Resistensi

Insulin pada
DM tipe 2

Dr Budi Enoch SpPD

16 Maret 2013
THE TOP 10 DM PREVALENCES OF THE 33 INDONESIAN PROVINCES AS REPORTED BY MINISTRY OF HEALTH – 2007
(The Results of RISKESDAS-INA Study-2007, Summarized and Illustrated : Tjokroprawiro 2012-2013)

*) Indonesia : DM 5.7% (Male 4.9% ; Female 6.4%), Population: 230 Millions Total DM: 10 Millions

* *
Diabetes Province Prevalencef (MILLIONS)

Indonesia : TGT 10.2% (Male 8.7%, Female 10%) Total IGT : 17.9 Millions
60 11.1 11.1 *
10.4
50 * * *
8.6 8.5 * *
8.1 7.8 7.7
40 * *
6.8 6.6
30

20

10

0
1 2 3 4 5 6 7 8 9 10
MAL-UT KAL-BAR RIAU BKBLT NAD SUL-UT JATENG GRTLO JATIM DKI
Study Data (33 Provinces of Indonesia): Age > 15 yrs, Samples 19.114, Urban Population. Diagnosis,
based on : Fasting 10-14 hrs, Oral Glucose Loading 75 g (WHO 1999-ADA 2003), IGT (if Postloading
Glucose : 140-200 mg/dL), DM (if Postloading Glucose : > 200 mg/dL)
• 2020 : Penduduk Indonesia diatas usia 20
tahun 178.000.000 orang dimana 7.000.000
orang (4%) adalah penderita DM tipe 2
• Berdasarkan hasil Riset Kesehatan Dasar
(Riskesdas) 2007, angka prevalensi diabetes
mellitus tertinggi terdapat di provinsi
Kalimantan Barat dan Maluku Utara (masing-
masing 11,1 persen), diikuti Riau (10,4 persen)
dan NAD (8,5 persen).
• NDDM : resiko CHD 2 – 4 kali lebih tinggi
dibanding non DM2
• Biaya perawatan DM, 10% dari total ongkos
perawatan kesehatan1
• Penyakit CV mengkonsumsi proporsi biaya
terbesar dari ‘direct costs2’

1. International Diabetes Federation, Diabetes Atlas, 4th Edition;

2. Diabetes - The Policy Puzzle. FEND 2003
 Biaya langsung dan tidak langsung untuk
diabetes
• 1 dari setiap 7 dollar biaya perawatan kesehatan
digunakan untuk orang dengan diabetes
• Biaya perawatan kesehatan untuk orang dengan
diabetes setiap tahun berlipat 3,6 kali lebih besar
daripada biaya perawatan kesehatan pada orang
tanpa diabetes
• Biaya langsung untuk kasus positif: 85 milyar dollar
• Perkiraan biaya secara keseluruhan: 92 – 100 milyar
dollar
Pathophysiology of type 2 diabetes
Where are we in 2013
 Natural history of Type 2 DM

Years from -10 -5 0 5 10 15

diagnosis Onset Diagnosis

Insulin resistance
Insulin secretion

Postprandial glucose
Fasting glucose Microvascular complications
Macrovascular complications
Pre-diabetes Type 2 diabetes

Ramlo-Halsted BA, Edelman SV. Prim Care 1999; 26: 771-789.

Nathan DM. N Engl J Med 2002; 347: 1342-1349.
 Komplikasi diabetes
Microvascular
• Retinopathy
• Neuropathy
• Nephropathy
Macrovascular
• Cerebrovascular disease
• Peripheral vascular disease
• Coronary heart disease
 Insulin Resistance

• A core defect in most type 2 diabetes patients

• Definition:
Impaired response to the physiological effects of
insulin, including those on glucose, lipid, protein
metabolism and vascular endothelial function

Diab Care 1999;22:562

Diab Care 2000; 23(Suppl 1):54
 Insulin Resistance Problem

Definition of Insulin Resistance :

Impaired response to the physiological effects of
insulin, including those on glucose, lipid, protein
metabolism and vascular endothelial function
• Receptor:
 Quantity / function
• Post-receptor:
 Translocation of GLUT
 Synthesis of GLUT
ADA. Consensus Development on Insulin Resistance. 1997
 Diagnosis

Pilar Pengobatan
I II III IV

edukasi Aktifitas nutrisi obat

fisik

Edukator Dokter
 Major Classes of Medications

1. Drugs that sensitize the Thiazolidinediones

body to insulin and/or Biguanides
control hepatic glucose
*Inlacin
production

2. Drugs that stimulate the Sulfonylureas

pancreas to make more Meglitinides
insulin

3. Drugs that slow the Alpha-

glucosidase
absorption of starches inhibitors
 Keuntungan intervensi yang berbeda
per 200 pasien diabetes yang dirawat selama 5
tahun
5
Per 4 mmHg Per 1 mmol/L Per 0.9%
lower SBP lower LDL-C lower HbA1c
0 2
1
CV events

-5 9% *
-2,9

-8,2
-10

-15 -12,5

-20

Ray KK et al. Lancet 2009;373:1765–72

 Tantangan pelaksanaan kontrol glukosa darah

Hypoglycaemia /
Weight gain

HbA1c
 Mengapa hypoglycaemia penting
• Hypoglycaemia mempunyai kaitan dengan bertambahnya
mortalitas 1
• Sampai 38% pasien dengan diabetes type 2 melaporkan
adanya symptomatic hypoglycaemia2
• Hypoglycaemia mengakibatkan menurunnya kualitas
hidup, kepuasan perawatan dan ketaatan terhadap
pengobatan 2
• Hypoglycaemia merupakan penghalang (barrier) bagi
titrasi dosis insulin optimal dan pencapaian kontrol
glycaemic
• Hanya 15% pasien dengan diabetes type 2 yang
mengalami hypoglycaemia, melaporkan kejadian
tersebut pada dokter mereka 3
1. Bonds DE et al 2010 Jan 8;340:b4909. doi: 10.1136/bmj.b4909
2. Diabetes Obesity and metabolism 2008 Jun;10 Suppl 1:25-32
3. McAulay V et al. Diabet Med. 2001; 18: 690–705
 Siapa saja yang mempunyai resiko?

• Tingkat hypoglycaemia yang lebih tinggi

berkaitan dengan dengan terapi intensif (3.14 vs.
1.03 dan 5.05 vs. 1.51 kasus / 100 orang tahun)
• Resiko bertambah di antara –
Manula
African Americans
Yang berpendidikan rendah
Menderita diabetes dalam jangka waktu lama
Insulin
Peripheral neuropathy
Disfungsi ginjal

Miller ME et al BMJ 2010

 Hypoglycaemia – clinical consequences
• Hypoglycaemia has proarrhythmic effects1
Q-T interval prolongation
Ca++ Channel overload
Suppression of K+ channel activation during repolarisation
Autonomic nervous system over activation
• Hypoglycaemia associated with cognitive
dysfunction and delayed recovery in the elderly2
• Hypoglycaemia associated with increased anxiety3
• Hypoglycaemia linked to pro-thrombotic and pro-
inflammatory effects4
1. Nordin Diabetologia (2010) 53:1552–1561
2. Zammitt Diabetes. 2008;57(3):732-6
3. Labad Diabetologia. 2010;53(3):467-71.
4. Wright Diabetes Care. 2010;33(7):1591-7
 How low should it go?
Adjusted hazard ratios for all-cause mortality by HbA1c deciles in people given
oral combination and insulin-based therapies

Metformin plus sulphonylureas Insulin-based regimens

Currie et al. Lancet 2010;375(9713):481–9

Composite end points that matter

HbA1c <7.0%
+
No weight gain
+
No hypoglycaemia
Improvement of Insulin Resistance with
Inlacin (Bioactive Fraction DLBS 3233)
 inlacin
• 5 komponen aktif dari kayumanis (cinnamomum
burmanii) dan daun bungur (lagerstroemia
speciosa)
• Produksi Indonesia dari Dexa Medika
• Presentasi AFES Vietnam 2011 dan IDF-WPR 2012
• Penelitian oleh Prof Sidartawan, Ketut Suastika,
Asman Manaf dan Askandar
• Sedang diusahakan izin pakai FDA & IDF
Normal Insulin Signalling
 Glukosa Insulin

Receptor Insulin

GLUT - 4
Auto phosphorilation
Prot
Kinase B
Phosphoinositide
Dependent-Kinase p110 p85 IRS
GLUT - 4 Atypical Phosphoisnositide-3
PK C Kinase
PPARg + RXR

GLUT - 4 GLUT - 4
mRNA
PPRE

transcription
Sel Otot Dinding sel
 Glukosa Insulin

Receptor Insulin

Auto phosphorilation

PPARg + RXR

mRNA
PPRE

transcription
Sel Otot Dinding sel
 Effects of Tyrosine and Serine Phosphorylations

Alpha Sub Unit Tyrosine Site of Insulin Binding

Kinase Receptor

α α Cell Membrane

Insulin Sensitivity β β
Cellular Response
Tyrosine
IRS
Phosporylation

Serine P Tyrosine: Increase

Insulin Sensitivity
Beta Sub Unit Tyrosine
Insulin Resistance Kinase Receptor P Serine: Causes Insulin
Resistance
Mechanism of Action of DLBS3233
 Effects of Inlacin in Inhibiting Serine
Phosphorylation
Site of Insulin Binding
I I

α α Cell Membrane
X β β
FFA Cellular Response
ATP ADP P Tyr P
P Tyr P
TNFα
_ P Tyr P Cellular Response

Inlacin:
Inhibit Serine Phosphorylation
 Reducing the action of TNF Alpha
 Reducing FFA
 Increasing Insulin Sensitivity
 Inlacin Increases Insulin Sensitivity by
Tyrosine Phosphorylation

Site of Insulin Binding

α α Cell Membrane

β β
P Tyr P Insulin Sensitivity
Phosporylation P Tyr P
ATP ADP
P Tyr P Insulin Sensitivity

P Tyrosine: Increase Insulin Sensitivity

How Increased Lipolysis
leads to Hyperglycemia
 Inlacin Decreases Lipolysis
INSULIN – RECEPTOR BINDING

IRS-PTyrosine
PKC  and PKC 
TRANSLOCATION

CELLULAR
 FFA P Tyr P
RESPONSE
P Tyr P
ATP ADP P Tyr P
CELLULAR
 TNF  RESPONSE

INLACIN®

 INSULIN  INSULIN
SENSITIVITY TYROSINE PHOSPHORYLATION SENSITIVITY
INLACIN (DLBS3233)
In Vivo Study
DLBS 3233 Monotherapy Decreases Random,
Fasting and Postprandial Glucose
Effects of DLBS32 +/- Metformin on
Fasting Glucose Levels

160

150

140
Insulin Resistant
Fasting BG 130
Metformin
(mg/dl)
120 DLBS3233
Metformin + DLBS3233
110

100
7 days high-glucose diet 7 days treatment
Before treatment 14 days high-glucose diet 14 days treatment
Effects of DLBS32 +/- Metformin on Fasting Total
Cholesterol and Trigliceride Levels
220

200

Total 180
Cholesterol Insulin Resistant
Metformin
(mg/dl) 160 DLBS3233
Metformin + DLBS3233
140

120
7 days high-glucose diet 7 days treatment
Before treatment 14 days high-glucose diet 14 days treatment

160

140

Triglyceride 120

(mg/dl) 100
Insulin Resistant
80
Metformin
60 DLBS3233
Metformin + DLBS3233
40

20

0
7 days high-glucose diet 7 days treatment
Before treatment 14 days high-glucose diet 14 days treatment
 Effects of DLBS32 +/- Glimepiride on
Fasting Glucose Levels

160

150

140

Insulin Resistant
Fasting BG 130
Glimepiride
(mg/dl) 120
DLBS3233
Glimepiride + DLBS3233

110

100
7 days high-glucose diet 7 days treatment
Before treatment 14 days high-glucose diet 14 days treatment
 Effects of DLBS32 +/- Glimepiride on Fasting Total
Cholesterol and Trigliceride Levels
220

200

Total 180
Insulin Resistant
Cholesterol 160
Glimepiride
DLBS3233
(mg/dl) Glimepiride + DLBS3233
140

120
7 days high-glucose diet 7 days treatment
Before treatment 14 days high-glucose diet 14 days treatment

160

140
Triglyceride 120

(mg/dl) 100
Insulin Resistant
80
Glimepiride
60 DLBS3233
Glimepiride + DLBS3233
40

20

0
7 days high-glucose diet 7 days treatment
Before treatment 14 days high-glucose diet 14 days treatment
 Prevention of Diabetes using
DLBS3233 (Inlacin)
180

160
Control
DLBS3233 2.25 mg/kg
140 BW
Fasting BG
DLBS3233 4.5 mg/kg
(mg/dl) BW
120 DLBS3233 9 mg/kg BW
DLBS3233 18 mg/kg BW

100
7 days treatment 7 days on high glucose diet
before treatment 14 days treatment 14 days on high glucose diet
Prevention of Diabetes using DLBS3233
(Inlacin)
220

200

Control
180
DLBS3233 2.25
mg/kg BW
Total 160 DLBS3233 4.5 mg/kg

Cholesterol 140
BW
DLBS3233 9 mg/kg
(mg/dl) BW
DLBS3233 18 mg/kg
120
BW

100
7 days treatment 7 days on high glucose diet
before treatment 14 days treatment 14 days on high glucose diet

120

Triglyceride 100

(mg/dl) 80 Control
DLBS3233 2.25 mg/kg
BW
60
DLBS3233 4.5 mg/kg
BW
40
DLBS3233 9 mg/kg BW
DLBS3233 18 mg/kg
20 BW

0
7 days treatment 7 days on high glucose diet
before treatment 14 days treatment 14 days on high glucose diet
 Inlacin Clinical Trial

RSU Sanglah – Denpasar

(Prof.Dr.dr.Ketut Suastika SpPD-KEMD)

40
 Inlacin Safety Data

• At the end of study, no significant changes of laboratory safety parameters

(AP, ALT, Creatinine) were found in each group
• No clinically significant adverse events were observed during the study
period
 Inlacin (DLBS3233) Reduces HbA1c level
HbA1c HbA1c reduction from baseline (6 wk of
treatment)
11.00
0.20 0.08
10.50
0.00

HbA1c reduction (%)

10.27
HbA1c level (%)

10.00 -0.20 PLC D50

-0.40
9.58 PLC
9.50 9.50 -0.60
D50 D-HbA1c 6 wk
9.13 -0.80
9.00 -1.00
-1.20
8.50 -1.13
-1.40
8.00 -1.60
B-HbA1c E-HbA1c Group

Diabetes Complication Complication Risk Reduction

Diabetes-related death 21%
Myocardial Infarction 14%
Stroke 12%
Peripheral vascular disease 43%
Microvascular diseases 37%
Heart Failure 16%
 Inlacin (DLBS3233) decreases Plasma Fasting
Glucose level after 6 week therapy

FPG Percentage of FPG reduction from baseline (at

6 wk of treatment)
300.00

20.00
250.00 14.00
15.00
211.20 216.10 10.00
FPG level (mg/dL)

200.00 205.80
191.20
182.88 5.00

% FPG reduction
160.13 PLC 0.00
150.00 143.62 140.00 D50
-5.00 PLC D50 Percentage D-FPG 6
100.00 -10.00 wk
-15.00
50.00 -20.00
-25.00 -23.36
0.00
-30.00
baseline- 2wk FPG 4 wk FPG 6-wk FPG
FPG -35.00
Group Group
 Inlacin (DLBS3233) decreases Postprandial
Glucose level after 6 week therapy

PPPG PPPG reduction from baseline (at 6 wk of

400.00
treatment)

350.00
337.33 100.00
300.00
288.44 80.00

PPPG Reduction
PPPG level (mg/dL)

250.00 249.53
237.14 60.00 48.89

(mg/dL)
PLC
200.00
D50 40.00 D-PPPG 6 wk
150.00
20.00
100.00
0.00
50.00 PLC D50
-20.00 -12.29
0.00
Group
Baseline-PPBP 6-wk PPBG
 Inlacin Clinical Trial

RSUP M.Djamil – Padang

(Prof.Dr.dr.Asman Manaf SpPD-KEMD)

45
2-hour Post Prandial glucose level
after 8 and 12 weeks of treatment
 Fasting Triglyceride

 : reduction from baseline

p : sig. of the reduction by DLBS3233 versus Placebo
 Liver Functions

ALT and alkaline phosphatase

levels in DLBS3233 Group were
reduced, NOT clinically
significant.
 Renal Function

Serum creatinine slightly increased in DLBS3233 Group,

but NOT clinically significant
Inlacin as mono and combination therapy

Mono therapy Combination Therapy

INLACIN 50 mg INLACIN + DPP4-INH
INLACIN 100 mg INLACIN + METFORMIN
INLACIN + SULFONILUREA
INLACIN + GLINID
INLACIN + INSULIN

It has been used by more than 50.000

patients as monotherapy or combination
therapy with the other OADs
 Conclusion

 Inlacin has the activity to control the level of blood

sugar, insulin and other lipoproteins including High
Density Lipoprotein (HDL), Low Density Lipoprotein
(LDL), triglycerides, and total cholesterol level.

 Inlacin works well in reducing fasting and

postprandial glucose as well as HbA1C levels.

 Inlacin well to be use in pre-diabetes / metabolic

syndrome patients.