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Genetic of Diabetes mellitus

Genetic of Diabetes mellitus. Endah Hamidah Abbas. Klasifikasi etiologi :. Diabetes tipe l : Defisiensi sel β  defisiensi absolut insulin Dimediasi oleh imunitas Idiopatik 2. Diabetes tipe 2 : Resistensi insulin dengan defisiensi relatif insulin. Klasifikasi,lanjutan :.

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Genetic of Diabetes mellitus

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  1. Genetic of Diabetes mellitus EndahHamidahAbbas

  2. Klasifikasietiologi : • Diabetes tipe l : • Defisiensiselβ defisiensiabsolut insulin • Dimediasiolehimunitas • Idiopatik 2. Diabetes tipe 2 : • Resistensi insulin dengandefisiensirelatif insulin

  3. Klasifikasi,lanjutan : 3. Defekpadafungsiselβ Maturity onset diabetes of the young (MODY) ygdisebabkanmutasipada : • Hepatocyte nuclear factor 4α(HNF-4α) (MODY I) • Glukokinase (MODY 2) • Hepatocyte nuclear factor 1α(HNF-1α) (MODY 3)

  4. Insulin promotor factor (IPF-1) (MODY 4) • Hepatocyte nuclear factor 1β (HNF-1β) (MODY 5) • Neurogenic differentiation factor 1 (Neuro D1) (MODY 6) Mutasimitokondria DNA

  5. Klasifikasi,lanjutan : 4. Defekgenetikpadapemrosesanataukerja insulin : • Defekpadakonversikerja insulin • Mutasi gen insulin • Mutasi receptor insulin

  6. Diabetes tipe 1 • Defisiensiabsolut insulin disebabkanolehdestruksiautoimunselβdlmpulaulangerhanspankreas (islet β cells) • Insulin dependent diabetes mellitus (IDDB) • Paling seringterjadipadaanak-anak, manifestasipadausiapubertas progresifdgnbertambahnyausia

  7. Patogenesis DM tipe 1 • Mekanismedestruksiselβ • Limfosit T bereaksidgn antigen selβ kerusakan sel. Sel-sel T meliputi : - Sel-sel T CD4+  jejas jar.dgn mengaktifkanmakrofag  kerusakandlmbentukhipersensitiftipelambat. - Limfosit T sitotoksik CD8+  membunuhselβ, mensekresisitokin yang mengaktifkanmakrofag

  8. Patogenesis, lanjutan : • Sitokin merusaksel-selβ. Jenissitokin : - INF-γ - TNF dan IL1 ( diproduksiolehsel-selmakrofagygdiaktifkanselamareaksiimun)

  9. Patogenesis, lanjutan : • Autoantibodithdsel-selpulaudan insulin (70-80% pasien). Autoantibodibersifatreaktifdgnsejumlah antigen selβ : enzimglutamic acid decarboxylase(GAD).

  10. Patogenesis, lanjutan : 2. Kerentanangenetik • Memilikikorelasidgnkl 20 lokusgenetik perubahantoleransiimunhospes  autoimunitas. • Kolerasidgn HLA MHC (major histocompatibility complex) kelas II.

  11. Patogenesis, lanjutan : • 90-95% orangkulitputihpengidap DM tipe 1 mempunyaihaplotipe HLA-DR3 atau DR4. alel DQβ1*0302. • Gen non MHC ygmemilikikerentananpenyakit : gen insulin dan gen ygmengkodereseptorinhibisisel-T CTLA-4

  12. Patogenesis, lanjutan : 3. FaktorLingkungan • Bbrp virus ygmemicuseranganautoimun : Virus coxsackie,Virusparotitis, Virus campak, Sitomegalovirus,Virusrubela,Mononukleusinfeksiosa Postulat : Virus memproduksi protein ygmirip antigen sendiridanresponimunthd protein virus bereaksisilangdenganjaringansendiri (mimikrimolekuler)

  13. Diabetes melitustipe 2 • Etiologi : - Resistensi insulin - Disfungsiselβ • NIDDM • 80-90 % pasien DM tipe 2

  14. Patogenesis DM tipe 2 • Resistensi Insulin • Berkurangnyakemampuanjaringanperiferuntukberesponsthdhormon insulin • Kelainankualitatifdankuantitatif pd lintasanpenyampaiansinyal insulin

  15. Patogenesis DM tipe 2 • Resistensi insulin  genetik Lingkungan • Genetik (misteri ?? ) • Lingkungan : Obesitas  asamlemakbebasdlmdarah & intrasel ↑  mempengaruhifungsi insulin (lipotoksisitas) danpengeluaransitokinolehseladiposa (leptin, adiponektin, resistin, PPAR-γ (peroxisomeproliferator-activated receptor gamma) ygdiaktifkanolehthiazolidinedion  resistensi insulin

  16. Insulin resistance

  17. Obesity and Insulin Resistance

  18. Patogenesis DM tipe 2 2. Disfungsisel- β • Manifestasi : sekresi insulin tidakadekuatdalammenghadapiresistensi insulin danhiperglikemia. • Kualitatif (hilangnyapolasekresi insulin normal) • Kuantitatif (p↓ massaselβ, degenerasipulaulangerhans, pengendapanamiloiddalampulaulangerhans)

  19. Genetic defect of the insulin receptor and insulin signaling pathway • Gene NameChromosomeComments • Insulin 11: only a few have been discovered • Insulin receptor 19: 40 varians that reduced the efficiency of the insulin signal • NIDDM1 2: the major contributor to development of type 2 DM • NIDDM3 20: not precisely identified

  20. Genetic defect of the insulin receptor and insulin signaling pathway • Gene NameChromosomeComments • GLUT4 17: a blueprint gene for protein in sugar processing • NEUROD1 2: gene that affect pancreas development • MAPK8IP1 11: a blueprint gene for protein in sugar movement in pancreas & other organ • tRNA-LEU mito: cause type 2 DM

  21. Genetic defect of the insulin receptor and insulin signaling pathway • Gene NameChromosomeComments • HNF4A 20: member of the steroid/thyroid hormone, 5 variants associated with DM (=MODY1) • Chromosom 7, mutation in glukokinase gene: reduce the ability of the β cell to sense glucose (= MODY2) • Chromosom 12: mutation in the hepatic nuclear factor-1α gene (HNF-1α): a weak transactivator of the insulin-I gene (=MODY3)

  22. BentukMonogenik Diabetes • Terjadikarena : - Defek primer pd fungsiselβ - Defekpadapenyampaiaansinyal insulin/reseptor insulin

  23. BentukMonogenik Diabetes • Maturity-onset diabetes of the young (MODY) : defek primer pd fungsiselβ tanda : - Pewarisanautosomaldominan - Onset dini (< 25 tahun ) - Tidakadaobesitas - Kekuranganautoantiboadiselpulaudansindromresistensi insulin

  24. BentukMonogenik Diabetes • Diabetes mitokondria : <1% kasusberkaitandgnpoint mutations pd gen tRNAmitokondria, tRNAleu(UUR).

  25. BentukMonogenik Diabetes • Mutasi gen insulin ataureseptor insulin : mutasiygmengenaipemrosesan insulin dariprekursornya (proinsulin), struktur insulin danpengikatan pd reseptor. Mutasireseptor insulin mempengaruhi : - sintesisreseptor - pengikatan insulin - Aktifitasreseptortirosinkinase ---- resistensi insulin (DM tipe 2)

  26. terimakasih

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