Efek Suplementasi Vitamin D Terhadap Polineuropati Diabetik Melalui Modulasi Jalur Aldose Reduktase dan Interleukin–8

Abstract

Background: Diabetic neuropathy is most commonly found in developing countries. The most common manifestation of DN is DPN. Activation of the polyol pathway is associated with increased activity of AR, which is involved in the development of DM complications. Patients with DPN have high serum levels of inflammatory cytokines. Vitamin D supplementation improves insulin sensitivity by preventing excessive synthesis of inflammatory cytokines. Vitamin D supplementation is needed to prevent the development of DPN in type 2 DM. Objective: To determine the effect of vitamin D supplementation on DPN through modulation of the AR and IL-8 pathways. Methods: The study was conducted at Haji Adam Malik Hospital in Medan with a total sample of 50 people, after being approved by the Health Research Ethics Committee of FK USU/Haji Adam Malik Hospital Medan (June 2018 – February 2019). The experimental study purely with the type of pre and post-test control group design, double blind, and randomly treatment. Samples were divided into 2 groups, 1 group received vitamin D3 (Natrol®) 50,000 IU and the other group received placebo in the form of lactic saccharine (dose of each treatment: 1 time 3 capsules, 1 time a week, for 10 weeks). All study subjects were examined for HbA1c, vitamin D25(OH), AR, and IL-8 levels, NCS, and DM duration, smoking status, number and type of anti-diabetic drugs, and metabolic syndrome. Ten weeks later, a re-examination of HbA1c levels, vitamins D25(OH), AR, and IL-8, and NCS were conducted, which consisted of DL, A, and NCV. Results: There was a significant difference in vitamin D25(OH) and NCS examination between subjects who received placebo with vitamin D supplementation (p <0.05). There was a significant positive correlation between change of AR and IL-8 level (p = 0.006; r = 0.380). There was a significant negative correlation between change of AR level and NCV of motor Tibial nerve (p = 0.017; r = -0.337). There was a significant negative correlation between IL-8 level with DL of sensory Ulnar nerve (p = 0.016; r = -0.340) and NCV of motor Tibial nerve (p = 0.007; r = -3.378). There was a significant correlation between vitamin D25(OH) levels with DL, A, and NCV of nerves examined, moderate strength with negative direction in DL, while positive direction at A and NCV (p <0.01). The effect of AR on NCV of motor Tibial nerve was significant (p = 0.017; B = -0.619). The effect of IL-8 on DL of sensory Ulnar nerve (p = 0.016; B = -0.003) and NCS of motor and Tibial nerve (p = 0.007; B = -0.027) were significant. Conclusion: The role of vitamin D supplementation to prevent the development of DPN was significant, characterized by shortening on DL and increasing on A and NCV of nerves examined, except for DL and NCV of sensory Median and Sural nerves, and NCV of motor Tibial nerve. The effect of vitamin D supplementation can prevent the severity of PND, but it could not be yet explained whether through modulation of the AR and IL-8 pathways.

Latar belakang: Neuropati diabetik paling sering ditemukan di negara berkembang. Manifestasi tersering dari ND adalah PND. Aktivasi jalur poliol berkaitan dengan peningkatan aktivitas AR, yang terlibat pada perkembangan komplikasi DM. Pasien PND mempunyai kadar serum sitokin inflamatorik yang tinggi. Suplementasi vitamin D memperbaiki sensitifitas insulin dengan mencegah sintesis sitokin inflamatorik berlebihan. Suplementasi vitamin D sangat diperlukan untuk mencegah perkembangan PND pada DM tipe 2. Tujuan: Mengetahui efek suplementasi vitamin D terhadap polineuropati diabetik melalui modulasi jalur AR dan IL-8. Metode: Penelitian dilaksanakan di RSUP Haji Adam Malik Medan dengan total sampel 50 orang, setelah disetujui Komite Etik Penelitian Kesehatan FK USU/RSUP Haji Adam Malik Medan (Juni 2018 – Februari 2019). Penelitian studi eksperimental murni dengan jenis rancangan kelompok kontrol uji pre dan post, tersamar ganda, dan acak perlakuan. Sampel dibagi menjadi 2 kelompok, yaitu 1 kelompok mendapat vitamin D3 (Natrol®) 50.000 IU dan 1 kelompok yang lainnya mendapat plasebo berupa sakarum laktis (dosis masing-masing perlakuan: 1x3 kapsul, 1x seminggu, selama 10 minggu). Seluruh subyek penelitian diperiksa kadar HbA1c, vitamin D25(OH), AR, dan IL-8, juga konduksi saraf, serta dinilai durasi DM, status merokok, jumlah dan jenis obat anti diabetik, dan sindroma metabolik. Sepuluh minggu kemudian, dilakukan pemeriksaan ulang kadar HbA1c, vitamin D25(OH), AR, dan IL-8, juga konduksi saraf, yang terdiri dari LD, A, dan KHS. Hasil: Terdapat perbedaan bermakna pada perubahan kadar vitamin D25(OH) dan pemeriksaan konduksi saraf antara subyek yang mendapat plasebo dengan suplementasi vitamin D (p <0,05). Terdapat korelasi positif bermakna antara perubahan kadar AR dengan IL-8 (p= 0,006; r= 0,380). Terdapat korelasi negatif bermakna antara perubahan kadar AR dengan KHS motorik N. Tibialis (p= 0,017; r= -0,337). Terdapat korelasi negatif bermakna antara perubahan kadar IL-8 dengan LD sensorik N. Ulnaris (p= 0,016; r= -0,340) dan KHS motorik N. Tibialis (p= 0,007; r= -0,378). Terdapat korelasi bermakna antara perubahan kadar vitamin D25(OH) dengan LD, A, dan KHS saraf-saraf yang diperiksa, dimana kekuatan sedang dengan arah negatif pada LD, sedangkan arah positif pada A dan KHS (p <0,01). Pengaruh AR terhadap KHS motorik N. Tibialis bermakna (p= 0,017; B= - 0,619). Pengaruh IL-8 terhadap LD sensorik N. Ulnaris (p= 0,016; B= -0,003) dan KHS motorik N. Tibialis (p= 0,007; B = -0,027) bermakna. Simpulan: Peranan suplementasi vitamin D untuk mencegah perkembangan PND bermakna, ditandai dengan pemendekan LD dan peningkatan A dan KHS sarafsaraf yang diperiksa, kecuali pada LD dan KHS sensorik N. Medianus dan N. Suralis, serta KHS motorik N. Tibialis. Efek suplementasi vitamin D dapat mencegah keparahan PND, namun belum dapat dijelaskan apakah melalui modulasi jalur AR dan IL-8.