Diabetes Melitus

Definisi DM
• American Diabetes Association
(ADA) tahun 2010
 suatu kelompok penyakit
metabolik dengan karakteristik
hiperglikemia yang terjadi
karena kelainan sekresi insulin,
kerja insulin, atau kedua-
duanya.

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Klasifikasi etiologis :

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Kriteria diagnosis DM

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PILAR PENATALAKSANAAN
DIABETES

• 1. Edukasi
• 2. Terapi gizi medis
• 3. Latihan jasmani
• 4. Intervensi farmakologis

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Algoritma pengelolaan DM tipe 2
tanpa disertai dekompensasi

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Pilihan terapi pada DM Tipe 2
• Sulfonylureas • -glucosidase inhibitors
• 1st generation e.g. chlorpropamide, • e.g. acarbose
tolbutamide
• 2nd generation e.g. glyburide, • Insulin
gliclazide, glipizide, gliquidone
• regular
• 3rd generation e.g. glimepiride
• intermediate/long acting
• Modified release
• pre-mixed
• analogs
• Glinides/meglitinides  rapid acting
• Non-sulfonylureic e.g. repaglinide  long acting
• Amino acid derivatives e.g. nateglinide
• Fixed-dose oral antidiabetic
• Biguanides drug combinations
• e.g. metformin • e.g. glyburide/metformin,
glipizide/metformin,
rosiglitazone/metformin
• Thiazolidinediones
• e.g. rosiglitazone, pioglitazone

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Mekanisme kerja, efek samping utama,
dan pengaruh terhadap penurunan A1c

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Terapi DM: safety and tolerability
ANTIDIABETIC AGENTS
SAFETY AND Insulin Metformin α-glucosidase TZDs* Insulin
TOLERABILITY secretagogues inhibitors

Risk of
hypoglycemia1,2

Weight gain1,2

Gastrointestinal
side effects1

Lactic acidosis1

Edema3

= treatment-related adverse event = not commonly seen in monotherapy

*TZDs = thiazolidinediones
1DeFronzo 10
RA. Ann Intern Med 1999; 131:281–303. 2UKPDS. Lancet 1998; 352:837–853.
3Nesto RW, et al. Circulation 2003; 108:2941–2948.
Choosing oral antidiabetic agents:
mechanism of action

-glucosidase Sulfonylureas/
inhibitors meglitinides Biguanides
Thiazolidinediones

 Carbohydrate  Insulin
 Glucose  Insulin
breakdown/ secretion
output resistance
absorption  Insulin resistance

1Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.

11 2Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.
Choosing antidiabetic agents: efficacy
ANTIDIABETIC AGENTS
EFFICACY Insulin Metformin α-glucosidase TZDs* Insulin
secretagogues inhibitors

Effect on FPG/HbA1c1

Effect on plasma
insulin1,2 –

Effect on insulin
resistance3 –
Effect on insulin
secretion4 –

= reduced levels = increased levels = no significant effect

*TZDs = thiazolidinediones
1DeFronzo RA. Ann Intern Med 1999; 131:281–303. 2Lebovitz HE. Endocrinol Metab Clin North Am 2001; 30:909–933.
3Matthaei S, et al. Endocrine Reviews 2000; 21:585–618. 4Raptis SA & Dimitriadis GD. J Exp Clin Endocrinol; 2001; 109 (Suppl.
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2):S265–S287.
Target Pengendalian DM

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Target Pengendalian DM
Parameter Risiko KV (-) Risiko KV (+)
IMT (kg/m2) 18,5 - < 23 18,5 - < 23
Tekanan darah < 130 < 130
sistolik (mmHg)
Tekanan darah < 80 < 80
diatolik (mmHg)
Glukosa darah puasa < 100 < 100
(mg/dL)
Glukosa darah 2 jam < 140 < 140
PP (mg/dL)
HbA1c (%) < 7 < 7
Kolesterol LDL < 100 < 70
(mg/dL)
Kolesterol HDL ( Pria > 40 Pria > 40
mg/dL) Wanita > 50 Wanita > 50
Trigliserid (mg/dL) < 150 < 150 14
Tabel : Korelasi antara kadar A1C dan
kadar GD rata-rata

A1C (%) GD Rata-rata (mg/dl)

6 135
7 170
8 205
9 240
10 275
11 310
12 345
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Indikasi terapi insulin

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Cara praktis penyesuaian dosis insulin basal

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Langkah pendekatan terapi pasien DMT2 dengan
konsep insulin basal, basalplus dan basal‐bolus

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Insulin premixed

• Terapi insulin premixed sebagai

terapi intensif setelah gagal
dengan insulin basal merupakan
salah satu pilihan dalam
pengelolaan pasien DMT2

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Algoritma pemberian insulin dan
OHO

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 Summary

Avoid hyperglycemia,
Avoid glucotoxicity,
Avoid oxydative stress

The best of choice in diabetes treatment

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What is our problem ?

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Degenerative Diseases :
The Coming Problem

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 Recognising the epidemic
of prediabetes – the growing burden

Prandial Blood glucose

140 – 200 mg /dl
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UKPDS: loss of glycemic control
over time with traditional agents
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Cohort, median values

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HbA1C (%)

Conventional
Glyburide
7 Chlorpropamide
Metformin
Insulin

Upper limit of of normal = 6.2%

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0 2 4 6 8 10
Years from randomization
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UK Prospective Diabetes Study (UKPDS) Group (UKPDS 33). Lancet 1998;
352:837–853.
The UKPDS demonstrated progressive
decline of -cell function over time
100

80 Start of treatment
-cell function (%)

60

40

20 P < 0.0001

0
–10 –9 –8 –7 –6 –5 –4 –3 –2 –1 1 2 3 4 5 6
Time from diagnosis (years)

HOMA model, diet-treated 27

n = 376
Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(Suppl.):S21–S25.
Cardiovascular disease and its relationship
with postprandial plasma glucose

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50
CHD risk per 1000

40 40-114 mg/dL
115-133 mg/dL
30 134-156 mg/dL
157-189 mg/dL
20 190-532 mg/dL
10

0
Fatal CHD Total CHD
P < 0.001 for fatal CHD comparing quintile 1 to 5
P < 0.01 for fatal CHD comparing quintile 1 to 5
n = 8006 men
Adapted from: Donahue, R.P. et al. Diabetes 36: 689-692, 1987 (The Honolulu Heart Study)
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Uncontrolled blood glucose and the risk
of microvascular complications

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13 Retinopati
Nefropati
Relative risk

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Neuropati
9 Mikroalbuminuria
7

1
6 7 8 9 10 11 12
HbA1C(%)

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*Endocrinol Metab Clin 1996;25:243 - 254 (Diabetes Control Complications Trial) ** NHANES III
Why

Glucotoxocity
( environmental factor )
&
Genetic factor ( s )

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 Genetic determinants
of individual
susceptibility

Repeated acute
changes in cellular
metabolism
Diabetic tissue
Hyperglycemia
damage
Cumulative long-term
changes in stable
macromolecules

Independent accelerating
factors (e.q. hypertension,
hyperlipidemia)

Diabetic tissue damages induced by hyperglycemia

( Brownlee, 2005 ) 31
Inhibition of complex III of electrone transportation system in
mytochondria will increase activation of UCP- 2, decrease the
ATP / ADP ratio, and decrease insulin secretion ( Brownlee, 2003 )32
A Unifying Mechanism : Over production of superoxide in mitochondria
caused by hyperglicaemia will induce many pathobiologic processes 33
of chronic complications of diabetes melitus ( Nishikawa, 2000 )
 KERJA GLIMEPIRIDE DALAM MERANGSANG
SEKRESI SEL BETA
Berikatan dengan
reseptor 65 kDa
Glime K+ Ca++
SU lain piride Depolarisasi
140 kDa 65 kDa
+ Pengeluaran K+
dihambat
reseptor SU
_
K+ + Depolarisasi

Sel beta pankreas

[Ca++]i

Saluran Ca++
cAMP
Metabolism

Glukosa [ATP] terbuka

& +
[ADP] ADP
Asam Amino

[Ca++] intrasel
Pro-insulin meningkat

Modified Kramer,W. et al. (1995) The Molecular interaction of 34

sulfonylureas with B-cell ATP-sensitive K+-channels. Sekresi Insulin Sekresi insulin
Diab.Res.Clin.Prac. 28 Suppl.,S67-S80
Metformin reduces insulin
resistance

Increase glycogenesis
Increased receptor binding
Increased IRTK
Decrease blood glucose level
Prevents glucotoxicity

Inhibited GLP-1 degradation

Promoted satiety
Decrease intestinal glucose absorption
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Glitazone

• Insulin sensitizer : anti hyperglycaemic agent

• Improve lipid profile *
• Improve hypertension *
• Reduce PAI-1, CRP, E-Selectine, TNF-α, IL- 6,
resistin, leptin *
• Anti proliferative *

* anti atherogenic

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 ROSIGLITAZONE reduces insulin resistance
Insulin Glucose

Insulin
receptor

Synthesis GLUT 4
PPARg + RXR mRNA

PPRE transcription
promoter Coding reg
Muscle
Cells
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Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
Acarbose
Its position in diabetic management

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 Work principle of Acarbose
Blood Glucose (mg/dl)

200 200 Acarbose

150 150

100 100

blood blood

small bowels colon small bowels colon

meal meal
+
Glucobay®
Carbohydrates
Enzymes transport glucose into the blood stream
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 Blood glucose before -
Blutzuckerspiegel
Blutzuckerspiegel vorund
vor und nach
nach 77 Wochen
WochenTherapie mitmit
Therapie
and 37x weeks
50 mg after
Acarbose/Tagtreatment with
(kontinuierliche Acarbose
Glukosemessung)
3 x 50 mg Acarbose/Tag (kontinuierliche Glucosemessung)
(continous glucose recording)
Blood Glucose mg%

Before acarbose

after acarbose

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time
Zick,Zick, AcarboseFibel
Acarbose Fibel 2001
2001
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Conservative management of glycemia:
traditional stepwise approach

Diet and OAD OAD +

exercise OAD* monotherapy OAD OAD + multiple daily
monotherapy up-titration combination basal insulin insulin injections
10
HbA1c (%)

HbA1c = 7%
7
HbA1c = 6.5%

6
Duration of diabetes *OAD = oral antidiabetic

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Campbell IW. Br J Cardiol 2000; 7:625–631.
Proactive management of glycemia:
early combination approach
Diet and
OAD*
exercise
monotherapy OAD
combinations
OAD
up-titration
10 OAD + basal
insulin
OAD + multiple daily
HbA1c (%)

9 insulin injections

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ACTION
POINT:
7 HbA1c = 7%
HbA1c = 6.5%
6

Duration of diabetes *OAD = oral antidiabetic

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How quickly should patients be
reaching HbA1c targets?
The Global Partnership
recommends:
Treat patients intensively so as to
achieve target HbA1c < 6.5%*
within 6 months of diagnosis
< 6.5%

*Or fasting/preprandial plasma glucose < 110 mg/dL (6.0 mmol/L) where assessment of HbA1c is not
possible
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Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.
When should combination therapy
be introduced?
The Global Partnership recommends:
After 3 months, if patients are
not at target HbA1c < 6.5%,*
consider combination therapy

*Or fasting/preprandial plasma glucose < 110 mg/dL (6.0 mmol/L) where assessment of HbA1c is not
possible 45
Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.
How should patients with high baseline
HbA1c be managed?
The Global Partnership recommends:

Initiate combination therapy or insulin

immediately for all patients with
HbA1c  9% at diagnosis

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Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.
What are the ideal components for
combination therapy?

The Global Partnership recommends:

Improved glycemic control

Use combinations of oral
antidiabetic agents with
complementary
mechanisms of action Agent B

Agent A

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Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.
Paradigm for early combination
treatment
If HbA1c  9%
at diagnosis
Initiate combination
therapy† or insulin
in parallel with
diet/exercise Treat to goal of
HbA1c < 6.5%*
by 6 months
If HbA1c < 9% If HbA1c > 6.5%*
at diagnosis at 3 months
Initiate monotherapy Initiate combination
in parallel with therapy† in parallel
diet/exercise with diet/exercise

0 1 2 3 4 5 6
Months from diagnosis
*Or fasting/preprandial plasma glucose < 110 mg/dL (6.0 mmol/L) where assessment of HbA1c is not possible
†Combination therapy should include agents with complementary mechanisms of action

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Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.
The main concept of treatment :
make plasma glucose concentration as
normal as possible

Novel therapeutic approaches

Transketolase activators : activated by thiamin,

benfotiamine
PARP inhibitors : block four major pathways
Antioxidant ( esp. Catalytic ) : endothelial enzymes 
such as eNOS &
prostacyclin synthase
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 Diagnosis DM dapat ditegakkan
melalui tiga cara:

1. Jika keluhan klasik ditemukan, maka pemeriksaan glukosa

plasma sewaktu >200 mg/dL sudah cukup untuk menegakkan
diagnosis DM
2. Pemeriksaan glukosa plasma puasa ≥ 126 mg/dL dengan
adanya keluhan klasik.
3. Tes toleransi glukosa oral (TTGO). Meskipun TTGO dengan
beban 75 g glukosa lebih sensitif dan spesifik dibanding
dengan pemeriksaan glukosa plasma puasa, namun
pemeriksaan ini memiliki keterbatasan tersendiri. TTGO sulit
untuk dilakukan berulang-ulang dan dalam praktek sangat
jarang dilakukankarena membutuhkan persiapan khusus.
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Tabel : Korelasi antara kadar A1C dan
kadar GD rata-rata

A1C (%) GD Rata-rata (mg/dl)

6 135
7 170
8 205
9 240
10 275
11 310
12 345
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 Tahap 1 Tahap 2 Tahap 3

Gaya hidup +
Gaya hidup +
Saat diagnosis: Metformin +
Metformin +
Gaya hidup Insulin basal
Insulin intensif
+
Metformin Gaya hidup +

Metformin +
Well validated core
therapies Sulfonilurea

Gaya hidup +
Gaya hidup +
Metformin +
Metformin +
Pioglitazon +
Pioglitazon sulfonilurea

Gaya hidup + Gaya hidup +

Less well validated Metformin + Metformin +
core therapies
GLP-1 agonis Basal insulin
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Nathan DM et al, Diabetes Care 32:193–203, 2009
Pengantar
• Saat ini di pasaran tersedia berbagai jenis
insulin. Ditinjau dari asalnya, terdapat
insulin manusia
dan insulin analog (sudah direkayasa
dengan kerja yang lebih baik dari insulin
manusia).
• Sedangkan bila ditinjau dari segi kerjanya
terdapat insulin kerja pendek (insulin
manusia) atau cepat (insulin analog), kerja
menengah (insulin manusia), dan kerja
panjang (insulin analog).

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Farmakokinetik sediaan insulin

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Profil farmakokinetik insulin manusia dan
insulin analog

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Efek biologis insulin

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Hubungan antara hiperglikemia
dan buruknya luaran rumah sakit.

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Konsep Insulin Basal dan
Insulin Prandial
• Insulin basal
• Insulin prandial

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Memulai terapi insulin injeksi
multipel harian pada pasien DMT1

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Berbagai rejimen suntikan insulin
multipel pada pasien DMT1

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Algoritme pengelolaan DMT2

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