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dr Susie Setyowati SpPD RSPAD Gatot Soebroto DIABETES MELITUS Patofisiologi, klasifikasi dan penatalaksanaan

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  • dr Susie Setyowati SpPDRSPAD Gatot SoebrotoDIABETES MELITUS Patofisiologi, klasifikasi dan penatalaksanaan

  • Resistensi Insulin

    DiabetesMelitus tipe 2DeFronzo et al. Diabetes Care 1992;15:318-68Definisi Diabetes MelitusDiabetes melitus : kumpulan penyakit metabolisme yang ditandai oleh kenaikan kadar gula darah akibat gangguan pada sekresi insulin baik absolut maupun relatif dan kemampuan kerja insulin Gangguan sel b-Pankreas

  • Diabetes = Aliran, Pancuran Mellitus = Madu

  • Penyebab DiabetesFaktor keturunanInsulin kurang jumlahnya Insulin kurang baik kerjanyaDIABETES Gula (glukosa) darah meningkatFaktor lingkungan

  • InsulinHormon yang dihasilkan oleh pankreas Berfungsi untuk metabolisme glukosa

  • KLASIFIKASI DIABETES MELLITUS ( PERKENI 2006)DM tipe 1DM tipe lain DEFEK GENETIK FUNGSI SEL BETA DEFEK GENETIK KERJA INSULIN PENYAKIT EKSOKRIN PANKREAS ENDOKRINOPATI KARENA OBAT/ZAT KIMIA INFEKSI IMMUNOLOGI SINDROMA GENETIK LAIN YG BERHUB DGN DMDM tipe 2DM Gestasional

  • Etiology of Type 1 DMVirusesGenetic Susceptibility(HLA-DQ)? Chemicals? NutritionAutoimmune ProcessBeta-Cell DestructionType 1 DMModified from: Schoffling, K.: Diabetologic in Klinik und Praxis, Thieme, 37-41, 1984.

  • Pathogenesis of Type 2 DiabetesInsulin resistance vs -cell dysfunction??

  • DM tipe 2Resistensi Insulin Sekresi insulin GD tetap tinggiHiperglikemia kronikHiperinsulinemia kronikGlucotoxicity to cell pancreas Cell exhaustionKegagalan pankreasDefisiensi insulinKegagalan fungsi pankreas

  • InsulinTenaga Pintu masuk selGlukosa dibakarNORMALInsulinPintu terbuka

  • InsulinTenaga Pintu masuk sel Tak ada yang dibakarDIABETESPintu tertutup

  • Resistensi Insulin

  • Gejala KhasBerat badan menurun Sering buang air kecil, terutama pada malam hariCepat merasa lapar dan haus

  • Gejala Tidak KhasKesemutanSering timbul bisulPenglihatan kabur Cepat lelah & mengantuk Kesemutan Gatal di daerah genital Keputihan Infeksi sulit sembuh Pengelihatan Kabur Cepat lelah Mudah mengantuk Sering timbul bisul

  • Risiko DM Usia > 45 tahun Kegemukan Hipertensi > 140/90 mmHg Riwayat melahirkan bayi > 4 kg Riwayat DM pada kehamilan Riwayat TGT atau GDPT Penderita PJK,TBC,Hipertiroid Kadar lemak abnorma ( HDL < 40 mg/dl, Trigliserida > 200 mg/dl, kolesterol total > 200 mg/ dl Penting Check up berkala !

  • Gejala khas +GD Sewaktu > 200 mg/dl atau Gejala khas +GD Puasa > 126 mg/dl atau Keluhan tidak khasGD Puasa > 126 mg/dl (2x)GD Sewaktu > 200 mg/dl (2x)TTGO 2 jam > 200 mg/dlKriteria Diagnosis DM :( PERKENI 2006 )

  • Pemeriksaan penyaring :Ditujukan :Yang mempunyai resiko DM namun gejala DM (-).Tujuan :Untuk menemukan pasien DM, TGT maupun GDPT dapat ditangani lebih dini secara tepat TGT & GDPT ( merupakan Pre Diabetes )

  • 100

    75

    50

    25

    0 -12 -10 -6 -2 0 2 6 10 14Fungsi selBeta (%)Tahun Sejak DiagnosisTGTHiperglikemiPostprandialFase IDM tipe 2Fase IIDM tipe 2

    Hubungan antara saat terdiagnosis diabetes dengan Fungsi Sel Beta Pankreas pada DM tipe 2Fase III

  • DM Tipe 2: Gangguan produksi insulin Ward WK, et al. Diabetes Care 1984;7:491502.NormalDiabetes 120100806040200300306090120Waktu makan (menit) 300306090120Waktu makan (menit)Kadar Insulin dalam darah (U/ml)12010080604020020g glucose20g glucosePlasma insulin (U/ml)

  • Pemeriksaan penyaring dikerjakan pada pasien yg memiliki salah satu faktor resiko DM :Usia 45 thUsia lebih muda tu IMT > 23 kg/m2 yang disertai dgn faktor resiko :- kebiasaan tidak aktif- keturunan pertama dari orang tua dg DM- riwayat melahirkan bayi dg BBLR > 4000 gr atau riwayat DM gestasional- Hipertensi ( 140/90 mmHg )- Cholesterol HDL 35 mg/dl dan atau trigliserida 250 mg/dl- Menderita PCOS atau keadaan klinis lain yang terkait dgn resistensi insulin- riwayat TGT / GDPT sebelumnya- Memiliki riwayat Kardiovaskuler

  • Penyulit Diabetes MellitusHipoglikemiaKetoasidosisNonketotic- HyperosmolarRetinopatiNephropatiNeuropatiMakroangiopatiKronikAkutMikroangiopatiCADPVDStroke

  • Penyulit KronikRetinopathy, glaucoma or cataractsNephropathyNeuropathyMICROVASCULARMACROVASCULARCerebrovascular diseaseCHDPeripheral vascular diseaseWorld Health Organization/International Diabetes Federation, 1999. Diabetes Care 2001; 24 (Suppl 1): S520.

  • Penyulit Kronik :Gangren DiabetikPenyakit Jantung KoronerStrokeImpotensiNefropati DiabetesRetinopati Diabetes

  • Penyulit kronik :PENURUNAN KEMAMPUAN SEXUAL50,9%KOMPLIKASI SYARAF (NEUROPATI)RETINOPATIKATARAKTBC PARU-PARUHIPERTENSIPJKGANGREN29,3%16,3%15,3%12,8%10%3,5%30,6%

  • Cara:Menormalkan kadar glukosa darah, Lipid (kolesterol, trigliserid), dan kadar insulinPengobatanJangka pendek :Menghilangkan gejala Menpertahankan rasa sehat/nyaman

    Jangka panjang : Mencegah komplikasi Mengurangi angka kesakitan dan kematian

    TUJUAN

  • Pilar Penatalaksanaan DM Terapi gizi medisLatihan JasmaniIntervensi farmakologisPenyuluhan/Edukasi

  • Pengelolaan Bertahap DM Tipe 2

  • Obat anti diabetik1. Anti Diabetik Oral ( ADO )2. Insulin

  • Anti Diabetik Oral1. Gol. Insulin secretagoge : a. Sulfonil urea : - glibenclamid - gliklazid - glipizide - gliquidon - glimepiride b. Meglitinide : - nateglinide - ripaglinide

    2. Meningkatkan sensitivitas insulin : a. Biguanid : - metformin b. Thiazolidinedion : - pioglitazone - rosigliyazone

    3. Penghambat alfa glukosidase : - acarbose

  • Tempat kerja obat BiguanidesTZDTZDBiguanidesMUSCLEADIPOSE TISSUELIVERModified: Ann Intern Med 1999;131:281INTESTINEAcarbosePANCREASGlucoseS.UMeglitinides

  • 4.1 Oral Hypoglycemic Drugs available in Indonesia Initial dose Maximal dose Frequency of administra - (mg/day) (mg/day) tion /day

    SulphonylureaGlibenclamide2,515-201-2 XGliclazide802401-2 XGlipizide : 5202-3 XGlipizide GITS5201-2 XGliquidone30120 1 XChlorpropamide 50500 1 XGlimepiride0,56 1 X

    Meglitinide :Nateglinide-360 3 X Ripaglinide0,5 6 3 X

    metformin 50030001-3 Xthiazolidinedion :-pioglitazone15 30 1 X-rosiglitazone 4 8 1 X

    Acarbose50300 3 X

    Insulin sekretagogeInsulin sensitisizerGlukosidase inhibitor

  • Indikasi Terapi InsulinTemporal :Kadar gula terlalu tinggiHamil Penyakit akut dg GD tinggiPenggunaan obat yang meningkatkan GDSekitar operasi Gagal ginjalSelama perawatan di rumah sakitSerangan jantung atau strok

    Permanen : gagal jantung yang tidak tahan obat minum Gagal kombinasi ADO Efek samping obat ADO DM tipe 1

  • Jenis-jenis insulin 1. Kerja cepat : Insulin lispro, aspart (Novorapid ), glulisine2. Kerja pendek : Actrapid, Humulin R3. Kerja sedang : Insulatard, Monotard, Humulin N4. Kerja campuran : Mixtard 30/70, Humulin 30/705. Kerja panjang : Lantus ( glargine )Berdasarkan cara kerjanya, insulin dibedakan :

  • Insulin preparationsShort acting(Humulin R, Actrapid )

    Intermediate acting(Humulin N, Insulatard)

    Long acting: glargine(Lantus)Premixed insulin(Humulin30/70,Mixtard)

    Rapid acting : Lispro,Aspart(Humalog, Novo rapid)

    Premixed Lispro/aspart(Humalog Mix25, Novomix )

    Onset of action 30-45 minutes

    1-2 hours

    2-4 hours

    30-45 minutes

    5-15 minutes

    5-15 minutes

    Peak of action 2-4 hours

    4-8 hours

    Unpredictable 2-4 hours

    1-2 hours

    1-2 hours

    Duration of action6-10 hours

    16-18 hours

    16-20 hours

    16-18 hours

    4 hours

    16-18 hours

    Jenis-jenis insulin di pasaran

  • Target Pengendalian Diabetes (PERKENI 2006)Gula darah puasa ( mg/dl)Gula darah 2 jam (mg/dl)

    A1c (%)

    Kolesterol total (mg/dl)Kolesterol LDL ( mg/dl)Kolesterol HDL (mg/dl)Trigliserida( mg/dl)

    IMT ( kg/m2)

    Tekanan darah (mmHg)Baik80-10080-144

    140/90

  • Penyebab kegagalan terapi Proses perjalanan penyakit DMPeranan obat-obatanKepatuhan pasien

  • LESSONS FROM UKPDS:BETTER CONTROL MEANS FEWER COMPLICATIONSEVERY 1% reduction in A1CREDUCED RISK*Deaths from diabetesHeart attacksMicrovascular complicationsPeripheral vascular disordersUKPDS 35. BMJ 2000; 321: 405-12.-37%-43%*p
  • Hal-hal yang Perlu DiperhatikanPerlu diingat : kadar glukosa darah yang tinggi kadang kadang tidak dirasakanJangan lupa : bukan tingginya kadar glukosa darah yang berbahaya,tetapi KOMPLIKASI-nya, karena :

    Pencegahan sangat penting Sulit Diperbaiki Menimbulkan Cacat Kematian

  • Yang harus dilakukan agar tetap nyaman dan sehat1. Kendalikan Gula Darah2. Hilangkan faktor risiko lain :Darah tinggi , Kolesterol , Rokok dll Gejala/keluhan diabetes hilangMencegah komplikasi

  • Terima Kasih

    Dual defect of type 2 diabetes: treating a moving targetThe pathophysiology of type 2 diabetes is complex, and characterised by remorseless progression of the dual metabolic defects of insulin resistance and b-cell dysfunction.Initially, insulin resistance causes the glucose-lowering actions of insulin to be blunted, so that the pancreas secretes more insulin to overcome the deficit. At this stage the subject may develop impaired glucose tolerance, but is not yet diabetic.As insulin resistance progresses, however, the pancreas is no longer able to secrete enough insulin to control glycaemia, and increased hepatic glucose output and reduced glucose disposal by muscle and fat contribute to the chronic fasting and postprandial hyperglycaemia characteristic of type 2 diabetes. Eventually, insulin secretion from the b-cell begins to decline and the severity of the hyperglycaemia increases further.

    Adapted from DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care 1992;15:318-68.Neuropathy affects around 70% of those with diabetes at the time of diagnosis, leading to 55,00060,000 amputations in the USA each year.Retinopathy, glaucoma or cataracts occur in around 10% of people after 15 years of diabetes. Blindness affects around 2%.Nephropathy is the leading cause of end-stage renal disease.CHD affects 7.520% of all people with diabetes over 45 years of age in the USA. The risk of CHD is two to four times higher than for those without diabetes.Cerebrovascular disease: the risk of stroke is two to four times higher in people with diabetes. 15% of people with type 2 diabetes die from stroke.The risk of peripheral vascular disease is four to eight times higher in people with type 2 diabetes.

    World Health Organization/International Diabetes Federation. The economics of diabetes and diabetes care: a report of the Diabetes health Economics Study Group. Geneva: WHO 1999.

    The classical approach to treating type 2 diabetes can be described as stepped managementThe first step is to encourage the patient to reduce hyperglycemia through a combination of diet and exercise followed by support with an oral anti-diabetic agent in monotherapyIf glycemic control continues to deteriorate, additional oral agents are added in a step-wise fashion followed by insulin where necessary Slide 16The major metabolic defects that are present in type 2 diabetes mellitus which lead to glucose elevation are: decreased glucose utilization at the level of muscle and adipose tissue, increased glucose production by the liver and relatively decreased insulin secretion by the pancreas. any dietary carbohydrate which is absorbed as glucose or converted to glucose during the absorption or postabsorptive process.The oldest agents used to increase pancreatic insulin secretion include the sulfonylureas. More recently, repaglinide, a meglitinide, has been added to the available agents that stimulate increased pancreatic insulin secretion. Insulin administration, the oldest pharmacologic therapy for diabetes is also a choice to increase circulating insulin levels in response to a failing beta-cell function. Biguanides increase the sensitivity of the liver to circulating insulin, thereby participating in a reduction in the level of excess glucose produced by the liver in type 2 diabetes.PPAR- activators act at a number of sites to lower blood glucose levels. They also improve insulin sensitivity at the level of the liver, thereby decreasing the excess glucose production by that organ. But they are more recognized for their action in increasing insulin sensitivity in muscle & adipose tissue peripherally. By improving this sensitivity, they allow for improvement in the utilization of glucose by these organs. Biguanides, in high doses, also have some mild effect on increasing peripheral glucose utilization. To decrease the rapid influx of carbohydrate from ingested food, alpha-glucosidase inhibitors are used to slow the digestion of starches and the absorption of glucose and several other sugars.

    Humalog onset peak duration Regular insulin Humalog Mix25 onset peak 70/30 insulin duration

    Better Control Equals Reduced Risk of ComplicationsThe UKPDS has proven beyond doubt that intensive glycaemic control is strongly associated with real clinical benefits for patients with type 2 diabetes.Every 1% decrease in HbA1C was associated with clinically important reductions in the incidence ofdiabetes-related death ( 21%)myocardial infarction ( 14%)microvascular complications ( 37%)peripheral vascular disease ( 43%)There is no lower limit beyond which reductions in HbA1C cease to be of benefit.Taking diabetes-related death as an example, this means that:a reduction in HbA1C of 2% delivers a 42% reduction in riska reduction in HbA1C of 3% delivers a 63% reduction in riskand so on.

    Therefore, the greater the reduction in HbA1C, the greater the protection against complications.

    Stratton MI Adler AI, Neil AW, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-12.