DM

Dr. M a h a t m a SpPD
SMF Penyakit Dalam F.K. UMS
SURAKARTA
EAGLE FLIES ALONE, MHT

-Cardiology
-Pulmonology
-Nephrology
-Hematology
-Gastrohepatoenterology
-Endocrinology
-Rheumatology
-Infectious Diseases
-Geriatri
-Immunology
-Psikosomatis
Topik
ELATAR BELAKANG
ETINJAUAN ANATOMIS FISIOLOGIS
EDEFINISI
EPATOFISIOLOGI
EDIAGNOSA
EPENATALAKSANAAN
EKOMPLIKASI



Topik

E LATAR BELAKANG




DM Prevalence
INDONESIA
2000 ¬ 5.6 million people with DM
2030 ¬ 21.3 million people with DM

The 4
th
of world largest prevalence !!
(International Diabetes Federation)
O Diabetes Mellitus ( DM ) :
- WHO (1993) : prevalensi DM 6%, >100 jt. 2003 : 177jt, 2025 : 300jt.
- Indonesia 1998 : 3,5 juta, 8,5 juta (tahun 2020)
- Pre-diabetes ??
- Faktor yg berperan dlm | jml DM : usia >40 tahun yg |,
kemakmuran|, pola hidup serba berkecukupan, + penyakit infeksi,
angka harapan hidup |
O Nefropati Diabetika (ND) :
- Prevalensi 20-30%
- 17 kali >> Non-DM
- Di AS > 50.000/ thn (GGT, ESRD) ÷ ND tertinggi
- Biaya dialisis ||| :
- Pencegahan komplikasi DM
- Menghambat progresivitas ND
Absolut
Topik

E TINJAUAN ANATOMIS FISIOLOGIS




Intake
glukosa
oral
Normal
DM
1/3 Bag Otot

1/3 Bag Hepar

1/3 Bag Jar. lain
Seimbang
Tidak tergantung
insulin
Hepatic glucose
uptake
lambat
Hiperglikemi
Postprandial
Overview of Carbohydrate metabolism
INS
INS
INS
INS
INS
INS
INS
INS
Adapted from Shepherd PR et al. Glucose transporters and insulin action. NEJM, July 22, 1999
GLUT 4 (Glucose transporters 4) and insulin action
Synthesis
Topik

E D E F I N I S I




Diabetes Mellitus
• Kelainan bersifat kronik
• Gangguan metabolisme KH-L-P
• Komplikasi Makro & Mikro Vaskuler
• Berkaitan dengan faktor genetik
• Gejala Utama Intoleransi Glukosa
Seimbang ( normal )
× Insulin
× Glukagon
× Hormon lain
Masuknya glukosa
usus ÷ darah
Berpindahnya glukosa
darah ÷ jaringan tubuh
Bahan Toksik
sel | Insulin +
sel o Glukagon +
Kurang
Protein
÷ Hiperglikemi
÷ Tidak Ketosis
Faktor
2
÷ Fungsi Endo. Pank ( DM )
¤ Genetik
¤ Virus & Bakteri
¤ Bahan Toksik
¤ Nutrisi
Topik

E PATOFISIOLOGI





Disfungsi Beta Cell dan Resistensi Insulin
B Cell Disfunction Signaling Defect
Post Prandial Glucosa
Insulin Resistance
Fasting Glucosa
HIPERGLYCAEMIA
Loss Of Insulin
G
l
u
c
o
s
a

T
o
x
i
c
i
t
y


Genetik
Lingkungan
Resistensi Insulin
CHD
IFG
Dislipidemi
Hipertensi
Mikroalbuminuria
Gg.Fibrinolitik
Inflamasi
Obesitas sentral
hypoX-jsk-7-99
IGT
Postprandial
Hyperglycemia
Type 2
Diabetes
Phase 1 Type 2
Diabetes
Phase 2
Type 2
Diabetes
Phase 3
- 12 - 10 - 6 - 2 0 2 6
10 14
Years from diagnosis
B
e
t
a

c
e
l
l

f
u
n
c
t
i
o
n

(
%
)
Stages of type 2 Diabetes in relationship to Stages of type 2 Diabetes in relationship to
| |- -cell function cell function
25
0
50
75
100
Problem Insulin Resistance :
• Reseptor:


• ―Post-receptor‖ (paling sering):
¬Translokasi GLUT 4
¬ Sintesis GLUT 4
¬ Kuantitias / fungsi
ADA. Consensus Development on Insulin Resistance. 1997
SlametS
Why Does the |-cell Fail?
Chronic
hyperglycemia
High circulating
free fatty acids
Pancreas
Amyloid
deposit
Hyperinsulinemia
to compensate for insulin
resistance
1,2
Glucotoxicity
2
Lipotoxicity
3
IR
|-cell
Dysfunction

IR
HGP
Uptake
Lipolysis
TNF o
SlametS
Hyperglycemia
Glucose auto oxidation
Sorbitol pathway
AGE formation
 Oxidative Sress
 Antioxidants
Lipid peroxidation
 Leukocyte adhesion
 Foam cell formation
 TNF a
Endothelial dysfunction
 NO  Endothelin
 Prostacyclin
 TXA
2
Hypercoagulability
Fibrinolysis
 Coagulability
 Platelet reactivity
Vascular complications
Retinopathy Nephropathy
Neuropathy
Topik

E D I A G N O S A




Criteria for the Diagnosis of Pre-DM
(IGT & IFG) and DM
A Dx of Diabetes must be confirmed on a subsequent day by any one of the 3 Methods.
Fasting means : No Calorie intake for at least 8 hours *IGT by OGTT; *IFG by FPG
Glucose Load : 75g Anhydrous Glucose in Water
FPG > 126

2-h PG > 200

CPG > 200
with Classical Symptoms
IGT IFG T2DM
2h-PG

140-199
FPG
110-125
FPG < 110

2-h PG < 140


Normal Pre - Diabetes Diabetes Mellitus
(mg/dl) (mg/dl) (mg/d l)
New IFG*:
100-125
Topik

E PENATALAKSANAAN



Criteria for Diabetes Control
Good Fair Poor
Fasting blood glucose (mg/dl) 80-109 110-125 ≥126
2hpp blood glucose (mg/dl 80-144 145-179 ≥180
A1C (%) <6.5 6.5-8 >8
Total- cholesterol (mg/dl) <200 200-239 ≥240
LDL-cholesterol (mg/dl) <100 100-129 >130
HDL-cholesterol (mg/dl) >45
Triglyceride (mg/dl) <150 150-199 ≥200
Body mass index (kg/m2) 18.5-22.9 23-25 >25
Blood pressure (mmHg) <130/80 130-140/80-90 >140/90
Perkeni, 2009

Treatment :
stepwise approach Blood
Glucose Control
1
2
3
4
5
+
+
+
SlametS
Medical Nutrition Therapy, Exercise , Education and SMBG
HbA
1c
< 7 %
Consider oral
monotherapy
Add insulin sensitizer
or secretagoque
Add insulin sensitizer
And secretagoque
Target not Met
Target not Met
Start Insulin Or
Add Third oral agent
Full Insulin therapy
With Or without Oral agent(s)
HbA
1c
7 - 8% HbA
1c
>8%
Target not Met
COMBO
(OHO + OHO)
INSULIN
+ INSULIN
(Continue 1 OAD)
+ OAD
Proposed New Treatment Paradigm
for Type 2 Diabetes ( )
1999 2002
SlametS
Goals :
Treatment Algorithm for Type 2 daibetes in Adults
2004 EASD
FPG
(<130 mg/dl)
SMBG
(<120mg/dl )
HbA1c
(< 7%)
Follow up
q 3-6 mo
Start monotherapy
Early dual OHA
OHA Insulin
or
Consider : Other OHA therapy
Or insulin/analog + OHA
Continue
q 3-6 mo
Add glargine or NPH at bedtime
Switch to split dose insulin
Basal + prandial insulin (Glargine + glulisine)
Refer to specialist
Goals met Goals not met after 1 mo
Adequate Not Adequate after 3 mo
Adequate Not Adequate after 3 mo
Continue
q 3-6 mo
Robert Henry EASD 2004
Penyuluhan Kesehatan
Penderita Dokter Pihak lain
Kerjasama Terpadu
Rinci
Sistematis
Praktis
Menuntun Penderita
¤ Memahami penyakitnya
¤ Menerima keadaan dirinya
¤ Menyongsong masa depan (Rasional)
DIET
¤ Disesuaikan dgn Pola diit
¤ Diberikan tiap jam
Kalori berdasar BBR / IMT
Olah Raga
Latihan Fisik (Olah Raga)
Dampak Positif
O Sensitifitas
Insulin - Reseptor |
O Perbaikan profil lipid
O Perbaikan kondisi
kardiovaskuler
Dampak
Negatif
× Ketosis
× Hipoglikemi
× Komplikasi kronik |
× Trauma sendi
Sesuai kondisi
• Fisik
• Metabolik
Olah Raga
¤ Meningkatkan afinitas insulin - reseptor
¤ Sesuai kemampuan fisik
¤ Teratur
Insulin
IDDM ( tipe 1 )
MRDM ( DMM )
NIDDM ( tipe 2 ) + Komplikasi akut & berat
+ sedang butuh insulin
Preparat insulin
• Lama bekerja
• Derajat kemurnian
Bagan 2. Algoritma Pengelolaan DM T2 pd diabetisi dg BB lebih dan Tidak Gemuk
Bagan 2a. Algoritma Pengelolaan DM tipe 2 yang belum mendapat terapi
HbA1C GD rata (mg/dl)
Terapi
6 -7
7 - 8
8 - 9
9 - 10
> 10
135 - 170
170 - 205
205 - 240
240 - 275
> 275
Monoterapi:
Terapi Kombinasi:
Terapi Kombinasi:
Terapi Kombinasi:
• Metformin
• TZD
• AGI
• Metiglinid
• AGI
• Metformin
• TZD
• SU
• Metformin
• TZD
• SU
• Glargine
• Metformin
• TZD
• SU
• Glargine
Terapi Insulin
KONSENSUS PERKENI 2006
Hipoglikemik Oral
¤ Sulfonilurea



¤ Biguanid




¤ o - Glucosidase
Inhibitor
E Memacu sel |
E Menghambat sel o
E | afinitas Insulin-Reseptor
E Menghambat
Glucose release
E Menghambat
Glucose utilization
E Menghambat absorbsi
Glucosa di usus
¤ Short acting
¤ Intermediate
¤ Long acting
HYPERGLYCEMIA
Glucotoxicity
Lipotoxicity
Increased
Free Fatty
Acids
INSULIN RESISTANCE DEFECTIVE INSULIN
SECRETION
o-Glucosidase
Inhibitors

Delay Intestinal
Carbohydrate
Absorption
Liver
Increased Glucose
Production
Adipose Tissue
Increased Lipolysis
Thiazolidinediones
(TZDs)
Increase Glucose
Uptake
TZDs
?
Biguanides
Decrease
Hepatic Glucose
Production
TZDs
Decrease
Lipolysis
Insulin Target Tissues
Pancreatic Beta Cells
Decreased Insulin
Secretion
Sulfonylureas
and
Nonsulfonylurea
Secretagogues

Increase Insulin
Secretion
Small Intestine
Carbohydrate
Absorption
Skeletal Muscle
Decreased
Glucose Uptake
Lipotoxicity
(type 2 diabetes)
Choice of agents in current use
Sulphonylureas
Metformin
Meglitinides
TZDs
o-glucosidase
inhibitors
Acarbose
Miglitol
Voglibose
Rosiglitazone
Pioglitazone
Glipizide
Gliclazide
Glimepiride
Glibenclamide
Repaglinide
Nateglinide
Normoglycemia
Increased insulin
secretion
Decrease in hepatic
glucose production
Increase in glucose uptake
Biguanides
Thiazolidinediones
Sulfonylureas
Meglitinides
Thiazolidinediones
Biguanides
Alpha-glucosidase
inhibitors
Decreased digestion of
complex sugars
Sites/Mechanisms of Action
hypoglycemic Agents
Generasi 1 ÷ Generasi 2 ÷ Generasi 3
DOSIS |
!
• Normoglikemi
• Hiperinsulinemi ÷
Hipoglikemi
Komplikasi
vaskuler
• Makin efektif
• Efek samping > kecil
SULFONILUREA
Paling banyak digunakan
dalam praktek
Glimepiride
(Generasi 3)
• Potensi ekstra pankreas
> efektif
• Kerja cepat & bertahan lama
• Dosis kecil
Efek samping
minimal
Memacu
sekresi insulin
SULFONILUREA
Meningkatkan
Afinitas Reseptor-Insulin
• Potensi Sel | +
• Masih mampu dipacu
NIDDM
NON OBESE
TIDAK KURUS
+ Dasar Pemikiran
Terapi Sulfonilurea
+ Bilamana
Terapi dimulai
+ Bagaimana cara
Pemberian obat
¤ Memacu sekresi insulin
¤ Memperbaiki Glucose
Clearance
¤ Memperbaiki profil lipid
¤ BB Normal
¤ Glukosa darah puasa
140 mg/dl
¤ Diit, OR biguanid ÷ gagal
¤ Belum butuh Insulin
¤ Mulai dosis kecil tunggal
| dosis
terbagi/berulang
¤ Ditelan 30 mnt AC
SULFONILUREA
INSULIN
Reseptor
Insulin Hepatosit
Hepatic Insulin
Clearance


Insulin > lama
dalam plasma
• Glikogenolisis
• Glukoneogenesis
Glycogen
Synthase


Glikogenesis
Pyruvate
dehydrogenase


Metabolik oksidatif
Glukosa intrasel
Muscle
Glucose uptake


Hiperglikemi
Post Prandial
Hepatic Glucoce
Production


Hiperglikemi
Puasa
( - )
( - )
( - )
( + )
( + )
( + )
( + )
SULFONILUREA
Metabolik
Vaskuler
Mencegah angiopati
¤ membersihkan
radikal bebas
¤ Memperbaiki
fungsi trombosit
¤ Memacu
fibrinolisis
Pengendalian
Kadar glukosa darah
SULFONILUREA
Pore-forming
Sub unit
Reseptor
Drug binding
Sub unit

K-ATP channel
Tertutup


Voltage-dependent
Calcium channels
Terbuka


Eksositosis
Granula insulin
SEL BETA
Abssorbsi Metabolisme Ekskresi
( Usus ) ( Hepar ) ( Ginjal )
Potensi Obat
Gangguan Faal
¤ Hepar
¤ Ginjal
> Mudah terjadi
Hipoglikemi
Farmakokinetik dari
Bermacam-macam Sulfonilurea
Obat
Waktu
Paruh
( Jam )
Jangka
Waktu
Kerja
( Jam )
Dosis/
hari
( mg )
Tablet/
hari
Metabolit
Aktif
ACETOHEXAMIDE
CHLORPROPAMIDE
GLICLAZIDE
GLIPIZIDE
GLIBURIDE
TOLBUTAMIDE
TOLAZAMIDE
0.8 - 2.4
24 - 48
6 - 15
1 - 5
2 - 4
3 - 28
4 - 7
12 - 18
24 - 72
10 - 15
14 - 16
20 - 24
6 - 10
16 - 24
250 - 1500
100 - 500
40 - 320
2.5 - 20
2.5 - 20
500 - 3000
100 - 1000
2
1
1 - 2
1 - 2
1 - 2
2 - 3
1 - 2
-
-
-
-
-
-
-
• Diabsorbsi sempurna (1 jam)
• Kadar maksimal dalam plasma (2 - 3 jam)
• Waktu paruh eliminasi (9.2 ± 3.6 jam)
• Jangka waktu kerja (2 jam)
• Metabolit 60% - urine
40% - feses
- Efek extra pankreas >
• Efek samping hipoglikemik < - Insulino Tropik <
- Metabolit > aktif
(Generasi ketiga terbaru)
• Hipoglikemi
• Alergi kulit
• Trombositopeni
• Agranulositosis
• Anemia hemolitik
• Dispepsia
• Nausea
• Icterus
• Gangguan faal hepar
• Flushing
• Retensi cairan
Pengaruh Sampingan
Model showing the potential contribution of the related loss of visceral adipose tissue to the beneficial
effects of metformin on the features of the metabolic syndrome FFA : free fatty acids
Hepatic
Glucose
production
FFA ?
Visceral
Adipose tissue ?
| Insulin
sensitivity
METFORMIN
| Insulin
sensitivity
| Muscle
glucose uptake
+ Glucose
(—)
(+)
(=)
Vascular benefits of metformin
AGE : advanced glycation end-products
Reduced cardiovascular risk
Metformin
Improved
Insulin sensitivity
Fibrinolysis
Nutritive capillary flow
Haemorrheology
Postischaemic flow
Reduced
Hypertriglyceridaemia
AGE formation
Cross-linked fibrin
Neovascularisation
Oxidative stress
Effects of metformin on non-conventional factors
(Grant PJ, 2003).
Risk marker Effect
PlAI-1
Factor VII
Fibrinogen

Factor XIII
Fibrin
C-reactive protein
Platelets


Blood flow
Marker reduction
Reduction
Equivocal , some studies report reduction, others
no effect
Reduces A and B subunit
Alters structure / function
Reduction
Reduction platelet growth factor 4 and
thromboglobulin, stabilises platelet and antioxidant
effect
Metformin increases hemodynamic responses to L-
arginine. Lowers levels of asymptomatic
dimethylarginine, improves post ischemic blood
flow and improves blood flow in both sekeletal
muscle and adipose tissue
Reciprocal effect of increased activity of the Randle
cycle and treatment with metformin on glucose / lipid
metabolism in T2DM (Del Prato 1995)

Item

Increased Randle
cycle activity

Metformin
Treatment


Lipid oxidation
Glucose tolerance
Glucose disposal
Glucose oxidation
Insulin sensitivity
Hepatic glucose production


↑
↓
↓
↓
↓
↑

↓
↑
↑
↑
↑
↓
• Ingested with meals
• Delay the digestion of complex
carbohydrate
• Competitive inhibition of alpha
glucosidase in the intestine
• Blunts postprandial glucose spikes
• Gastrointestinal side effects
Alpha Glucosidase Inhibitors
(AGIs)
The use of acarbose
1. It has direct effect on postprandial glucose
2. Does not cause hypoglycemia when given alone
3. Does not cause weight gain
4. Side effects are trivial
5. It can be used as first - line drug therapy
6. It can be used as an adjunct to existing and
conventional therapy
7. Modulates peaks and delays glucose absorption
8. Hypothesized that AGI administration to IGT cases
may delay or prevent T2DM and CVD risks

promoter
Coding reg
transcription
mRNA
Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2
nd
Ed.
Synthesis GLUT 4
PPAR¸
PPRE
Insulin
receptor
Insulin
RXR
Glucose
PPAR¸
promoter
Coding reg
+RXR
Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2
nd
Ed.
PPRE
receptor
Insulin
Resistensi Insulin
Glucose
mRNA
Synthesis GLUT 4
X
X
transcription
promoter
Coding reg
transcription
mRNA
Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2
nd
Ed.
Synthesis GLUT 4
PPRE
Insulin
receptor
Insulin
Glucose
Pioglitazone reduced Insulin resistance
Pio
PPAR¸
+RXR
Normal Islet
Pioglitazone
Degenerated
Nateglinide
Pancreatic β cell of db/db mice
Ishida, Metabolism 2004
6
th
weeks treatment
Normal Islet
Pioglitazone
Degenerated
Nateglinide
Pancreatic β cell of db/db mice
Ishida, Metabolism 2004
6
th
weeks treatment
Comparison of therapies for T2DM when used as
monotherapy (Nathan 2003)
Diet Sulfonyl
urea
Bigua
nide
Glucosidase
Inhibitor
Thiazoli -
dinedione
Insulin
Metabolic effects
Improves resistance
Improves secretion
Overnight HGP
Postprandial excursion
HbA1c
Lowers FFA
Weight gain
Hypoglycemia
Allergic phenomena

+
+
+
+
+
+
-
-
-

+
++
+
++
++
+
+
+
+

++
+
++
+
++
+
-
-
+

+
+
+
++
+
+
+
-
-

+++
+
+
+
+
+
+
-
+

++
+
+
++
+++
++
++
++
+
Other side effects
Anabuse effect
Hyponatremia
Lactic acidosis
Gastrointestinal
Hepatic dusfunction

-
-
-
-
-

+*
+*
-
-
-

-
-
+
+
-

_
_
_
++
-

-
-
-
-
+ #

-
-
-
-
-
* common with 2nd generation sulfonylureas (glipizide, gliburide), most common chlorpropamide
# severe idiosyncratic failure in 1/35.000 – 1/50000 patients treated with troglitazons (others less)
• Kegagalan
Primer
Kesalahan Indikasi
• Kegagalan
Sekunder
Terapi
Kombinasi
• Biguanide ?
• Insulin ?
• Penderita
• Diit tidak benar
• OR Kurang
• Stress
• Penyakit lain
yang menghambat
Pengobatan
• Resitensi insulin
• Defisiensi insulin
• Dosis kurang
• Resistensi obat
• Hambatan absorbsi
• Obat-obat penyerta
• Metabolik
• Terapi
Combination / co-administration and
combined-drugs :
Available combined-drugs
Avandamet (Metformin – Rosiglitazone)
Metaglib (Metformin - Glipizide)
Glucovance (Metformin - Glibenclamide)
Amaryl-M (Metformin – Glimepiride)
Actoplusmet (Metformin - Pioglitazone)
Topik

E K O M P L I K A S I



KOMPLIKASI DIABETES MELLITUS
• Akut :

- Hipoglikemia
- Koma Asidosis Dia-
betika
- Hiperosmoler Non
Ketotik
- Koma Laktat Asi-
dosis

• Kronik :

- Mikroangiopati :
- Nefropati D M
- Retinopati DM
- Kardiomiopati DM
- Neuropati DM
- Makroangiopati :
- PJK
- CVA
- Ulkus/ ganggren
- Neuropati DM
- Rentan Infeksi :
- TB Pulmo, dll.

Overview
COMPLICATIONS OF DIABETES
KOMPLIKASI AKUT DM
LIFE THREATENING METABOLIC DISORDERS
(KEGAWATAN)
HIPERGLIKEMI HIPOGLIKEMI
KETOASIDOSIS LAKTOASIDOSIS HIPEROSMOLER
• Kontraktilitas miokard +
• Cardiac output +
• Tensi +
• Perfusi ke organ
2
+
• Respons vaskuler thd katekolamin +
• Syok hipovolemi
• Syok hipovolemi
• Trombo-emboli
• Edema cerebri
• Kerusakan SSP
Koma Diabetikum
Kesadaran + ÷ Koma

¤ Hipoglikemi
¤ Hiperglikemi
¤ Ketoasidosis
¤ Honk
¤ Laktoasidosis
Koma Ketoasidosis
Insulin +
Glukagon |
• Hiperglikemi
• Ketosis
• Asidosis
• Infeksi akut

• Penghentian
Insulin /
dosis kurang

• New onset DM
• Gangguan
metabolisme
KH, L, P

• Gangguan
keseimbangan
cairan, elekt,
asam-basa
• Hiperglikemi berat
• Ketonemi
• Asidosis metab
• Dehidrasi s/d syok
• nafas kussmaul
• kesadaran +
s/d koma
30% kasus dapat tampil
Dalam kondisi hiperosmoler

KETOASIDOSIS
¤ Poliuri, Polidipsi
¤ Nausea, Vomitus
¤ Kulit & Mukosa kering
¤ Nafas kuszmaul
¤ Dehidrasi ÷ syok
¤ Lemah, Depresi, Kejang
¤ Kesadaran + ÷ koma
Diagnosis laborat
O Hiperglikemi berat
O Glukosuri berat
O Ketonuri berat
O pH darah +
O PO O
2
+
O Tekanan osmose plasma |
Tujuan terapi
Ketoasidosis
× Menurunkan
glukosa darah

× Membersihkan
serum & urine
dari ketoacids

× Koreksi
gangguan keseimbangan
cairan & elektrolits

× Menghilangkan
faktor presipitasi
INSULIN
• NaCL isotonik
• Kalium
• Bikarbonat
• Fosfat
DEHIDRASI REHIDRASI
Sudah dapat makan
Seperti biasa
Koreksi
Sliding Scale
@ 4 jam
s.c
• > 300 mg/dl ÷ 20 u
• 251 – 300 mg/dl ÷ 15 u
• 201 – 250 mg/dl ÷ 10 u
• 150 – 200 mg/dl ÷ 5 u
• < 150 mg/dl ÷ -
• Short acting
3x / hari
30 menit sebelum
porsi makan utama

• Intermediate acting
malam hari
15 – 20 unit
0.3 – 0.4 unit/KgBB
50% i.v

50% s.c
• s.c

• Continous
infusion
Tergantung
sarana × Banyak diminati
dalam praktek
= efek terapi cepat
= komplikasi minimal
• Hipoglikemi
• Hipokalemi
• 0.1 u/kgBB/jam — me | insulin plasma — memenuhi
(100 – 200 µ u/mL) kapasitas maksimal
reseptor insulin

• Glukosa + (< 50-100 mg/dl) ÷ dosis | (2x)

• Dosis | s/d 100 u/jam ÷ + kortikosteroid
(menekan resist. Insulin)

• Glukosa + (250 mg/dl) ÷ dosis + 50% • mencegah hipoglikemi
+ dextrose • menekan ketoasidosis
+ KALIUM
+ BIKARBONAT
+ ANTIBIOTIKA
• Indikasi
K
+
< 5.5 mEq/L

• KCL ( 2/3 )
• Preparat
• KPO
4
( 1/3 )
• Indikasi
• pH < 7 (darah arteri)
• HCO
3
< 5.0 mEq/L
• K
+
> 6.5 mEq/L
• Hipotensi respon ( - )
thd pemb. cairan
• Payah jantung kiri
• Depresi pernafasan
• Indikasi
infeksi akut
HIPEROSMOLER
 Hiperglikemi > berat
 Peningkatan osmolalitas
> tinggi
 Ketoasidosis (-)
 Tromboemboli
 Insulin |
(tdk adekwat mengatasi
hiperglikemi)
 Counter regulatory hormones
|
(tdk setinggi pada
ketoasidosis)
 Osmolalitas ||
÷ menekan lipolisis
( sumber elemen keton bodies
)
Perbedaan dng Ketoasidosis
Mengapa
Berbeda
?
Data Laboratorium klinik
LABORATORIUM KAD HONK
Glukosa plasma (mg/dl) > 250 > 600
pH < 7.3 > 7.3
HCO
3
serum (mEq/L) < 15 > 20
Keton urine > 3
+
s 1
+

Keton serum (+) pengenceran 1:2 (-) pada pengenceran 1:2
Osmolalitas serum (mOsm/Kg) Bervariasi > 330
Natrium serum (mEq/L) 130 – 140 145 – 155
Kalium serum (mEq/L) 5 – 6 4 – 5
BUN (mg/dl) 18 - 25 20 - 40
Panduan klinik praktis untuk membedakan KAD & HONK
Dengan pengertian sekitar 30% penderita KAD dapat
Tampil dalam kondisi HONK
LAKTOASIDOSIS
 Hipoksia jaringan
= Hipovolemia
= Disfungsi miokard
= Syok sepsis
 Gangguan fungsi hepar
÷ laktic hepatic clearance +
 Biguanid
÷ laktat |
 DM lansia
PERBEDAAN DENGAN
KETOASIDOSIS & HIPEROSMOLER
+ DIAGNOSIS
 Faktor presipitasi +
 Laktat > 5 meq/L
 PH < 7.0
+ TERAPI
 Koreksi perfusi jaringan
 Terapi thd faktor pencetus
 Continous infusion
bikarbonat
s/d pH | ( mencapai 7.2 )
& bikarbonat | (mencapai 12 meq/L)
 Hemodialisis
 Dichloronacetate
÷ memacu piruvat dehidrogenase
÷ inotropik +
Koma Hipoglikemi
Insulin |
Koma
Diet + OHO |
+ lapar + Berdebar
+ Lemah + Pusing
+ Gemetar + Gelisah
+ Keringat dingin + Kesadaran +
Reaksi tubuh yang normal akibat
keadaan hipoglikemi :
Aktivasi saraf otonom :
Berdebar, lapar, gemetar, keringat dingin, nausea

Neuro-glycopenia :
Mengantuk, perilaku aneh, sukar konsentrasi
inkoordinasi, sulit bicara.

Akibat berat :
hemiparesis, konvulsi, chore-atetosis
ataxia, dekortikasi.



Otak dalam keadaan normal :
butuh 50% produksi glukosa basal
( 1 mg/kg/menit )
Kerusakan otak tergantung dari
lama, berat, cepat

Bila Hipoglikemia akan merusak
korteks serebri
hipokampus
batang otak /spinal bebas.

Bila Hipoksia menyebabkan
neuropati sensorimotor perifer


4.6 mmol/l
inhibition of endo-
genous insulin se-
cretion
3.8 mmol/l
counter-regulatory
hormone release:
- glucagon
- adrenalin
3.2-2.8 mmol/l
onset of symptom
- autonomic
- neuroglycope
n
3.0-2.4 mmol/l
neurophysiological
dysfunction.
-evoked responses
2.8 mmol/l
cognitive
dysfunct:
inability perform
complex tasks
2.0 mmol/l –onset
of EEG changes
<1.5 mmol/l severe
neuroglycopenia:
reduced conscious-
ness level,convuls-
ions, coma.
¤ Hipoglikemi Murni
( True Hypoglycemia )
¤ Reaksi Hipoglikemi
( Hypoglycemic Reaction )
¤ Hipoglikemi Reaktif
( Reactive Hypoglycemia )
¤ Koma Hipoglikemi
( Hypoglycemic Coma )
< 60 mg%
+ Cepat
3-5 jam pp
< 30 mg%
Terapi :
¤ Ekstra diet
¤ Minum bergula
¤ Glukosa 40% I.V
¤ Glukosa 10% infus
Penanganan hipoglikemia
Glukosa :

• kalori reaksi cepat , oral/parenteral
•Glukagon 1 mg i.m
•adrenalin ( bukan CS )

• Infus D5 diberikan selama 1 – 2 hari

•Belum sadar ??
•Pikirkan penyebab lain


Diabetes and Vascular
Complications
Microangiopathy
Coronary artery disease
Peripheral vascular
disease
Stroke

Nephropathy
Retinopathy
Neuropathy

Diabetes

Macroangiopathy
Mortalitas
Kardiovaskuler
 Disfungsi
endotel
 Aterogenesis
Glukosa
Post Prandial
 Hiperglikemi
 Hipertrigliseridemi
Korelasi
PJK
MORBIDITAS
&
MORTALITAS
• Kebutaan ÷ 30% DM (Retinopati)
• Komplikasi P. Darah perifer
÷ 40 x non-DM
Amputasi tungkai ÷ 10% DM
• Kematian 2-5 x non-DM
• Penyakit Jantung
• Gagal Ginjal Kronik
• Penyakit Serebro Vaskular
• Life Expectacy + (5 - 10 th)
Mikroangiopati
Penebalan MB Basalis
P. Darah Kapiler
Perubahan
Viskositas darah
& fungsi trombosit
Gangguan
Hemodinamic
Gangguan
hemodinamik
Penyempitan
kapiler
Critical
Vaskular Beds

• Retina
• Glomeruli
• Vasa nervorum
• GFR | ekskresi protein
• Retina
• aliran darah |
• Tekanan i.v |
• dilatasi
• Ekstremitas
• Aliran darah |
• Transportasi prot. Plasma trans. Kapiler |
Produksi
Prostasiklin +

Produksi
Aktivator
Fibrinolisis +

Produksi
Thromboxane A
2
|
• Viskositas
• Mikrotrombus
• Penyempitan vaskuler
Deformabilitas
eritrosit
Hambatan
aliran darah
tissue factor
Permeabel
INTIMA
Hiperinsulin
S S S i i i i i
PAI-1
SS
S = selectin
i = imunoglobulin( VCAM dll)

tissue factor PAI-1
Makrofag
SEL OTOT POLOS
MEDIA
Radikal
Bebas.
AGEs
DM
INTIMA
MONOSIT
SS
S S S i i i i i
SEL BUSA
LDL
ox
LDL
kecil
LDL
LUMEN
SEL OTOT POLOS
Sitokin+ f. pertumbuhan
MEDIA
fibrinolisis
agregasi tr.
PLAQUE
Migrasi
Hiperinsulin
Proliferasi
SS
Radikal
Bebas.
AGEs
LDL
kecil
Glukose
LDL
DM
Makrofag
SEL BUSA
LDL
ox
PLAQUE
INTIMA
MONOSIT
tissue factor
PAI-1
S S S i i i i i
Glucose
AGEs
Glycolysis Autoxidation Glycation Sorbitol
Pathway
Generation of reactive
oxygen species
ROS
Ca signalling Protein kinase C NFkB
Reactive intermediates
Mitochondrial resp. chain
GSH reduction
Reactive intermediates
RAGE
Vascular disease
NAD(P)H
Oxidase
?
Pro-oxidant effects of glucose
leading to increased CV risks
Perjalanan penyakit pd nefropati diabetik
Awal DM
- Makroalbuminuri/ gross protein
- Kreatinin |
ESRD
• GFR |
• Albuminuria reversible
• Ginjal membesar
• Hyperfiltration
• Penebalan membrana basalis
• Ekspansi mesangium
• Hyperperfusion
• Hiperfiltrasi
• Mikroalbuminuria
• Hipertensi
0 2 5
Waktu (tahun)
15 20 25
||
ACE Inhibitor
(dikutip dari Harrison Ed 16 : Adapted RA defronzo 1998 )
- GFR ml/mnt 150
- Serum
creat mg/dl 0,8
120

1
60

> 2,0
< 10

> 5
Perubahan fungsi
Incipiens Nephropathy
Perubahan struktur Overt nephropathy
DIABETIC RETINOPATHY
ERECTILE DYSFUNCTION
Kita lahir & besar
bersama.
Tapi mengapa
kamu mati
duluan ?
Mekanisme Rentan Infeksi Pada DM
• Keadaan Nutrisi intra sel berkurang
(malnutrisi, dehidrasi)
• Insufisiensi Vaskular
( makro dan mikroangiopati )
• Neuropati
• Fungsi Leukosit Berkurang
- Penurunan kemampuan Intracelluler Killing PMN, MN
- Defisiensi Komplemen
- Berkurangnya jumlah T- helper
- Disfungsi Makrofag

Patofisiology
Mekanisme Rentan Infeksi TB
Pada DM
• Fungsi Leukosit Berkurang

Penurunan Intracelluler Killing PMN, MN

Defisiensi Komplemen

Berkurangnya jumlah T- helper

Disfungsi Makrofag

Patofisiology
Disfungsi Makrofag
Penurunan kemampuan Intracelluler Killing PMN, MN
Perlekatan
Intracellular Killing
Eksositosis
Fagositosis
Kemotaksis
H2O2, spesies oksigen aktif
THE CONCEPTS OF INSULIN
• Insulin ditemukan pada
tahun 1921
• Marjorie (anjing) adalah
pasien pertama yang
menerima ekstrak
pankreas
• 1922 Eli Lilly memproduksi
insulin secara massal
• Insulin hewan digunakan
sampai tahun 1983
Insulin secretion in normal individu
· An amount of insulin will be secreted by human pancreas
about 49-50 units insulin / day
· Two phases of insulin secretion :
· Basal insulin secretion :
fasting 10 microU/ml
post prandial 100 microU/ml
peak at 30 – 40 minutes
without eksogen stimuli
· Stimulated insulin secretion
with eksogen stimuli
burst insulin release
decreased with gradually
Kronologik Kerja Insulin
Detik
Insulin terikat pada reseptor
Otofosfolirasi reseptor
Aktifasi protein kinase reseptor
Menit
Aktifasi transport glukosa
Aktifasi transport ion
Inhibisi glukoneogenesis
Stimulasi glikogenesis
Insulin-induced receptor internalisation
Jam
Sintesis protein
Sintesis lipid
Maximal insulin-induced down regulation
Pertumbuhan sel
Insulin
DM Tipe - 1
Insulin
DM Tipe – 2
Komplikasi
Akut
Insulin
DM Tipe – 2
Pengendalian
Glukosa darah
¤ Perkembangan Ilmu
¤ Perkembangan Teknologi Farmasi
¤ Pengalaman Praktek
INSULIN
Short acting
Intermediate acting
Long acting
Rapid acting
Extended acting
Konvensional
Human Mono - Component
× Insulin konvensional
÷ Transpeptidasi ÷ Purifikasi
× Biosintesis • E. Coli
• Saccharomyces
Twenty four hours profiles of blood insulin and
glucose concentration in normal Human
a.m p.m
Time of day
Basal
glucose
Basal
insulin
GLUCOSE
INSULIN
Supper Lunch Breakfast
I
n
s
u
l
i
n

(
µ
U
/
m
L
)

G
l
u
c
o
s
e

(
m
g
/
d
L
)

150 –
100 –
50 –
0 –
8 7 10 9 11 12 1 2 3 4 5 6 7 8 9
75 –
50 –
25 –
0 –
Twenty four hours profiles of blood insulin and
glucose concentration in normal Human
Menjelang
Makan Pagi
Menjelang
Makan Siang
Menjelang
Makan Malam
Menjelang
Tidur Malam
Short – Acting Short – Acting Short – Acting Extended – Action
Menekan
Hiperglikemi Post Prandial
Mengendalikan
Glukosa darah
Basal
Menekan Hepatic
Glucose Production
IDEAL
( Program Insulin )
a.m p.m
Time of day
Basal
glucose
Basal
insulin
GLUCOSE
INSULIN
Supper Lunch Breakfast
I
n
s
u
l
i
n

(
µ
U
/
m
L
)

G
l
u
c
o
s
e

(
m
g
/
d
L
)

150 –
100 –
50 –
0 –
8 7 10 9 11 12 1 2 3 4 5 6 7 8 9
75 –
50 –
25 –
0 –
Twenty four hours profiles of blood insulin and
glucose concentration in normal Human











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
Comparative profiles Secretion of blood insulin Normally and
D M
Distribution
Absorption
Insulin preparation
(human/bovine insulin)
Administration
Elimination
Renal excretion
(1%)
Antibody-bound
-^
Free insulin
Circulating Insulin
Degradation
Tissue
depot
Dissolution
Dissociation
Diffusion
Target cells Degradation
• Liver 60-80%
• Kidney 10-20%
• Muscle % fat
10-20%
B cell
Diet
Exercise
Counter-
regulation
Action
Biological effects
The various processes determining the absorption
of insulin, its distribution in the circulation
Factors:
site, depth,
temperature,
preparation,
exercise
Metabolic benefit of insulin therapy
(Edelman 1995)
1. Reduce fasting and postprandial glucose levels
2. Suppresses HGP hepatic glucose production
3. Stimulates peripheral glucose utilization
4. Increase glucose oxidation/storage in muscles
5. Improves lipoprotein composition
6. Reduces AGEP advanced glycosylation end products
7. Reduces glucose toxicity
8. Improves endogenous insulin secretion ability

1-4 maintain normoglycemia
5-6 prevent complications
7-8 preserving β-cell function

Profiles of injectable insulin

No human insulin can mimick
physiological insulin response to meals
No human insulin can mimick
physiological insulin response to meals
Bloodstream
Molar
concentration
Dissociation
Diffusion
Capillary
membrane
10
-3
10
-4

10
-5
10
-8

Hexamers Dimers Monomers
Zn
2+

?
Scheme of putative process Zn-insulin hexamer complex
dissociates into smaller units ( ADA )
• 1983: Human Insulin
Menggunakan bakteri untuk menghasilkan
insulin manusia (rekombinan DNA)

• Insulin terbaru :
- analog insulin : Humalog & Humalog Mix25
- insulin nasal

APAKAH BENAR BAHWA
PEND. DM ( INSULIN REQUIRING )
MEMBUTUHKAN PREPARAT BARU
LONG – ACTING INSULIN
PERTANYAAN
YANG HARUS
DI JAWAB

Jawaban
Rasional
¤ Preparat Konvensional
• Intermediate – Acting : - NPH
- Lente
• Long – Acting : Ultra Lente

¤ Insulin Glargine
÷ Homeostasis Glukosa
Inter Prandial &
Nokturnal
Peak-Action Profile
= Insulin Fisiologik
Peakless Extended-Action
Profile
= Insulin Fisiologik
LONG-ACTING BASAL
INSULIN ANALOGUE
¤ Konsep baru dalam pengobatan
DM tipe–1 & DM tipe–2
¤ Subkutan malam menjelang tidur
¤ Delayed Onset
¤ Constant
¤ Peakless
4 Potensi pengendalian
glukosa = NPH
4 Efek Hipoglikemi +++
24 jam
NATIVE
HUMAN INSULIN
*
Modifikasi
Struktur biokimiawi
EFEKTIF
&
AMAN
Þ US FOOD & DRUG ADMINISTRATION
( APRIL 2000 )
Þ EUROPEAN AGENCY FOR THE EVALUATION
OF MEDICINAL PRODUCTS
( JUNI 2000 )
Harapan
Dunia Medik
Preparat insulin
Memenuhi kebutuhan insulin basal
Human
Insulin
Recombinant
DNA
( 21A – Gly – 30 BA – L – Arg – Human Insulin )
¤ DELAYED ONSET
¤ CONSTANT
¤ PEAKLESS

Sekresi Insulin Basal
pada non-diabetes
kondisi Post-Absorbtive
Meal + SC
Insulin injection
Insulin Lispro
Regular human insulin
3 –
4 –
5 –
6 –
7 –
8 –
9 –
10 –
11 –
12 –
-60 -30 0 30 60 90 120 150 180 210 240
Time (min)
A
Blood glucose exursions of ten T1DM patients after consumption of a meal rich in rapidly-absorbable
carbohydrates [pizza, sugar-sweetened cola, tiramisu (total caloric content was 1016 kcal)]. After subcutaneous
injection of 15.4 ± 3.5 U at time zero, the meal was eaten within 20 min. On one of two study days, insulin
Lispro (open circles) was injected : on the other day regular human insulin (solid circles) was injected. Blood
Glucose was kept constant at 6.7 mmol/L
-1
in the 3 hours prior to the meal by means of glucose clamp. Free
plasma insulin concentrations.(Heinemann 1996 – De Felippis 2003 )
(Humalog)
Meal
Lispro or
Hum-R
Hum-R
— Hum-R (- 5 min)
— Hum-R (-30 min)
— Lispro (humalog)
— 6 nondiabetics
12.30
11.0
10.0
9.0
8.0
7.0
6.0
5.0
4.0
0 60 120 180 240 300 360 420
190
170
150
130
110
90
70
P
l
a
s
m
a

g
l
u
c
o
s
e
,

m
m
o
l
/
L

P
l
a
s
m
a

g
l
u
c
o
s
e
,

m
g
/
d
L

Time, min
Postprandial blood glucose after subcutaneous Lispro (Eli Lilly, Indianapolis, IN) administration at mealtime
versus human insulin (Hum-R) given either at mealtime or 30 min prior to the meal in patients with insulin-
dependent diabetes mellitus of short duration & residual |-cell function, N = 6 patients with insulin-dependent
Diabetes mean ± SEM (Bolli 1999)
FARMAKOKINETIK
&
FARMAKODINAMIK
Þ PROLONGED ABSORBTION
Þ FLAT METABOLIC PROFILE
CSII
=
ONSET OF ACTION

DURATION OF ACTION
4 Glargine 1,3 jam
4 NPH 0,7 jam
4 Glargine 22 jam
4 NPH 14 jam
VARIASI KECEPATAN ABSORBSI
INTER INDIVIDUAL
GLARGINE
Ultra
Lente
<
24 jam — 90 menit GLARGINE
14 jam 3 – 6 jam 50 menit NPH
AKHIR PUNCAK MULAI
SHORT – ACTING
Menjelang makan
Pagi – Siang – Malam

GLARGINE
Menjelang tidur malam
Glukosa darah
Post Prandial
& Inter Prandial


Hipoglikemi
Terkendali
Tidak Terjadi
Early Insulinisation
for Type 2 Diabetes Management
76.42%
6.17%
4.00%
3.48%
9.93%
Diet only
Insulin only
OHA only
OHA + Insulin
Others
Diabetes Management
(Region)
DCCT & UKPDS :
1. Reducing hyperglycaemia reduces incident risk &
progression of diabetic complications
2. Target HbA
1C
6.5% to 7%


UKPDS Data – Lowered 1% HbA
1C
leads to
reduction of :
• 21% diabetes-related mortality
• 14% MI
• 37% microvascular complications
• 43% PVD
Early Insulinisation
Challenge of Type 2 DM Control
Type 2 DM – a progressive disease

• Progressive decline of |–cell function
• Late diagnosis – average 12 years
• Loss of initial BG control within few years
• Exogenous Insulin becomes necessary
• Often, Insulin therapy need intensified

Early Insulinisation
When Insulin Becomes Necessary ?
UKPDS Study Data

• 50% of Type 2 patients need long-term insulin
after 6 years
• Lowest |-cell function at diagnosis ¬ greatest
risk of OAD failure


Marre M. Int J Obesity (2002) ; 26 (Suppl 3) : S25-S30
Early Insulinisation
Target
• Improve BG control – target :
HbA
1
C < 6.5%
• Fasting sugar of < 108 mg/dL
• PP sugars of < 144 mg/dL

Initiating Insulin
in Type 2 DM
Insulins : Types and Examples
Bolus Insulins
• Rapid-acting Humalog
• Short-acting Regular (Humulin R)

Basal Insulins
• Intermediate-acting NPH, Lente (Humulin N)
• Long-acting Ultralente, Lantus

Pre-Mixed Insulins
• NPH/Regular Based 30/70 (Humulin)
• NPL/Lispro Based Humalog Mix 25
• NPA/Aspart Based Novolog Mix 30
Penyimpanan Insulin
_ Dalam lemari es 2
0

- 8
0

hingga
kadaluarsa
_ Pada suhu ruang (30 derajat Celcius),
insulin stabil selama 30 hari

_ Hindari suhu yang ekstrim (terlalu panas
atau terlalu dingin)



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