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Metabolomic signature of type 1 diabetes-induced sensory loss and nerve damage in diabetic neuropathy

  • Daniel Rangel Rojas
  • Rohini Kuner
  • Nitin AgarwalEmail author
Original Article

Abstract

Diabetic-induced peripheral neuropathy (DPN) is a highly complex and frequent diabetic late complication, which is manifested by prolonged hyperglycemia. However, the molecular mechanisms underlying the pathophysiology of nerve damage and sensory loss remain largely unclear. Recently, alteration in metabolic flux has gained attention as a basis for organ damage in diabetes; however, peripheral sensory neurons have not been adequately analyzed with respect to metabolic dysfunction. In the present study, we attempted to delineate the sequence of event occurring in alteration of metabolic pathways in relation to nerve damage and sensory loss. C57Bl6/j wild-type mice were analyzed longitudinally up to 22 weeks in the streptozotocin (STZ) model of type 1 diabetes. The progression of DPN was investigated by behavioral measurements of sensitivity to thermal and mechanical stimuli and quantitative morphological assessment of intraepidermal nerve fiber density. We employed a mass spectrometry-based screen to address alterations in levels of metabolites in peripheral sciatic nerve and amino acids in serum over several months post-STZ administration to elucidate metabolic dysfunction longitudinally in relation to sensory dysfunction. Although hyperglycemia and body weight changes occurred early, sensory loss and reduced intraepithelial branching of nociceptive nerves were only evident at 22 weeks post-STZ. The longitudinal metabolites screen in peripheral nerves demonstrated that compared with buffer-injected age-matched control mice, mice at 12 and 22 weeks post-STZ showed an early impairment the tricaoboxylic acid (TCA cycle), which is the main pathway of carbohydrate metabolism leading to energy generation. We found that levels of citric acid, ketoglutaric acid (2 KG), succinic acid, fumaric acid, and malic acid were observed to be significantly reduced in sciatic nerve at 22 weeks post-STZ. In addition, we also found the increase in levels of sorbitol and L-lactate in peripheral nerve from 12 weeks post-STZ injection. Amino acid screen in serum showed that the amino acids valine (Val), isoleucine (Ile), and leucine (Leu), grouped together as BCAA, increased more than twofold from 12 weeks post-STZ. Similarly, the levels of tyrosine (Tyr), asparagine (Asn), serine (Ser), histidine (His), alanine (Ala), and proline (Pro) showed progressive increase with progression of diabetes. Our results indicate that the impaired TCA cycle metabolites in peripheral nerve are the primary cause of shunting metabolic substrate to compensatory pathways, which leads to sensory nerve fiber loss in skin and contribute to onset and progression of peripheral neuropathy.

Keywords

Hyperglycemia DPN TCA Streptozotocin Sensory neurons 

Abbreviations

ROS

reactive oxygen species

STZ

streptozotocin

DPN

diabetic peripheral neuropathy

SN

sciatic nerve

SNS

sensory neuron-specific

MS

mass spectrometry

Notes

Acknowledgments

The authors thank Rose LeFaucheur for the secretarial help, Karin Meyer, Dunja Baumgartl-Ahlert and Hans-Joseph Wrede for technical assistance, and Vijayan Gangadharan (V.G) for scientific discussion. We would like to thank the Metabolomics Core Technology Platform of the Excellence Cluster CellNetworks for support with amino acid and metabolite quantification.

Author contributions

NA and RK designed the study; DRR and NA performed and analyzed the experiments; NA and RK wrote the manuscript. All authors approved the final version.

Funding information

This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG) in the Collaborative Research Center 1118 (SFB1118 Project B06) to N.A. and R.K. and (SFB1158, Project A03) to V.G. and R.K.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

References

  1. 1.
    Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 3(11):e442CrossRefGoogle Scholar
  2. 2.
    Vincent AM, Callaghan BC, Smith AL, Feldman EL (2011) Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol 7(10):573–583CrossRefGoogle Scholar
  3. 3.
    Feldman EL, Nave KA, Jensen TS, Bennett DLH (2017) New horizons in diabetic neuropathy: mechanisms, bioenergetics, and pain. Neuron. 93(6):1296–1313CrossRefGoogle Scholar
  4. 4.
    Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107(9):1058–1070CrossRefGoogle Scholar
  5. 5.
    Rolo AP, Palmeira CM (2006) Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol 212(2):167–178CrossRefGoogle Scholar
  6. 6.
    Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414(6865):813–820CrossRefGoogle Scholar
  7. 7.
    Obrosova IG, Pacher P, Szabó C, Zsengeller Z, Hirooka H, Stevens MJ, Yorek MA (2005) Aldose reductase inhibition counteracts oxidative-nitrosative stress and poly(ADP-ribose) polymerase activation in tissue sites for diabetes complications. Diabetes. 54(1):234–242CrossRefGoogle Scholar
  8. 8.
    Lashin OM, Szweda PA, Szweda LI, Romani AM (2006) Decreased complex II respiration and HNE-modified SDH subunit in diabetic heart. Free Radic Biol Med 40(5):886–896CrossRefGoogle Scholar
  9. 9.
    Yang JY, Yeh HY, Lin K, Wang PH (2009) Insulin stimulates Akt translocation to mitochondria: implications on dysregulation of mitochondrial oxidative phosphorylation in diabetic myocardium. J Mol Cell Cardiol 46(6):919–926CrossRefGoogle Scholar
  10. 10.
    Kelley DE, He J, Menshikova EV, Ritov VB (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51(10):2944–2950CrossRefGoogle Scholar
  11. 11.
    Mogensen M, Sahlin K, Fernström M, Glintborg D, Vind BF, Beck-Nielsen H et al (2007) Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes 56(6):1592–1599CrossRefGoogle Scholar
  12. 12.
    Akude E, Zherebitskaya E, Chowdhury SK, Smith DR, Dobrowsky RT, Fernyhough P (2011) Diminished superoxide generation is associated with respiratory chain dysfunction and changes in the mitochondrial proteome of sensory neurons from diabetic rats. Diabetes 60(1):288–297CrossRefGoogle Scholar
  13. 13.
    Hsieh YL, Lin CL, Chiang H, Fu YS, Lue JH, Hsieh ST (2012) Role of peptidergic nerve terminals in the skin: reversal of thermal sensation by calcitonin gene-related peptide in TRPV1-depleted neuropathy. PLoS One 7(11):e50805CrossRefGoogle Scholar
  14. 14.
    Koulmanda M, Qipo A, Chebrolu S, O'Neil J, Auchincloss H, Smith RN (2003) The effect of low versus high dose of streptozotocin in cynomolgus monkeys (Macaca fascilularis). Am J Transplant 3:267–272CrossRefGoogle Scholar
  15. 15.
    Leiter EH (1982) Multiple low-dose streptozotocin-induced hyperglycemia and insulitis in C57BL mice: influence of inbred background, sex, and thymus. Proc Natl Acad Sci U S A 79(2):630–634CrossRefGoogle Scholar
  16. 16.
    Rajashree R, Kholkute SD, Goudar SS (2011) Effects of duration of diabetes on behavioral and cognitive parameters in streptozotocin-induced juvenile diabetic rats. Malays J Med Sci 18(4):26–31Google Scholar
  17. 17.
    Yagihashi S, Mizukami H, Sugimoto K (2011) Mechanism of diabetic neuropathy: where are we now and where to go? J Diabetes Investig 2(1):18–32CrossRefGoogle Scholar
  18. 18.
    Sveen KA, Karimé B, Jørum E, Mellgren SI, Fagerland MW, Monnier VM et al (2013) Small- and large-fiber neuropathy after 40 years of type 1 diabetes: associations with glycemic control and advanced protein glycation: the Oslo Study. Diabetes Care 36(11):3712–3717CrossRefGoogle Scholar
  19. 19.
    Themistocleous AC, Ramirez JD, Serra J, Bennett DL (2014) The clinical approach to small fibre neuropathy and painful channelopathy. Pract Neurol 14(6):368–379CrossRefGoogle Scholar
  20. 20.
    Beiswenger KK, Calcutt NA, Mizisin AP (2008) Epidermal nerve fiber quantification in the assessment of diabetic neuropathy. Acta Histochem 110(5):351–362CrossRefGoogle Scholar
  21. 21.
    Wolfe RR (2017) Branched-chain amino acids and muscle protein synthesis in humans:myth or reality? J Int Soc Sports Nutr 22(14):30CrossRefGoogle Scholar
  22. 22.
    Barrett AM, Lucero MA, Le T, Robinson RL, Dworkin RH, Chappell AS (2007) Epidemiology, public health burden, and treatment of diabetic peripheral neuropathic pain: a review. Pain Med 2:S50–S62CrossRefGoogle Scholar
  23. 23.
    Hinder LM, Vivekanandan-Giri A, McLean LL, Pennathur S, Feldman EL (2013) Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with peripheral nervous system oxidative stress in a murine model of type 2 diabetes. J Endocrinol 216(1):1–11CrossRefGoogle Scholar
  24. 24.
    Ola MS, Berkich DA, Xu Y, King MT, Gardner TW, Simpson I, et.al (2006) Analysis of glucose metabolism in diabetic rat retinas. Am J Physiol Endocrinol Metab 290(6):E1057–E1067Google Scholar
  25. 25.
    Piccolo BD, Graham JL, Stanhope KL, Fiehn O, Havel PJ, Adams SH (2016) Plasma amino acid and metabolite signatures tracking diabetes progression in the UCD-T2DM rat model. Am J Physiol Endocrinol Metab 310(11):E958–E969CrossRefGoogle Scholar
  26. 26.
    Tretter L, Adam-Vizi V (2000) Inhibition of Krebs cycle enzymes by hydrogen peroxide: a key role of [alpha]-ketoglutarate dehydrogenase in limiting NADH production under oxidative stress. J Neurosci 20(24):8972–8979CrossRefGoogle Scholar
  27. 27.
    Figliomeni B, Bacci B, Panozzo C, Fogarolo F, Triban C, Fiori MG (1992) Experimental diabetic neuropathy. Effect of ganglioside treatment on axonal transport of cytoskeletal proteins. Diabetes 41(7):866–871CrossRefGoogle Scholar
  28. 28.
    Hellmuth C, Kirchberg FF, Lass N, Harder U, Peissner W, Koletzko B, Reinehr T (2016) Tyrosine is associated with insulin resistance in longitudinal metabolomic profiling of obese children. J Diabetes Res 2016:2108909CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Daniel Rangel Rojas
    • 1
  • Rohini Kuner
    • 1
  • Nitin Agarwal
    • 1
    Email author
  1. 1.Institute of PharmacologyHeidelberg UniversityHeidelbergGermany

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