genetic of diabetes mellitus
DESCRIPTION
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 :. - PowerPoint PPT PresentationTRANSCRIPT
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1. Diabetes tipe l :• Defisiensi sel β defisiensi absolut
insulin• Dimediasi oleh imunitas• Idiopatik
2. Diabetes tipe 2 :• Resistensi insulin dengan defisiensi
relatif insulin
Klasifikasi etiologi :
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3. Defek pada fungsi sel βMaturity onset diabetes of the young (MODY) yg disebabkan mutasi pada :
Hepatocyte nuclear factor 4α (HNF-4α) (MODY I) Glukokinase (MODY 2) Hepatocyte nuclear factor 1α (HNF-1α) (MODY 3)
Klasifikasi,lanjutan :
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Insulin promotor factor (IPF-1) (MODY 4) Hepatocyte nuclear factor 1β (HNF-1β)
(MODY 5) Neurogenic differentiation factor 1
(Neuro D1) (MODY 6) Mutasi mitokondria DNA
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4. Defek genetik pada pemrosesan atau kerja insulin :
Defek pada konversi kerja insulin Mutasi gen insulin Mutasi receptor insulin
Klasifikasi,lanjutan :
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Defisiensi absolut insulin disebabkan oleh destruksi autoimun sel β dlm pulau langerhans pankreas (islet β cells)
Insulin dependent diabetes mellitus (IDDB) Paling sering terjadi pada anak-anak,
manifestasi pada usia pubertas progresif dgn bertambahnya usia
Diabetes tipe 1
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1. Mekanisme destruksi sel β Limfosit T bereaksi dgn antigen sel β kerusakan sel.
Sel-sel T meliputi :
- Sel-sel T CD4+ jejas jar.dgn mengaktifkan makrofag
kerusakan dlm bentuk hipersensitif tipe lambat.
- Limfosit T sitotoksik CD8+ membunuh sel β,
mensekresi sitokin yang mengaktifkan makrofag
Patogenesis DM tipe 1
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Sitokin merusak sel-sel β.
Jenis sitokin :
- INF-γ
- TNF dan IL1 ( diproduksi oleh sel-sel makrofag yg diaktifkan selama reaksi imun)
Patogenesis, lanjutan :
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Autoantibodi thd sel-sel pulau dan insulin (70-80% pasien). Autoantibodi bersifat reaktif dgn sejumlah antigen sel β : enzim glutamic acid decarboxylase (GAD).
Patogenesis, lanjutan :
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2. Kerentanan genetik- Memiliki korelasi dgn kl 20 lokus genetik
perubahan toleransi imun hospes autoimunitas.
- Kolerasi dgn HLA MHC (major histocompatibility complex) kelas II.
Patogenesis, lanjutan :
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- 90-95% orang kulit putih pengidap DM tipe 1 mempunyai haplotipe HLA-DR3 atau DR4. alel DQβ1*0302.
- Gen non MHC yg memiliki kerentanan penyakit : gen insulin dan gen yg mengkode reseptor inhibisi sel-T CTLA-4
Patogenesis, lanjutan :
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3. Faktor Lingkungan - Bbrp virus yg memicu serangan autoimun : Virus
coxsackie,Virus parotitis, Virus campak,
Sitomegalovirus,Virus rubela,Mononukleus infeksiosa
Postulat : Virus memproduksi protein yg mirip antigen sendiri dan respon imun thd protein virus bereaksi silang dengan jaringan sendiri (mimikri molekuler)
Patogenesis, lanjutan :
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Etiologi :
- Resistensi insulin
- Disfungsi sel βNIDDM
80-90 % pasien DM tipe 2
Diabetes melitus tipe 2
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1. Resistensi Insulin Berkurangnya kemampuan jaringan perifer
untuk berespons thd hormon insulin Kelainan kualitatif dan kuantitatif pd
lintasan penyampaian sinyal insulin
Patogenesis DM tipe 2
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Resistensi insulin genetik
Lingkungan Genetik (misteri ?? ) Lingkungan :
Obesitas asam lemak bebas dlm darah & intrasel ↑ mempengaruhi fungsi insulin (lipotoksisitas) dan pengeluaran sitokin oleh sel adiposa (leptin, adiponektin, resistin, PPAR-γ (peroxisome proliferator-activated receptor gamma) yg diaktifkan oleh thiazolidinedion resistensi insulin
Patogenesis DM tipe 2
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Insulin resistance
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Obesity and Insulin Resistance
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2. Disfungsi sel- β Manifestasi : sekresi insulin tidak adekuat dalam
menghadapi resistensi insulin dan hiperglikemia. Kualitatif (hilangnya pola sekresi insulin normal) Kuantitatif (p↓ massa sel β, degenerasi pulau
langerhans, pengendapan amiloid dalam pulau langerhans)
Patogenesis DM tipe 2
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Genetic defect of the insulin receptor and insulin signaling pathway
Gene Name Chromosome Comments◦ 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
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Genetic defect of the insulin receptor and insulin signaling pathway Gene Name Chromosome Comments
◦ 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
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Genetic defect of the insulin receptor and insulin signaling pathway• Gene Name Chromosome Comments
– 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)
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Terjadi karena :
- Defek primer pd fungsi sel β
- Defek pada penyampaiaan sinyal
insulin/reseptor insulin
Bentuk Monogenik Diabetes
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Maturity-onset diabetes of the young (MODY) :
defek primer pd fungsi sel β tanda :
- Pewarisan autosomal dominan
- Onset dini (< 25 tahun )
- Tidak ada obesitas
- Kekurangan autoantiboadi sel pulau dan
sindrom resistensi insulin
Bentuk Monogenik Diabetes
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Diabetes mitokondria : <1% kasus berkaitan dgn point mutations pd gen tRNA mitokondria, tRNA leu(UUR).
Bentuk Monogenik Diabetes
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Mutasi gen insulin atau reseptor insulin : mutasi yg mengenai pemrosesan insulin dari prekursornya (proinsulin), struktur insulin dan pengikatan pd reseptor.Mutasi reseptor insulin mempengaruhi :- sintesis reseptor- pengikatan insulin- Aktifitas reseptor tirosin kinase
---- resistensi insulin (DM tipe 2)
Bentuk Monogenik Diabetes
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