Skip to main content

Advertisement

SpringerLink
Log in

Biomarkers of response to alpha-lipoic acid ± palmitoiletanolamide treatment in patients with diabetes and symptoms of peripheral neuropathy

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

To evaluate the effect of oral alpha-lipoic acid (ALA) ± palmitoyl-ethanolamide (PEA) on neuropathic symptoms in patients with diabetic peripheral neuropathy (DPN) and to identify factors related to the efficacy of the treatment.

Methods

This is a retrospective observational pilot study evaluating 49 patients with diabetes and positive Neuropathy Symptoms Score (NSS). Clinical and biochemical variables, including NSS, were compared between untreated patients and patients treated with oral 600 mg/day ALA ± 600 mg/day PEA at baseline (first occurrence of NSS ≥ 3) and at least 2 months after baseline. Number of days between treatment initiation and symptoms’ relief and related factors were also investigated.

Results

Thirty subjects were treated with ALA ± PEA and 19 subjects did not receive any specific treatment for neuropathy symptoms. Follow-up visits occurred after 98 ± 46 days. NSS significantly decreased in patients treated with ALA ± PEA (5.4 ± 1.3 at baseline vs. 1.7 ± 2.4 at follow-up, p < 0.001), but not in untreated patients (p = 0.164). Subjects treated with ALA ± PEA reported a mean time from treatment initiation to symptoms’ relief of 18.4 ± 9.0 days. The number of days of treatment needed for symptoms’ relief was inversely related to HDL-cholesterol levels (r = −0.503, p = 0.010) and to eGFR (r = −0.428, p = 0.033), whereas there was no significant relationship between time to symptoms’ relief and age, HbA1c, lipid profile and the severity of symptoms at baseline.

Conclusions

This study documents that oral administration of ALA ± PEA helps in controlling neuropathy symptoms in diabetes. Moreover, our data show that higher HDL-c levels and better renal function are associated to a faster therapeutic effect, suggesting them as biomarkers of response to therapy with ALA ± PEA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. E. Maddaloni, F. Sabatino, In vivo corneal confocal microscopy in diabetes: where we are and where we can get. World J. Diabetes 7(17), 406–411 (2016)

    Article  Google Scholar 

  2. E. Maddaloni et al. In vivo corneal confocal microscopy as a novel non-invasive tool to investigate cardiac autonomic neuropathy in Type 1 diabetes. Diabet. Med. 32, 262–266 (2015)

    Article  CAS  Google Scholar 

  3. Z. Iqbal et al. Diabetic peripheral neuropathy: epidemiology, diagnosis, and pharmacotherapy. Clin. Ther. 40, 828–849 (2018)

    Article  Google Scholar 

  4. D.A. Greene, A.A.F. Sima, M.J. Stevens, E.L. Feldman, S.A. Lattimer, Complications: neuropathy, pathogenetic considerations. Diabetes Care 15, 1902–1925 (1992)

    Article  CAS  Google Scholar 

  5. S.D. Solomon et al. Diabetic retinopathy: a position statement by the American Diabetes Association. Diabetes Care 40, 412–418 (2017)

    Article  Google Scholar 

  6. E. Maddaloni, R. Buzzetti, Why only macro and not micro in type 2 diabetes? Time to change the goals of clinical trials in diabetes. Diabetes/Metab. Res. Rev 34(6), e3012 (2018). https://doi.org/10.1002/dmrr.3012

    Article  Google Scholar 

  7. M. Brownlee, The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615–1625 (2005)

    Article  CAS  Google Scholar 

  8. R. Pop-Busui, A. Sima, M. Stevens, Review: diabetic neuropathy and oxidative stress. Diabetes. Metab. Res. Rev. 22, 257–273 (2006)

    Article  CAS  Google Scholar 

  9. N. Papanas, D. Ziegler, Efficacy of α-lipoic acid in diabetic neuropathy. Expert Opin. Pharmacother. 15, 2721–2731 (2014)

    Article  CAS  Google Scholar 

  10. N. Vallianou, A. Evangelopoulos, P. Koutalas, Alpha-lipoic acid and diabetic neuropathy. Rev. Diabet. Stud. 6, 230–236 (2009)

    Article  Google Scholar 

  11. N.A. Darmani et al. Involvement of the cannabimimetic compound, N-palmitoyl-ethanolamine, in inflammatory and neuropathic conditions: review of the available pre-clinical data, and first human studies. Neuropharmacology. 48, 1154–1163 (2005)

    Article  CAS  Google Scholar 

  12. S. Petrosino, V.Di Marzo, The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. Br. J. Pharmacol. 174, 1349–1365 (2017)

    Article  CAS  Google Scholar 

  13. J.W.G. Meijer, A.J. Smit, E.V. Sonderen, J.W. Groothoff, W.H. Eisma, T.P. Links, Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the diabetic neuropathy symptom score. Diabet. Med. 19, 962–965 (2002)

    Article  CAS  Google Scholar 

  14. C.A. Abbott et al. The North-West Diabetes Foot Care Study: Incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet. Med. 19, 377–384 (2002)

    Article  CAS  Google Scholar 

  15. D. Ziegler, H. Nowak, P. Kempler, P. Vargha, P.A. Low, Treatment of symptomatic diabetic polyneuropathy with the antioxidant α-lipoic acid: a meta-analysis. Diabet. Med. 21, 114–121 (2004)

    Article  CAS  Google Scholar 

  16. T. Han, J. Bai, W. Liu, Y. Hu, A systematic review and meta-analysis of α-lipoic acid in the treatment of diabetic peripheral neuropathy. Eur. J. Endocrinol. 167, 465–471 (2012)

    Article  CAS  Google Scholar 

  17. D. Ziegler et al. Oral treatment with α-lipoic acid improves symptomatic diabetic polyneuropathy. Diabetes Care 29, 2365–2370 (2006)

    Article  CAS  Google Scholar 

  18. K.J. Ruhnau et al. Effects of 3-week oral treatment with the antioxidant thioctic acid (α- lipoic acid) in symptomatic diabetic polyneuropathy. Diabet. Med. 16, 1040–1043 (1999)

    Article  CAS  Google Scholar 

  19. G.S. Mijnhout, B.J. Kollen, A. Alkhalaf, N. Kleefstra, H.J.G. Bilo, Alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. Int. J. Endocrinol. 2012, 456279 (2012)

    Article  Google Scholar 

  20. P.A. Low, K.K. Nickander, H.J. Tritschler, The roles of oxidative stress and antioxidant. Treatment in experimental diabetic neuropathy. Diabetes 46(Suppl 2), S38–S42 (1997)

    Article  CAS  Google Scholar 

  21. L. Rochette, S. Ghibu, A. Muresan, C. Vergely, Alpha-lipoic acid: molecular mechanisms and therapeutic potential in diabetes. Can. J. Physiol. Pharmacol. 93, 1021–1027 (2015)

    Article  CAS  Google Scholar 

  22. D. Ziegler, H. Schatz, F. Conrad, F.A. Gries, H. Ulrich, G. Reichel, Effects of treatment with the antioxidant α-lipoic acid on cardiac autonomic neuropathy in NIDDM patients: a 4-month randomized controlled multicenter trial (DEKAN study). Diabetes Care 20, 369–373 (1997)

    Article  CAS  Google Scholar 

  23. F. Guida et al. Palmitoylethanolamide reduces pain-related behaviors and restores glutamatergic synapses homeostasis in the medial prefrontal cortex of neuropathic mice. Mol. Brain 8, 47 (2015)

    Article  CAS  Google Scholar 

  24. L. Di Cesare Mannelli et al. Antineuropathic profile of N-Palmitoylethanolamine in a rat model of oxaliplatin-induced neurotoxicity. PLoS ONE 10, e0128080 (2015)

    Article  Google Scholar 

  25. Antonella Paladini, MariellaFusco, Teresa Cenacchi, P.Carlo Schievano, Alba Piroli, Giustino Varrassi, Palmitoylethanolamide, a special food for medical purposes, in the treatment of chronic pain: a pooled data meta-analysis. Pain Physician 19, 11–24 (2016)

    PubMed  Google Scholar 

  26. H.L. Hébert, A. Veluchamy, N. Torrance, B.H. Smith, Risk factors for neuropathic pain in diabetes mellitus. Pain 158, 560–568 (2017)

    Article  Google Scholar 

  27. R. Pop-Busui, L. Roberts, S. Pennathur, M. Kretzler, F.C. Brosius, E.L. Feldman, The management of diabetic neuropathy in CKD. Am. J. Kidney Dis. 55, 365–385 (2010)

    Article  Google Scholar 

  28. K.-A. Rye, P.J. Barter, Cardioprotective functions of HDL. J. Lipid Res. 55(2), 168–179 (2014).

    Article  CAS  Google Scholar 

  29. E. Maddaloniet al. High density lipoprotein modulates osteocalcin expression in circulating monocytes: a potential protective mechanism for cardiovascular disease in type 1 diabetes. Cardiovasc. Diabetol. 16(1), 116 (2017)

    Article  Google Scholar 

  30. S. Tesfaye et al. Vascular risk factors and diabetic neuropathy. N. Engl. J. Med. 352, 341–350 (2005)

    Article  CAS  Google Scholar 

  31. R.E. Maser et al. Epidemiological correlates of diabetic neuropathy. report from Pittsburgh epidemiology of diabetes complications study. Diabetes 38, 1456–1461 (1989)

    Article  CAS  Google Scholar 

  32. M. Jaiswal, et al. Prevalence of and risk factors for diabetic peripheralneuropathy in youth with type 1 and type 2 diabetes: Search for diabetes in youth study. Diabetes Care 40, 1226–1232 (2017)

    Article  CAS  Google Scholar 

  33. F. Kannenberg et al. Characterization of cholesterol homeostasis in telomeraseimmortalized tangier disease fibroblasts reveals marked phenotype variability. J. Biol. Chem. 288, 36936–36947 (2013)

    Article  CAS  Google Scholar 

  34. J. Katz, N.B. Finnerup, R.H. Dworkin, Clinical trial outcome in neuropathic pain: relationship to study characteristics. Neurology 70, 263–272 (2008)

    Article  Google Scholar 

Download references

Acknowledgements

This study was in part supported by an unrestricted grant from LJ Pharma.

Author information

Author notes

  1. These authors contributed equally: Silvia Pieralice, Riccardo Vari

Authors and Affiliations

  1. Department of Medicine, Unit of Endocrinology and Diabetes, Campus Bio-Medico University of Rome, Rome, Italy

    Silvia Pieralice, Riccardo Vari, Alessandra Minutolo, Anna Rita Maurizi, Elvira Fioriti, Nicola Napoli, Paolo Pozzilli, Silvia Manfrini & Ernesto Maddaloni

Authors
  1. Silvia Pieralice
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Riccardo Vari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alessandra Minutolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Rita Maurizi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elvira Fioriti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nicola Napoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paolo Pozzilli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Silvia Manfrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ernesto Maddaloni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ernesto Maddaloni.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the ethics committee of Campus Bio-Medico University of Rome, Italy. For this retrospective study, formal consent is not required. No patient identifiable information has been used in this study and only data from which identifying factors have been removed were used for statistical analysis.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pieralice, S., Vari, R., Minutolo, A. et al. Biomarkers of response to alpha-lipoic acid ± palmitoiletanolamide treatment in patients with diabetes and symptoms of peripheral neuropathy. Endocrine 66, 178–184 (2019). https://doi.org/10.1007/s12020-019-01917-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-019-01917-w

Keywords

Search

Navigation