do micronutrients really help diabetes
TRANSCRIPT
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CURRICULUM VITAE
Name : Dr. Pandji Moeljono, Sp.PD K-
EMD,FINASIM
Office Address : Rumah Sakit Angkatan Laut Dr. RamelanJl. Gadung No. 1 Surabaya Indonesia
Tel 62031-8438153
Fax : 031-8437511Home Address : Jl. Raya Dukuh Kupang 120 Surabaya
Indonesia
-Mobile : 08123216601/ O317O4715O5
E-mail : [email protected] 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 DalamIndonesia
2OO6 Konsultan endokrinologiMetabolik Diabet
Organization Membership
PERKENI Organization of Endocrinologist in IndonesiaPAPDI Organization of Indonesians Internist
IDI Organization of Medical Doctor in Indonesia
Present Position
1974-1981Medical 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
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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,
menin katkan roduksi radikal bebas, menekanproduksi antioksidan alami Terjadi gangguan keseimbangan oksidan-
antioksidan (stress Oxidative) meningkatkankomplikasi vaskuler
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Pemberian terapi antioksidan
Diabetisi dengan komplikasi vaskuler, pemberianantioksidan dapat mencegah perburukan penyakit
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Managing Diabetes From prevention till complications
CMEF Manila, Philippines, 29th, -30th May 2010
Insulin resistance
Diabetes
Type 2 DiabetesDiagnosis
? ? ?
Makrovaskular
Normal
Glucose tolerance
impairedGlukose tolerance Diabetes
Blood glucose
Proinsulin secretion
modifiziert nach: DeFronzo RA et al., Diabetes Care 1998
IFG
Insulin
FFA
Mikrovaskular
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{ FREE RADICAL }
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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)
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Intracellular Glucose
AGEsDAG Fruc-6-P
Sorbitol
Hyperglycemia
Aldose
reductase
Power AC (2006) : Diabetes Mellitus.
Harrisons Endocrinology
Circulating
AGEs
Altered CellFunction
Renal,Vascular,
Connective
tissue effectCytokines,
Growth Factor
Abnormalprotein
Function
Alterationsin redox
potential ,ROS
PKCactivation
Altered
Cell function
AlteredEnzymefunction(Cpla2),
eNOS
Altered gene
expressionGrowthFactors
Flux in
hexosamine
pathway
PAI-1,
growth
factors
Complication
of Diabetes
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Oksidan dan Radikal Bebas
Radikal bebas digolongkan oksidan,walaupuntidak semua oksidan radikal bebas
Lebih berbahaya dibandingkan oksidan yangbukan radikal
Reaktivitasnya yg tinggi,dan kecenderunganmembentuk radikal bebas baru
Daya rusak radikal bebas jauh lebih besar daripadaoksidan biasa
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Senyawa Oksigen Reaktif
Pembentukan senyawa oksigen
O2 + e O2
-
O2 + e- + H+ -OOH
O + 2 e-
+ 2H+
H O O2 + 3 e
- +3 H+ -OH+ H2O
O2 + 4 e- + 4 H + 2 H2O
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Oxidative Stress in Diabetes
Reactive Oxygen Species (ROS)
-O2* superoxide
-OH* hydroxyl
-RO2 peroxyl
-HRO2 hydroperoxyl
-H2O2 hydrogen peroxide
-
Reactive Nitrogen Species (RNS)
-NO* nitric oxide
-ONOO- peroxynitrite
-NO2* nitrogen dioxide
-HNO2 nitrous oxide
-RONOO alkyl peroxynitrates
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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 (*antibonding) orbital.Oxygen is a free radical
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Oxygen is
the first
ma or a rpollutant
Halliwell B and Gutteridge MC, 1999
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Oxidative Damage
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MITOCHONDRIA ARE THE MAJOR
SOURCE OF ATP PRODUCTION
Electron carriers (NAD, FMN, FAD, Cytochrome oxidase)
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ROS/RNS Antioxidantcapacity
ADAPTATION / DAMAGE /
CELL DEATHOXIDATIVE STRESS
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Antioxidants Antioksidan Internal
+ EnzimatikSuperoksid dismutaseGlutation PeroksidaseKatalase
+Protein mengikat metalAlbumin, 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
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lly
Form
ulat
edfor D
a eticPatients-Glu
c
A
Terkait sekresi insulin, membantumengontrol glukosa darah
ZINC 15 mg
B
Menurunkan resiko kematian
mendadak dikarenakan aritmiaMAGNESIUM 87,5 mg
C
Meningkatkan ambilan glukosadan 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
Speci
oBION
Sp
ecia
llyFo
rmulate
dforDiabetic Pati
ents
-Glu
coB
ION
BALANCE LOW DOSEBALANCE LOW DOSE
COCKTAILCOCKTAIL
ANTIOXIDANTSANTIOXIDANTS
VITAMINS, MINERALSVITAMINS, MINERALS
VitA,
C
Vit E
VIT A 3300 iu, VIT C 100 mg
Penting dalam mekanismekolagen 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 homosisteindan resiko kardiovaskular
4
Chromium
D
Berperan dalam metabolismeglukosa, insulin dan lemak darah.
Mempunyai efek yang baik pada IGT
CHROMIUM 50 mcg
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Kebutuhan tubuh: > 100 mg/hrKebutuhan tubuh: > 100 mg/hr
Termasuk : Natrium, Kalsium, Kalium, Magnesium,Termasuk : Natrium, Kalsium, Kalium, Magnesium,
Chlor FosforChlor FosforMagnesium/ MgMagnesium/ Mg
Erat hubungannya dg Ca, K, NaErat hubungannya dg Ca, K, Na
Kekurangan MgKekurangan Mgmengganggu metab Ca,Na,Kmengganggu metab Ca,Na,K
Kofaktor utk mengaktivasi enzim tertentuKofaktor utk mengaktivasi enzim tertentu
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Kebutuhan tubuh < 100 mg/hrKebutuhan tubuh < 100 mg/hr
Antara lain: Fe, Zn, Se dllAntara lain: Fe, Zn, Se dll
ZnZnEssensiil utk berbagai enzimEssensiil utk berbagai enzim
Erat hubungannya dg insulinErat hubungannya dg insulin
SeleniumSelenium
Kofaktor glutation peroksidase dan vit EKofaktor glutation peroksidase dan vit EFungsi lengkap: belum jelasFungsi lengkap: belum jelas
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FunctionsFunctions
Antioxidant systemAntioxidant system
Thyroxine and immune functionThyroxine and immune function
DeficiencyDeficiency
Keshan diseaseKeshan disease
Impaired immune response, cognitive function,Impaired immune response, cognitive function,muscle pain, wastingmuscle pain, wasting
DiwadkarDiwadkar--Navsariwala andNavsariwala andDiamondDiamond
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Clinical benefits in patients with diabetes:Clinical benefits in patients with diabetes:
Overall positive, but few randomized controlled trials inOverall positive, but few randomized controlled trials in
Benefits may be greatest in patients with poorly controlledBenefits may be greatest in patients with poorly controlleddiabetes (highest rate of loss from diuresis)diabetes (highest rate of loss from diuresis)
Not yet enough evidence to recommend for all diabeticNot yet enough evidence to recommend for all diabeticpatientspatients
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Free Radicals in Vascular System
(experimental data)
Vasculardisturbed endothelial-depending relaxation
activation of thrombocytes
activation of mononuclear cells
proliferation of smooth muscles
a o tosis of endothelial cellsdisturbed endothelial barrier function
Cellularincreased intracellular calcium signal
activation of protein kinase C
activation of NFBoxidation of LDL
oxidation of functional proteins
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Methode of Evaluating Oxidative Stress in
Clinical Trials and Animal Models
CategoryCategory Product measuredProduct measured CommentsComments MethodMethod
IndirectIndirect
Oxidized proteinOxidized protein
Oxidized LipidOxidized Lipid
33--Nitro Tyrosine (NT)Nitro Tyrosine (NT)
TBARsTBARs
Marker of ONOOMarker of ONOO
Plasma MDAPlasma MDA
Gas chromato., HPLC,Gas chromato., HPLC,
NT tissue stainingNT tissue staining
Colorimetric, HPLCColorimetric, HPLC
EnzymaticEnzymatic
activitiesactivitiesAntioxidantAntioxidant
vitaminsvitamins
x zex ze
88--isoprostaglandinisoprostaglandin
F2 alphaF2 alpha
CAT, SOD, GSPHx,CAT, SOD, GSPHx,
GSHR, ACOGSHR, ACOE, C,E, C, --carotene, vitamincarotene, vitaminEE--toto--lipid rationlipid ration
n p sn p s
F2F2--isoprostanoidisoprostanoid
Peroxidation ofPeroxidation of
arachidonic acidarachidonic acid
Influence by foodInfluence by foodintakeintake
as c roma ograp y,as c roma ograp y,spectro., Immunohisspectro., Immunohis--
TochemistryTochemistry
ELISA, EIA, MassELISA, EIA, Mass
SpectrometrySpectrometry
SpectrophotometricSpectrophotometric
HPLCHPLC
Blendea MC, Winer N, Sowrs JR, 2006
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Methode of Evaluating Oxidative Stress in Clinical
Trials and Animal Models
CategoryCategory Product measuredProduct measured CommentsComments MethodMethod
DirectDirectmeasurement (freemeasurement (freeradicals producedradicals produced
by tissue)by tissue)
Superoxide anionSuperoxide anion
(O(O22))
Various sources:Various sources:
NO synthaseNO synthase
NAD(P)H oxidaseNAD(P)H oxidase
xanthine oxidasexanthine oxidase
Lucigenib enhanceLucigenib enhance
chemiluminescencechemiluminescence
assyassy
Cytochrome c reductionCytochrome c reduction
Urinary ONOOUrinary ONOO
TRAP (total radicalTRAP (total radicaltrapping potential intrapping potential inpalsma)palsma)
m oc on r am oc on r aoxidaseoxidase
Perfused organ orPerfused organ or
neutrophil burstneutrophil burst
Sum ofSum ofantioxidantantioxidantcapacities (plasmacapacities (plasmaor urine)or urine)
SpectrophotometrySpectrophotometry
ImmunohistochemistryImmunohistochemistry
Mass spectrometryMass spectrometry
LuminolLuminolchemiluminescencechemiluminescence
Blendea MC, Winer N, Sowrs JR, 2006
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F2-isoprostanMeninggi padaMeninggi pada ::
DiabetesDiabetesDislipidemiDislipidemi
ESRDESRDObesitas tanpa komplikasiObesitas tanpa komplikasiAteroklerosisAteroklerosis
Stress Oksidatif yang BerkepanjanganStress Oksidatif yang BerkepanjanganHigdon & Frei,2003Higdon & Frei,2003
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Lymphocyte Vit. C in subjects with T2DM
Free Radicals
Anti Oxidant
Micro & Macrovascularcomplication
Lymphocyte Vit. C in subjects with T2DM
in T2DM without complication
in T2DM with complication
Yamada, 2004
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Diabetic Nephropathy
+ Vit. C, Vit. E
,
Albuminuria
Farid, 2005
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Diabetes statusDiabetes status
NormalNormal
glucoseglucose
tolerancetolerance
(n= 1145)(n= 1145)
ImpairedImpaired
glucoseglucose
metabolismmetabolism
(n= 320)(n= 320)
Type 2Type 2
diabetesdiabetes
(n= 132)(n= 132)
PP for trendfor trend
Serum carotenoids (Serum carotenoids (mol/L)mol/L)
Diabetes and serum carotenoids: Population-based
study in Queensland, Australia
--carotenecarotene 0.130.13(0.10, 0.18)(0.10, 0.18)
0.120.12(0.09, 0.16)(0.09, 0.16)
0.100.10(0.08, 0.14)(0.08, 0.14)
0.0110.011
--carotenecarotene 0.590.59(0.47, 0.73)(0.47, 0.73)
0.500.50
(0.38, 0.64)(0.38, 0.64)
0.420.42
(0.30, 0.58)(0.30, 0.58)
0.010.01
--cryptoxanthincryptoxanthin 0.220.22(0.19, 0.25)(0.19, 0.25)
0.200.20
(0.17, 0.23)(0.17, 0.23)
0.190.19
(0.16, 0.22)(0.16, 0.22)
0.0410.041
Lutein/zeaxanthiLutein/zeaxanthinn 0.420.42(0.35, 0.50)(0.35, 0.50) 0.390.39(0.35, 0.43)(0.35, 0.43) 0.350.35(0.33, 0.38)(0.33, 0.38) 0.0260.026
LycopeneLycopene 0.440.44
(0.40, 0.49)(0.40, 0.49)
0.390.39
(0.34, 0.45)(0.34, 0.45)
0.350.35
(0.27, 0.44)(0.27, 0.44)
0.0530.053
Coyne et al. Am J Clin Nutr 2005;82:685-93
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Increase of Human Plasma Antioxidant Capacity with
a Novel Formulation of Antioxidants
Ivonne Maria Olivares-Corichi1, Roberto Medina-Santilln2, Cecilia Fernndezdel Valle-Laisequilla2,Pndaro Alvarez2 and Juan Jos Hicks-Gomez2
Proc. West. Pharmacol. Soc. 46: 45-47 (2003)
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GLUCOSE TOLERANCE FACTOR
RCT IN TYPE 2 DIABETES IN CHINA:SUPPLEMENTAL CHROMIUM REDUCED
FASTING GLUCOSE, HbA1c, INSULIN, &
CHOLESTEROL LEVELS. ( ANDERSON,
, ;1997 12 STUDIES REPORTED, CHROMIUM
SUPPLEMENTATION IMPROVED THE
EFFICIENCY OF INSULIN OR HAD
BENEFICIAL EFFECTS ON THE BLOOD
LIPID PROFILES
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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 thiamineconcentration 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
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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:
Hammes et al., Nature Medicine (2003) 9; 294-299
. . PKC activity
AGE formation:
capillary leak
oxygen supply
oxidative stressdamaging membranes
interfering w/ proteins axoplasmic transp
Starting point in mitochondria: GAP-DH
blocked by superoxide anion concentr.
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Status vitamin & mineral pasien diabetes tipe 2
(Mooradian et all 1987)
Vitamin AVitamin A
Vitamin CVitamin C
Vitamin EVitamin E
Vitamin B6Vitamin B6 N/N/
Vitamin B12Vitamin B12 N/N/
MagnesiumMagnesium
ChromiumChromium //SeleniumSelenium
ZincZinc
Asam FolatAsam Folat
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C O NT A IN I NG D E FI C IE N T N UT R IE N TS I N
Supplements in Type-2Diabetes Mellitus
D OSE I N A GR EE WI TH DA IL Y N OR MA LR E Q U I R E M E N T S
A VO I D P RO O X ID A NT CO MP O UND S , SU CHA S CU PP E R A N D I R O N
A VO I D VI T A MI N K, BE CA U S E IN CR E A S E SB L O O D C L O T T I N G
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SUPPLEMENTATION WITH ESSENTIAL
NUTRIENTS IN DIABETIC PATIENTS:
Restore the nutritive deficiency induced by the diabetic
state
Increase the activity of antioxidant system
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Vitamins Daily RequirementsMarion et al., Diabetes Care 25(1):148-198, 2002
VitaminMinimal
Requirement/dayMaximaltolerated
Glucobion
A(retinol) 900 g (h) 3000 g 1000 g
C(ascorbate)
75 mg (m)90 mg (h) 2000 mg 100 mg
E(-tocopherol) 15 mg 1000 mg 100 mg
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VitaminMinimal
Requirement/dayMaximal dose
toleratedGlucobion
B1 1.1 mg (m) insufficient 5 mg
Vitamins Daily RequirementsMarion et al., Diabetes Care 25(1):148-198, 2002
B6(piridoxin) 1.3 mg 100 mg 5 mg
B12(cobalamine) 2.4 g
insufficientdata 5 g
Folic Acid 400 g 1000 g 400 g
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Minerals Daily RequirementMarion et al., Diabetes Care 25(1):148-198, 2002
MineralMineralMinimalMinimal
Requirement/dayRequirement/dayMaximalMaximaltoleratedtolerated
GlucobionGlucobion
ChromiumChromium2525 g (m)g (m)3535 g (h)g (h) UnknownUnknown 5050 gg
MagnesiumMagnesium320 m320 mg (m)g (m)420 mg (h)420 mg (h) 350 mg350 mg 87.5 mg87.5 mg
SeleniumSelenium 5555 gg 400400 gg 7070 gg
ZincZinc8 mg (m)8 mg (m)11 mg (h)11 mg (h)
40 mg40 mg 15 m15 mgg
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GLUCOBIONAND DIABION IN SUMMARY WITH 5 KEY POINTS
(Summarized : Tjokroprawiro 2010)
The Novel MAOX or FDC of ANTIOXIDANTS, VITAMINS, and MINERALS1
27
2 SMALL DOSE ANTIOXIDANT COCKTAIL: GLUCOBION
- 7 Vitamins : A, C, E, B1, B6, B12, Folic Acid
- 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 Mineralsin GlucoBion Enables the Establishment of the Rationale
Therapeutic Approaches for Decreasing Oxidative Stress in T2DM
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29
SUMMARY AND CONCLUSIONSSUMMARY AND CONCLUSIONS
GLUCOBION, THE NOVEL FIXED DOSE COMPOUNDof
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
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TERIMA KASIH