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: 2569–70.

 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
100–125 mg/dl (5.6–6.9 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
140–199 mg/dl (7.8–11.1 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:S5–S10.

 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.
 5–10% of those with diabetes;
 absolute insulin deficiency (insulin dependent
diabetes, type I diabetes, or juvenile-onset diabetes)
 cellular-mediated autoimmune destruction of the β-
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; Cushing’s 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; Anti–insulin receptor antibodies.
H. Other genetic syndromes sometimes associated
with diabetes
 Down’s syndrome; Klinefelter’s syndrome; Turner’s
syndrome; Wolfram’s syndrome; Friedreich’s ataxia;
Huntington’s 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)
 Minimalkan risiko komplikasi jangka panjang
(mikrovaskuler dan makrovaskuler) yang
dihasilkan dari berkelanjutan gula darah
tinggi.
 Gain adequate control of diabetes by ensuring
compliance with a management plan.
 Maintain a healthy lifestyle as near normal as
possible.
 The principle of
management
 Education of diabetes
 Lifestyle management
 Diet
 Exercise

 Interventional of pharmacology
 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 -- Three important components
• Enough nutrition to meet energy demands
• Food intake distributed throughout the day
• Feeding pattern and amounts should be
consistent
 Exercise
• Helps decrease blood glucose levels
• Have physician approve exercise program
• Adjust meals & medications accordingly
• 3-4 times per week usually recommended
(30 minute)
 Nutritional
Recomendation
 Energy needs
 Basal energy requirements (BER) : 25-30 kcal/kg
of desirable body weight
 Desirable body weight/Ideal body weight (IBW) :
 Formula Brocca modified: 90%x {Body Length (cm)-
100}x1kg
 Additional energy required :
 Activity level
 Sedentary – 10% of BER
 Moderate – 20% of BER
 Strenuous – 50% of BER
 Infections :10-20%
 Obese patients : reduced energy 20-30% of BER
Nutritional Recommendations
for All Persons with Diabetes
 Protein : 15–20% 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 : 60–70% of total calories
 Use of caloric sweeteners, including sucrose, is
acceptable.
 Fiber (20–35 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.
 Recommendations of
physical activity
 Initial physical activity recommendations
should be modest, based on the patient’s
willingness and ability, gradually
increasing the duration and frequency to
30 – 45 min of moderate aerobic activity
3–5 days per week, when possible.
 Greater activity levels of at least 1 h/day
of moderate (walking)or 30 min/day of
vigorous (jogging) activitymay be needed
to achieve successfullong-term weight
loss.
 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
 Specific receptor on the surface of pancreatic beta cell
bind the suflfonilurea receptors (SUR)
 There is a family of SUR, Sur 1/Kir6.2 is found in B
cellsand the brain.
 SUR 2A/Kir6.2 is found in cardiac and skeletal muscle
 Extrapancreatic effect
 Studied in vitro and vitro
 In human studies; enhances insulin-stimulated
perpheral glucose utilization in both adipose tissue
and skeletal muscle.
 Sulfonylureas: Mechanism
of Action
Sulfonylureas
GLUT2 Na+
K+ -
Na+ KIR K+
K+
Vm
K
+

Ca2+ -
Pancreatic Ca2+
Voltage-gated
ß 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 ß-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 5’AMP-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 90–130 5.0–7.2 < 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: S15–35; 2. ADA Diabetes Care 2002; 25: S35–49;
3. Feld S. Endocrine Pract 2002; 8 (Suppl 1): 40–82; 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