DIABETES MELLITUS

Diabetes Mellitus (DM) salah satu sindrom

metabolik atau penyakit gangguan metabolisme kronik
yang ditandai oleh hiperglikemia.

Klasifikasi

DM Tipe 1

Kerusakan sel beta

Adanya defisiensi produksi insulin, baik karena proses
autoimun maupun idiopatik

DM Tipe 2

Resistensi insulin
Defisiensi relatif insulin

Pathophysiology

Insulin resistance means that body cells

do not respond appropriately when insulin
is present
Other important contributing factors:

increased hepatic glucose production (e.g.,

from glycogen degradation), especially at
inappropriate times
decreased insulin-mediated glucose transport
in (primarily) muscles & adipose tissues
(receptor and post-receptor defects)
impaired beta-cell functionloss of early
phase of insulin release in response to
hyperglycemic stimuli

Underlying causes of type 2

diabetes
Insulin
resistance

Hyperinsulinaemia
Impaired
glucose
tolerance

Obesity

-cell
defect

Decreased insulin
secretion
Early
diabetes

-cell failure

Late
diabetes
Adapted from Saltiel AR. J Clin Invest 2000;106:163164.

The progressive nature of

type 2 diabetes
Normal
Insulin
sensitive

Impaired
glucose
toleranc
e

Type 2
diabetes

Late type 2
diabetes
complicatio
ns

Hyperglycaemi
a

Normal
insulin
secretion

Insulin
resistanc
e
-cell
exhaustion

Normoglycaemia

Insulin resistance

Fasting plasma
glucose
Insulin sensitivityAdapted from Bailey CJ et al. Int J Clin Pract 2004;58:867876.
Groop LC. Diabetes Obes Metab 1999;1 (Suppl. 1):S1S7.
Insulin secretion

Screening

Widespread use of the fasting plasma glucose (FPG)

as a screening test for T2DM is recommended
because:

A large number of individuals who meet the current criteria

for DM are asymptomatic & unaware
Epidemiologic studies suggest that T2DM may be present for
up to a decade before diagnosis
As many as 50% of individuals with T2DM have one or more
diabetes-specific complications at the time of their diagnosis
Treatment may favorably alter the natural history of DM

ADA recommends screening all individuals >45 years

every 3 years & screening individuals at an earlier age
if they are overweight (BMI > 25km/m2) & have one
additional risk factor for diabetes

Diagnosis

Keluhan Khas Klinis DM (+)

GDP
GDS

12
6
20
0

Keluhan Khas Klinis DM (-)

<126
<200

12
6
20
0

110125
110199
TTGO
GD 2 JAM

Ulangi

126
200

DM

<126
<200

<11
0

200

TGT

140 199

<14
0

GDPT

NORMAL

Hyperglycemia between normal & diabetes levels is

classified as prediabetes & includes two categories:
Impaired fasting glucose (IFG) which is present with
fasting plasma glucose between 6,1 6,9 mmol/liter
(110 126 mg/dl)
Impaired glucose tolerance (IGT) which is diagnosed
with an oral glucose tolerance test that results in 2h plasma of 7,811 mmol/liter (140 199 mg/dl)

Natural History of Type 2

Diabetes
Genetics
Environment
nutrition
obesity
exercise

Impaired
glucose
tolerance

Insulin resistance
Hyperinsulinemia
Hypertension
Decreased HDL-C
Increased TG

Onset
of
diabete
s

Complications
Disability

Ongoing
hyperglycemia

Retinopathy
Nephropathy
Neuropathy
Atherosclerosis

Death

Blindness
Renal failure
Coronary disease
LE amputation

Glukosa Darah
-

Darah arteri 5-10 % lebih tinggi daripada darah vena,

serum / plasma 10-15 % lebih tinggi daripada darah utuh
(kapiler)

Jenis sampel yang dianjurkan adalah plasma vena

Pemisahan serum / plasma dari sel-sel darah harus segera

dilakukan ( jam) karena adanya glikolisis & konsumsi oleh
eritrosit & lekosit, dapat dicegah dengan antikoagulan NaF

Variasi intraindividual (non-DM: 5-10%) tergantung ritme

sirkadian, intake makanan & kerja otot

 GDP

Pengukuran kadar glukosa serum setelah puasa

12-14 jam sebelum dilakukan pemeriksaan
Tujuan: screening DM & monitoring terapi DM
Nilai normal 70 100 mg/dL

GD2JPP

Pengukuran kadar glukosa serum 2 jam setelah

makan makanan yang mengandung 100 g
karbohidrat
Tujuan: screening DM & monitoring terapi DM
Nilai normal: 140 mg/dL

 TTGO

TTGO (Tes Toleransi Glukosa Oral) dilakukan

dengan mengambil sampel darah & urin puasa, 30
menit, 1 jam, 2 jam & 3 jam setelah minum 75 g
glukosa

Tujuan: memastikan DM yang masih diragukan,

diagnosis hipoglikemia & sindrom malabsorbsi

Nilai normal:
Kadar glukosa tertinggi 160 199 mg/dL pada
menit ke-60 & menurun ke kadar normal pada
jam ke-2 & jam ke-3
Semua sampel urin glukosa negatif

Faktor-faktor tahap preanalitik

Makan/minum
Kopi meningkatkan glikogenolisis &
glukoneogenesis
Merokok rangsangan nikotin pada medula adrenal
yang meningkatkan kadar epinefrin plasma
Demam peningkatan sekresi GH & glukagon
Stress mental meningkatkan sekresi hormon &
kadar glukosa darah
Obat-obatan

Antidiabetik oral & insulin

Tiazid hiperglikemia & menurunkan toleransi glukosa

Ketaatan pasien

Puasa sekresi insulin menurun, sekresi

glukagon meningkat
Alkohol menghambat glukoneogenesis hepatik
Obat-obatan (insulin & antidiabetik oral)
Aktivitas fisik aktivitas fisik yang berat
menyebabkan perubahan volume cairan karena
perpindahan antara kompartemen intravaskular
& interstitial, kehilangan cairan melalui keringat,
peningkatan epinefrin, norepinefrin, glukagon &
penurunan insulin
Ketaatan pasien

Glucose Assay
Hexokinase

Methods

glucose + ATP glucose-6-phosphate + ADP

glucose-6-phosphate + NADP 6phosphoguconate + NADPH + H
The most used glucose measure system
The increase in absorbance at 340 nm is
proportional to the amount of NAADPH
formed, this requires an UV
spectrophotometer

 Glucose

Oxidase Methods

Glucose + H2O + O2 gluconic acid + 2H2O2

Another common & versatile methods
A peroxidase enzyme catalizes the oxidization of an indicator dye
by the peroxide (H2O2) to form a pigment
A visible spectrophotometer monitors production of thes pigment in
chemistry analyzers
Urine dipsticks also use this method, which permits the analyst to
detect & estimate visually the amount of glucose in urine without
an instrument
2H2O2 4H + 2O2 + 4e 2H2O2 + O2
Another method variation monitors peroxide production
electrochemically
Movement of the charged intermediates from anode to cathode
forms a complete electrical circuit
Electron move through wiring to produce measurable, whereas the
oppositely charged hydrogen ions move through the reaction
mixture

 Metode

heksokinase memiliki akurasi & presisi

yang sangat baik & merupakan metode
referens, karena enzim yang digunakan spesifik
untuk glukosa.

Metode

GOD memiliki akurasi & presisi yang

baik (karena enzim GOD spesifik untuk reaksi
pertama), tapi reaksi kedua rawan interferen
(tak spesifik). Interferen yang bisa
mengganggu antara lain bilirubin, asam urat &
asam askorbat.

Microalbuminuria
Pemeriksaan

untuk memantau komplikasi

nefropati: mikroalbuminuria serta heparan sulfat
urine (pemeriksaan ini jarang dilakukan)

Pemeriksaan

lainnya yang rutin adalah

pemeriksaan serum ureum & kreatinin untuk
melihat fungsi ginjal

Mikroalbuminuria

= ekskresi albumin di urin

sebesar 30-300 mg/24 jam atau 20-200
mg/menit

 Mikroalbuminuria

ini dapat berkembang

menjadi makroalbuminuria. Sekali
makroalbuminuria terjadi maka akan terjadi
penurunan yang menetap dari fungsi ginjal.

Kontrol

DM yang ketat dapat memperbaiki

mikroalbuminuria pada beberapa pasien,
sehingga perjalanan menuju ke nefropati bisa
diperlambat.

kategori albuminuria
Albuminuria normal (<20 mg/menit)
Mikroalbuminuria (20 200 mg/menit)
Overt Albuminuria (>200 mg/menit)

 Pengukuran

mikroalbuminuria secara
semikuantitatif dengan menggunakan strip atau
tes latex agglutination inhibition, tetapi untuk
memonitor pasien tes-tes ini kurang akurat
sehingga jarang digunakan.

Yang

sering adalah cara kuantitatif: metode

Radial Immunodiffusion (RID), Radio
Immunoassay (RIA), Enzym-linked
Immunosorbent assay (ELISA) &
Immunoturbidimetry. Metode kuantitatif memiliki
presisi, sensitivitas & range yang mirip, serta
semuanya menggunakan antibodi terhadap
human albumin. Sampel yang digunakan untuk
pengukuran ini adalah sampel urine 24 jam.

Algorithm for the interpretation of albumin

excretion rate in people with diabetes

Ketone
Synthesized

by the liver from fatty acids when a lack of

glucose causes the body to use fat for energy

In

a low insulin state such as diabetes, fat & fatty acids are
metabolized less efficiently that normal, resulting in a
buildup of serum ketones

Ketone

bodies consist of acetone, acetoacetic acid & hydroxybutyric acid (predominant type of ketone body
occurring in diabetic ketoacidosis)

This

test only measures acetone & acetoacetate acid & is

used in conjunction with the -hydroxybutyrate blood test
to help differentiate coma (hyperosmotic / ketoacidosis)

 after anesthesia, alcoholism, carbohydrate

deficiency, DM, eclampsia, pregnant diabetic woman,
fasting, reducing diets, glycogen storage disease, highfat diet, hyperglycemia, ketoacidosis, starvation,
prolonged exercise, von Gierkes disease & drugs
(methyldopa & propranolol)

Positive

Factors

that affect result

Hemolysis of the specimen invalidates the results

A low carbohydrate diet may cause elevated results
After 7 day of storage at -20C, level of acetoacetate 40%
lower than a time of specimen collection
Not useful for monitoring response to treatment in DKA,
because acetoacetate levels tend to remain stable, even with
treatment
Ketones appear in urine before there is a significant increase
in the amount in the blood

Metabolic Syndrome, Insulin

Resistance, and Atherosclerosis
Hyperinsulinemia/hyperproinsulinemia

Insulin resistance
Glucose
intolerance

Increased
triglycerides

Decreased
HDL cholesterol

Increased
PAI-1

Small, dense
LDL
Atherosclerotic
cardiovascular
disease
MacFarlane S et al. J Clin Endocrinol Metab. 2001;86:713718.

Increased BP
Endothelial
dysfunction

Pemeriksaan resistensi
insulin

Gold standar pemeriksaan laboratoris untuk

mengetahui adanya resistensi insulin adalah
euglycemic hyperinsulinemic clamps test.
(Govindarajan. et al, 2006). Dengan rumus berikut:
HOMA-IR = fasting insulin (U/ml) x fasting glucose
(mmol/L)
22,5

Pemeriksaan monitoring
pasien DM

emeriksaan HbA1C :
monitoring kadar gula darah rerata 3 bula
engan mengukur glycated haemoglobin
Normal : < 7%

emeriksaan GLA :
monitoring kadar gula darah rerata 2 mingguan
engan mengukur glycated albumin
ilai normal masih dalam research