do micronutrients really help diabetes

7/30/2019 Do Micronutrients Really Help Diabetes

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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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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

do micronutrients really help diabetes

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