Abstract
Objective: Proinflammatory and neurovascular changes are blamed in the pathogenesis of diabetic neuropathy. Although it is accepted that diabetes is a trigger for vascular inflammation, it has been suggested that inflammation itself may trigger diabetes. Interleukin-23 (IL-23) is a pro-inflammatory cytokine secreted by activated macrophages and dendritic cells. Interleukin-23R is known to have a critical role in chronic inflammatory diseases. The aim of this study is to determine the relationship between IL-23R polymorphism and diabetic peripheral neuropathy.
Method: 50 diabetic peripheral neuropathy patients who applied to Neurology outpatient clinic, and 52 healthy controls compatible with the patient group in terms of age and gender were included. Electromyography was performed on all of the volunteers, who agreed to participate in the study, and 2 ml of blood samples were taken into tubes with EDTA, and the IL-23R gene polymorphism was analyzed using the pyrosequencing method.
Results: IL-23R gene variants rs2201841, rs199542433, rs201052419, rs11209026 were analyzed in diabetic peripheral neuropathy (DPN) patients and control group. While we investigate IL23R polymorphisms we didn’t find any significant differences between patient and control groups. But when we use odds ratios, rs2201841 seems to have a protective role, and rs199542433 in both dominant and recessive models and rs11209026 only recessive model seem to be related 10 fold higher risks for DPN.
Conclusion: IL-23R gene polymorphism has been shown to be associated with many autoimmune and inflammatory diseases. It is known that inflammation has an important effect on diabetes. The frequency of IL-23R gene polymorphism was not significant in diabetic peripheral neuropathy. Our study is the only and first study investigating the role of IL-23R gene polymorphism in diabetic peripheral neuropathy. Ethnicity is very important in genetic studies, and it will give us more clear information for the future to carry out this study in patients with other ethnic origins and to recruit larger study groups.
Keywords
Diabetic peripheral neuropathy inflammation genetics interleukin-23R (IL-23R) gene polymorphism
Supporting Institution
Çanakkale Onsekiz Mart University Scientific Research Projects Coordination Unit
Project Number
TSA-2020-3471
References
- Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843.
- He Z, King GL. Microvascular complications of diabetes. Endocrinol Metab Clin North Am. 2004;33:215-38.
- Panzer C, Brieke A, Ruderman N. Prevention of type 2 diabetes and its macrovascular complications: whom, when, and how should we treat? Curr Opin Endocrinol Diabetes. 2003;10(4):229-36.
- Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacol Ther. 2008;120(1):1-34.
- Ahern PP, Izcue A, Maloy KJ, Powrie F. The interleukin-23 axis in intestinal inflammation. Immunol Rev. 2008;226:147-59.
- Stritesky G, Yeh N, Kaplan MH. IL-23 Promotes maintenance but not commitment to the Th17 lineage. J Immunol. 2008;181(9):5948-55.
- Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201(2):233–40.
- Mensah-Brown EPK, Shahin A, Al-Shamsi M, Lukic ML. New members of the interleukin-12 family of cytokines: IL-23 and IL-27 modulate autoimmune diabetes. Ann N Y Acad Sci. 2006;1079:157-60.
- Abbasi F, Amiri P, Sayahpour FA, et al. TGF-𝛽 and IL23 gene expression in unstimulated PBMCs of patients with diabetes. Endocrine. 2012;41(3):430-4.
- Roohi A, Tabrizi M, Abbasi F, et al. Serum IL-17, IL-23, and TGF-ß levels in type 1 and type 2 diabetic patients and age-matched healthy controls. Biomed Res Int. 2014;2014:718946.
- Costa V, Santos A, Fukui R, Mattana T, Matioli S, Silva M. Protective effect of interleukin-23A (IL-23A) haplotype variants on type 1A diabetes mellitus in Brazilian population. Cytokine. 2013;62(2):327-33.
- Mensah-Brown EP, Shahin A, Al-Shamisi M, Wei X, Lukic ML. IL-23 leads to diabetes induction after subdiabetogenik treatment with multiple low doses of streptozocin. Eur J Immunol. 2006;36(1):216-23.
- Magrinelli F, Briani C, Romano M, et al. The association between serum cytokines and damage to large and small nerve fibers in diabetic peripheral neuropaty. J Diabetes Res. 2015;2015:547834.
- Alkanlı N, Ay A, Alkanlı SS. Investigation of the relationship between microvascular complications of diabetes mellitus and proinflammatory cytokine interleukin-18 gene variations. Gevher Nesibe Journal of Medical & Health Sciences. 2020;5(7):67-76.
- Navarro-Gonzalez JF, Mora-Fernandez C. The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol. 2008;19:433–42.
- Witzel II, Jelinek HF, Khalaf K, Lee S, Khandoker AH, Alsafar H. Identifying common genetic risk factors of diabetic neuropathies. Front Endocrinol (Lausanne). 2015;6:88.
- Basile KJ, Johnson ME, Xia Q, Grant SF. Genetic susceptibility to type 2 diabetes and obesity: follow-up of findings from genome-wide association studies. Int J Endocrinol. 2014;2014:769671.
- Abraham C, Cho J. İnterleukin-23/Th17 patways and inflammatory bowel disease. Inflamm Bowel Dis. 2009;15(7):1090-100.
- Elmaagacli AH, Koldehoff M, Landt O, Beelen DW. Relation of an interleukin-23 receptor gene polymorphism to graft-versus-host disease after hematopoietic-cell transplantation. Bone Marrow Transplant. 2008;41(9):821-6.
- Liu M, Zhu W, Wang J, et al. Interleukin-23 receptor genetic polymorphisms and ulcerative colitis susceptibility: A meta-analysis. Clin Res Hepatol Gastroenterol. 2015;39(4):516-25.
- Baird AM, Dockry E, Daly A, Stack E, Doherty DG, O'Byrne KJ, Gray SG. IL-23 is epigenetically regulated and modulated by chemotherapy in Non-Small Cell Lung Cancer. Front Oncol. 2013;3:162.
- Ye D, Fairchild TJ, Vo L, Drummond PD. Painful diabetic peripheral neuropathy: Role of oxidative stress and central sensitisation. Diabet Med. 2022;39(1):e14729.
- Mertoglu C, Gunay M. Neutrophil-Lymphocyte ratio and Platelet-Lymphocyte ratio as useful predictive markers of prediabetes and diabetes mellitus, Diabetes Metab Synd. 2017;11(Supl 1):S127-31.
- Garcia C, Feve B, Ferré P, et al. Diabetes and inflammation: fundamental aspects and clinical implications. Diabetes Metab. 2010;36(5):327–38.
- Bruun M, Lihn AS, Verdich C, et al. Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab. 2003;285(3):E527–33.
Abstract
Amaç: Diyabetik nöropatinin patogenezinde proinflamatuar ve nörovasküler değişiklikler suçlanmaktadır. Diyabetin vasküler inflamasyonu tetiklediği kabul edilse de inflamasyonun da diyabeti tetikleyebileceği öne sürülmüştür. İnterlökin-23 (IL-23) aktive makrofajlar ve dendritik hücreler tarafından salgılanan proinflamatuar bir sitokindir. Interleukin-23R'nin kronik inflamatuar hastalıklarda kritik bir rolü olduğu bilinmektedir. Bu çalışmanın amacı, IL-23R polimorfizmi ile diyabetik periferik nöropati arasındaki ilişkiyi incelemektir.
Yöntem: Nöroloji polikliniğine başvuran 50 diyabetik periferik nöropati hastası ve hasta grubuna yaş ve cinsiyet açısından uyumlu 52 sağlıklı kontrol çalışmaya dahil edildi. Çalışmaya katılmayı kabul eden gönüllülerin tamamına elektromiyografi uygulandı ve EDTA'lı tüplere 2 ml kan örneği alındı. Pyrosequencing yöntemi ile IL-23R gen polimorfizmi analiz edildi.
Bulgular: IL-23R gen varyantları rs2201841, rs199542433, rs201052419, rs11209026 diyabetik periferik nöropati (DPN) hastalarında ve kontrol grubunda analiz edildi. IL23R polimorfizmleri sıklıkları açısından hasta ve kontrol grupları arasında anlamlı bir fark saptanmadı. Ancak, odd’s oranlarına bakıldığında, rs2201841'in koruyucu rolü var gibi görünmekte, rs199542433 hem baskın hem de çekinik modellerde ve rs11209026 sadece çekinik modelde, DPN için 10 kata kadar daha yüksek risklerle ilişkili olabileceği görünmektedir.
Sonuç: IL-23R gen polimorfizminin birçok otoimmün ve inflamatuar hastalık ile ilişkili olduğu gösterilmiştir. İnflamasyonun diyabet üzerinde önemli bir etkisi olduğu bilinmektedir. Diyabetik periferik nöropatide IL-23R gen polimorfizminin sıklığı anlamlı değildi. Çalışmamız diyabetik periferik nöropatide IL-23R gen polimorfizminin rolünü araştıran tek ve ilk çalışmadır. Etnik köken, genetik çalışmalarda çok önemlidir ve bu çalışmanın başka etnik kökene sahip hastalarda yapılması ve daha geniş çalışma gruplarının alınması, bize ilerisi için daha net bilgiler verecektir.
Project Number
TSA-2020-3471
References
- Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843.
- He Z, King GL. Microvascular complications of diabetes. Endocrinol Metab Clin North Am. 2004;33:215-38.
- Panzer C, Brieke A, Ruderman N. Prevention of type 2 diabetes and its macrovascular complications: whom, when, and how should we treat? Curr Opin Endocrinol Diabetes. 2003;10(4):229-36.
- Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacol Ther. 2008;120(1):1-34.
- Ahern PP, Izcue A, Maloy KJ, Powrie F. The interleukin-23 axis in intestinal inflammation. Immunol Rev. 2008;226:147-59.
- Stritesky G, Yeh N, Kaplan MH. IL-23 Promotes maintenance but not commitment to the Th17 lineage. J Immunol. 2008;181(9):5948-55.
- Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201(2):233–40.
- Mensah-Brown EPK, Shahin A, Al-Shamsi M, Lukic ML. New members of the interleukin-12 family of cytokines: IL-23 and IL-27 modulate autoimmune diabetes. Ann N Y Acad Sci. 2006;1079:157-60.
- Abbasi F, Amiri P, Sayahpour FA, et al. TGF-𝛽 and IL23 gene expression in unstimulated PBMCs of patients with diabetes. Endocrine. 2012;41(3):430-4.
- Roohi A, Tabrizi M, Abbasi F, et al. Serum IL-17, IL-23, and TGF-ß levels in type 1 and type 2 diabetic patients and age-matched healthy controls. Biomed Res Int. 2014;2014:718946.
- Costa V, Santos A, Fukui R, Mattana T, Matioli S, Silva M. Protective effect of interleukin-23A (IL-23A) haplotype variants on type 1A diabetes mellitus in Brazilian population. Cytokine. 2013;62(2):327-33.
- Mensah-Brown EP, Shahin A, Al-Shamisi M, Wei X, Lukic ML. IL-23 leads to diabetes induction after subdiabetogenik treatment with multiple low doses of streptozocin. Eur J Immunol. 2006;36(1):216-23.
- Magrinelli F, Briani C, Romano M, et al. The association between serum cytokines and damage to large and small nerve fibers in diabetic peripheral neuropaty. J Diabetes Res. 2015;2015:547834.
- Alkanlı N, Ay A, Alkanlı SS. Investigation of the relationship between microvascular complications of diabetes mellitus and proinflammatory cytokine interleukin-18 gene variations. Gevher Nesibe Journal of Medical & Health Sciences. 2020;5(7):67-76.
- Navarro-Gonzalez JF, Mora-Fernandez C. The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol. 2008;19:433–42.
- Witzel II, Jelinek HF, Khalaf K, Lee S, Khandoker AH, Alsafar H. Identifying common genetic risk factors of diabetic neuropathies. Front Endocrinol (Lausanne). 2015;6:88.
- Basile KJ, Johnson ME, Xia Q, Grant SF. Genetic susceptibility to type 2 diabetes and obesity: follow-up of findings from genome-wide association studies. Int J Endocrinol. 2014;2014:769671.
- Abraham C, Cho J. İnterleukin-23/Th17 patways and inflammatory bowel disease. Inflamm Bowel Dis. 2009;15(7):1090-100.
- Elmaagacli AH, Koldehoff M, Landt O, Beelen DW. Relation of an interleukin-23 receptor gene polymorphism to graft-versus-host disease after hematopoietic-cell transplantation. Bone Marrow Transplant. 2008;41(9):821-6.
- Liu M, Zhu W, Wang J, et al. Interleukin-23 receptor genetic polymorphisms and ulcerative colitis susceptibility: A meta-analysis. Clin Res Hepatol Gastroenterol. 2015;39(4):516-25.
- Baird AM, Dockry E, Daly A, Stack E, Doherty DG, O'Byrne KJ, Gray SG. IL-23 is epigenetically regulated and modulated by chemotherapy in Non-Small Cell Lung Cancer. Front Oncol. 2013;3:162.
- Ye D, Fairchild TJ, Vo L, Drummond PD. Painful diabetic peripheral neuropathy: Role of oxidative stress and central sensitisation. Diabet Med. 2022;39(1):e14729.
- Mertoglu C, Gunay M. Neutrophil-Lymphocyte ratio and Platelet-Lymphocyte ratio as useful predictive markers of prediabetes and diabetes mellitus, Diabetes Metab Synd. 2017;11(Supl 1):S127-31.
- Garcia C, Feve B, Ferré P, et al. Diabetes and inflammation: fundamental aspects and clinical implications. Diabetes Metab. 2010;36(5):327–38.
- Bruun M, Lihn AS, Verdich C, et al. Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab. 2003;285(3):E527–33.
Details
| Primary Language | English |
|---|---|
| Subjects | Health Care Administration |
| Journal Section | Articles |
| Authors | |
| Project Number | TSA-2020-3471 |
| Publication Date | June 29, 2022 |
| Acceptance Date | June 21, 2022 |
| Published in Issue | Year 2022 Volume: 14 Issue: 2 |
