Peran autoimunitas pada diabetes melitus tipe 2 yang memerlukan insulin :: Suatu kajian kasus kontrol

SANTOSO, Mardi, Promotor Prof.dr. H. Ahmad Husain Asdie, SpPD.,KEMD

2004 | Disertasi | S3 Ilmu Kesehatan

Tujuan penelitian: Tujuan umum penelitian ini adalah untuk membuktikan apakah penderita dengan diagnosis awal DM tipe 2 (DMTD) yang mengalami kegagalan sekunder terapi obat-obat hipoglikemik oral (OHO) standar, sebenarnya adalah DM tipe baru. Tujuan khusus penelitian ini adalah: 1) mempelajari prevalensi petanda antibodi autoimun (Aab) pada DMTD, 2) menentukan korelasi Aab tunggal atau kombinasi dengan kejadian DMTS pada DMTD, 3) membandingkan karakteristik gambaran klinis DMTD yang berlanjut menjadi DMTS dengan DMTD dan DMTS klasik menurut konsensus Perkeni 1998/ADA 1997. Metode: Penelitian ini menggunakan/merupakan studi kasus kontrol yang dicangkokkan (nested). Kasus diambil secara random dari kelompok penderita DMTD yang berobat ke poli diabetes 5-15 tahun di RS Kodja dan RS Pelni,berumur antara 30-70 tahun tidak ada komplikasi DM berat atau kegagalan fungsi organ. DM terkendali dengan diet, olahraga dan OHO masuk kedalam kelompok B (kontrol 1) dan kelompok DMTD yang mengalami kegagalan sekunder OHO serta hanya terkendali dengan insulin monoterapi masuk kedalam kelompok A (kelompok studi). Kelompok kontrol 2 (C) adalah kelompok non DM diambil dari keluarga garis pertama kelompok A dan B. Pada kelompok A, B dan C tersebut dikumpulkan datadata gambaran klinik, pemeriksaan fisik dan laboratorik yaitu: Jenis kelamin, TB, BB, IMT, LP, WHR, lama DM, lama terapi OHO/insulin, darah tepi, gula darah N/PP, HbA₁C, C-peptida, LFT, fungsi ginjal, kolesterol total, LDL, HDL, trigliserida, rontgen toraks dan EKG. Pada kelompok A, B, C yang memenuhi kriteria inklusi, eksklusi, penyetaraan (matching) dan pengendalian DM baik sampai sedang (Perkeni 1998) dilakukan pemeriksaan petanda Aab: ICA, AB GAD, IAA, IA2, AGM, CD₄, CD₈, rasio CD₄/CD₈ dan C-peptida basal. Jumlah sampel dihitung dengan rumus Schesselman. Analisis statistik data-data klinik dan laboratorik terhadap prevalensi, OR, korelasi dan asosiasi, penyetaraan diolah dengan uji statistik: t test for equality of mean, Lavene’s test for equality of variances, Anova, Duncan test, Chi-square test, Pearson r correlation, Mantel Haenzel test for linier association di Clinical Epidemiology and Biostatistic Unit (CE&BU) UGM dengan program SPSS versi 9. Hasil dan pembahasan: Dalam periode 9 bulan (Juni 2000-Maret 2001) telah terseleksi 60 sampel kelompok A dari 278 kasus DMTD dengan monoterapi insulin, 60 sampel kelompok B dari 384 kasus DMTD dengan terapi standar OHO dan 60 sampel kelompok C dari 231 non DM. Frekuensi gambaran klinik poliuria, polidipsi, polifagia, nokturia, neuropati dan astenia pada kelompok A berturut-turut: 71,7%, 76,7%, 66,7%, 90%, 73,3% dan 60%; sedang kelompok B: 51,7%, 70%, 51,7%, 76,7%, 51,7% dan 63,3%, dan kelompok C: hanya ada astenia 30%. Gambaran klinik diantara 3 kelompok A, B, C berbeda bermakna (p<0,05). Komplikasi DM pada mata, frekuensi katarak kelompok A, B, C berturut-turut 21,7%, 28,3%, 5%. NPRD: 20%, 21,7%, 0%. Terdapat perbedaan bermakna frekuensi katarak dan NPRD diantara 3 kelompok (p<0,05). Demikian pula kelainan foto Rontgen paru kelompok A 10%, B 18,3%, C 5%. Kelainan EKG: A 21,7%, B 55%, C 8,3%. Terdapat perbedaan bermakna kelainan foto Rontgen paru dan EKG diantara 3 kelompok tersebut (p<0,05). Prevalensi petanda Aab humoral dan seluler berturut-turut ICA, AB GAD, IAA, IA2, AGM, CD₄⁺/CD₈⁺. Pada kelompok studi (A): 73,3%, 73,3%, 61,7%, 13,3%, 23,3%, 95%; pada kelompok kontrol 1 (B): 10%, 10%, 15%, 1,7%, 6,7%, 68,3%, pada kelompok kontrol 2 (C): 8,3%, 10%, 8,3%, 1,7%, 5%, 55%. Nilai OR B? A berturut-turut: ICA 24,7, Ab GAD 24,8, IAA 9,1 IA2 9,1, AGM 3,3 dan CD₄⁺/CD₈⁺ 8,8 dan OR C? A: ICA 30,3, Ab GAD 24,8, IAA 17,7, IA₂ 9,1, AGM 8,6, CD₄⁺/CD₈⁺ 15,5. Prevalensi Aab humoral dan seluler pada kelompok kasus lebih besar secara bermakna dibanding kelompok kontrol (p<0,01). OR B? A dan C? A cukup besar. Hal ini berarti terdapat kecenderungan dependensi insulin cukup besar pada kelompok kasus. Pada kelompok A ditemukan 32 kasus (subkelompok A1) petanda Aab positif multipel dan kadar C-peptida kurang dari 0,9ng/ml. Pada sub kelompok A1 prevalensi Aab ICA 78,1%, Ab GAD 75%, IAA 65%, IA₂ 15,6%, AGM 28,1%, CD⁴₊/CD⁸₊ 93,7% dengan OR ICA 35, Ab GAD 27, IAA 16,7, IA₂ 10,9, AGM 7,2 dan CD⁴₊/CD⁸₊ 28,8. Subkelompok A1 adalah kelompok yang awalnya DMTD kemudian mengalami kegagalan sekunder OHO sebenarnya adalah DMTS tipe lambat. Diketemukan juga 24 macam kombinasi Aab humoral dan seluler yang merupakan prediktor untuk memprediksi adanya dependensi insulin.

Purpose: In general the aim of this study was to investigate whether TTDM patients that secondary fail with the standard OAD therapy were actually a new type of DM? More specifically the aims of this research were: 1) to measure/determine the prevalence of autoimmune antibody marker (Aab) among TTDM, 2) to investigate correlation /association single or multiple combination of Aab among TODM that developed from TTDM.; 3) to observe the characteristic of clinical manifestation of TTDM that developed to TODM comparing with classical TTDM and TODM according to Perkeni Consensus 1998/ADA 1997. Methods: Design of this study was a nested case control study. Samples were chosen randomly (cases) from TTDM outpatients Diabetic Clinic Kodja and Pelni hospital, trial varied between 30 to 70 years old, without severe diabetic complication /organic failure. TTDM patients under control with standard therapy OAD, diet and exercise were grouped in control 1 (group B), TTDM patients failed to OAD1 but under control with insulin monotherapy only, were put in group A (as a group study). And group C was control group 2 (non diabetic group from A+B group first line family member). Information and collecting data’s from clinical pictures, physical examination and laboratory test: Age, sex, height, weight, BMI, the length DM suffering, the length of OAD/insulin therapy, routine perifer blood, blood sugar N/PP, HbA₁C, C-peptide, LFT, renal function, routine urine, total cholesterol, LDL-C, HDL-C, trigliceride, chest x-ray and ECG. After A, B, C group completely selected using statistic criteria, consist of inclusion and exclusion criteria, samples matching, good or fairly diabetic regulation using the Perkeni (1998) criteria; then laboratory Aab marker were tested. The Aab marker include of ICA, AB GAD, IAA, IA2, AGM, CD₄/CD₈, ratio CD₄/CD₈ and fasting C-peptide level. Sample size was calculated with Schesselman formula. Statistical analysis of clinical picture and laboratory data’s as prevalence, odds ratio, correlation and association, matching, with statistical test: t test for equality of mean, Lavene’s test for equality of variance/multivariance, Duncan test, Chi-square test, Pearson r correlation, Mantel Haenzel test for linier association, were done by Clinical Epidemiological and Biostatistic unit UGM (CE&BU) that using SPSS version 9 programs. Result and discussion: During nine month period (June 2000-March 2001) 60 cases were selected from 278 TTDM that require insulin monotherapy as A group (study group), 60 cases were selected from TTDM that use OAD as B group (control group 1) and 60 cases were selected from 231 non diabetic (first line family member of A & B group) as group C (control group 2). Clinical picture prevalence of polyuria, polydipsia, polyphagia, nocturia, neuropathy and asthenia on A group respectively: 71,7%, 76,7%, 66,7%, 90%, 73,3% and 60%. On B group respectively: 51,7%, 70%, 51,7%, 76,7%, 51,7% and 63%. On C group: only found asthenia 30%. Clinical pictures among the 3 groups were significantly different (p<0,05). The diabetic complications were on the eye, heart and pulmonary diseases. Cataract prevalence in group A 21,7%, B 28,3%, C 5%; NPRD prevalence in group A 20%, B 21,7%, C 0%. Cataract and NPRD were significantly different among the 3 groups (p<0,05). The prevalence of CAD respectively on A group 21,7%, B 55%, C 8,3%. The prevalence of pulmonary diseases on A group 10%, B 18,3%, C 5%. The prevalence of CAD and pulmonary complication were significantly different among the 3 groups (p<0,05). The prevalence of Aab humoral and cellular consists of ICA, AB GAD, IAA, IA2, AGM, and CD₄⁺/CD₈⁺ occur respectively in the study group (A) were: 73,3%, 73,3%, 61,7%, 13,3%, 23,3%, 95%. In control group 1 (B) respectively: 10%, 10%, 15%, 1,7%, 6,7%, 68,3% and in control group 2(C): 8,3%, 10%, 8,3%, 1,7%, 5%, 55% respective ly. Odds ratio B? A respectively for ICA 24,7, Ab GAD 24,8, IAA 9,1, IA2 9,1, AGM 3,3 and CD₄⁺/CD₈⁺ and OR C? A: ICA 30,3, Ab GAD 24,8, IAA 17,7, IA₂ 9,1, AGM 8,6, CD₄⁺/CD₈⁺ 15,5 respectively. The prevalence of Aab humoral and cellular, in the study group was significantly higher than the control group (p<0,01). OR B? A and C? A were high enough; so that the tendency of insulin dependent from the study group was high enough. In the A group was discovered 32 cases (subgroup A1) positive Aab marker multiple and Cpeptide< 0,9ng/ml. In subgroup A1 the prevalence of Aab was ICA 78,1%, Ab GAD 75%, IAA 65%, IA₂ 15,6%, AGM 28,1%, CD₄⁺/CD₈⁺ 93,7, with OR ICA 35, Ab GAD 27, IAA 16,7, IA₂ 10,9, AGM 7,2, CD₄⁺/CD₈⁺ 28,8. Subgroup A1 that early diagnosed as TTDM, than OAD secondary failure occurred, which was actually TODM slowly progressive. This study also discovered 24 kinds of combination Aab marker that can be used as a predictor to detect insulin dependency in TTDM patients.

Kata Kunci : Diabetes Melitus Tipe 2,Autoimunitas,Insulin