humans. Am J Med. 1984;77:79–82.PubMedCrossRefGoogle Scholar
  12. 12.
    Chan AW, MacFarlane IA, Bowsher D. Short term fluctuations in blood glucose concentrations do not alter pain perception in diabetic-patients with and without painful peripheral ­neuropathy. Diabetes Res. 1990;14:15–9.PubMedGoogle Scholar
  13. 13.
    Jain R, Jain S, Raison CL, Maletic V. Painful diabetic neuropathy is more than pain alone: examining the role of anxiety and depression as mediators and complicators. Curr Diab Rep. 2012;11:275–84.CrossRefGoogle Scholar
  14. 14.
    Doupis J, et al. Microvascular reactivity and inflammatory cytokines in painful and painless peripheral diabetic neuropathy. J Clin Endocrinol Metab. 2009;94:2157–63.PubMedCrossRefGoogle Scholar
  15. 15.
    Bril V, et al. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2012;76:1758–65.CrossRefGoogle Scholar
  16. 16.
    Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010;150:573–81.PubMedCrossRefGoogle Scholar
  17. 17.
    Veves A, Backonja M, Malik RA. Painful diabetic neuropathy: epidemiology, natural history, early diagnosis, and treatment options. Pain Med. 2008;9:660–74.PubMedCrossRefGoogle Scholar
  18. 18.
    Smith HS, Argoff CE. Pharmacological treatment of diabetic neuropathic pain. Drugs. 2011;71:557–89.PubMedCrossRefGoogle Scholar
  19. 19.
    Misawa S, et al. Neuropathic pain is associated with increased nodal persistent Na(+) currents in human diabetic neuropathy. J Peripher Nerv Syst. 2009;14:279–84.PubMedCrossRefGoogle Scholar
  20. 20.
    Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21:114–21.PubMedCrossRefGoogle Scholar
  21. 21.
    Hur J, et al. The identification of gene expression profiles associated with progression of human diabetic neuropathy. Brain. 2011;134:3222–35.PubMedCrossRefGoogle Scholar
  22. 22.
    Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev. 2001;53:597–652.PubMedGoogle Scholar
  23. 23.
    Jourdan D, Ardid D, Eschalier A. Analysis of ultrasonic vocalisation does not allow chronic pain to be evaluated in rats. Pain. 2002;95:165–73.PubMedCrossRefGoogle Scholar
  24. 24.
    van Lunteren E, Moyer M, Pollarine J. Reduced amount and disrupted temporal pattern of spontaneous exercise in diabetic rats. Med Sci Sports Exerc. 2004;36:1856–62.PubMedCrossRefGoogle Scholar
  25. 25.
    Calcutt NA, Jorge MC, Yaksh TL, Chaplan SR. Tactile allodynia and formalin hyperalgesia in streptozotocin-diabetic rats: effects of insulin, aldose reductase inhibition and lidocaine. Pain. 1996;68:293–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Brussee V, et al. Distal degenerative sensory neuropathy in a long-term type 2 diabetes rat model. Diabetes. 2008;57:1664–73.PubMedCrossRefGoogle Scholar
  27. 27.
    Hoybergs YM, Meert TF. The effect of low-dose insulin on mechanical sensitivity and ­allodynia in type I diabetes neuropathy. Neurosci Lett. 2007;417:149–54.PubMedCrossRefGoogle Scholar
  28. 28.
    Kamiya H, Murakawa Y, Zhang W, Sima AA. Unmyelinated fiber sensory neuropathy differs in type 1 and type 2 diabetes. Diabetes Metab Res Rev. 2005;21:448–58.PubMedCrossRefGoogle Scholar
  29. 29.
    Calcutt NA, Freshwater JD, Mizisin AP. Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor. Diabetologia. 2004;47:718–24.PubMedCrossRefGoogle Scholar
  30. 30.
    Calcutt NA. Modeling diabetic sensory neuropathy in rats. Methods Mol Med. 2004; 99:55–65.PubMedGoogle Scholar
  31. 31.
    Bianchi R, et al. Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proc Natl Acad Sci U S A. 2004;101:823–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Beiswenger KK, Calcutt NA, Mizisin AP. Dissociation of thermal hypoalgesia and epidermal denervation in streptozotocin-diabetic mice. Neurosci Lett. 2008;442:267–72.PubMedCrossRefGoogle Scholar
  33. 33.
    Ahlgren SC, Levine JD. Protein kinase C inhibitors decrease hyperalgesia and C-fiber hyperexcitability in the streptozotocin-diabetic rat. J Neurophysiol. 1994;72:684–92.PubMedGoogle Scholar
  34. 34.
    de Carvalho FV, et al. Suppression of allergic inflammatory response in the skin of alloxan-diabetic rats: relationship with reduced local mast cell numbers. Int Arch Allergy Immunol. 2008;147:246–54.CrossRefGoogle Scholar
  35. 35.
    Brandner JM, Zacheja S, Houdek P, Moll I, Lobmann R. Expression of matrix metalloproteinases, cytokines, and connexins in diabetic and nondiabetic human keratinocytes before and after transplantation into an ex vivo wound-healing model. Diabetes Care. 2008;31:114–20.PubMedCrossRefGoogle Scholar
  36. 36.
    Evans L, Andrew D, Robinson P, Boissonade F, Loescher A. Increased cutaneous NGF and CGRP-labelled trkA-positive intra-epidermal nerve fibres in rat diabetic skin. Neurosci Lett. 2011;506:59–63.PubMedCrossRefGoogle Scholar
  37. 37.
    Manni L, Florenzano F, Aloe L. Electroacupuncture counteracts the development of thermal hyperalgesia and the alteration of nerve growth factor and sensory neuromodulators induced by streptozotocin in adult rats. Diabetologia. 2011;54:1900–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Calcutt NA, Freshwater JD, Hauptmann N, Taylor EM, Mizisin AP. Protection of sensory function in diabetic rats by Neotrofin. Eur J Pharmacol. 2006;534:187–93.PubMedCrossRefGoogle Scholar
  39. 39.
    Fernyhough P, Diemel LT, Brewster WJ, Tomlinson DR. Altered neurotrophin mRNA levels in peripheral nerve and skeletal muscle of experimentally diabetic rats. J Neurochem. 1995; 64:1231–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Hong S, Agresta L, Guo C, Wiley JW. The TRPV1 receptor is associated with preferential stress in large dorsal root ganglion neurons in early diabetic sensory neuropathy. J Neurochem. 2008;105:1212–22.PubMedCrossRefGoogle Scholar
  41. 41.
    Hong S, Wiley JW. Early painful diabetic neuropathy is associated with differential changes in the expression and function of vanilloid receptor 1. J Biol Chem. 2005;280:618–27.PubMedGoogle Scholar
  42. 42.
    Alessandri-Haber N, Dina OA, Joseph EK, Reichling DB, Levine JD. Interaction of transient receptor potential vanilloid 4, integrin, and SRC tyrosine kinase in mechanical hyperalgesia. J Neurosci. 2008;28:1046–57.PubMedCrossRefGoogle Scholar
  43. 43.
    Wei H, et al. Roles of cutaneous versus spinal TRPA1 channels in mechanical hypersensitivity in the diabetic or mustard oil-treated non-diabetic rat. Neuropharmacology. 2010;58:578–84.PubMedCrossRefGoogle Scholar
  44. 44.
    Wei H, Hamalainen MM, Saarnilehto M, Koivisto A, Pertovaara A. Attenuation of mechanical hypersensitivity by an antagonist of the TRPA1 ion channel in diabetic animals. Anesthesiology. 2009;111:147–54.PubMedCrossRefGoogle Scholar
  45. 45.
    Koivisto A, et al. Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy. Pharmacol Res. 2012;65:149–58.PubMedCrossRefGoogle Scholar
  46. 46.
    Burchiel KJ, Russell LC, Lee RP, Sima AA. Spontaneous activity of primary afferent neurons in diabetic BB/Wistar rats. A possible mechanism of chronic diabetic neuropathic pain. Diabetes. 1985;34:1210–3.PubMedCrossRefGoogle Scholar
  47. 47.
    Khan GM, Chen SR, Pan HL. Role of primary afferent nerves in allodynia caused by diabetic neuropathy in rats. Neuroscience. 2002;114:291–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Ahlgren SC, White DM, Levine JD. Increased responsiveness of sensory neurons in the saphenous nerve of the streptozotocin-diabetic rat. J Neurophysiol. 1992;68:2077–85.PubMedGoogle Scholar
  49. 49.
    Ahlgren SC, Wang JF, Levine JD. C-fiber mechanical stimulus-response functions are ­different in inflammatory versus neuropathic hyperalgesia in the rat. Neuroscience. 1997; 76:285–90.PubMedCrossRefGoogle Scholar
  50. 50.
    Chen X, Levine JD. Hyper-responsivity in a subset of C-fiber nociceptors in a model of painful diabetic neuropathy in the rat. Neuroscience. 2001;102:185–92.PubMedCrossRefGoogle Scholar
  51. 51.
    Cao XH, Byun HS, Chen SR, Cai YQ, Pan HL. Reduction in voltage-gated K+ channel activity in primary sensory neurons in painful diabetic neuropathy: role of brain-derived neurotrophic factor. J Neurochem. 2010;114:1460–75.PubMedGoogle Scholar
  52. 52.
    Chattopadhyay M, Mata M, Fink DJ. Continuous delta-opioid receptor activation reduces neuronal voltage-gated sodium channel (NaV1.7) levels through activation of protein kinase C in painful diabetic neuropathy. J Neurosci. 2008;28:6652–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Craner MJ, Klein JP, Renganathan M, Black JA, Waxman SG. Changes of sodium channel expression in experimental painful diabetic neuropathy. Ann Neurol. 2002;52:786–92.PubMedCrossRefGoogle Scholar
  54. 54.
    Hong S, Wiley JW. Altered expression and function of sodium channels in large DRG neurons and myelinated A-fibers in early diabetic neuropathy in the rat. Biochem Biophys Res Commun. 2006;339:652–60.PubMedCrossRefGoogle Scholar
  55. 55.
    Shah BS, et al. Beta3, a novel auxiliary subunit for the voltage gated sodium channel is upregulated in sensory neurones following streptozocin induced diabetic neuropathy in rat. Neurosci Lett. 2001;309:1–4.PubMedCrossRefGoogle Scholar
  56. 56.
    Luo ZD, et al. Injury type-specific calcium channel alpha 2 delta-1 subunit up-regulation in rat neuropathic pain models correlates with antiallodynic effects of gabapentin. J Pharmacol Exp Ther. 2002;303:1199–205.PubMedCrossRefGoogle Scholar
  57. 57.
    Umeda M, Ohkubo T, Ono J, Fukuizumi T, Kitamura K. Molecular and immunohistochemical studies in expression of voltage-dependent Ca2+ channels in dorsal root ganglia from streptozotocin-induced diabetic mice. Life Sci. 2006;79:1995–2000.PubMedCrossRefGoogle Scholar
  58. 58.
    Yusaf SP, et al. Streptozocin-induced neuropathy is associated with altered expression of voltage-gated calcium channel subunit mRNAs in rat dorsal root ganglion neurones. Biochem Biophys Res Commun. 2001;289:402–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Hall KE, Sima AA, Wiley JW. Voltage-dependent calcium currents are enhanced in dorsal root ganglion neurones from the Bio Bred/Worchester diabetic rat. J Physiol. 1995;486(Pt 2): 313–22.PubMedGoogle Scholar
  60. 60.
    Jagodic MM, et al. Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons. J Neurosci. 2007;27:3305–16.PubMedCrossRefGoogle Scholar
  61. 61.
    Calcutt NA, Chaplan SR. Spinal pharmacology of tactile allodynia in diabetic rats. Br J Pharmacol. 1997;122:1478–82.PubMedCrossRefGoogle Scholar
  62. 62.
    Messinger RB, et al. In vivo silencing of the Ca(V)3.2T-type calcium channels in sensory neurons alleviates hyperalgesia in rats with streptozocin-induced diabetic neuropathy. Pain. 2009;145:184–95.PubMedCrossRefGoogle Scholar
  63. 63.
    Field MJ, McCleary S, Hughes J, Singh L. Gabapentin and pregabalin, but not morphine and amitriptyline, block both static and dynamic components of mechanical allodynia induced by streptozocin in the rat. Pain. 1999;80:391–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Lee WY, et al. Molecular mechanisms of lipoic acid modulation of T-type calcium channels in pain pathway. J Neurosci. 2009;29:9500–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Mizisin AP, Jolivalt CG, Calcutt NA. Spinal cord. In: Veves A, Malik RA, editors. Clinical diabetes: diabetic neuropathy: clinical management. Totowa, NJ: Humana Press Inc.; 2007. p. 165–85.CrossRefGoogle Scholar
  66. 66.
    Selvarajah D, et al. Early involvement of the spinal cord in diabetic peripheral neuropathy. Diabetes Care. 2006;29:2664–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Malisza KL, et al. Functional magnetic resonance imaging of the spinal cord during sensory stimulation in diabetic rats. J Magn Reson Imaging. 2009;30:271–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Malmberg AB, O’Connor WT, Glennon JC, Cesena R, Calcutt NA. Impaired formalin-evoked changes of spinal amino acid levels in diabetic rats. Brain Res. 2006;1115:48–53.PubMedCrossRefGoogle Scholar
  69. 69.
    Calcutt NA, Stiller C, Gustafsson H, Malmberg AB. Elevated substance-P-like immunoreactivity levels in spinal dialysates during the formalin test in normal and diabetic rats. Brain Res. 2000;856:20–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Svensson CI, Brodin E. Spinal astrocytes in pain processing: non-neuronal cells as therapeutic targets. Mol Interv. 2010;10:25–38.PubMedCrossRefGoogle Scholar
  71. 71.
    Chen SR, Pan HL. Hypersensitivity of spinothalamic tract neurons associated with diabetic neuropathic pain in rats. J Neurophysiol. 2002;87:2726–33.PubMedGoogle Scholar
  72. 72.
    Calcutt NA, Freshwater JD, O’Brien JS. Protection of sensory function and antihyperalgesic properties of a prosaposin-derived peptide in diabetic rats. Anesthesiology. 2000;93:1271–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Freshwater JD, Svensson CI, Malmberg AB, Calcutt NA. Elevated spinal cyclooxygenase and prostaglandin release during hyperalgesia in diabetic rats. Diabetes. 2002;51:2249–55.PubMedCrossRefGoogle Scholar
  74. 74.
    Ramos KM, Jiang Y, Svensson CI, Calcutt NA. Pathogenesis of spinally mediated hyperalgesia in diabetes. Diabetes. 2007;56:1569–76.PubMedCrossRefGoogle Scholar
  75. 75.
    Hotta N, et al. Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebo-controlled double-blind parallel group study. Diabetes Care. 2001;24:1776–82.PubMedCrossRefGoogle Scholar
  76. 76.
    Young RJ, Ewing DJ, Clarke BF. A controlled trial of sorbinil, an aldose reductase inhibitor, in chronic painful diabetic neuropathy. Diabetes. 1983;32:938–42.PubMedCrossRefGoogle Scholar
  77. 77.
    Daulhac L, et al. Phosphorylation of spinal N-methyl-d-aspartate receptor NR1 subunits by extracellular signal-regulated kinase in dorsal horn neurons and microglia contributes to diabetes-induced painful neuropathy. Eur J Pain. 2011;15(2):169.e1–169.e12.CrossRefGoogle Scholar
  78. 78.
    Daulhac L, et al. Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms. Mol Pharmacol. 2006;70:1246–54.PubMedCrossRefGoogle Scholar
  79. 79.
    Tsuda M, Ueno H, Kataoka A, Tozaki-Saitoh H, Inoue K. Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signaling. Glia. 2008;56:378–86.PubMedCrossRefGoogle Scholar
  80. 80.
    Toth CC, Jedrzejewski NM, Ellis CL, Frey II WH. Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain. Mol Pain. 2010;6:16.PubMedCrossRefGoogle Scholar
  81. 81.
    Talbot S, Chahmi E, Dias JP, Couture R. Key role for spinal dorsal horn microglial kinin B1 receptor in early diabetic pain neuropathy. J Neuroinflammation. 2010;7:36.PubMedCrossRefGoogle Scholar
  82. 82.
    Afsari ZH, Renno WM, Abd-El-Basset E. Alteration of glial fibrillary acidic proteins ­immunoreactivity in astrocytes of the spinal cord diabetic rats. Anat Rec (Hoboken). 2008; 291:390–9.CrossRefGoogle Scholar
  83. 83.
    Coleman ES, Dennis JC, Braden TD, Judd RL, Posner P. Insulin treatment prevents diabetes-induced alterations in astrocyte glutamate uptake and GFAP content in rats at 4 and 8 weeks of diabetes duration. Brain Res. 2010;1306:131–41.PubMedCrossRefGoogle Scholar
  84. 84.
    D’Mello R, Dickenson AH. Spinal cord mechanisms of pain. Br J Anaesth. 2008;101:8–16.PubMedCrossRefGoogle Scholar
  85. 85.
    Jolivalt CG, Lee CA, Ramos KM, Calcutt NA. Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters. Pain. 2008; 140:48–57.PubMedCrossRefGoogle Scholar
  86. 86.
    Morgado C, Pinto-Ribeiro F, Tavares I. Diabetes affects the expression of GABA and ­potassium chloride cotransporter in the spinal cord: a study in streptozotocin diabetic rats. Neurosci Lett. 2008;438:102–6.PubMedCrossRefGoogle Scholar
  87. 87.
    Coull JA, et al. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature. 2003;424:938–42.PubMedCrossRefGoogle Scholar
  88. 88.
    Mixcoatl-Zecuatl T, Jolivalt CG. A spinal mechanism of action for duloxetine in a rat model of painful diabetic neuropathy. Br J Pharmacol. 2011;164:159–69.PubMedCrossRefGoogle Scholar
  89. 89.
    Sima AA. Encephalopathies: the emerging diabetic complications. Acta Diabetol. 2010; 47(4): 279–93.PubMedCrossRefGoogle Scholar
  90. 90.
    Jolivalt CG, et al. Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer’s disease and correction by insulin. J Neurosci Res. 2008;86:3265–74.PubMedCrossRefGoogle Scholar
  91. 91.
    Sorensen L, Siddall PJ, Trenell MI, Yue DK. Differences in metabolites in pain-processing brain regions in patients with diabetes and painful neuropathy. Diabetes Care. 2008;31: 980–1.PubMedCrossRefGoogle Scholar
  92. 92.
    Selvarajah D, Wilkinson ID, Gandhi R, Griffiths PD, Tesfaye S. Microvascular perfusion abnormalities of the thalamus in painful but not painless diabetic polyneuropathy: a clue to the pathogenesis of pain in type 1 diabetes. Diabetes Care. 2011;34:718–20.PubMedCrossRefGoogle Scholar
  93. 93.
    Selvarajah D, et al. Thalamic neuronal dysfunction and chronic sensorimotor distal symmetrical polyneuropathy in patients with type 1 diabetes mellitus. Diabetologia. 2008;51:2088–92.PubMedCrossRefGoogle Scholar
  94. 94.
    Cauda F, et al. Altered resting state attentional networks in diabetic neuropathic pain. J Neurol Neurosurg Psychiatry. 2010;81:806–11.PubMedCrossRefGoogle Scholar
  95. 95.
    Cauda F, et al. Low-frequency BOLD fluctuations demonstrate altered thalamocortical connectivity in diabetic neuropathic pain. BMC Neurosci. 2009;10:138.PubMedCrossRefGoogle Scholar
  96. 96.
    Cauda F, et al. Altered resting state in diabetic neuropathic pain. PLoS One. 2009;4:e4542.PubMedCrossRefGoogle Scholar
  97. 97.
    Paulson PE, Wiley JW, Morrow TJ. Concurrent activation of the somatosensory forebrain and deactivation of periaqueductal gray associated with diabetes-induced neuropathic pain. Exp Neurol. 2007;208:305–13.PubMedCrossRefGoogle Scholar
  98. 98.
    Fischer TZ, Tan AM, Waxman SG. Thalamic neuron hyperexcitability and enlarged receptive fields in the STZ model of diabetic pain. Brain Res. 2009;1268:154–61.PubMedCrossRefGoogle Scholar
  99. 99.
    Rajbhandari SM, Jarratt JA, Griffiths PD, Ward JD. Diabetic neuropathic pain in a leg amputated 44 years previously. Pain. 1999;83:627–9.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of PathologyUniversity of California San DiegoLa JollaUSA

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