INSULIN DAN ANTIDIABETIK

DefinitionDiabetes mellitus is a group of metabolic diseases characterized by hyperglycemiaresulting from defects in insulin secretion, insulin action, or both (Expert Committee on the Diagnosis and Classification of Diabetes mellitus 2002)Long-term damage, dysfunction, and failure of various organs especially the eyes, kidneys, nerves, heart, and blood vessels

The diabetes epidemic:171 million in 2000 to 366 million people in 2030*IndiaChinaUSAIndonesiaPakistanBrazilBangladeshJapanPhilippinesEgyptCountry203079.442.330.321.313.911.311.18.97.86.7People with diabetes (millions)IndiaChinaUSAIndonesiaJapanPakistanRussian Fed.BrazilItalyBangladeshCountry200031.720.817.78.46.85.24.64.64.33.2People with diabetes (millions)12345678910Ranking

Symptoms :PolyuriaPolydipsiaWeight lossSometimes polyphagiaBlurred vision

50% of type 2 diabetes patients have complications at the time of diagnosisRetinopathy, glaucoma or cataractsNephropathyNeuropathyMICROVASCULARMACROVASCULARCerebrovascular diseaseCoronary heart diseasePeripheral vascular disease

KELOMPOK RESIKO TINGGI DMUmur diatas 45 tahunKegemukan > 120% BB ideal atau IMT > 27 kg/m2), Hipertensi >140/90 mmHg, Riwayat keluarga DM, Pernah melahirkan anak BB lahir bayi >4000 gram, Riwayat DMGDislipidemi, HDL 250 mg/dl

III. Klasifikasi Etiologis DM1. Diabetes Tipe-1 (destruksi sel beta)AutoimunIdiopatik2. Diabetes Tipe-2 ( resistensi insulin disertai defek sekresi insulin atau sebaliknya)3. Diabetes Tipe lainA. Defek genetik fungsi sel beta MODY 1,2,3. DNA mitokondriaB. Defek genetik kerja insulinC. Penyakit eksokrin pankreas; Pankreatitis, tumor pankreas, pankreatektomi, pankreopati fibrokalkulus

D. EndokrinopatiAcromegali, sindroma Cushing, Feokromositoma, hipertiroidismeE. Karena obat/zat kimia Vacor, pentamidin, asam nikotinat, Glukokortikoid, hormontiroid, tiazid, Dilantin, interferon alfaF. Infeksi : rubellakongenital, CMVG. Sebab imunologi yang jarang : Antibodi anti insulinH. Sindroma genetik lain: Sindroma Down, Klinefelter, Turner dll.4. Diabetes Gestasional

Type 2 diabetes: a growing problemA serious, progressive diseaseCharacterised by two fundamental defects:insulin resistance-cell dysfunctionAccounts for 90% of diabetes cases worldwideAssociated with serious microvascular and macrovascular complicationsRepresents a significant disease burdenRepresents a considerable economic burden

LIVERADIPOSE TISSUEPancreasInsulin supply or actionG L UC O S EG LYCOGENGLUCONEOGENESISThe Pathophysiology of Type 2 DMLIPOLYSISFFA +

Management A. Aim

Prinsip Dasar Terapi Diabetes Mellitus1PENGATURAN MAKANLATIHANOBAT HIPOGLIKEMIKPENYULUHANCANGKOK PANKREASKonsensus Perkeni, 19982354Pengaturan makanOlahragaPenyuluhanObat hipoglikemikCangkok Pankreas

Exercise

30 minutes: 3 - 4 times / weekContinuousRhytmicalIntervalProgressiveEndurance training

OBAT HIPOGLIKEMIK ORAL

Adipose tissueSites of Action of Antihyperglycemic AgentsPancreas1. Insulin GLUCOSEGLUCONEOGENESISHGP-Intestine2. Insulin secretagogue4. Acarbose3. MetforminTZD3. MetforminTZD++-++

Oral Hypoglycemic Drugs Available in Indonesia Initial dose Maximal dose Frequency of mg/day mg/dayadministration /daySulphonylureaGlibenclamide2,515-201-2 XGliclazide802401-2 XGlipizide : 5202-3 XGliquidone30120 1 XChlorpropamide 50500 1 XGlimepiride0,56 1 XMeglitinideRepaglinide1.5 mg8 mg 3XNateglinide120 mg360 mg 3XMetformin 50030001-3 XAlpha glucosidase inhibitor Acarbose50300 3 XDerivat ThiozolidindionesPioglitazoneRoziglitazoneFix Dose ( Campuran )Glucovance1,25/2502,5/5001-2 x

MonotherapyInsulin therapyCombination oral therapyLifestyle modificationExpected HbA1c (time allotted)1% (3 months) 1 to 2%(13 months) 1 to 2% fall peradditional OHA(13 months) Unlimited T2DM treatment strategies**Individualise

Diet/ exerciseOral monotherapyOral combinationInsulinEarly aggressive combination therapyStepwise treatmentOral +/- insulinNew treatment paradigms for type 2 diabetes

SulphonylureasHave been a mainstay of type 2 diabetes treatment for > 40 yearsBind to an SU receptor (SUR) on the b-cell which leads to depolarisation of b-cell membrane and stimulates insulin secretionFirst generation : chlorpropamideSecond generation : glibenclamide, glipizide, gliclazideThird generation : glimepirideAttention : Hypoglycemia (less in glipizide GITS and glimepiride)

Depola-risationCa 2+Voltage DependentCa 2+Channel (VDCC)ProinsulinClosedATP SensitiveK+ ChannelSS 01OpenCa 2+INSULIN C-PEPTIDESUSURATPADPATPADPGlucose Am. acid Glucokinase MetabolismMode of Action of Sulphonylureas

LIVERADIPOSE TISSUEThe Stimulation of Glucose UptakePancreasInsulin GLUCOSEGLUCONEOGENESISHGP-GLYCOGENOLYSISG LYCOGENG L UC O S E+

Glucose Transporter

Cont...

Evaluate 4-8 wksEvaluate 4-8 wks

Type 2 DM Overweight Not Overweight Severe metab. decompensationStressing onMeal planning ExerciseMetformin or AcarboseM / A + SUM +A + SUSU or AcarboseSU + A / MSU + A + MUncontrolledDepends on the response: Diet or OHAInsulin C O N T I N U E C O N T I N U EEducationMeal planningExerciseEducationMeal planningExercisecontrolledUncontrolledUncontrolledUncontrolledUncontrolledUncontrolledUncontrolledUncontrolledUncontrolledcontrolledcontrolledcontrolledcontrolledcontrolledcontrolledcontrolledcontrolled

Current ADA treatment targetsHbA1c < 7%Blood pressure < 130/80 mmHgLDL-cholesterol < 100 mg/dl (2.6 mmol/l)HDL-cholesterol Men> 40 mg/dl (1.1 mmol/l)Women > 50 mg/dl (1.3 mmol/l)Triglycerides < 150 mg/dl (1.7 mmol/l)

Treatment Priorityof Type 2 DMMicrovascular diseaseMacrovascular disease

1a. Insulin Insulin actions include :Ability of insulin to lower circulating glucose concentrations

Suppress glucose production : liverStimulate glucose utilization : muscle plus fat

Additional metabolic, vascular & mitogenic actions

JENIS INSULIN Jenis insulin menurut cara kerjaMulai KerjaKerja MaksimalLama Kerja(Jam)(Jam)(Jam)Actrapid0,52,5 - 54 - 8Humulin R0,52,5 - 54 - 8Monotard1 - 24 - 68 - 24Insulatard1 - 24 - 168 - 24Humulin N1 - 24 - 88 - 22Kerja LamaUltratard

2 - 48 - 2428Lama KerjaNama InsulinKerja SingkatKerja Sedang

Indications of Insulin Treatment

Indication for the use of insulin in Type 2 DMIn severe metabolic decompensationKetoacidosisHyperosmolar non ketotic coma Lactic acidosis Severe stress :Systemic infectionMajor surgeryWeight loss within a short period of timePregnancy if diet does not succeed to control glycemia

Combination Therapy in T2DM:Insulin Plus Oral Hypoglycemic AgentsInsulin Plus Sulphonylurea - BIDS Some insulin is endogenous, with natural secretory patternBiguanide Plus InsulinReduces hepatic insulin resistanceMay achieve better control with less insulinCan reduce weight gainAlpha Glucosidase Inhibitor Plus InsulinReduces posotprandial glucose levelThiazolidinedione Plus InsulinReduces peripheral insulin resistanceReduces insulin requirementMust balance TZD and insulin carefully to minimize weight gain

Complications :

KetoacidosisNonketotic Hyperosmolar syndromeRetinopathyNephropathyNeuropathyMacroangiopathyChronic :Acute :MicroangiopathyCADPVDStroke

KOMPLIKASI AKUTMetabolik Ketoasidosis diabetikKoma hiperglikemik hiperosmoler non-ketotikHipoglikemiAsidosis laktat2. Infeksi berat

KETOASIDOSIS DIABETIK (1)Klinis- Dehidrasi, kesadaran menurun sampai koma, hipotensi-syok, panas

2. Laboratorium - Hiperglikemi, GDS > 300 mg/dl- Asidosis, pH arteri

KETOASIDOSIS DIABETIK (2) PENATALAKSANAANCairan- Infus NaCl 0.9% sebanyak 500 ml selama 15 menit pertama, diteruskan sesuai kebutuhan - Bila GDS < 250 mg/dl, NaCl 0.9% diganti Dextrose 5%Insulin- Pada awal diberikan 10 U insulin kerja singkat i.v secara bolus (Actrapid, Humulin R) diteruskan dengan insulin drips 6 U/jamPotassium - Pada pemberian insulin biasanya kalium plasma menurun oleh karena itu perlu diberikan tambahan potassiumAntibiotik bila ada infeksi

KETOASIDOSIS DIABETIK (3) Komplikasi Infeksi

2. Gagal ginjal akut

RETINOPATI DIABETIK (1)Dikenal empat bentuk yaitu :Tipe backgroundTipe pre-proliferatifTipe proliferatifMakulopatiTipe background adalah paling ringan, sedang tipe proliferatif penyebab kebutaan

RETINOPATI DIABETIK (2)

RETINOPATI DIABETIK (3)

Kendali glukosa darah sebaik mungkin (HbA1c < 7%)Pengobatan terhadap hipertensi, dislipidemia bila adaHentikan merokokAspirin RETINOPATI DIABETIK (4)Pengobatan

NEFROPATI DIABETIK (1)Merupakan penyebab utama gagal ginjal terminal di negara maju

2.Diperkirakan 40% DM tipe 1 menjadi nefropati diabetik setelah menderita DM 20 tahun dan 5-10% pada DM tipe 2 dengan riwayat DM 20 tahun

NEFROPATI DIABETIK (2)Diagnosis Adanya proteinuri menunjukkan nefropati diabetikNefropati diabetik klinik bila tes Albustix positif sedikitnya 3 kali dengan interval beberapa miliNefropati diabetik dini bila ditemukan mirkroalbuminuri 2 sampai 3 kali pemeriksaan dalam 6 bulan

PengobatanKendali glukosa darah sebaik mungkin (HbA1c < 7%)Pengobatan terhadap hipertensi, dislipidemia bila ada Catatan : TD sistolik < 135 mmHg, diastolik =< 80 mmHg NEFROPATI DIABETIK (3)

NEFROPATI DIABETIK (5)Hemodialisa

2.Transplantasi ginjal Pengobatan gagal ginjal terminal :

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The prevalence of diabetes worldwide is estimated to increase from 2.8% of the population in 2000 to 4.4% in 2030

ReferenceWild S et al. Diabetes Care 2004;27:104753

**In the UKPDS, 50% of patients had a diabetes-related complication at diagnosis.1Neuropathy affects around 70% of those with diabetes at the time of diagnosis, leading to 55,00060,000 amputations in the USA each year.2Retinopathy, glaucoma or cataracts occur in around 10% of people after 15 years of diabetes. Blindness affects around 2%.2Nephropathy is the leading cause of end-stage renal disease.2Coronary heart 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.2Cerebrovascular disease: the risk of stroke is two to four times higher in people with diabetes. Fifteen percent of people with type 2 diabetes die from stroke.2The risk of peripheral vascular disease is four to eight times higher in people with type 2 diabetes.2

UKPDS Group. UKPDS 33. Lancet 1998; 352: 83753.World Health Organization/International Diabetes Federation. The economics of diabetes and diabetes care: a report of the Diabetes Health Economics Study Group. 1999 (WHO).**

***Untuk menjaga agar kadar gula darah pada pasien tetap seimbang maka prinsip terapi DM disini ada 5 yaitu :1. Pengaturan makan (diet rendah lemak, karbohidrat dan protein)2. Latihan fisik sedang3. Penyuluhan ( supaya pasien berobat dengan teratur)4. Dan yang paling terpenting adalah pengobatan dengan obat hipoglikemik oral , karena seperti kita ketahui dari survei data epidemiologi bahwa 70% pasien DM akan selalu tergantung pada obat hipoglikemik oral untuk menjaga agar kadar gula darahnya tetap seimbang5. Cangkok pankreas , hanya dilakukan jika pankreas pasien sudah tidak mampu memproduksi insulin****The progressive nature of T2DM, caused by the decline in -cell function, means that oral hypoglycaemic agents have limited effectiveness and, despite being used to their maximum capacity, insulin will eventually be required to reach and sustain target glycaemic levels.

DeFronzo R, et al (eds). International Textbook of Diabetes Mellitus. 3rd ed. Chichester, New York: John Wiley & Sons; 2004:9951015.*Stepwise approachThe traditional stepwise approach aims primarily to control acute symptoms.Dietary measures and exercise are not usually sufficient to control glycaemia beyond the first year of therapy. If oral monotherapy proves inadequate, combination therapy is usually started. If this also proves unsuccessful, conversion to insulin is the next step, either alone or in combination with an oral agent.In the majority of cases, the stepwise approach does not lead to sustained control.Many physicians intensify treatment only when symptoms of poor glycemic control become apparent, rather than when glycaemic targets are not reached.

Early, aggressive approachThis approach to type 2 diabetes management avoids the risk of early treatment failure by adopting an intensive therapeutic strategy immediately upon diagnosis. Combinations of agents with complementary modes of action targeting the dual defects underlying type 2 diabetes (insulin resistance and -cell dysfunction) are most likely to support tight, long-term glycaemic control.Furthermore, combination therapy should be considered earlier in the regimen to provide additional glycaemic control.

Campbell IW. Br J Cardiol 2000; 7: 62531.

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