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DIABETES

MELLITUS
BAGIAN PENYAKIT DALAM FK
UISU MEDAN
Countries with the highest
numbers of estimated cases of
diabetes for 2030
Egypt
Philippines
Japan
Bangladesh
Brazil
Pakistan
Indonesia
USA
China
India
0 20 40 60 80 100

People with diabetes (millions)

Adapted from Wild SH et al. Diabetes Care 2004; 27: 256970.


DEFINISI DIABETES
MELITUS
Diabetes melitus adalah sekelompok
penyakit metabolik yang ditandai dengan
hiperglikemia akibat cacat pada sekresi
insulin, kerja insulin, atau keduanya.
Hiperglikemia kronik diabetes
berhubungan dengan kerusakan jangka
panjang, disfungsi, dan kegagalan
berbagai organ, terutama mata, ginjal,
saraf, jantung, dan pembuluh darah.
GEJALA UMUM
Gejala Klasik Gejala Lainnya
Kelaparan Rasa Lelah

Meningkat Kesemutan atau mati


Haus Meningkat rasa pada kaki
Infeksi berulang
Sering Buang Air
Gusi, kulit, paru,
Kecil
kandung kemih.
Penurunan Berat Penyembuhan lambat
Badan
Pandangan kabur
Rasa Kebas Pada pruritus vulvae
Seluruh Tubuh Disfungsi ereksi
DIAGNOSA DIABETES
MELITUS
1. Gejala diabetes dan glukosa plasma kasual 200 mg / dl (11,1 mmol / l). Kasual
didefinisikan sebagai setiap saat sepanjang hari tanpa memperhatikan waktu sejak
makan terakhir. Gejala klasik diabetes meliputi poliuria, polidipsia, dan penurunan
berat badan yang tidak dapat dijelaskan.
Atau
2. FPG 126 mg / dl (7.0 mmol / l). Puasa didefinisikan sebagai tidak ada asupan kalori
selama minimal 8 jam.
Atau
3. 2 jam pp glukosa plasma 200 mg / dl (11,1 mmol / l) selama OGTT. Tes harus dilakukan
seperti yang dijelaskan oleh Organisasi Kesehatan Dunia, menggunakan beban glukosa
yang mengandung setara dengan 75-g glukosa anhidrat dilarutkan dalam air.
ADA definition of
hyperglycaemic states
Criteria for the diagnosis of diabetes
Symptoms of diabetes plus casual plasma glucose 200 mg/dl (11.1 mmol/l)
or

FPG
< 100 mg/dl (5.6 mmol/l) normal fasting glucose
100125 mg/dl (5.66.9 mmol/l) impaired fasting glucose
126 mg/dl (7.0 mmol/l) diabetes

or
OGTT 2-h post-load glucose
< 140 mg/dl (7.8 mmol/l) normal glucose tolerance
140199 mg/dl (7.811.1 mmol/l) impaired glucose tolerance
200 mg/dl (11.1 mmol/l) diabetes

ADA = American Diabetes Association

Adapted from American Diabetes Association. Diabetes Care 2004; 27:S5S10.


Criteria for screening for
diabetes in asymptomatic
adult individuals
Testing for diabetes should be considered in all
individuals :
at age 45 years (BMI >25 kg/m2)
at a younger age ; overweight (BMI >23 kg/m2*)
and have additional risk factors, as follows:
are habitually physically inactive
have a first-degree relative with diabetes
have delivered a baby weighing >4 kg or have been diagnosed
with GDM
are hypertensive (>140/90 mmHg)
have an HDL-C level 35 mg/dl and/or a TG level 250 mg/dl
have PCOS
on previous testing, had IGT or IFG
have other clinical conditions associated with insulin resistance
have a history of vascular disease
KLASIFIKASI DIABETES MELITUS

1. Diabetes tipe 1 (destruksi sel, biasanya


menyebabkan kekurangan insulin absolut)
2. Diabetes tipe 2 (mulai dari resistensi
insulin terutama dengan kekurangan
insulin relatif terhadap sebagian besar
cacat sekretorik insulin dengan resistensi
insulin)
3. Diabetes type lainnya
4. Gestational diabetes mellitus (GDM)
Type 1 diabetes
Immune-mediated diabetes.
510% of those with diabetes;
absolute insulin deficiency (insulin dependent
diabetes, type I diabetes, or juvenile-onset diabetes)
cellular-mediated autoimmune destruction of the -
cells of the pancreas.
markers of the immune destruction of the -cell
include
islet cell autoantibodies, autoantibodies to insulin,
autoantibodies to glutamic acid decarboxylase (GAD65),
autoantibodies to the tyrosine phosphatases IA-2 and IA-2.

Idiopathic diabetes.
no known etiologies
Other specific types of
diabetes
A. Genetic defects of -cell function
Chromosome 12, HNF-1 (MODY3); Chromosome 7, glucokinase (MODY2);
Chromosome 20, HNF-4 (MODY1); Chromosome 13, insulin promoter factor-1 (IPF-
1; MODY4); Chromosome 17, HNF-1 (MODY5); Chromosome 2, NeuroD1
(MODY6); Mitochondrial DNA
B. Genetic defects in insulin action
Type A insulin resistance; Leprechaunism; Rabson-Mendenhall syndrome;
Lipoatrophic diabetes.
C. Diseases of the exocrine pancreas
Pancreatitis; Trauma/pancreatectomy; Neoplasia; Cystic fibrosis; Hemochromatosis;
Fibrocalculous pancreatopathy.
D. Endocrinopathies
Acromegaly; Cushings syndrome; Glucagonoma; Pheochromocytoma;
Hyperthyroidism; Somatostatinoma; Aldosteronoma.
Other specific types of
diabetes
E. Drug- or chemical-induced
Vacor; Pentamidine; Nicotinic acid; Glucocorticoids;
Thyroid hormone; Diazoxide; adrenergic agonists;
Thiazides; Dilantin; Interferon.
F. Infections
Congenital rubella; Cytomegalovirus.
G. Uncommon forms of immune-mediated diabetes
Stiff-man syndrome; Antiinsulin receptor antibodies.
H. Other genetic syndromes sometimes associated
with diabetes
Downs syndrome; Klinefelters syndrome; Turners
syndrome; Wolframs syndrome; Friedreichs ataxia;
Huntingtons chorea; Laurence-Moon-Biedl syndrome;
Myotonic dystrophy; Porphyria; Prader-Willi syndrome
Gestational diabetes
mellitus (GDM)
Derajat apapun intoleransi glukosa dengan
onset selama kehamilan.
Glukosa darah kembali normal setelah
melahirkan.
Peningkatan morbiditas dan mortalitas
perinatal jika tidak diobati.
Gestational diabetes
mellitus (GDM)
Kriteria diagnostik untuk 100-g OGTT
adalah sebagai berikut:
95 mg/dl fasting, 180mg/dl at 1 h,
155 mg/dl at 2 h, and 140 mg/dl at 3 h.
Two or more of the plasma glucose values
must be met or exceeded for a positive
diagnosis.
Tes harus dilakukan pada pagi hari
setelah puasa 8-14 jam.
DIABETES TYPE 2

Karakteristik Diabetes Type 2 :


hiperglikemia kronis dengan
gangguan karbohidrat, lemak dan
metabolisme protein
cacat pada sekresi insulin (disfungsi
sel- ) dan resistensi insulin.
Apa yang dimaksud dgn Resistensi Insulin
Definisi Resistensi Insulin :
Tanggapan Gangguan terhadap efek
fisiologis insulin, termasuk pada
glukosa, lipid, metabolisme protein
dan fungsi endotel vaskular
Receptor:
Quantity / function
Post-receptor (mostly):
Translocation of GLUT
Synthesis of GLUT
Insulin Glucose
transloca
tion
Insulin
receptor

PPAR RXR
Synthesis GLUT 4
mRNA

PPRE transcription
promoter
Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
Insulin resistance
Insulin Glucose

Translocation
Insulin
receptor
X

X Synthesis GLUT 4
PPAR +RXR mRNA

PPRE transcription
promoter Coding reg
Muscle
Cells

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
Insulin resistance and -cell
dysfunction are fundamental to
typeNormal
2 diabetes
diabetes
IGT Type 2

Insulin Increased insulin


resistan resistance
ce
Insulin Hyperinsulinaem
secreti then -cell failur
on
Post- Abnormal
prandial glucose toleranc
glucose
Fasting Hyperglycaemia
glucose

Adapted from Type 2 Diabetes BASICS. International Diabetes Center, Minneapolis, 2000.
Insulin Resistance and -Cell
Dysfunction Produce
Hyperglycemia in Type 2 Diabetes
-Cell Dysfunction Insulin Resistance
Increased
Pancreas Lipolysis

Elevated
Liver Plasma FFA

Islet -Cell Degranulation;


Reduced Insulin Content
+ -
Muscle Adipose Tissue
Increased Glucose Output

Reduced
Plasma Insulin
Decreased Glucose Transport
& Activity (expression) of GLUT4
Hyperglycemia

Courtesy of S. Smith, GlaxoSmithKline


Role of Free Fatty Acids in
Hyperglycemia
Adipose
tissue insulin
resistance
ADIPOSE TISSUE

MUSCLE
Lipolysis LIVER

Muscle FFA mobilization


insulin
resistance Liver insulin
resistance
FFA oxidation FFA oxidation

Glucose utilization Gluconeogenesis

Hyperglycemia

Boden G. Proc Assoc Am Physicians. 1999;111:241-248.


Insulin Resistance: An
Underlying Cause of Type 2
Diabetes
Aging
Obesity and Medications
inactivity

Genetic Rare
abnormalities disorders
INSULIN
RESISTANCE
Type 2
diabetes PCOS

Hypertension Atherosclerosis
Dyslipidemia
Reaven GM. Physiol Rev. 1995;75:473-486
Clauser, et al. Horm Res. 1992;38:5-12.
Disfungsi Sel-
Mengurangnya kemampuan
sel- untuk mensekresikan
insulin
Gangguan kemampuan sel-
untuk mengkompensasi
resistensi insulin.
Patofisiologi genetik dan
lingkungan.
Multiple factors may drive
progressive decline of b-cell
function
Hyperglycaemia
(glucose toxicity)
Insulin resistance

Protein -cell lipotoxicity


glycation (genetic background) elevated FFA,TG

Amyloid
deposition
Penatalaksanaan
Diabetes Mellitus
Tujuan Terapi Umum
Mencapai tingkat glukosa darah normal
(gejala berkurang)
Meminimalkan resiko komplikasi jangka
panjang (mikrovaskuler dan makrovaskuler)
yang dihasilkan dari berkelanjutannya gula
darah yang tinggi.
Mendapatkan kontrol yang memadai dari
diabetes dengan memastikan kepatuhan
dengan rencana pengelolaan.
Menjaga gaya hidup sehat.
Prinsip Manajemen
Edukasi pada diabetes
Gaya Hidup
Diet
Exercise

Intervensi Farmakologi
Oral treatment
Insulin
Basic Education
1. Survival skills
How to make prescribe medication
Timing, action of medication, technique
for administration (insulin)
How to test blood glucose
Warning sign of hypo/hyperglycemia
Basic nutrition guidelines
Food types, timing of meal, balancing
content and quantity
2. Lifestyle management issues
Lifestyle Management
Diet & Exercise
Diet - Tiga komponen penting.
Nutrisi yang cukup untuk memenuhi
kebutuhan energi.
Asupan makanan didistribusikan sepanjang
hari.
Pola dan jumlah Feeding harus konsisten

Latihan / Exercise
Membantu penurunan kadar glukosa darah.
Apakah dokter menyetujui program latihan.
Sesuaikan makanan & obat-obatan sesuai.
3-4 kali per minggu biasanya dianjurkan (30
menit)
Rekomendasi Nutrisi
Energi yang dibutuhkan
Kebutuhan energi basal (BER): 25-30 kkal / kg berat
badan yang diinginkan.
Berat badan yang diinginkan badan / berat badan
ideal (IBW):
Formula Brocca dimodifikasi: 90% x {Panjang Tubuh (cm)
-100} x 1kg.
Energi tambahan yang diperlukan.
Tingkat aktivitas
Menetap 10% of BER
Sedang 20% of BER
Berat 50% of BER
Infeksi :10-20%
Pasien obesitas: energi dikurangi 20-30% dari BER.
Rekomendasi gizi untuk
Semua Orang dengan
Diabetes
Protein : 1520% of kcal/d (10% for those with
nephropathy)
Saturated fat : <7% of kcal/d (7% for those with
elevated LDL)
Polyunsaturated fat :<10% of kcal;avoid trans-
unsaturated fatty acids
Carbohydrate : 6070% of total calories
Use of caloric sweeteners, including sucrose, is
acceptable.
Fiber (2035 g/d) and sodium (<3000 mg/d) levels
as recommended for the general healthy population
Cholesterol intake <300 mg/d
Physical exercise and insulin
resistance
Exercise
muscle glucose uptake
} acute &
whole body glucose disposal long-
risk of developing Type 2 DM
term
GLUT4 is recruited to the plasma membrane
independently of insulin
Effective in Type 2 diabetics because muscle
GLUT4 expression is normal
Regular exercise has been shown to improve

blood glucose control, reduce cardiovascular


risk factors, contribute to weight loss, and
improve well-being.
Rekomendasi Aktivitas
Fisik
Awal rekomendasi aktivitas fisik harus
sederhana, berdasarkan kesediaan pasien
dan kemampuan, secara bertahap
meningkatkan durasi dan frekuensi 30 - 45
menit aktivitas aerobik moderat 3-5 hari per
minggu, bila memungkinkan.
Tingkat aktivitas yang lebih besar minimal 1
jam / hari sedang (berjalan) atau 30 menit /
hari kuat (jogging) activitymay diperlukan
untuk mencapai keberhasilan penurunan
berat badan jangka panjang penuh.
Oral Therapy for Type 2
Diabetes
Target Sites of Action
Sulfonylureas
Pancreas
Repaglinide Gut
Adipose
Insulin secretion
tissue
Glucose Acarbose
uptake
Miglitol
FFA output
Glucose
Rosiglitazone Hyperglycemia absorption
Pioglitazone

Liver Muscle
Metformin Rosiglitazone
Rosiglitazone Hepatic Pioglitazone Glucos
Pioglitazone glucose Metformin e uptake
output
Oral Drug Therapy for
Type 2 DM
Sulfonylureas

}
Repaglinide
Nateglinide
Insulin
Biguanides
secretagogues
Thiazolidinediones
Acarbose

}
Insulin
sensitizers

}
Inhibitors of
CHO
absorption
Sulfonylureas :
Mechanism action
Pancreatic effect
Reseptor spesifik pada permukaan sel beta pankreas
mengikat reseptor suflfonilurea (SUR).
Ada keluarga SUR, Sur 1 / Kir6.2 ditemukan di B
cellsand otak.
SUR 2A / Kir6.2 ditemukan dalam otot jantung dan
rangka
Extrapancreatic effect
Studied in vitro and vitro.
Dalam penelitian pada manusia; meningkatkan
pemanfaatan glukosa perpheral insulin-dirangsang
baik jaringan adiposa dan otot rangka.
Sulfonylureas: Mechanism
of Action
Sulfonylureas
GLUT2 Na+
K+ -
Na+ KIR K+
K+
Vm
K
+

Ca2+ -
Pancreatic Ca2+
Voltage-gated
cell Ca2+ channel
Ca2+

Insulin granules
First Generation
Sulfonylureas
Name Daily Max daily Doses/day
dose dose
range (mg/day)
Tolbutamide* 500- 3000 2-3
Chlorpropam 3000 500 1
ide 100- 1000 1-2
Tolazamide * 500 1500 1-2
Acetohexami 100-
de* 1000
*not available
250-
1500
Second Generation
Sulfonylureas
Name Daily Max daily Doses/day
dose dose
range (mg/day)
(mg/da
y)
Glibenclamid 1.25- 20 1-2
e 2.50 40 1-2
Glipizide 2.5-40 20 1
Glipizide XL 5-20 320 1-2
Gliclazide 40-320 8 1
Glimepiride 4-8
Adverse Effects of
Sulfonylureas
Severe hypoglycemia
Overdose
Early in treatment
Most common with glybenclamide
Weight gain
Erythema, skin reactions
Blood dyscrasias (abnormal cellular
elements)
Hepatic dysfunction and other GI
disturbances
Contraindications for
Sulfonylureas
Pregnancy
Surgery
Severe infections
Severe stress or trauma
Severe hepatic or renal failure

Insulin therapy should be used in


all of these
Repaglinide and
Nateglinide
Mechanism of action:
decrease ATP-sensitive K+
conductance
Additional high affinity binding site
identified in mouse -cells for
repaglinide
Action is glucose dependent
High potency
Elicited insulin release is rapid
and brief
Taken with meals for postprandial
hyperglycemia
Biguanide
s
First Generation- Phenformin
Phenethylbiguanide
Adverse Effects
Lactic acidosis
Risk of cardiovascular disorder
Second Generation- Metformin
1,1-Dimethylbiguanide
Rarely produces lactic acidosis except under predisposing conditions
Biguanides
Mechanism of action:
antihyperglycemic
Correct elevated hepatic glucose output
Inhibit gluconeogenesis
Inhibit glucose-6-phosphatase activity
glycogen sparing
insulin resistance
Mediated by activation of 5AMP-activated
protein kinase (AMPK) in hepatocytes and
muscle
Do not increase insulin secretion
Not hypoglycemic, even at high doses
Thiazolidinediones
CH3
Antihyperglycemic N N
O
S O
Do not increase NH
ROSIGLITAZONE O
insulin secretion
Increase insulin
sensitivity in liver N O
S O

and muscle PIOGLITAZONE O


NH

Reduce hepatic glucose output


Improve lipid profiles
Thiazolidinediones: Mechanism
of Action
Ligands for PPAR :
(Peroxisome proliferator-activated receptor
Nuclear hormone receptor superfamily
Expressed primarily in fat, regulates differentiation
More limited expression in muscle, heart, liver, kidney, gut,
macrophages
Heterodimerizes with RXR, binds to hormone response
elements, regulates gene transcription
Known natural ligands (low affinity)
Prostanoid 15-deoxy 12,14PG J2
Polyunsaturated fatty acids, such as linoleic acid
Insulin resistance
Insulin Glucose

Translocation
Insulin
receptor
X

X Synthesis GLUT 4
PPAR +RXR mRNA

PPRE transcription
promoter Coding reg
Muscle
Cells

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
TZD reduce insulin resistance
Insulin Glucose
Transloca
ti on
Insulin
receptor

Synthesis GLUT 4
PPAR + RXR mRNA
D

D
TZV

TZ
A

PPRE transcription
promoter Coding reg
Muscle
Cells

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
glucosidase inhibitors
(Acarbose)
Mechanism of action: competitive and
reversible inhibitors of a glucosidase in the
small intestine
Delay carbohydrate digestion and
absorption
Clinicalrise
Smaller use in postprandial glucose
For mild to moderate fasting hyperglycemia with
significant postprandial hyperglycemia
Taken with the first bite of a meal

Adverse effects:
Gastrointestinal disturbances; Flatulence,
nausea, diarrhea
Use gradual dose titration
Clinical Uses of Insulin
Type 1 diabetes mellitus
Type 2 diabetes mellitus uncontrolled on
maximal combination therapy with oral agents
Gestational diabetes
Hyperglycemic emergencies
Total pancreatectomy patients
Acute or chronic hyperglycemia provoked
by:
Infection or trauma
Steroid therapy
Endocrinopathies such as hyperthyroidism
Other types of secondary diabetes
Summary of bioavailability
characteristic of the insulin
Insulin Type Onset Peak Action Duration

Ultra short Insulin 5-15 1-1,5 hours 3-4 hours


acting lispro/aspart minutes
Short-acting regular 15-30 1-3 hours 5-7 hours
minutes
Intermediate Lente, NPH 2-4 hours 8-10 hours 18-24 hours
acting
Long acting Ultralente 4-5 hours 8-14 hours 25-36 hours

Insulin 6-8 hours - 24 hours


glargine
Insulin Preparations
Ultra Lispro/aspart
fast/ultra
short-acting regular
Short-acting
Plasma [Insulin]
NPH
Intermediate-
acting lente
ultralente

Long-acting glargine

Ultra long- 0 4 8 12 16 20 24
Assesment of glycemic
Urinalysis
control
Glycosuria
Limitations of urinalysis : renal threshold (varies between
individual); urinary concentration (fluid intake and urine
concentration may effect); neuropathic bladder (reduce the
accuracy); hypoglycemia (this can not be detect)
Urinary ketones
Semi-quantitatif test for acetoacetat; Ketosis-prone diabetes
Glycated haemoglobin
HbA1c is formed by the post-translational, non-enzymatic
glycation
Glycaemic targets
Frequency of measurement (every 3 or 6 months)
Limitations of HbA1c measurements : daily patern of blood
glucose levels?; blood loss/haemolysis/reduced red cell (low
HbA1c)
Blood glucose
Before breakfast (fasting)
2 hour post prandial
ADA, AACE and IDF glycaemic goals
Biochemical ADA1,2 IDF4
AACE (Western
index 3
Pacific
region)
HbA1c (%) <7 < 6.5 < 6.5
mg/dl mmol/l mg/dlmmol/lmg/dlmmol/l
Fasting/prepra 90130 5.07.2 < 110 < 6.0 < 110 < 6.1
ndial plasma
glucose
Postprandial
< 180 < 10.0 < 140 < 7.8 < 145 <8.0
plasma
glucose

1. ADA. Diabetes Care 2004; 27: S1535; 2. ADA Diabetes Care 2002; 25: S3549;
3. Feld S. Endocrine Pract 2002; 8 (Suppl 1): 4082; 4. Asian-Pacific Type 2 Diabetes Policy Group.
Type 2 diabetes: Practical targetsand treatment. 4th Edn; Hong Kong: Asian-Pacific Type 2 Diabetes Policy Group, 2005.
Current Indonesian Society of
Endocrinology (Perkeni) treatment targets
HbA1c < 7%
Fasting BG < 100 mg/dl
Post prandial BG < 140 mg/dl
Blood pressure < 130/80 mmHg
LDL-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)
Konsensus PERKENI
2005

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