Improvement of Insulin Resistance with Inlacin (Bioactive Fraction DLBS 3233)

Oleh :Billy

PT Dexa Medica

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PHYTOCHEMICALS

Dexa Laboratories of Biomolecular Science (DLBS) was conceived and started with occupying the present facility and being active

drug discovery and nutraceuticals research

THE HOME OF OUR RESEARCH ACTIVITIES

Drug Discovery: from Basics to Clinic

DEVELOPMENT PROCESS

DLBS, 2010

Drying

Extraction

Extraction & Fractionation

Fractionation followed by Molecular Screening

Fractionation, Isolation, SynthesisInlacin

FACILITIES

Tandem Chemistry Expression Bioassay System (TCEBS)

is a systematic screening methodology dedicated to find the most active and potent candidates for DLBS products. It is usually followed by bioassay system that utilizes gene expression and

protein array techniques

January 2011

June 2011

August 2011

October 2010

Target gen/Target Protein

DLBS3233(Lagerstroemin dan Cinamommum

sebagai bioactive)

Lagerstroemin, an ellagitanninMolecullar Weight 1200

Bioactive Fraction DLBS3233

Improvement of Insulin Resistance with INLACIN (DLBS3233)

Inlacin (DLBS3233) MECHANISM

Phosporylation on the right insulin receptor

Up regulator PPAR γ and PPAR

↑ GLUT-4 translocation from citoplasma to membran

↓ TNF

DLBS3233 promotes Tyrosine phosphorylation of the Insulin Receptor Protein – Increasing PI3 Kinase and Akt

1,7x lebih besar dari kontrol 1,5x lebih besar dari kontrol

DLBS 3233 INCREASES PPAR GAMMA & PPAR DELTA EXPRESSION

1,8x lebih besar dari kontrol

DLBS3233 INCREASES TOTAL GLUT-4 IN ADIPOCYTES

DLBS 3233 meningkatkan sintesis & translokasi GLUT4

DLBS 3233 INCREASES ADIPONECTIN EXPRESSION, WHILE DECREASES RESISTIN EXPRESSION

CLINICAL STUDY

No Trial ID Projects Therapy Sample size

1. DLBS3233-0209

Safety study in Healthy volunteers (Phase-1)Prof. K Suastika, Dr. RR Tjandrawinata

6

2. DLBS3233-0309

Preliminary study in T2DMRS Sanglah, DenpasarProf. Ketut Suastika

Inlacin vs Placebo 20

3. DLBS3233-0411

T2DM : Inlacin + any other OADRS Soetomo, SurabayaProf. Askandar Tjokroprawiro

DLBS3233 capsule 100 mg (od) + current OAD treatment (stable dose)

54

INLACIN CLINICAL STUDY

No Trial ID Projects Therapy Sample size

4. DLBS3233-0711

Pre DMRS M.Djamil, PadangProf. Asman Manaf

DLBS3233 capsule 50 mg (od), titration at W4 to 100 mg (if necessary) vs placebo capsule of DLBS3233 (od), titration at W4 (if necessary

80

5. DLBS3233-0811

PCOSRS Cipto Mangunkusumo,Dr. Andon + RSHS, Bandung, Dr. Wiryawan

DLBS3233 capsule 100 mg (once daily) and placebo tablet of Metformin (twice daily) vs Metformin tablet 500 mg (twice daily) and placebo capsule of DLBS3233 (once daily)

124

6. DLBS3233-0912

T2DM (newly diagnosed): Inlacin RS KariadiProf. Djoko Moeljanto, Prof. Darmono, Dr. Heri Nugroho, Dr. Toni Suhartono

DLBS3233 capsule 100 mg (od) vs placebo capsule of DLBS3233 (od)

104

SAFETY STUDY IN HEALTHY VOLUNTEERS (PHASE-1) – DLBS 3233

PRELIMINARY STUDY IN T2DM (INLACIN vs PLACEBO)

Fasting Plasma Glucose

Post-prandial Plasma Glucose

HbA1c level

HOMA-IR

Lipid Profile

FASTING PLASMA GLUCOSE

FPG

191.20205.80 211.20 216.10

182.88

143.62160.13

140.00

0.00

50.00

100.00

150.00

200.00

250.00

300.00

baseline-FPG

2wk FPG 4 wk FPG 6-wk FPG

Group

FPG

leve

l (m

g/dL

)

PLC

D50

Percentage of FPG reduction from baseline (at 6 wk of treatment)

14.00

-23.36

-35.00

-30.00

-25.00

-20.00

-15.00

-10.00

-5.00

0.00

5.00

10.00

15.00

20.00

PLC D50

Group

% F

PG re

duct

ion

Percentage D-FPG 6wk

POST-PRANDIAL PLASMA GLUCOSE

PPPG reduction from baseline (at 6 wk of treatment)

48.89

-12.29-20.00

0.00

20.00

40.00

60.00

80.00

100.00

PLC D50

Group

PPPG

Red

uctio

n (m

g/dL

) D-PPPG 6 wk

PPPG

288.44

337.33

249.53237.14

0.00

50.00

100.00

150.00

200.00

250.00

300.00

350.00

400.00

Baseline-PPBP 6-wk PPBG

PPPG

leve

l (m

g/dL

)

PLC

D50

HbA1c REDUCTION – 6 WEEKSHbA1c

9.50 9.58

10.27

9.13

8.00

8.50

9.00

9.50

10.00

10.50

11.00

B-HbA1c E-HbA1c

HbA

1c le

vel (

%) PLC

D50

0,08

-1,13

-1,60-1,40-1,20-1,00-0,80-0,60-0,40-0,200,000,20

PLC D50

HbA1

c re

ductio

n (%

)

Group

HbA1c reduction from baseline (6 wk of treatment)

D-HbA1c 6 wk

Diabetes Complication Complication Risk ReductionDiabetes-related death 21%Myocardial Infarction 14%Stroke 12%Peripheral vascular disease

43%

Microvascular diseases 37%Heart Failure 16%

HOMA-IR REDUCTION

HOMA-IR changes from baseline (6 wk of treatment)

0.28

-10.88

-25.00

-20.00

-15.00

-10.00

-5.00

0.00

5.00

PLC D50

Group

Chan

ges

in H

OM

A IR

D- HOMA-IR 6 wk

LIPID PROFILE

-18.75

-13.25

-1.75

15.25

-24.67

-18.67

-1.00

-12.00

-50.00

-40.00

-30.00

-20.00

-10.00

0.00

10.00

20.00

D-TC 6 wk D-LDL 6 wk D-HDL 6 wk D-TG 6 wk

plas

ma

leve

l cha

nges

(mg/

dL)

Parameters

Lipid profile changes from baseline (6 wk of treatment)

PLC

D50

PROFILE SAFETY

Parameter Group Baseline Mean (SD)

End of studyMean (SD)

SGPT Placebo 18.20 (12.38) 18.33 (13.63)DLBS 50 mg 30.50 (10.81) 21.86 (16.28)

Alkalin Phosphatase

Placebo 77.30 (6.05) 77.22 (6.40)DLBS 50 mg 75.63 (21.59) 73.43 (9.67)

Serum Creatinin

Placebo 0.76 (0.14) 0.76 (0.19)

DLBS 50 mg 0.78 (0.15) 0.79 (0.16)

Phase-III Clinical Study

DLBS3233 IN PRIMARY PREVENTION OF TYPE 2

DIABETES MELLITUS[DIPPER-DM]

Study site : M.Djamil Hospital, PadangPrincipal Investigator : Prof. Dr. dr. Asman Manaf, SpPD-KEMD

2-HOUR POST PRANDIAL GLUCOSE LEVEL AFTER 8 AND 12 WEEKS OF TREATMENT

Baseline Week 8 Week 12120

125

130

135

140

145

150

155

160

165

170

160.37

143.36

137.95

164.97

151.06

145.94DLBS 3233Placebo

Gluc

ose

Leve

l (m

g/dL

)

Week 8 Week 12

-30

-25

-20

-15

-10

-5

0

-26.2

-28.5

-12.71

-15.06

Reduction in Fasting Tryglyceride

DLBS 3233Placebo

Trig

lyce

ride

Leve

l (m

g/dL

)

*P = 0.007

*P = 0.082

*P = 0.003

*P = 0.080

p = versus baseline level in each group

REDUCTION IN FASTING TG

SURABAYA INLACIN STUDY

Study in patient with diabetes

DLBS3233 Dec 2010, Tjandrawinata et al 2010, 2013, Nailufar et al 2011, Tandrasasmita et al 2011(Illustrated : Tjokroprawiro 2011-2013)

DLBS-3233 : LAGERSTROEMIA SPECIOSA & CINNAMOMUM BURMANIIBIOACTIVE FRACTION DLBS3233 : LAGERSTROEMIN, AN ELLAGITANNIN

INSULIN – RECEPTOR BINDING AFFINITY1

FFA, then PKC & , thus SERINE PHOSPHORYLATION (I.R.)

DECREASED TNF (due to PPAR & Apn)5 TYROSINE PHOSPHORYLATION : INSULIN RESISTANCE (I.R.) TYROSINE PHOSPHORYLATION :2

GLUT-4 SYNTHESIS & NUMBER, HDL

PPAR & PPAR UP REGULATOR :3

Inlacin® (DLBS3233) : the Novel Insulin Sensitizer with 8 Unique Mechanisms

FROM CYTOPLASM TO CELL MEMBRANE

STIMULATE GLUT-4 TRANSLOCATION4

DLBS-3233

THE NOVELINSULIN SENSITIZER

2016

(INLACIN®) RESISTIN7 ADIPONECTIN6

ACC1 & ACC2, Malonyl CoA β-Oxidation, FFA

8

FASTING PLASMA GLUCOSE Mean SDDelta vs baseline SD

p versus baseline

Fasting plasma glucose at baseline (mg/dL) 187,10 72,25Fasting plasma glucose at Week 6 (mg/dL) 167,00 58,85 -18,98 69,14 0,072

Fasting plasma glucose at Week 12 (mg/dL) 175,64 65,42 -11,71 64,21 0,298

-18.98-11.71

Week

Delta

Fas

ting

Plas

ma

Gluc

ose

(mg/

dL)

0.00

-5.00

-10.00

-15.00

-20.00

-25.00

-30.00

-35.00

Week 12Week 6

REDUCTION IN FASTING PLASMA GLUCOSE (FPG)1

p = 0.072

p = 0.298

FPG

THE RESULTS OF SURABAYA-INLACIN STUDY (SIS) 2012-2013

1-hr POST PRANDIAL GLUCOSE Mean SDDelta vs baseline SD

p versus baseline

One hour plasma glucose at baseline (mg/dL) 275,46 80,88One hour plasma glucose at Week 6 (mg/dL) 250,22 70,84 -23,31 76,14 0,047*One hour plasma glucose at Week 12 (mg/dL) 249,92 74,13 -26,06 70,08 0,021*

* p = 0.021

-23.31 -26.06

Week

Delta

1-h

Pos

t Pra

ndia

l Pla

sma

Gluc

ose

(mg/

dL)

0.00

-5.00

-10.00

-15.00

-20.00

-25.00

-30.00

-35.00

-40.00

Week 12Week 6

* p = 0.047

PPG

SIGNIFICANT REDUCTION IN 1-h POST PRANDIAL GLUCOSE (PPG)1

THE RESULTS OF SURABAYA-INLACIN STUDY (SIS) 2012-2013

12% subjects reached A1c < 7.0% within 12 weeks of treatment

A1C Mean SDDelta vs baseline SD

p versus baseline

A1c at baseline (%) 9,67 2,11A1c at Week 6 (%) 9,34 2,21 -0,36 1,13 0,009*

A1c at Week 12 (%) 9,02 2,04 -0,65 1,58 0,001*

* p = 0.001

-0.36

-0.65

Week

Delta

A1C

(%)

0.00-0.10-0.20-0.30-0.40-0.50

-0.70-0.80-0.90

-0.60

-1.00

Week 12Week 6

* p = 0.009

A1C

SIGNIFICANT REDUCTION IN A1C2

THE RESULTS OF SURABAYA-INLACIN STUDY (SIS) 2012-2013

HOMA-R Mean SDDelta vs baseline SD

p versus baseline

HOMA-R calculation at baseline 4,59 3,45

HOMA-R calculation at Week 6 3,69 2,41 -0,77 3,19 0,043*

HOMA-R calculation at Week 12 4,09 2,72 -0,50 3,45 0,281

-0.77-0.50

Week

Delta

HO

MA-

IR

0.00

-0.20

-0.40

-0.60

-0.80

-1.00

-1.20

-1.40

Week 12Week 6

* p = 0.043

p = 0.281

HOMA-R

SIGNIFICANT REDUCTION IN HOMA-R3

THE RESULTS OF SURABAYA-INLACIN STUDY (SIS) 2012-2013

FASTING PLASMA GLUCOSE1–18.98 mg/dL (W 6: –10.14%) p = 0.072

–11.71 mg/dL (W 12: –6.26%) p = 0.298 (NS)

+0.45g/mL (W 6: 8.99%) p = 0.148 (NS)

ADIPONECTIN (Apn)8

+1.05g/mL (W 12: 21.18%) p = 0.001

–23.31 mg/dL (W 6: – 8.46%) p = 0.047)

1h PRANDIAL PLASMA GLUCOSE2

–26.06 mg/dL (W 12: – 9.46%) p = 0.021)

-0.77 (W 6: –16.84%) p = 0.043

HOMA-R4

-0.50 (W 12: –10.88%) p = 0.281 (NS)-11.49 mg/dL (W 6: –5.05%) p = 0.002

TOTAL CHOLESTEROL6

-10.39 mg/dL (W 12: –4.56%) p = 0.013

TRIGLYCERIDE7-8.39 mg/dL (p = 0.405)

-8,00 mg/dL (p = 0217)

-0.36 % (W 6: –3.69%) p = 0.009

A1C3

-0.65 % (W 12: –6.76%) p = 0.001

LDL CHOLESTEROL5-10.04 mg/dL (W 6: –6.93%)

p = 0.006-10.59 mg/dL (W 12: –7.31%)

p = 0.020

RESULTS OF THE STUDYADD-ON Tx WITH 100 mg INLACIN®

n = 50, STUDY PERIOD 12 WEEKSSURABAYA DIABETES AND NUTRITION

CENTER2013

+0.42 kg (W 6) p = 0.218

BODY WEIGHT9

+0.42 kg (W 12) p = 0.412

W-12, HOMA-R Pts (n=25 no routine excercise NS) (n=25 routine excercise, S : p = 0.050)

RESULTS, SUMMARY AND CONCLUSIONS OF THE SURABAYA-INLACIN STUDY (SIS) 2012-2013

PRODUCT PACK HNA/BOX HNA/CAPSULE DOSAGE

INLACIN 50 mg BOX, 5 STRIPS @ 6 CAPSULES

Rp. 120.000,- Rp. 4.000,- Once daily

INLACIN 100 mg BOX, 5 STRIPS @ 6 CAPSULES

Rp. 150.000,- Rp. 5.000,- Once daily

DOSAGE AND PACK OF INLACIN

DOSAGE: Newly Diagnosed DM: 1 x 50-100 mg/ day ADD ON with the other OADs: 1 x 100 mg/day

CONCLUSIONS

• 80% incidence of type 2 diabetes is caused by insulin resistance

• INLACIN is a bioactive fraction DLBS3233

• INLACIN can improve insulin resistance through four working mechanisms, namely:1) Phosporylation on the right insulin receptor2) Up regulator PPAR γ and PPAR 3) ↑ GLUT-4 translocation from citoplasma to membran4) ↓ TNF

INLACIN PUBLICATION

http://www.foodnavigator-asia.com/Business/Indonesian-herbal-diabetic-drug-to-target-EU-and-Asia

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