CURRICULUM VITAE

Name : Dr. Pandji Moeljono, Sp.PD K-

EMD,FINASIM
Office Address : Rumah Sakit Angkatan Laut Dr. Ramelan
Jl. Gadung No. 1 Surabaya Indonesia
Tel 62031-8438153
Fax : 031-8437511
Home Address : Jl. Raya Dukuh Kupang 120 Surabaya
Indonesia
Tel : 62031-5683062 Tel : 62031-5683062
Mobile : 08123216601/ O317O4715O5
E-mail : pandjimulyono@yahoo.com
Date of Birth : 20th Desember 1946
Nationality : Indonesian
Educational and Professional Qualifications
University of Airlangga :1973 General Practicioner (MD)
University of Airlangga :1986 Internal Medicine Specialist
Kolegium Penyakit Dalam
Indonesia
2OO6 Konsultan endokrinologi
Metabolik Diabet
Organization Membership
PERKENI Organization of Endocrinologist in Indonesia
PAPDI Organization of Indonesians Internist
IDI Organization of Medical Doctor in Indonesia
Present Position
1974-1981
Medical Docter at PUSKESMAS Kandangan ,
Pare, Kediri.
1986 - at date Internal Medicine specialist at Navy Hospital DR
Ramelan Surabaya
1990 at date Lecturer at Medical Faculty ,Hangtuah University
Surabaya
Pendahuluan
DM faktor risiko kardiovaskuler
Saat ini (2010) T2DM umur 20-79 th, Indonesia
rangking 9; diperkirakan 2030 jadi rangking 6
Berbagai reaksi yang terkait hiperglikemia,
meningkatkan produksi radikal bebas, menekan
produksi antioksidan alami
meningkatkan produksi radikal bebas, menekan
produksi antioksidan alami
Terjadi gangguan keseimbangan oksidan-
antioksidan (stress Oxidative) meningkatkan
komplikasi vaskuler
Pemberian terapi antioksidan
Diabetisi dengan komplikasi vaskuler, pemberian
antioksidan dapat mencegah perburukan penyakit
Managing Diabetes From prevention till complications
CMEF Manila, Philippines, 29
th
, -30
th
May 2010
Insulin resistance
Diabetes
Type 2 Diabetes
Diagnosis
? ? ?
Makrovaskular
Normal
Glucose tolerance
impaired
Glukose tolerance
Diabetes
Blood glucose
Proinsulin secretion
modifiziert nach: DeFronzo RA et al., Diabetes Care 1998
IFG
Insulin
FFA
Mikrovaskular
{ FREE RADICAL }
Pathobiology of Diabetic Vacsular Complication
The Role of Oxidative Stress
(Michael Brownlee, Banting Lecture 2004)
1. Polyol Pathway (1966)
2. AGE Pathway (1980)
3. PKC Pathway (early 1990)
4. Hexosamine Pathway (late 1990)
Intracellular Glucose
AGEs
DAG Fruc-6-P
Sorbitol
Flux in
Hyperglycemia
?
Aldose
reductase
Power AC (2006) : Diabetes Mellitus.
Harrisons Endocrinology
Circulating
AGEs
Altered Cell
Function
Renal
,Vascular,
Connective
tissue effect
Cytokines,
Growth Factor
Abnormal
protein
Function
Alterations
in redox
potential ,
ROS
PKC
activation
Altered
Cell function
Altered
Enzyme
function
(Cpla
2
),
eNOS
Altered gene
expression
Growth
Factors
Flux in
hexosamine
pathway
PAI-1,
growth
factors
Complication
of Diabetes
?
Oksidan dan Radikal Bebas
Radikal bebas digolongkan oksidan,walaupun
tidak semua oksidan radikal bebas
Lebih berbahaya dibandingkan oksidan yang
bukan radikal
Reaktivitasnya yg tinggi,dan kecenderungan
membentuk radikal bebas baru
Daya rusak radikal bebas jauh lebih besar daripada
oksidan biasa
Senyawa Oksigen Reaktif
Pembentukan senyawa oksigen
O
2
+ e

O
2
-
O
2
+ e
-
+ H
+
-OOH
O
2
+ 2 e
-
+ 2H
+
H
2
O
2
O
2
+ 2 e + 2H H
2
O
2
O
2
+ 3 e
-
+3 H
+
-OH+ H
2
O
O
2
+ 4 e
-
+ 4 H
+
2 H
2
O
Oxidative Stress in Diabetes
Reactive Oxygen Species (ROS)
-O
2
* superoxide
-OH* hydroxyl
-RO
2
peroxyl
-HRO
2
hydroperoxyl
-H
2
O
2
hydrogen peroxide
-HOCl hypochlorite -HOCl hypochlorite
Reactive Nitrogen Species (RNS)
-NO* nitric oxide
-ONOO- peroxynitrite
-NO
2
* nitrogen dioxide
-HNO
2
nitrous oxide
-RONOO alkyl peroxynitrates
Free Radical is any species capable of independent
existence that contains one or more unpaired electrons
Oxygen (dioxygen) has two unpaired electrons, each
located in a different (t*antibonding) orbital.
Oxygen is a free radical
Oxygen is
the first
major air major air
pollutant
Halliwell B and Gutteridge MC, 1999
Oxidative Damage
MITOCHONDRIAARE THE MAJOR
SOURCE OF ATP PRODUCTION
Electron carriers (NAD, FMN, FAD, Cytochrome oxidase)
| ROS/RNS + Antioxidant
capacity
ADAPTATION / DAMAGE /
CELL DEATH
OXIDATIVE STRESS
Antioxidants
Antioksidan Internal
+ Enzimatik
Superoksid dismutase
Glutation Peroksidase
Katalase
+Protein mengikat metal
Albumin, Ferritin, Seruplasmin Albumin, Ferritin, Seruplasmin
Antioksidan Eksternal
+ Non-enzimatik
Larut dlm air: Vit C, Tiol
Larut dalam lipid: Vit E,beta karoten, ko-
Q10,flavonoid + Obat-obat Antioksidan
S
p
e
c
i
a
l
l
y
F
o
r
m
u
l
a
t
e
d
fo
r
Diabetic
P
a
t
i
e
n
t
s
-
G
l
u
c
o
A
- Terkait sekresi insulin, membantu
mengontrol glukosa darah
ZINC 15 mg
B
- Menurunkan resiko kematian
mendadak dikarenakan aritmia
MAGNESIUM 87,5 mg
C
- Meningkatkan ambilan glukosa
dan mengatur proses metabolik.
- Enzym anti oksidan yang penting.
SELENIUM 70 mcg
(Illustrated : Merck 2009, Tjokroprawiro 2010)
GLUCOBION

: the FDC of 7 ANTIOXIDANTS, VITAMINS, and 4 MINERALS

2
Magnesium
S
p
e
c
i
a
l
l
n
t
s
-
G
l
u
c
o
B
I
O
N
S
p
e
c
i
a
l
l
y
F
o
r
m
u
l
a
t
e
d
fo
r
Diabetic
P
a
t
i
e
n
t
s
-
G
l
u
c
o
B
I
O
N

BALANCE LOW DOSE BALANCE LOW DOSE

COCKTAIL COCKTAIL
ANTIOXIDANTS ANTIOXIDANTS
VITAMINS, MINERALS VITAMINS, MINERALS
V
i
t
A
,
C
Vit E
VIT A 3300 iu, VIT C 100 mg
- Penting dalam mekanisme
kolagen dan sintesa glioprotein
1
VIT B1 5 mg, B6 5 mg, B12 5 mcg
- Berperan penting bagi transmitter saraf.
- Memperbaiki metabolisme karbohidrat.
2
VIT E 100 mg
- Berfungsi sebagai anti oksidan.
- Berguna dalam menurunkan efek oksidan
3
FOLIC ACID 400 mcg
- Menurunkan homosistein
dan resiko kardiovaskular
4
C
h
r
o
m
i
u
m
D
- Berperan dalam metabolisme
glukosa, insulin dan lemak darah.
- Mempunyai efek yang baik pada IGT
CHROMIUM 50 mcg
Kebutuhan tubuh: > 100 mg/hr Kebutuhan tubuh: > 100 mg/hr
Termasuk : Natrium, Kalsium, Kalium, Magnesium, Termasuk : Natrium, Kalsium, Kalium, Magnesium,
Chlor, Fosfor Chlor, Fosfor Chlor, Fosfor Chlor, Fosfor
Magnesium/ Mg Magnesium/ Mg
Erat hubungannya dg Ca, K, Na Erat hubungannya dg Ca, K, Na
Kekurangan Mg Kekurangan Mg mengganggu metab Ca,Na,K mengganggu metab Ca,Na,K
Kofaktor utk mengaktivasi enzim tertentu Kofaktor utk mengaktivasi enzim tertentu
Kebutuhan tubuh < 100 mg/hr Kebutuhan tubuh < 100 mg/hr
Antara lain: Fe, Zn, Se dll Antara lain: Fe, Zn, Se dll
Zn Zn
Essensiil utk berbagai enzim Essensiil utk berbagai enzim
Erat hubungannya dg insulin Erat hubungannya dg insulin
Selenium Selenium
Kofaktor glutation peroksidase dan vit E Kofaktor glutation peroksidase dan vit E
Fungsi lengkap: belum jelas Fungsi lengkap: belum jelas
Functions Functions
Antioxidant system Antioxidant system
Thyroxine and immune function Thyroxine and immune function
Deficiency Deficiency
Keshan disease Keshan disease
Impaired immune response, cognitive function, Impaired immune response, cognitive function,
muscle pain, wasting muscle pain, wasting
Diwadkar Diwadkar--Navsariwala and Navsariwala and
Diamond Diamond
Clinical benefits in patients with diabetes: Clinical benefits in patients with diabetes:
Overall positive, but few randomized controlled trials in Overall positive, but few randomized controlled trials in
large numbers of patients large numbers of patients large numbers of patients large numbers of patients
Benefits may be greatest in patients with poorly controlled Benefits may be greatest in patients with poorly controlled
diabetes (highest rate of loss from diuresis) diabetes (highest rate of loss from diuresis)
Not yet enough evidence to recommend for all diabetic Not yet enough evidence to recommend for all diabetic
patients patients
Free Radicals in Vascular System
(experimental data)
Vascular
disturbed endothelial-depending relaxation
activation of thrombocytes
activation of mononuclear cells
proliferation of smooth muscles
apoptosis of endothelial cells apoptosis of endothelial cells
disturbed endothelial barrier function
Cellular
increased intracellular calcium signal
activation of protein kinase C
activation of NFkB
oxidation of LDL
oxidation of functional proteins
Methode of Evaluating Oxidative Stress in
Clinical Trials and Animal Models
Category Category Product measured Product measured Comments Comments Method Method
Indirect Indirect
Oxidized protein Oxidized protein
Oxidized Lipid Oxidized Lipid
33--Nitro Tyrosine (NT) Nitro Tyrosine (NT)
TBARs TBARs
Oxidized LDL Oxidized LDL
Marker of ONOO Marker of ONOO

Plasma MDA Plasma MDA

ONOO ONOO in lipids in lipids
Gas chromato., HPLC, Gas chromato., HPLC,
NT tissue staining NT tissue staining
Colorimetric, HPLC Colorimetric, HPLC
Gas chromatography, Gas chromatography,
Enzymatic Enzymatic
activities activities
Antioxidant Antioxidant
vitamins vitamins
Oxidized LDL Oxidized LDL
88--isoprostaglandin isoprostaglandin
F2 alpha F2 alpha
CAT, SOD, GSPHx, CAT, SOD, GSPHx,
GSHR, ACO GSHR, ACO
E, C, E, C, ||--carotene, vitamin carotene, vitamin
EE--to to--lipid ration lipid ration
ONOO ONOO in lipids in lipids
F2 F2--isoprostanoid isoprostanoid
Peroxidation of Peroxidation of
arachidonic acid arachidonic acid
Influence by food Influence by food
intake intake
Gas chromatography, Gas chromatography,
spectro., Immunohis spectro., Immunohis--
Tochemistry Tochemistry
ELISA, EIA, Mass ELISA, EIA, Mass
Spectrometry Spectrometry
Spectrophotometric Spectrophotometric
HPLC HPLC
Blendea MC, Winer N, Sowrs JR, 2006
Methode of Evaluating Oxidative Stress in Clinical
Trials and Animal Models
Category Category Product measured Product measured Comments Comments Method Method
Direct Direct
measurement (free measurement (free
radicals produced radicals produced
by tissue) by tissue)
Superoxide anion Superoxide anion
(O (O
22

))
Various sources: Various sources:
NO synthase NO synthase
NAD(P)H oxidase NAD(P)H oxidase
xanthine oxidase xanthine oxidase
mitochondrial mitochondrial
Lucigenib enhance Lucigenib enhance
chemiluminescence chemiluminescence
assy assy
Cytochrome c reduction Cytochrome c reduction
Urinary ONOO Urinary ONOO
TRAP (total radical TRAP (total radical
trapping potential in trapping potential in
palsma) palsma)
mitochondrial mitochondrial
oxidase oxidase
Perfused organ or Perfused organ or
neutrophil burst neutrophil burst
Sum of Sum of
antioxidant antioxidant
capacities (plasma capacities (plasma
or urine) or urine)
Spectrophotometry Spectrophotometry
Immunohistochemistry Immunohistochemistry
Mass spectrometry Mass spectrometry
Luminol Luminol
chemiluminescence chemiluminescence
Blendea MC, Winer N, Sowrs JR, 2006
F2-isoprostan
Meninggi pada Meninggi pada ::
Diabetes Diabetes
Dislipidemi Dislipidemi
ESRD ESRD ESRD ESRD
Obesitas tanpa komplikasi Obesitas tanpa komplikasi
Ateroklerosis Ateroklerosis
Stress Oksidatif yang Berkepanjangan Stress Oksidatif yang Berkepanjangan
Higdon & Frei,2003 Higdon & Frei,2003
Lymphocyte Vit. C in subjects with T2DM
Free Radicals
Anti Oxidant
Micro & Macrovascular
complication
Lymphocyte Vit. C in subjects with T2DM
in T2DM without complication
in T2DM with complication
Yamada, 2004
Diabetic Nephropathy
+ Vit. C, Vit. E
Mg, Zn Mg, Zn
Albuminuria
Farid, 2005
Diabetes status Diabetes status
Normal Normal
glucose glucose
tolerance tolerance
(n= 1145) (n= 1145)
Impaired Impaired
glucose glucose
metabolism metabolism
(n= 320) (n= 320)
Type 2 Type 2
diabetes diabetes
(n= 132) (n= 132)
PP for trend for trend
Serum carotenoids ( Serum carotenoids (mol/L) mol/L)
oo--carotene carotene 0.13 0.13 0.12 0.12 0.10 0.10 0.011 0.011
Diabetes and serum carotenoids: Population-based
study in Queensland, Australia
oo--carotene carotene 0.13 0.13
(0.10, 0.18) (0.10, 0.18)
0.12 0.12
(0.09, 0.16) (0.09, 0.16)
0.10 0.10
(0.08, 0.14) (0.08, 0.14)
0.011 0.011
||--carotene carotene 0.59 0.59
(0.47, 0.73) (0.47, 0.73)
0.50 0.50
(0.38, 0.64) (0.38, 0.64)
0.42 0.42
(0.30, 0.58) (0.30, 0.58)
0.01 0.01
||--cryptoxanthin cryptoxanthin 0.22 0.22
(0.19, 0.25) (0.19, 0.25)
0.20 0.20
(0.17, 0.23) (0.17, 0.23)
0.19 0.19
(0.16, 0.22) (0.16, 0.22)
0.041 0.041
Lutein/zeaxanthi Lutein/zeaxanthi
nn
0.42 0.42
(0.35, 0.50) (0.35, 0.50)
0.39 0.39
(0.35, 0.43) (0.35, 0.43)
0.35 0.35
(0.33, 0.38) (0.33, 0.38)
0.026 0.026
Lycopene Lycopene 0.44 0.44
(0.40, 0.49) (0.40, 0.49)
0.39 0.39
(0.34, 0.45) (0.34, 0.45)
0.35 0.35
(0.27, 0.44) (0.27, 0.44)
0.053 0.053
Coyne et al. AmJ Clin Nutr 2005;82:685-93
Increase of Human Plasma Antioxidant Capacity with
a Novel Formulation of Antioxidants
Ivonne Maria Olivares-Corichi1, Roberto Medina-Santilln2, Cecilia Fernndez
del Valle-Laisequilla2,Pndaro Alvarez2 and Juan Jos Hicks-Gomez2
Proc. West. Pharmacol. Soc. 46: 45-47 (2003)
GLUCOSE TOLERANCE FACTOR
RCT IN TYPE 2 DIABETES IN CHINA:
SUPPLEMENTAL CHROMIUM REDUCED
FASTING GLUCOSE, HbA1c, INSULIN, &
CHOLESTEROL LEVELS. ( ANDERSON,
CHENG, BRYDEN;1997) CHENG, BRYDEN;1997)
12 STUDIES REPORTED, CHROMIUM
SUPPLEMENTATION IMPROVED THE
EFFICIENCY OF INSULIN OR HAD
BENEFICIAL EFFECTS ON THE BLOOD
LIPID PROFILES
Thiamine deficiency in clinical diabetes linked
to renal dysfunction
27% decrease in plasma thiamine in type 1 diabetic patients; no
decrease in type 2 patients - Norway
(Haugen HN, Scand J Clin Lab Invest 16, 260-266, 1964)
76% of diabetic patients (7 type 1, 39 type 2) had plasma thiamine lower
than the normal range minimum Japan
(Saito N et al., J Nutr Sci Vitaminol 33, 421-430, 1987)
18% of 100 type 2 diabetic patients red blood cell TK activity lower than
the normal range minimum Israel
(Havivi E et al., Internat J Vit Nutr Res 61, 328-33, 1991).
Type 1 diabetic children (n = 10) with normal renal function had plasma
thiamine concentration deceased by 34%. Plasma thiamine
concentration was normalized by benzoxymethyl-thiamine, 50 mg/day
(Valerio G et al., Acta Diabetol 36, 73-76, 1999)
Diabetic patients are at risk of thiamine deficiency
Major Pathways in Hyperglycemic Damage
Vit. B1
Vit. B1-stimulated transketolase activity blocks deleterious pathways
Hexosamines:
insulin resist.
PKC activity
Polyol pathway:
oxidative stress
PKC activity
DAG pathway:
capill. vascul.
Hammes et al., Nature Medicine (2003) 9; 294-299
capill. vascul.
PKC activity
AGE formation:
capillary leak
oxygen supply
oxidative stress
damaging membranes
interfering w/ proteins
axoplasmic transp.
Starting point in mitochondria: GAP-DH
blocked by superoxide anion concentr.
Status vitamin & mineral pasien diabetes tipe 2
(Mooradian et all 1987)
Vitamin A Vitamin A
Vitamin C Vitamin C
Vitamin E Vitamin E
Vitamin B1 Vitamin B1 Vitamin B1 Vitamin B1
Vitamin B6 Vitamin B6 N/ N/
Vitamin B12 Vitamin B12 N/ N/
Magnesium Magnesium
Chromium Chromium //
Selenium Selenium
Zinc Zinc
Asam Folat Asam Folat
CONTAINING DEFICIENT NUTRIENTS IN
DIABETIC PATIENTS ONLY
Supplements in Type-2
Diabetes Mellitus
DIABETIC PATIENTS ONLY
DOSE IN AGREE WITH DAILY NORMAL
REQUIREMENTS
AVOID PROOXIDANT COMPOUNDS, SUCH
AS CUPPER AND IRON
AVOID VITAMIN K, BECAUSE INCREASES
BLOOD CLOTTING
SUPPLEMENTATION WITH ESSENTIAL
NUTRIENTS IN DIABETIC PATIENTS:
Restore the nutritive deficiency induced by the diabetic
state state
Increase the activity of antioxidant system
Vitamins Daily Requirements
Marion et al., Diabetes Care 25(1):148-198, 2002
Vitamin
Minimal
Requirement/day
Maximal
tolerated
Glucobion

700 g (m)
A
(retinol)
700 g (m)
900 g (h)
3000 g 1000 g
C
(ascorbate)
75 mg (m)
90 mg (h)
2000 mg 100 mg
E
(o-tocopherol)
15 mg 1000 mg 100 mg
Vitamin
Minimal
Requirement/day
Maximal dose
tolerated
Glucobion

B1
(thiamine)
1.1 mg (m)
1.3 mg (h)
insufficient
data
5 mg
Vitamins Daily Requirements
Marion et al., Diabetes Care 25(1):148-198, 2002
(thiamine)
1.3 mg (h) data
B6
(piridoxin)
1.3 mg 100 mg 5 mg
B12
(cobalamine)
2.4 g
insufficient
data
5 g
Folic Acid 400 g 1000 g 400 g
Minerals Daily Requirement
Marion et al., Diabetes Care 25(1):148-198, 2002
Mineral Mineral
Minimal Minimal
Requirement/day Requirement/day
Maximal Maximal
tolerated tolerated
Glucobion Glucobion

Chromium Chromium
25 25 g (m) g (m)
35 35 g (h) g (h)
Unknown Unknown
50 50 gg
Magnesium Magnesium
320 m 320 mg (m) g (m)
420 mg (h) 420 mg (h)
350 mg 350 mg 87.5 mg 87.5 mg
Selenium Selenium 55 55 gg 400 400 gg 70 70 gg
Zinc Zinc
8 mg (m) 8 mg (m)
11 mg (h) 11 mg (h)
40 mg 40 mg
15 m 15 mgg
GLUCOBION

AND DIABION

IN SUMMARY WITH 5 KEY POINTS

(Summarized : Tjokroprawiro 2010)
The Novel MAOX or FDC of ANTIOXIDANTS, VITAMINS, and MINERALS
1
27
2 SMALL DOSE ANTIOXIDANT COCKTAIL: GLUCOBION

- 7 Vitamins : A, C, E, B1, B6, B12, Folic Acid

- 4 Minerals : Mg, Zn, Se, Cr - 4 Minerals : Mg, Zn, Se, Cr
3 Such Vitamins and Minerals in DM are in Deficient Status
4
Deficiencies of K
+
, Mg
++
, Zn
++
, and Cr
++
: | CBH INTOLERANCE
5 Such a Balance Formula of Antioxidants, Vitamins, and Minerals
in GlucoBion

Enables the Establishment of the Rationale

Therapeutic Approaches for Decreasing Oxidative Stress in T2DM
29
SUMMARY AND CONCLUSIONS SUMMARY AND CONCLUSIONS
GLUCOBION, THE NOVEL FIXED DOSE COMPOUND
of
Antioxidants, Vitamins, Minerals
in
SMALL DOSE COCKTAIL : ONE TABLET DAILY
THE RATIONALE THERAPEUTIC APPROACH FOR
DECREASING OXIDATIVE STRESS IN DIABETES MELLITUS
AS AN ADJUVANT FOR THE TREATMENT OF T2DM
TERIMA KASIH
ATAS PERHATIANNYA ATAS PERHATIANNYA