CURRICULUM VITAENama : DR.Dr. Aris Wibudi, SpPDTgl. Lahir : Walikukun, 27 April 1954Pendidikan .1980 : Lulus FK UI 1991 : Lulus Spesialis Peny. Dalam (FKUI) 1996 : Modul DM 1 (Endokrin FKUI) 1998: Modul DM 2 (Endokrin FKUI) 1992: Edukator DM (PERKENI) 2006: S-3, IPB Bogor Pekerjaan 2005 -: Staf Ahli RSPAD

Pengelolaan Rasional Diabetes Tipe-2Aris Wibudi

Distribution of oral glucose to tissues of the bodyCherrington, A.D. Diabetes 1999; 48:1198-1214

Gangguan Metabolik Utama pada DM-2Resistensi Insulin *

Defek sekresi insulin*

Peningkatan Produksi Glukosa*Diabetes Care, 1999; 22:562

backResistensi Insulin

Insulin secretion profiles in Type 2diabetic patients and healthy people8006amInsulin secretion (pmol/min)Time10am2pm6pm10pm2am6am700600500400300200100Healthy peopleType 2 diabetic patientsPolonsky KS. Et al., 1988

Patterns of Insulin Response to IV Glucose: Non-Diabetic and Diabetic IndividualsInsulinSecretion1STPhase2NDPhaseNon-DiabeticType 2 DiabetesTime (minutes)InsulinSecretion

IGT

Postprandial Hyperglycemia

Type 2DiabetesPhase 1

Type 2DiabetesPhase 2

Type 2DiabetesPhase 3

- 12

- 10

- 6

- 2

0

2

6

10

14

Years from diagnosis

Beta cell function (%)

Stages of type 2 Diabetes in relationship to -cell function

25

0

50

75

100

hypoX-jsk-7-99

backInsulin eksogen

INSULINGLIKOGEN SINTASEProduksi Glukosa Hati

DMdefek

HIPER GLIKEMIA

prandial hiperglikemia

fasting hiperglikemiaSU-SR

combinationinsulininsulinOADOAD

insulinOADOADinsulin

Site of action of OADPencernaanGlukosa ekstraselSekresi insulin selbeta pankreasAGIProduksiglukosahepatikAmbilanglukosaototInsulin sensitizernutrisiAcarboseInsulin sensitizerMetforminInsulin Metforminglinid SU Sekretagog insulininsulinIslet Enhancer

Oral Anti DiabeticInsulinobat*

OADBiguanid MetforminInsulin sekretagoka. Sulfonilurea: glibenclamide gliclazide glipizid - glikuidon glimepirideb. glinide-glukosidase inhibitor (PGA)Insulin sensitizerIslet Enhancer

Kir 6.2SUR 1ATP Binding SiteSulphonylurea Binding SiteBenzoic Acid Binding SiteK+ATPDepolarizationCa++Ca++Mode of Action ofInsulin SecretagoguesThe KATP channel consists of subunits that comprise the inwardrectifying channel (Kir 6.2) and regulatory components (SUR 1). The SUR 1 regulates whether the inward rectifying K channel is open or closed. The SUR 1 subunit contains unique binding sites for ATP, Sulphonylurea, and Benzoic Acid Derivative

Percobaan in vitro menunjukkan bahwa glimepiride berikatan pada subunit reseptor sulfonilurea yang berbeda 1Ref.1. Kramer W et al. Diab Res Clin Pract 1995; 28 (Suppl): S67-S80.

Pada kondisi resistensi insulin, insulin tidak mampu menggerakkan jumlah GLUT 4 yang cukup ke permukaan sel

Terima Kasih

SHORT ACTING INTERMEDIATE ACTING

Diagnosis

DMNormoglikemiKomplikasiTerapi

makromikro

regulasi glukosa

FARMAKO TERAPI Dokter Pasien

Aspek pasienGemuk / kurusUsiaGangguan fungsi hati / ginjalLamanya DMHasil pemantauan glukosa darah

ASPEK DOKTERPengetahuan tentang obat

Pedoman PenatalaksanaanAlgoritmeKerja obatPatofisiologi

Pedoman PenatalaksanaanAlgoritmeKerja obatPatofisiologi

Algoritme Penatalaksanaan DM Tipe 2

INSULIN

SU + B / PG INSULINSU + B + PG

Pedoman PenatalaksanaanAlgoritmeKerja obatPatofisiologi

Natural History of Type 2 DiabetesNormal glucose metabolismImpaired glucose metabolismType 2 diabetesInsulin sensitivityInsulin secretion30%70%100%50%150%100%Diabetes Obes Metab 1999; 1(1): S1IGT50%70-100%

IGT

Postprandial Hyperglycemia

Type 2DiabetesPhase 1

Type 2DiabetesPhase 2

Type 2DiabetesPhase 3

- 12

- 10

- 6

- 2

0

2

6

10

14

Years from diagnosis

Beta cell function (%)

Stages of type 2 Diabetes in relationship to -cell function

25

0

50

75

100

hypoX-jsk-7-99

Development of Type 2 DiabetesINSULIN RESISTANCEInsulin Resistance and Hyperinsulinemia with Normal Glucose ToleranceInsulin Resistance and Declining Insulin Levels With Impaired Glucose ToleranceType 2 DiabetesImpaired Beta-Cell FunctionAdapted from Diabetes 1996;45:1661

Historical Algorithm ofTherapy for Type 2 DiabetesAdapted from Mudaliar S et al. In: Ellenberg and Rifkins Diabetes Mellitus, 6th ed. New York, NY: Appleton and Lange; 2003:531-557.Inadequate nonpharmacologic therapy

Proposed Algorithm ofTherapy for Type 2 DiabetesSevere symptomsSevere hyperglycaemiaKetosisPregnancyInadequate non-pharmacologic therapy

DOSISmulai dosis keciltingkatkan bertahap ataukombinasi

Monitor PemantauanGlukosa darahPuasa Prandial

Kemungkinan yang didapat Glukosa darahINormal Normal Puasa Post Prandial

- Insulin basal- Insulin prandial

IIIGDN / PP

IIGDN / PP

Insulin prandial

Ringkasan ( 1 )Penatalaksanaan DMTailored to the patientTeam Work NetworkPenurunan Glukosa segeraPenyerta

Ringkasan (2)Pilar PenatalaksanaanEdukasiTerapi NutrisiAktifitas FisikObat (bila perlu)

Ringkasan (3)Pedoman Farmakologik ALGORITMA PATOFISIOLOGI KERJA OBAT

Ringkasan (4)Tersedia pilihan OAD INSULIN

Ringkasan (5)INSULIN Short acting Intermediate Mixed

Ringkasan (6) OAD Sulfonilurea : Generasi I Generasi II Generasi III RepaglinidBiguanidPG Insulin Sensitiser

Ringkasan (7)Terapi Kombinasi Kapan saja Jangan golongan sama

Nature. 2003 Mar 13;422(6928):173-6. Epub 2003 Feb 23. Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Itoh Y et al. Takeda Chemical Industries, Ltd,

Related Articles, Links

Fig. Increase cellular levels of malonyl-CoA and FACoAs as a common mechanism causing glucolipotoxicity in various tissues in obesity associated type 2 diabetesPrentki et al. Diabetes 51 (Suppl. 53): S405-S413, 200

Increasedmass

Diabetescomplications

AlteredBlood flow andcontractility

ExcessiveGlucoseproduction

AlteredSecretionCell death

Insulinresistance

Hyperglycemia

Malonyl-CoA

FACoA

Hyperlipidemia

Adipose tissue

Muscle

b-cell

Neural

Vascular

Liver

(+) FA/glucose storage (+) FA oxidationAdipose tissue(+) glucose oxidation (-) FA oxidationMuscle(-) gluconeogenesis PEPCK liverPPAR FFAFFAEndocrinology(142);3,2001

GlucoseGlucoseG-6-PGlucokinaseMetabolismSignal (S)ATPADPK+ATPDepolarizationCa++Ca++SecretoryGranulesGLUT-2Insulin SecretionMechanism of Glucose-MediatedInsulin Secretion

Shepherd and Kahn. NEJM 1999; 341:248-257Insulin regulation of GLUT-4 translocation

Metabolic Effects of Insulin on Muscle and Fat Cells123

Signaling Molecule 1Signaling Molecule 2Plasma MembraneGPI-PLCGlut 4Insulin ReceptorPGlut 4TranslocationGlucoseTransport???GPI-PLCInsulin Saving Mechanism of Glimipiride(Muller et al 1996)abLipid Synthesis GlycogenSynthesisSUR-GLIMGLIM = Glimepiride15

10%20%70%dokterpasienedukator

Glukosa Darah Sel InsulinResistensi

The endocrine characteristics of type 2 diabetes include peripheral insulin resistance in muscle and fat tissue, decreased pancreatic insulin secretion, and increased hepatic glucose output.35. Insulin secretion profiles in Type 2 diabetic patients and healthy peopleUnder fasting conditions the insulin secretion rate is similar between healthy people and Type 2 diabetic patients. In normal people, insulin secretion increases rapidly after food intake and is followed by a return to basal levels before the next meal. In Type 2 diabetic patients, meal-related increases in insulin secretion are delayed and reduced, and secretion does not return to basal levels between meals.

It has been common practice to reserve insulin therapy until relatively late in the treatment plan for patients with type 2 diabetes. Typically, it is introduced after patients have failed to achieve glycaemic control with diet and with combination therapy using 2 or 3 oral hypoglycaemic agents of escalating dosages1,2Based on the time associated with various oral agent alterations (eg, titration and combination therapy), patients are often out of control for lengthy periods and thus increase the risk of complications related to chronic hyperglycaemia11.Mudaliar S, Henry R. The oral antidiabetic agents. In: Porte D, Jr, Sherwin RS, Baron A. Ellenberg and Rifkins Diabetes Mellitus, 6th ed. New York, NY: Appleton and Lange; 2003:531-557. 2.Riddle MC. Tactics for type II diabetes. Endocrinol Metab Clin North Am. 1997;26:659-677.Clinicians may consider this proposed algorithm for the treatment of patients with type 2 diabetes. In this algorithm, insulin can be integrated into a patients regimen at various stages of the disease