Hunter, Sandra K.

Senefeld, Jonathon

English

epublications@Marquette

Marquette Universitye-Publications@MarquetteExercise Science Faculty Research and Publications Exercise Science, Department of7-1-2016Molecular Underpinnings of DiabeticPolyneuropathyJonathon SenefeldMarquette UniversitySandra K. HunterMarquette University, sandra.hunter@marquette.eduAccepted version. Journal of Applied Physiology, Vol. 121, No. 1 ( July 2016): 360. DOI. © 2016American Physiological Society. Used with permission.NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Journal of Applied Physiology, Vol 121, No. 1 (July 2016): pg. 360. DOI. This article is © American Physiological Society and permission has been granted for this version to appear in e-Publications@Marquette. American Physiological Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Physiological Society. 1    Molecular Underpinnings of Diabetic Polyneuropathy    Jonathon Senefeld Exercise Science Program, Department of Physical Therapy, Marquette University, Milwaukee, WI Sandra K. Hunter Exercise Science Program, Department of Physical Therapy, Marquette University, Milwaukee, WI    To the Editor: Allen and colleagues2 provided an in-depth review of the pathophysiology and functional outcomes of diabetic polyneuropathy (DPN) among patients with diabetes mellitus (DM). As explained,2 DPN often manifests in a symmetrical and length-dependent pattern affecting distal portions of long peripheral nerves of patients with DM,11 Here we highlight the molecular pathogenesis within the soma of the motoneuron, which may also inform clinical treatment. Although DPN manifests in neuronal axons, the deleterious molecular cascade begins within the soma of the peripheral nerve located within the anterior horn of the spinal cord. Glucose is transported into the milieu of nervous tissue independent of insulin,5 NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Journal of Applied Physiology, Vol 121, No. 1 (July 2016): pg. 360. DOI. This article is © American Physiological Society and permission has been granted for this version to appear in e-Publications@Marquette. American Physiological Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Physiological Society. 2  which results in a hyperglycemic metabolic milieu of nervous system tissue in patients with DM. Excessive glucose is metabolized into sorbitol and fructose, and both activate advanced glycation end products (AGEs), resulting in molecular oxidative stress.3 Oxidative stress within the soma triggers withdrawal of the longest (typically most distal) nerve axons from their distal terminals without cellular death.12 This observation is clinically relevant, because there is the potential for recovery from structural damage to the axon before death of the nerve soma.9 The precise mechanism by which oxidative stress triggers distal axonal retraction is unclear but likely involves disruption of sodium-potassium pump activity (Na+/K+-ATPase)10 and downregulation of insulin-like growth factor 1 (IGF-1),8 leading to disruption of the neuromuscular junction. Consequently, denervation of distal muscle fibers occurs and the soma signals lateral sprouting of the retracted distal axon to innervate more proximal muscle fibers.4 The net result is a loss of motor unit numbers,12 an increase in the size of surviving motor units,12 and subsequent reduction of maximal muscle force1 and control of muscle force. The distinction between the pathogenesis beginning within the neuronal axon or soma could have important implications for clinical interventions. For example, the nerve soma could be targeted with interventions (e.g., pharmacological) to preserve the function of the neuron. Clinically, the most sensitive tools identified to date for assessing DPN-related impairments of neuromuscular function (compared with DM patients without DPN) are isometric strength of distal muscles (e.g., plantar and dorsiflexors)1,6 and the timed up and go (TUG) test.7 Thus the molecular underpinnings of DPN are likely related to the functional outcomes discussed by Allen and colleagues,2 and further understanding the involved mechanisms may help guide clinical practice. Disclosures No conflicts of interest, financial or otherwise, are declared by the author(s). Author Contributions J.S. drafted manuscript; J.S. and S.K.H. edited and revised manuscript; J.S. and S.K.H. approved final version of manuscript. NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Journal of Applied Physiology, Vol 121, No. 1 (July 2016): pg. 360. DOI. This article is © American Physiological Society and permission has been granted for this version to appear in e-Publications@Marquette. American Physiological Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Physiological Society. 3  References 1Allen MD, Choi IH, Kimpinski K, Doherty TJ, Rice CL. Motor unit loss and weakness in association with diabetic neuropathy in humans. Muscle Nerve 48: 298–300, 2013. 2Allen MD, Doherty TJ, Rice CL, Kimpinski K. Physiology in Medicine: Neuromuscular consequences of diabetic neuropathy. J Appl Physiol; doi:10.1152/japplphysiol.00733.2015. 3Chung SS, Ho EC, Lam KS, Chung SK. Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol 14: S233–236, 2003. 4Fahim MA, el-Sabban F, Davidson N. Muscle contractility decrement and correlated morphology during the pathogenesis of streptozotocin-diabetic mice. Anat Rec 251: 240–244, 1998. 5Hasselbalch SG, Knudsen GM, Videbaek C, Pinborg LH, Schmidt JF, Holm S, Paulson OB. No effect of insulin on glucose blood-brain barrier transport and cerebral metabolism in humans. Diabetes 48: 1915–1921, 1999. 6Ijzerman TH, Schaper NC, Melai T, Blijham P, Meijer K, Willems PJ, Savelberg HH. Motor nerve decline does not underlie muscle weakness in type 2 diabetic neuropathy. Muscle Nerve 44: 241–245, 2011. 7IJzerman TH, Schaper NC, Melai T, Meijer K, Willems PJB, Savelberg HHCM. Lower extremity muscle strength is reduced in people with type 2 diabetes, with and without polyneuropathy, and is associated with impaired mobility and reduced quality of life. Diabetes Res Clin Pr 95: 345–351, 2012. 8Janssen JA, Lamberts SW. Circulating IGF-I and its protective role in the pathogenesis of diabetic angiopathy. Clin Endocrinol 52: 1–9, 2000. 9Kennedy JM, Zochodne DW. Experimental diabetic neuropathy with spontaneous recovery: is there irreparable damage? Diabetes 54: 830–837, 2005. 10Krishnan AV, Lin CS, Kiernan MC. Activity-dependent excitability changes suggest Na+/K+ pump dysfunction in diabetic neuropathy. Brain 131: 1209–1216, 2008. 11Said G. Diabetic neuropathy—a review. Nat Clin Pract Neurol 3: 331–340, 2007. 12Souayah N, Potian JG, Garcia CC, Krivitskaya N, Boone C, Routh VH, McArdle JJ. Motor unit number estimate as a predictor of motor dysfunction in an animal model of type 1 diabetes. Am J Physiol Endocrinol Metab 297: E602–E608, 2009.  

Molecular Underpinnings of Diabetic Polyneuropathy

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Molecular Underpinnings of Diabetic Polyneuropathy

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