12.9 dr.suhaimi diabetes mellitus
DESCRIPTION
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DIABETES MELLITUSEpidemiologi dan Permasalahannya
Dr. SUHAEMI, SpPD, FINASIM
Diabetes Mellitus
Suatu Sindroma kelainan metabolik, ditandai adanya hiperglikemia, akibat
defek sekresi insulin, defek kerja insulin, atau kombinasi keduanya.
Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance, World Health Organization, Geneva 1999.
Definition of Type 2 Diabetes
Type 2 diabetes is characterised by:
• chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism
• defects in insulin secretion (-cell dysfunction) and insulin action (insulin resistance)
Diabetes care 2004
Diabetes Care 2004 27:1047-53
¡Viva la Vida con Salud!
Diabetes in the World
millions
India
31.731.7
China
20.820.8
USA
17.717.7
Indonesia
8.48.4
Japan
6.86.8
YearYear20002000
Reference: Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes. Diabetes Care. 2004; 27(5): 1047-1053.
¡Viva la Vida con Salud!
Diabetes in the World
millions
India
79.479.4
China
42.342.3
USA
30.330.3
Indonesia
21.321.3
Japan
8.98.9
YearYear20102010
Reference: Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes. Diabetes Care. 2004; 27(5): 1047-1053.
Fast Food and Obesity
• 200% fast-food visits 1977-1995• 30% of US children (4-19 yrs) consume fast
food daily
Fast Food and Obesity
• Fast-foods fat and energy – Big Mac + medium fries = 83% daily fat intake
• Adversely affects dietary quality• Less fiber, fruits, vegetables and milk• Mega-meals
Mega – Meals
Super Size
• Each 12 oz soda has 10 tsp sugar (150 cal)
• One can of soda/day child’s risk obesity 60%
• Most popular Canadian drink– > 110 L/ person/yr
• 1942-1998: – US production increased 9X
Diabetes Today: An Epidemic
Relative risks associated with obesityGreatly increased (>3) Moderately increased (2-3) Slightly increased (1-2)
DM tipe 2 CHD CANCER breast cancer (in post menopausal women), endometrial, colon
Gallbladder disease HypertensionHypertension Reproductive hormone abnormalities
Dyslipidaemia OsteoarthritisOsteoarthritis Polycystic ovary syndrome
Insulin Resistance
Breathlessness
Sleep apnoea
Hyperuricaemia and Hyperuricaemia and goutgout
Table 4.1 WHO TRS 894 Obesity: Preventing and Managing the Global Epidemic
Impaired fertility
Low back painAnaesthesia complicationsFetal defects in maternal obesity
ChylomicronRemnants
VLDL
IDL
LDL
HDL2
HDL3
Lp(a)Endothelial cellsEndothelial cells
Inflammation
Macrophage
Calcium
Intimal thickening
Lp-pla2Lp-pla2
Endothelial function
Traffic patterns in the blood
Glucose
TriglyceridesLDL Receptor
Liver
ProteinsHomocysteineHs-CRPApo-AApo-B
Hb A1C
Resistensi Insulin
DiabetesDiabetesTipe 2Tipe 2
DeFronzo et al. Diabetes Care 1992;15:318-68DeFronzo et al. Diabetes Care 1992;15:318-68
Diabetes MelitusDiabetes Melitus
Definisi :Definisi :
- gangguan metabolisme gangguan metabolisme
- kenaikan kadar glukosa darah kroniskenaikan kadar glukosa darah kronis
- disebabkan oleh adanya gangguan produksi insulin akibat disebabkan oleh adanya gangguan produksi insulin akibat kerusakan kerusakan
sel beta pankreas dan atau kerja insulin.sel beta pankreas dan atau kerja insulin.
Kerusakan selKerusakan selBeta pankreasBeta pankreas
Evolusi diabetes
NormalFase
KompensasiDiabetes
DeFronzo R.A. et al., Diabetes Care (1998)
Resistensi Insulin & Defisiensi Insulin:
2 mekanisme yang saling berhubungan
Pada saat diagnosis ditegakkan, sudah ada defek pada kedua-nya
ResistensiInsulin
ResistensiInsulin
Glukosa darah Puasa
SekresiInsulin
SekresiInsulin
History of DM
Diabetes Greek for “passing water like a siphon”
Mellitus Latin for “sweetened with honey”
“Ebers Papyrus” (Egyptian, 1500 B.C.)first depiction of diabetes mellitus - urination of excess amounts - manipulation of diet therapy
• Sudah dikenal sejak zaman Ebers Papyrus 1550 SM• Willis : mencatat ada rasa manis pada urine• IBNU SINA : Gangren Diabetic• Matthew Dobson : Rasa manis karena gula• 1815 : Chevreul (ahli Kimia) membuktikan bahwa gula
dalam urine adalah glukosa• 1921 : Frederic Grant Banting, Charles Best berhasil
mengekstraksi insulin pertama kali dari pankreas anjing• 11 Jan 1922 : Leonardo Thompson, remaja merupakan
pasien pertama yang mendapat insulin di RS Toronto Kanada
• 1979 : Goedde menghasilkan human insulin dengan rekayasa genetik
Faktor Resiko untuk Terjadinya DM
• Kelompok Usia > 45 tahun• Gemuk : BB > 120% BBI (IMT > 27 kg/m2)• Hypertensi• Riwayat Keluarga DM• Riwayat melahirkan bayi > 4 kg.• Riwayat DM pada waktu hamil (DM Gestasi)• Dislipidemia : HDL < 35 mg/dl, Trigliserida > 250
mg/dl• Pernah mengalami gangguan toleransi glukosa
Etiologi
• Herediter, diperlukan faktor lain yang disebut faktor risiko atau faktor pencetus
• Virus– Pada DM tipe 1 dijumpai HLA gen yang rentan terhadap
infeksi virus tertentu.– Virus yang selalu menimbulkan insulitis adalah : Coxackie,
Mumps, Rubella, Cytomegalovirus, Herpes, dll.• Obesitas
– Kadar Insulin cukup tetapi tidak efektif (Resistensi Insulin )• Memakai obat-obatan yang menyebabkan Kadar
Gula Darah meningkat
Not specifiedNot specifiedOthersOthers
TuberculosisTuberculosis
Accident / suicideAccident / suicideGangreneGangrene
Renal insufficiencyRenal insufficiency
Diabetic comaDiabetic coma
InfectionsInfections
TumorsTumorsStrokeStroke
Myocardial Myocardial infarctioninfarction
00 1010 2020 3030 4040
% deaths in diabetics% deaths in diabetics3.43.4
11.411.4
0.90.9
2.12.1
2.72.7
2.92.9
3.13.16.76.7
10102222
34.734.7
Panzram G. Diabetologia 1987; 30: 120-31Panzram G. Diabetologia 1987; 30: 120-31
Causes of Mortality in Diabetic Patients
Pankreas
• Terletak dibelakang lambung• Berat : 200 – 250 gram• Bentuk : Kerucut terbaring• Bagian yang lebar : Kepala (Caput)• Bagian yang kecil : Ekor (Cauda)• Terdapat kumpulan sel disebut pulau-pulau Langerhans yang
berisi sel Beta dan mengeluarkan hormon Insulin.• Disamping sel Beta terdapat sel Alfa yang mengeluarkan
Glukagon yang bekerja berlawanan dengan insulin yaitu meningkatkan kadar gula darah. Juga ada sel Delta yang mengeluarkan Somatostatin
INSULIN
Definisi :Definisi :
Insulin adalah hormon yang Insulin adalah hormon yang dikeluarkan oleh sel beta dikeluarkan oleh sel beta pankreas yang berperanan pankreas yang berperanan dalam mengatur kadar dalam mengatur kadar glukosa darahglukosa darah
Insulin diibaratkan sbg anak Insulin diibaratkan sbg anak kunci yang membuka pintu kunci yang membuka pintu masuknya glukosa ke masuknya glukosa ke dalam sel dalam sel
KERJA FISIOLOGIS INSULIN& PENGLEPASAN INSULIN
Insulin dibentuk dari pro insulin distimulasi dg pe glukosa darah menghasilkan insulin & C-peptide yg akan masuk ke dlm aliran darah & akan me kan kadar glukosa darah
Insulin membantu meningkatkan sintesa protein, meningkatkan penyimpanan lemak, menstimulasi mesuknya glukosa ke dlm sel utk sumber energi dan membantu penyimpanan glikogen dlm lemak dan hati
Insulin : endogen & eksogen
Fasting
K+
Glu t-2
+
-cell
Normal glycemia
Ca2+
Insulin
proinsulin
In the unstimulated b-cell, KATP channels are open and the outward movement of K+ ions holds the membrane potential at a negative level.
-- - -
Resting Resting -cell-cell
Postprandial
ATP
Glucose
G-6-P
GK
PKPyruvate
K+
Insulin
Depolarization
Glu t-2
+++-
--
+ +- - -
+
cell
Glycemia
Krebs cycle
Ca2+
The flux of K+ is regulated by intracellular ATP.
A surge in blood glucose leads to increased production of ATP.
Stimulated Stimulated -cell-cell
InsulinInsulin
Tenaga
Glukosa darah Pintu masuk sel
Insulin
Insulin
Insulin
Glukosa dibakar
pembawa glukosa
NORMAL
Insulin InsulinPintu terbuka
InsulinInsulin
Tenaga
Glukosa darah Pintu masuk sel
Tak ada yang dibakar
Pembawa glukosa
DIABETES
Pintu tertutup
Glukosa darah
F A S E 1 F A S E - 2
F A S E - 1 F A S E - 2
Individu normal
Penderita DM tipe-2
Insulin
plasma
waktu
Insulin
plasma
(Tumpul) (Lebih tinggi dan lama)
(Delayed Insulin secretion)Waktu
3-5 mnt 50-60 menit
60 ng/ml
Insulin secretion
time
Type 2 diabetic
Non-diabetic
IV Glucose stimulus
Loss of the early peak of insulin secretion
Why does the -cell Fail?
Chronic hyperglycemia
Oversecretion of insulin to compensate for insulin resistance1,2
High circulating free fatty acids
Glucotoxicity2
Pancreas
Lipotoxicity3
-celldysfunction
1Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23.2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22.
3Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27.
100
80
60
40
20
0
Years from Diagnosis
Beta
-Cel
l Fun
ction
(%)
Beta-Cell Function in the UKPDS
-12 -10 -8 -6 -4 -2 0 2 4 6
Diagnosis
KERJA FISIOLOGIK INSULIN• MEMASUKKAN GLUKOSA DARI DALAM DARAH KE:
– Hati: • Glukosa di robah jadi glikogen (Glikogenesis)• Glikogen hati menjadi cadangan gula dalam tubuh
– Otot: • Glukosa di robah jadi Glikogen (Glikogenesis)• Glikogen otot dibakar menjadi sumber kalori.
– Adiposa: • Glucosa dirobah (?) jadi trigliserida• Mencegah pemecahan lemak (Antilipolisis)
– Mengaktifkan Lipoprotein Lipase di sel sel endotel P.darah – Jaringan lain: Meningkatkan sintesa protein dari A.Amino
• INSULIN MENURUNKAN KADAR GLUKOSA DARAH
SlametS 37
100
75
50
25
0
100
75
50
25
0
UKPDS :Natural Deterioration of -Cell FunctionUKPDS :Natural Deterioration of -Cell Function
Years from DiagnosisYears from DiagnosisLebovitz H. Diabetes Review 1999;7:139-53
Be
ta C
ell
Fun
ctio
n (%
)B
eta
Ce
ll F
unct
ion
(%)
-12 –10 -6 -2 0 2 6 10 14 -12 –10 -6 -2 0 2 6 10 14
Th/Expectation
Facts
ResistensiInsulin
DiabetesTipe-2
Disfungsi Sel Beta
InsulinInsulinResistanceResistance
Hyperglycaemia
Hyperglycaemia
InsulinInsulinConcentrationConcentration
Insulin Action
Insulin Action
EuglycaemiaEuglycaemia
-cell Failure-cell Failure
NormalNormal IGT IGT ± Obesity± Obesity Diagnosis Diagnosis oofftype 2 diabetestype 2 diabetes
Progression oProgression offtype 2 diabetestype 2 diabetes
DEFEK GANDA PADA DIABETES TIPE-2PENANGAN SASARAN YANG JELAS
DeFronzo et al. Diabetes Care 1992;15:318-68DeFronzo et al. Diabetes Care 1992;15:318-68
Insulin release in vitro in response to glucose stimulation
1st phase
2nd phase
0 5 100
minutes
Basal
Normal
Type 2 DM
Insulin Release: Normal & Type 2 DM
Polonsky et al., 1988b
Insulin Secretion Profiles in Type 2 Diabetic Patients and Healthy Persons
Type 2 diabetesHealthy
Insu
lin s
ecre
t ion
(pm
o l/m
in)
100
200
300
400
500
600
700
800
Time6 a.m. 10 a.m. 2 p.m. 6 p.m. 6 a.m.10 p.m. 2 a.m.
SlametS 41
Hyperglycemia
Glucose autoxidationGlucose autoxidation Sorbitol pathwayrSorbitol pathwayrAGE formationAGE formation
Oxidative Sress Oxidative Sress Antoxidants Antoxidants
Lipid peroxidation Leukocyte adhesion Foam cell formation
TNF
Lipid peroxidation Leukocyte adhesion Foam cell formation
TNF
Endothelial dysfunction NO Endothelin
Prostacyclin TXA2
Endothelial dysfunction NO Endothelin
Prostacyclin TXA2
HypercoagulabilityFibrinolysis
Coagulability Platelet reactivity
HypercoagulabilityFibrinolysis
Coagulability Platelet reactivity
Vascular complicationsVascular complications
RetinopathyRetinopathy NephropathyNephropathy NeuropathyNeuropathy
Stehouwer CDA et al. 2004
Effect of Hyperglycemia
Effect of Hyperglycemia
Oxidative stressOxidative stress
Sorbitol pathwaySorbitol pathway
DAG-PKCpathwayDAG-PKCpathway
Hexosaminepathway
Hexosaminepathway
AGEpathway
AGEpathway
Increase of :• Extracellular
matrix• Collagen• Fibronectin
Increase of :• Extracellular
matrix• Collagen• Fibronectin
Increase of pro- coagulant proteins
• von Willebrandt factor • tissue factor
Increase of pro- coagulant proteins
• von Willebrandt factor • tissue factor
Decrease of proliferation, migration, and fibrinolytic potential
Decrease of proliferation, migration, and fibrinolytic potential
Increase of apoptosisIncrease of apoptosis
Vascular complicationsVascular complications
RESISTENSI INSULIN INSULIN DALAM JUMLAH YANG NOR MAL TIDAK DAPAT BEKERJA SECARA OPTIMAL DI JARINGAN SASARAN NYASEPERTI DI OTOT, HATI DAN ADIPOSA.
Sel sel β pancreas mengkompensasi keadaan inidengan meningkatkan produksi insulin dan menyebabkan HIPERINSULINEMIA
Insulin Resistance
Evolution of Type 2 DiabetesWhen do the Complications Begin ?
NGT IGT IFG DM Early Late
Normal Prediabetes Clinical Diabetes
Insulin resistance Insulin resistance Insulin resistance
GlucotoxicityLipotoxicity
• Macrovascular complications : present at different stages in the evolution of DM, often before DM is establish
• Insulin resistance, glucotoxicity and lipotoxicity : arise during prediabetic phase
Birth Death
Hyperglycemia (Type 2 DM)Hyperglycemia (Type 2 DM)
Increase LipolysisDecrease
Lipogenesis
Increase LipolysisDecrease
Lipogenesis
Adipose tissue(Obesity)
Adipose tissue(Obesity)
ElevatedPlasma
FFA
ElevatedPlasma
FFAElevated
TNF-Elevated
TNF-
Insulin secretionInsulin secretion Insulin resistanceInsulin resistance
HyperinsulinemiaHyperinsulinemia
Amyloid deposit
Islet -cell degranulation;Reduced insulin content
Islet -cell degranulation;Reduced insulin content
Reduced plasma insulin
Reduced plasma insulin
Increased hepatic glucose output
Increased hepatic glucose output
+
-
Gluconeogenesis
decreased glucose uptake
decreased glucose uptake
Glucose toxicity
Lipotoxicity
04/22/23 Dr Risa Anwar -Glucophage Page 48
SEBELUM metformin
SESUDAH metformin
insulin
glukosaglucosetransporter
Efek pada RESITENSI INSULIN
Action of Insulin on the CellMetabolism
Glucose Transporters
• GLUT – 1 : Endothelium• GLUT – 2 : Liver, B-cells of Pancreas• GLUT – 3 : Neurons• GLUT – 4 : Muscle, Adipose Tissue• GLUT – 5 : Intestine
promoterCoding reg
transcription
mRNA
Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2 nd Ed.
Synthesis GLUT 4
translocation
PPAR
PPRE
Insulinreceptor
Insulin
RXR
Glucose
Insulin Action
PPAR
promoter Coding reg
+RXR
Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2 nd Ed.
PPRE
Insulin
Insulin ResistanceGlucose
mRNA
Synthesis GLUT 4
X
X
transcription
Insulinreceptor
Translocation
Muscle Cells
4:004:00
2525
5050
8:008:00 12:0012:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
Plas
ma
insu
lin (
Plas
ma
insu
lin (µ
U/m
l) U
/ml)
TimeTime8:008:00
Physiological Serum Insulin Secretion Profile
InsulinKGD pp
KGD p.
I III IV V
GTGDM
Perjalanan Klinis D.M Tipe-2
II
DiabeticretinopathyLeading causeof blindnessin working-ageadults1
DiabeticnephropathyLeading cause of end-stage renal disease2
Cardiovasculardisease
Stroke1.2- to 1.8-fold increase in stroke3
DiabeticneuropathyLeading cause of non-traumatic lower extremity amputations5
75% diabetic patients die from CV events4
Type 2 Diabetes is NOT a mild disease
1Fong DS, et al. Diabetes Care. 2003; 26 (Suppl. 1): S99–S102. 2Molitch ME, et al. Diabetes Care. 2003; 26 (Suppl. 1): S94–8. 3Kannel WB, et al. Am Heart J. 1990; 120: 672–6. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.
5Mayfield JA, et al. Diabetes Care. 2003; 26 (Suppl. 1): S78–S79.
Microvascular Macrovascular
Type 2 Diabetes: A Complex Metabolic Disorder
DyslipidaemiaDyslipidaemia
ImpairedImpairedinsulininsulin
secretionsecretion
MacrovascularMacrovascularcomplicationscomplications
CentralCentralobesityobesity
InsulinInsulinresistanceresistance
MicrovascularMicrovascularcomplicationscomplications
HypertensionHypertension
“INSULINRESISTANCESYNDROME”
Adapted from Beckman JA et al. JAMA. 2002; 287: 2570- 81
InsulinMetforminSulfonylureasThiazolidinediones
AspirinClopidogrel
ACE inhibitorsARBsBeta blockersCalcium-channel blockersDiuretics
StatinsFibratesNicotinic Acid Atherosclerosis
Dyslipidaemia Hypertension
HyperglycemiaInsulin
resistanceObesity
OrlistatSibutramineRimonabant
Anti-atherosclerosis Therapy in T2DM and the Metabolic Syndrome
Platelet activation
and aggregation
liver
pancreas
liver
Regulation of Blood Sugar
blood sugar level(90mg/100ml)
insulin
body cells takeup sugar from blood
liver storessugar
reducesappetite
glucagon
pancreas
liver releasessugar
triggershunger
high
low
FeedbackEndocrine System Control
Glucose regulation
Bila insulin tidak ada sama sekali (DM tipe 1) atau :Insulin tidak cukup atau efisiensi kerjanya rendah (DM tipe 2)
PEMASUKAN GLUKOSA KE HATI, OTOT, ADIPOSA
AKAN TERGANGGUHIPERGLIKEMIA
GLUKOSURIA
GLIKOGENOLISIS &GLUKONEOGENESIS
TIDAK DIHAMBAT
GANGGUAN SINT.PROTEIN LIPOLISIS TAK DIHAMBAT
POLIURI POLIDIPSILEMAS /MUDAH LELAH
BERAT MAKIN MENURUN
Klinis Diabetes Melitus :
Polifagia : sel mengalami starvasi karena cadangan KH,Lemak, Protein berkurang ( tdk ada pengisian depot yg biasanya dilakukan oleh Insulin )
Polidipsia : glukosuria (diuresis osmotik) → dehidrasi intraselular dan stimulasi pusat haus di hipotalamus) kompensasi: penderita banyak minum
Poliuria : glukosuria (diuresis osmotik) → penderita banyak kencing
Penurunan BB : cairan tubuh berkurang karena diuresis osmotik, protein dan lemak berkurang karena dipecah sbg sumber energi.
Lelah : Metabolisme tdk berjalan sebagaimana mestinya.
KLASSIFIKASI DIABETES MELLITUS
1. DM tipe-1 (Autoimun dan Idiopatik)2. DM tipe-2
– Gemuk : Resistensi Insulin > Disfungsi sel ß
– Tak gemuk : Disfungsi sel ß > Resistensi Insulin
3. DM tipe lain : MODY; Peny.Eksokrin pancreas,Cushing S dll
4. DM Gestasi (Kalau hamil DM, tak hamil DM nya sembuh).
Pathogenesis of Type II DMEnvironmentEnvironment
Obesity ???Obesity ???ß cell defectß cell defect
GeneticGenetic
ß cell ß cell
exhaustionexhaustion Type II DMType II DM
Insulin resistanceInsulin resistance
Relative Insulin Def.Relative Insulin Def.
IDDMIDDM
Abnormal SecretionAbnormal Secretion
G
L
U
C
O
S
E
Intestine
Absorbed
Blood Glucose
ß cell pancreasGlucose Insulin
(+)
Glycogen
Non Sugar
(-)
Glucose
Glycogen
(+)
Adipose Tissue
Antilipolysis
Trigliserida
NORMAL /PHYSIOLOGIC CARBOHYDRATE METABOLISM
H A T I O T O T
Insulin
L.P.L+
Asam Lemak
NORMAL /PHYSIOLOGIC CARBOHYDRATE METABOLISM
GLUCOSE
Intestine
Blood Glucose ↑
AbsorbedAdipose TissueAntilipolysisTrigliserida
ß cell pancreas
Non Sugar
Glycogen
Glucose
Glycogen
H A T I O T O T
Insulin
Insulin
Asam LemakLPL
(+)(-)
(+)
Glucose
+
Liver glucose output responds to multiple hormonal signals
Antonio Vidal-Puig & Stephen O'rahilly (2001) Nature 413, 125 – 126.
GEJALA KLASIK DM
• 4 P
• 1. POLI DIPSIA• 2. POLIFAGIA• 3. POLI URIA• 3. PENURUNAN BERAT BADAN
Kriteria Diagnosa DM• Gejala Klasik DM + Kadar Gula Darah Sewaktu > 200
mg/dl • Gejala Klasik DM + Kadar Gula Darah Puasa > 126
mg/dl • Kadar Gula Darah 2 jam TTGO > 200 mg/dl
• Puasa diartikan tidak mendapat kalori tambahan sedikitnya 8 jam TTGO dengan standar WHO, menggunakan beban glukosa yang setara dengan 75 gram glukosa anhidrous yang dilarutkan dalam air
OGTT 1
TEST TOLERANSI GLUKOSA ORAL (T.T.G.O)
1. Makan minum seperti biasa 3 hari sebelum pemeriksaan2. Kegiatan jasmani dilakukan seperti biasa3. Berpuasa 10-12 jam sebelum pemeriksaan4. Pagi diperiksa KGD puasa5. Minum larutan 75 gr glukosa dalam 250cc air (5 menit)6. Pasien menunggu selama 2 jam dan tidak merokok7. Diperiksa KGD 2 jam sesudah minum larutan glukosa
• TGT – KGD puasa normal. KGD 2 jam paska pembebanan – 75 gram glukosa antara 140-200 mg%
• GDPT– KGD Puasa 110-126 mg%,KGD 2 j PG Normal.
GEJALA KLINIS DIABETES MELLITUS TIPE-2
GEJALA KHAS GEJALA TIDAK KHAS Poliuria KesemutanPolidipsia Gatal di daerah genitalPolifagia Keputihan BB turun cepat Infeksi sukar sembuh
Bisul hilang timbul. Penglihatan kabur
Cepat lelahMudah mengantuk
Complications of Diabetes Mellitus
• Chronic Complications of Diabetes Mellitus– Microvascular
• Retinopathy (nonproliferative/proliferative)
• Nephropathy • Neuropathy• Sensory and motor (mono-
and polyneuropathy)• Autonomic
– Macrovascular• Coronary artery disease• Peripheral vascular disease• Cerebrovascular disease
• Acute Complications of Diabetes Mellitus– Hyperglycemia crisis
• Diabetic ketoacidosis• Hyperglycemia
hyperosmolar State • Lactic acidosis
– Hypoglycemia
GAMBARAN KLINIS DM TIPE-1 DAN DM TIPE-2
• GEJALA DM tipe-1 DM tipe-2– Poliuria dan Polidipsia ++ + – Lemas dan mudah lelah ++ +– Kuat makan tapi tambah kurus ++ -– Penglihatan sering berulang kabur + ++– Gatal /radang kemaluan + ++– Neuropati periferal (kebas/kesemutan) + ++– Selalu ngompol malam (Enuresis Noct) ++ -– Sama sekali tanpa gejala - ++
KARAKTERISTIK DM TIPE 1DAN DM TIPE 2
• DM TIPE 1 – Mudah terjadi ketoasidosis– Pengobatan harus dgn insulin– Onsetnya akut– Biasanya kurus /Umur muda– Terkait dgn HLA-DR3 & DR4– ICA; GADA; & IAA selalu (+)– Riwayat keluarga (+) pd 10%– 30-50% kembar identik terkena
• DM TIPE 2– Jarang ketoasidosis (HONK bisa)– Tidak mesti diberi insulin– Onsetlambat (pelan-pelan)– Gemuk atau tak gemuk / > 45 thn– Tak ada kaitan dengan HLA– Tak ada autoantibodi– Riwayat keluarga (+) pada 30% – ± 100% kembar identik terkena
Kriteria Pemantauan Diabetes Mellitus
BAIK LUMAYAN BURUKKGD puasa 80-109 110-139 > 140KGD 2 jam pp 110-159 160-199 > 200HbA1c* 4 - 5.9% 6 – 8% > 8%Kolesterol total* < 200 200-239 > 240Kolest. LDL (PJK-)* < 130 130-159 > 160Kolest.LDL (PJK+)* < 100 100-129 > 130Trigliserida (PJK-)* < 200 200-249 > 250 Trigliserida (PJK+)* < 150 150-199 > 200
* = diperiksa tiap 3 hingga 6 bulan
Glycated Hemoglobin (HbA1c) 1
PADA TIAP KUNJUNGAN HARUS DIPANTAU
• KGD Sewaktu • Tekanan darah (diukur dalam keadaan duduk)
• Indeks Massa Tubuh = BB (kg) / TB (M)2
PEMERIKSAAN BAIK LUMAYAN BURUKTD sistolik (mmHg) < 130 130-150 >150TD diastolik < 80 80-85 >85IMT Pria (Kg/M2) 20-24.9 25- 27 < 20 atau >27 IMT wanita (Kg/M2) 18.5-22.9 23- 25 < 18.5 atau >25
ACUTE COMPLICATION OF DIABETES
• Diabetic ketoacidosis (DKA)
• Hyperosmolar nonketotic (HONK)
• Hypoglycemia
Hyperglycemia
• Drowsy• Flushed• Thirsty
Diabetic Emergencies Accordingto Blood Glucose Level
Signs of Diabetic Coma• Kussmaul respirations• Dehydration• “Fruity” breath odor• Rapid, weak pulse• Normal or slightly low blood pressure• Varying degrees of unresponsiveness
Hypoglycemia
• Weak, sweaty• Confused/irritable/
disoriented
HypoglycemiaSymptoms of hypoglycemiaSymptoms of hypoglycemia
Neurogenic (autonomic)Neurogenic (autonomic) NeuroglycopeniaNeuroglycopenia
TremblingTrembling
PalpitationsPalpitations
SweatingSweating
AnxietyAnxiety
HungerHunger
NauseaNausea
TinglingTingling
Difficulty concentratingDifficulty concentrating
ConfusionConfusion
WeaknessWeakness
DrowsinessDrowsiness
Vision changesVision changes
Difficulty speakingDifficulty speaking
HeadacheHeadache
DizzinessDizziness
tirednesstiredness
Drugs associated with Hypoglycemia
• ACE inhibitors• Alcohol• Antimalarials• Beta-blockers (non-cardioselective)• Disopyramide• Fluoroquinolones (e.g. gatifloxacin)• Quinidine• Salicylates (high doses only)
Baseline Vital Signs
• Hypoglycemia– Respirations = normal to rapid– Pulse = normal to rapid– Skin = pale and clammy– Blood pressure = low
• Hyperglycemia– Respirations = deep and rapid– Pulse = normal to fast– Skin = warm and dry– Blood pressure = normal
Tujuan Pengelolaan Diabetes Mellitus
• Menghilangkan gejala• Mempertahankan rasa sehat• Memperbaiki kualitas hidup• Mencegah komplikasi (akut dan kronis)• Mengurangi laju komplikasi yang sudah ada• Menurunkan jumlah kematian
Edukasi
Tujuan:
Pencegahan Primer Pencegahan Sekunder
Pencegahan Tertier
Diabetes Mellitus
• Complications of chronic hyperglycemia– Macrovascular complications
• Cardiovascular disease (heart attack)• Cerebrovascular disease (strokes)
– Microvascular• Blindness (retinal proliferation, macular degeneration)• Amputations• Diabetic neuropathy (diffuse, generalized, or focal)• Erectile dysfunction
Microvascular Complications
Hyperglycemia
Pericyteloss
Hyperperfusion Capillary/Endothelial
damage
Loss ofautoregulation
Capillaryocclusion
Vasoactivefactors Loss of tight
junction
Retinal ischemia
New vessels -Low resistance
- No pericyte/autoregulation
Growth factors
Macularoedema
Pathophysiology of diabetic retinopathy
94
Diabetic retinopathy
Two types of diabetic retinopathy:
• Nonproliferative diabetic retinopathy (NPDR)– Early stage diabetic retinopathy
• Proliferative diabetic retinopathy (PDR)– Later stage diabetic retinopathy
Treatment – Eye Disease
• Cataract removal• Laser surgery for
retinopathy
96
Nonproliferative diabetic retinopathy (NPDR)
• Also called background diabetic retinopathy.
• Earliest stage of diabetic retinopathy.
• Damaged blood vessels in the retina leak extra fluid and small amounts of blood into the eye.
• Cholesterol or other fat deposits from blood, called hard exudates, may leak into retina.
Top: Healthy retina
Bottom: Retina with NPDR, containing hard exudates
Diabetic nephropathy
Pathophysiology of diabetic nephropathyHyperglycemia
Renal vasodilatation Increased
intraglomerular capillary pressure
Protein glycation
Increased glomular filtration rate
Hypertension
Increased protein excretion
Microalbuminuria or macroalbuminuria
Nephropathy
Glomurular damage
Treatment - Nephropathy
• ACE inhibitors• MNT – protein
restriction
Diabetic neuropathy
Mechanism of nerve damage in diabetes
METABOLIC VASCULAR
glucose
sorbitol
H2O
nerve oedema
myoinositol
NOproduction
AGEformation
vasoconstriction
Arterial narrowing
Vesselocclusion
Slow nerveconduction
Impairingaxonal transport
Altered membrane potensial
Burning, feeling like the feet are on fire Freezing, like the feet are on ice, although they feel warm to touch
Stabbing, like sharp knives Lancinating, like electric shocks
Autonomic Neuropathy
Case 4
“How do you know if the ulcer is infected then?” Assessing foot ulcers for the presence of infection is vital. All open wounds are likely to get colonised with microorganisms, such as Staphylococcus aureus, and not necessarily infected. Therefore, the presence of infection needs to be defined clinically rather than microbiologically.
An infected ulcer
Signs suggesting infection include;
1. purulent secretions
2. presence of friable tissue
3. undermined edges4. foul odour
Page 105 of 67
Assessment Infected Ulcers
Autonomic Neuropathy• DM-related autonomic neuropathy can involve multiple
systems, including the cardiovascular, gastrointestinal, genitourinary, sudomotor, and metabolic systems.
• Autonomic neuropathies affecting the cardiovascular system cause a resting tachycardia and orthostatic hypotension.
• Gastroparesis and bladderemptying abnormalities are often caused by the autonomic neuropathy seen in DM (discussed below).
• Hyperhidrosis of the upper extremities and anhidrosis of the lower extremities result from sympathetic nervous system dysfunction.
• Anhidrosis of the feet can promote dry skin with cracking, which increases the risk of foot ulcers.
• Autonomic neuropathy may reduce counterregulatory hormone release, leading to an inability to sense hypoglycemia appropriately ((hypoglycemia unawareness)
Macrovascular complications
Atherothrombosis Has Multiple Manifestations
Adapted from: Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6
Transient ischemic attack
Angina:• Stable• Unstable
Ischemic stroke
Myocardial infarction
Peripheral arterial disease:• Intermittent claudication• Rest pain• Gangrene• Necrosis
Diabetes and Macrovascular Disease
Libby and Plutsky. Circulation. 2002.
100 100
7575
5050
2525
0 0
-12 -10 -6 -2 0 2 6 10 14-12 -10 -6 -2 0 2 6 10 14
Fungsi selFungsi selBeta (%)Beta (%)
Tahun Sejak DiagnosisTahun Sejak Diagnosis
TGTHiperglikemiPostprandial Fase I
DM tipe 2Fase II
DM tipe 2
Fase IIIFase IIIDM tipe 2DM tipe 2
Hubungan kegagalan terapi dg Stadium pada DM Tipe 2 dan Fungsi Sel Beta Pankreas
Matching Pharmacology to Pathophysiology
Hyperglycemia
Biguanides(TZD)
TZD(Biguanides)
Alpha-glucosidaseinhibitors
SulfonylureasMeglitinidesNateglinide
Glucose influx
↓ Peripheralglucose uptake
↓ Insulinsecretion
Hepaticglucoseoutput
Sejarah Insulin• 1921 Insulin ditemukan
oleh Banting dan Best
• 1922 Leonard Thompson adalah pasien pertama yang mendapat suntikan insulin
• 1923 Novo Nordisk mulai produksi Insulin Hewan (Sapi dan Babi)
• 1973 Insulin Hewan Monokomponen
• 1987 Insulin Human• 1990 Insulin Analog
INDIKASI PENGGUNAAN INSULIN
1.1. DM tipe 1DM tipe 1
2.2. Penurunan berat badan yg cepatPenurunan berat badan yg cepat
3.3. Hiperglikemia yg berat disertai dg ketosisHiperglikemia yg berat disertai dg ketosis
4.4. Ketoasidosis diabetikKetoasidosis diabetik
5.5. Hiperglikemia hiperosmolar non ketotikHiperglikemia hiperosmolar non ketotik
6.6. Hiperglikemia dg asidosis laktatHiperglikemia dg asidosis laktat
7.7. Gagal dg kombinasi OHO dosis hampir maxGagal dg kombinasi OHO dosis hampir max
8.8. Stress beratStress berat
9.9. Kehamilan dg DM atau DM GestasionalKehamilan dg DM atau DM Gestasional
10.10. Gangguan fs. ginjal atau hati yg beratGangguan fs. ginjal atau hati yg berat
11.11. Kontraindikasi dan atau alergi thp OHOKontraindikasi dan atau alergi thp OHO
KEGUNAAN METABOLIK TERAPI INSULIN
• Menurunkan kadar GD puasa & pp• Supresi produksi glukosa oleh hati• Stimulasi utilisasi glukosa perifer oksidasi gluk / penyimpanan di otot• Perbaiki komposisi lipoprotein abnormal• Mengurangi glucose toxicity• Perbaiki kemampuan sekresi endogen• Mengurangi glycosilated end products
KAPAN INSULIN DIPERLUKAN?
Data UKPDS :Data UKPDS : 50% DMT2 perlu insulin setelah 6 50% DMT2 perlu insulin setelah 6
tahuntahun Fungsi B-cell yg rendah pd saat Fungsi B-cell yg rendah pd saat
diagnosis diagnosis risiko kegagalan OHO risiko kegagalan OHO lebih tinggilebih tinggi
Marre M. Int J Obesity (2002) ; 26 (Suppl 3) : S25-S30Marre M. Int J Obesity (2002) ; 26 (Suppl 3) : S25-S30
Modern "Aggressive" Rx of Type 2 DM from Time of Diagnosis
• HbA1c > 10 % – or
• FPG >260 mg/dl– or
• Symptomatic– or
• Ketotic
IMMEDIATE INSULIN
Modern "Aggressive" Rx 4
• HbA1c not < 7% by 6 months Start
Insulin
DM Treatment Steps (OLD THEORY)
1
2
3
4
5
Combination oforal medicines
Oral plus insulin
Insulin
One oral medicine
Diet &exercise
+
++
A chainA chainGly IIe Val Gl
uGln
Cys Cys Thr
Ser
Ile Cys Ser
Leu Tyr Glu
Leu Glu
Asn Tyr Cys Asn
11 55 1100
1155
2211
SS SS
11 55 1010 1515 2020
2525
3300
B chainB chain SS
SS SS
SS
Phe
Val Asn Gln His LeuCys Gly Ser His Leu
Val Glu Ala Leu Tyr
Leu
Val
Cys Gly Glu Arg GlyPhe
PheTyrThr
LysPro
The
Phe
HUMAN INSULIN HUMAN INSULIN
Human insulinA chain 21 amino acidsB chain 30 amino acids
JENIS INSULIN• Natural (animal) insulin : ekstraksi dari
pankreas hewan• Semisynthetic human insulin : insulin dari
hewan yg dimodifikasi secara enzimatik• Biosynthetic human insulin : dibuat
dengan DNA rekombinan menggunakan ragi atau bakteri
• Insulin analog : biosynthetic human insulin yg direkayasa dgn mempertukarkan posisi asam amino atau menambahkan satu atau lebih asam amino/asam lemak pada rantai molekul insulin
Tipe insulin berdasarkan puncak dan jangka waktu kerjanya :
1. Insulin kerja sangat cepat : NovoRapid, Humalog, Apidra
2. Insulin kerja pendek : Actrapid , Humulin R 3. Insulin kerja sedang : Insulatard, Humulin N
4. Insulin campur : Mixtard, Humulin 30/70, NovoMix 30, Humalog 25
5. Insulin kerja panjang : Levemir, Lantus
Adanya anggapan :Adanya anggapan : Sekali dimulai, tidak pernah bisa berhenti Sekali dimulai, tidak pernah bisa berhenti Akan membatasi aktivitas sehari-hariAkan membatasi aktivitas sehari-hari Memulai terapi Insulin berarti: Memulai terapi Insulin berarti:
Saya telah gagalSaya telah gagalDM-nya sudah menjadi serius DM-nya sudah menjadi serius
Suntikan insulin akan sangat sakit/nyeriSuntikan insulin akan sangat sakit/nyeri Suntikan insulin menyebabkan kebutaanSuntikan insulin menyebabkan kebutaan Frank’s storyFrank’s story: “Jika anda tidak bekerja keras, : “Jika anda tidak bekerja keras,
anda akan saya suntik insulin lho” anda akan saya suntik insulin lho”
Kendala Terapi InsulinKendala Terapi Insulin
Prinsip Terapi
• Insulin Basal menurunkan gula darah puasa
• Insulin Bolus menurunkan gula darah post prandial (setelah makan)
• Insulin Premixed menurunkan GD puasa dan GD 2 jam PP
Macam-macam Rejimen Insulin
• Basal Bolus 4 suntikan per hari (3 bolus dan 1 basal)
• Satu kali suntikan insulin basal pada malam hari ditambah dengan obat oral
• Premixed Insulin, sekali sampai 3 kali sehari, sebelum makan.
• Premixed dikombinasi dengan short acting
4 Suntikan per Hari 3 Short + 1 Intermediate/Long Acting
(Basal Bolus)
6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5
Breakfast Lunch Evening Meal Sleep
time
Insu
lin
in b
lood
Dua kali Suntikan Premixed Insulin Per Hari
6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5
Breakfast Lunch Evening Meal Sleep
Insu
lin
in b
lood
time
45 -60 31 -45
61 -75 16 -30
75 -90 1 -15
Tempat Penyuntikan Insulin Subkutan : Searah Jarum Jam
Efek Samping Insulin
• Hipoglikemia (kadar glukosa darah terlalu rendah)
• Peningkatan berat badan• Reaksi Alergi (kemerahan, gatal-gatal di tempat
penyuntikkan)• Lipodistrofi
Diabetes Diabetes
dan Peran dan Peran InsulinInsulin Dalam Penanganannya Dalam Penanganannya
Dr. SUHAEMI, SpPD, FINASIM
Leonard Thompson
1922 – 1923
Meninggal tahun 1935
Perkembangan Terakhir Injeksi Insulin
Trans-dermal insulin delivery
Oral insulin delivery
Buccal insulin deliveryPulmonary insulin delivery
Non-Injectable InsulinNon-Injectable Insulin
Insulin Delivery Devices 3
Inhaled Insulin
• Exubera
Inhaled Insulin
1-1-08
voluntary discontinuation
4-6-08
Cancer Warning
Other Injectable Drugs 1
• Exenatide (Byetta)– insulin secretagogue– peptide– gila monster saliva– use with other drugs– no hypoglycemia– bid
Other Injectable Drugs 1
• Pramlintide (Symlin)– analogue of hormone
amylin– polypetide– slows gastric emptying– induces satiety– opposes glucagon
reduces posprandial BG
– give with mealsused with insulin
Glycated Hemoglobin (HbA1c) 2
SMBG
• Value in Type 2 DM not established
• Useful for titrating insulin