Gatot S Lawrence

DOCAR (Diabetes-Obesity-Cardiovascular) Forum DOCAR (Diabetes-Obesity-Cardiovascular) Forum

Vascular Researc !nit" De#t o$ %atolo&y" Faculty o$ 'edicine Vascular Researc !nit" De#t o$ %atolo&y" Faculty o$ 'edicine
(asanuddin !niverstiy (asanuddin !niverstiy

Makassar, 2 June 2009
Perkiraan Prevalensi Diabetes Dunia 2010
DM seluruh dunia: 160 juta (thn 2000) 221 juta (thn 2010)
TGT sia Ten!!ara: 9" juta ji#a
)* +
,* +
-* +
.* +
/* +
* +
/0,* /0)* /01* /02* /03* /00* .*** .*/*
221 $illi%n 221 $illi%n
IDF 2003; CDC. National Diabetes Fact Sheet. 2002.; Amos AF, et al. DiabMed. 1997;1!S1 "S#$.
)* +
* +
/0,* /0)* /01* /02* /03* /00* .*** .*/*
+
/0,* /0)* /01* /02* /03* /00* .*** .*/*
221 $illi%n 221 $illi%n
IDF 2003; CDC. National Diabetes Fact Sheet. 2002.; Amos AF, et al. DiabMed. 1997;1!S1 "S#$.
Perkiraan Prevalensi Diabetes Dunia 2010
DM seluruh dunia: 160 juta (thn 2000) 221 juta (thn 2010)
TGT sia Ten!!ara: 9" juta ji#a
)* +
,* +
-* +
.* +
/* +
* +
/0,* /0)* /01* /02* /03* /00* .*** .*/*
221 $illi%n 221 $illi%n
IDF 2003; CDC. National Diabetes Fact Sheet. 2002.; Amos AF, et al. DiabMed. 1997;1!S1 "S#$.
)* +
* +
/0,* /0)* /01* /02* /03* /00* .*** .*/*
+
/0,* /0)* /01* /02* /03* /00* .*** .*/*
221 $illi%n 221 $illi%n
IDF 2003; CDC. National Diabetes Fact Sheet. 2002.; Amos AF, et al. DiabMed. 1997;1!S1 "S#$.
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TTGO meningkat TTGO meningkat
Hiperinsulinemia Hiperinsulinemia
Resistensi Insulin Resistensi Insulin
Gen Diabetes Gen Diabetes
Stadium III Stadium III
DM-2
Komplikasi DM Komplikasi DM
TGN=Toleransi Glukosa Normal TGN=Toleransi Glukosa Normal HD renda! HD renda!
Adapted from Beck-Nielsen, Groop, Haffner Adapted from Beck-Nielsen, Groop, Haffner
Obesitas Obesitas
"roduksi Glukosa meningkat "roduksi Glukosa meningkat
Transportasi glukosa menurun Transportasi glukosa menurun
"engeluaran insulin berkuang "engeluaran insulin berkuang
#t!erogenesis #t!erogenesis
Stadium II Stadium II
Stadium I
TGT= Toleransi Glukosa Terganggu TGT= Toleransi Glukosa Terganggu
TG tinggi TG tinggi
DM tipe-2$ %enomena Gunung &s DM tipe-2$ %enomena Gunung &s
TTGO meningkat TTGO meningkat
Hiperinsulinemia Hiperinsulinemia
Resistensi Insulin Resistensi Insulin
Gen Diabetes Gen Diabetes
TGN=Toleransi Glukosa Normal TGN=Toleransi Glukosa Normal HD renda! HD renda!
Adapted from Beck-Nielsen, Groop, Haffner Adapted from Beck-Nielsen, Groop, Haffner
Obesitas Obesitas
"roduksi Glukosa meningkat "roduksi Glukosa meningkat
Transportasi glukosa menurun Transportasi glukosa menurun
"engeluaran insulin berkuang "engeluaran insulin berkuang
#t!erogenesis #t!erogenesis
Stadium Stadium
II II
Stadium I
TGT= Toleransi Glukosa Terganggu
TG tinggi TG tinggi
TTGO meningkat
Hiperinsulinemia Hiperinsulinemia
Resistensi Insulin Resistensi Insulin Gen Diabetes Gen Diabetes
Stadium III Stadium III
DM-2
Komplikasi DM Komplikasi DM
TGN=Toleransi Glukosa Normal TGN=Toleransi Glukosa Normal HD renda! HD renda!
Adapted from Beck-Nielsen, Groop, Haffner Adapted from Beck-Nielsen, Groop, Haffner
Obesitas Obesitas
"roduksi Glukosa meningkat
Transportasi glukosa menurun
"engeluaran insulin berkuang
#t!erogenesis #t!erogenesis
Stadium II Stadium II
Stadium I
TGT= Toleransi Glukosa Terganggu TGT= Toleransi Glukosa Terganggu
TG tinggi TG tinggi
DM tipe-2$ %enomena Gunung &s DM tipe-2$ %enomena Gunung &s
%RO<9'!S 'OR:!S
Gatot S Lawrence .**3
Lair Lair
Diabetes Mellitus
Diabetes Mellitus
"rediabetes "rediabetes
Obesit' Obesit'
M&D M&D
Sering sakit kepala
Kadang sakit kepala
Peningkatan Tekanan Intraknial
8RA7SLA897G %47D!L!' (6%O8(4S9S 8RA7SLA897G %47D!L!' (6%O8(4S9S
.**) .**)
(ealty (ealty
Diabetes 'ellitus
Diabetes 'ellitus
ROS ROS
'icro-environment 'icro-environment
Disturbance Disturbance
9n$lammation 9n$lammation
Geneti( Sus(eptibilit' Geneti( Sus(eptibilit'
&n)ironment Sus(eptibilit' &n)ironment Sus(eptibilit'
T1
8-
T2
Risk Factors
Pre-diaetes
!iaetes "ellit#s
"icro-$n%ironment !ist#rance
%RO<9'!S 'OR:!S
Gatot S Lawrence .**3
Intermediate "!enot'pe Intermediate "!enot'pe *S+ *S+
Intermediate "!enot'pe Intermediate "!enot'pe
Intermediate "!enot'pe Intermediate "!enot'pe
Intermediate "!enot'pe Intermediate "!enot'pe
Intermediate "!enot'pe Intermediate "!enot'pe
Intermediate "!enot'pe Intermediate "!enot'pe
8RA7SLA897G %47D!L!' (6%O8(4S9S
8RA7SLA897G %47D!L!' (6%O8(4S9S
Pr%&%sed 'asi( Me(hanis$ )* Diseases
Mi(roen)ironment
Mi(roen)ironment
Genot'pe
Genot'pe
M%le(ular
Gat%t + ,a#ren(e 200-
Intermediate "!enot'pe *I"+
4ARL6 S8AG4S OF
4ARL6 S8AG4S OF
8(4 '48A:OL9C D9S4AS4 %ROC4SS
8(4 '48A:OL9C D9S4AS4 %ROC4SS
'9CRO-47V9RO7'478
'9CRO-47V9RO7'478
D9S8!R:A7C4
D9S8!R:A7C4
S9C= >97FLA''A89O7? FA8 C4LLS
Kat&r'm $( )ellen- Gok&an S Hotamisligil( J Clin Invest(**+,*-./-*-..,+001
Insulin Resistan(e Insulin Resistan(e
Insulin Resistan(e Insulin Resistan(e
%%# %%#
%%# %%#
&ndot!elial D's,un(tion
&ndot!elial D's,un(tion
&ndot!elial D's,un(tion
&ndot!elial D's,un(tion
#dipone(tin #dipone(tin
#dipone(tin #dipone(tin
TN% TN% - I-.- "#I-/- - I-.- "#I-/-
(eramide (eramide
TN% TN% - I-.- "#I-/- - I-.- "#I-/-
(eramide (eramide
H'pergl'(emia H'pergl'(emia
H'pergl'(emia H'pergl'(emia
!s0R" !s0R"
In,lammation In,lammation
#poptosis #poptosis
!s0R" !s0R"
In,lammation In,lammation
#poptosis #poptosis
ROS ROS
ROS ROS
Hepatic Hepatic
gl#coneogenesis gl#coneogenesis
FFA o2idation FFA o2idation
Si(k 1In,lammation2 %at Si(k 1In,lammation2 %at
0ells 0ells
0oronar' #rter'
0oronar' #rter'
Disease
Disease
0oronar' #rter'
0oronar' #rter'
Disease
Disease
Obesit' Obesit'
Obesit' Obesit'
%att' %att'
i)er i)er
%att' %att'
i)er i)er
Insulin Resistan(e Insulin Resistan(e
Insulin Resistan(e Insulin Resistan(e
%%# %%#
%%# %%#
&ndot!elial D's,un(tion
&ndot!elial D's,un(tion
&ndot!elial D's,un(tion
&ndot!elial D's,un(tion
#dipone(tin #dipone(tin
#dipone(tin #dipone(tin
TN% TN% - I-.- "#I-/- - I-.- "#I-/-
(eramide (eramide
TN% TN% - I-.- "#I-/- - I-.- "#I-/-
(eramide (eramide
H'pergl'(emia H'pergl'(emia
H'pergl'(emia H'pergl'(emia
Hepatic Hepatic
gl#coneogenesis gl#coneogenesis
FFA o2idation FFA o2idation
Si(k 1In,lammation2 %at Si(k 1In,lammation2 %at
0ells 0ells

ROS ROS

ROS ROS

ROS ROS

ROS ROS

ROS ROS

ROS ROS

ROS ROS

ROS ROS

ROS ROS

ROS ROS

ROS ROS

ROS ROS


ROS
ROS


ROS
ROS
9G8 9G8
9G8 9G8
#t!eros(leros #t!eros(leros
is is
#t!eros(leros #t!eros(leros
is is
Obesit Obesit
y y
Obesit Obesit
y y
Fatty Liver Fatty Liver
Fatty Liver Fatty Liver
"re "re
H'pertension H'pertension
"re "re
H'pertension H'pertension
9n$lammation and Anti-in$lammation
dysarmony
Rasio Adi#one@tin A AL: B ))
Rasio Adi#one@tin A %A9-/ B .")
Rasio Adi#one@tin A sCR% B 3
Rasio SA8 A AL: B -
Rasio SA8 A %A9-/ B *"/)
Rasio SA8 A sCR% B /
9nde@s Anti-9n$lamasi 9nde@s Anti-9n$lamasi
9nde@s Anti-O@sidan 9nde@s Anti-O@sidan
9ndeC Anti in$lamasi Renda D .
9ndeC Anti in$lamasi Sedan& .-3
9ndeC Anti in$lamasi 8in&&i E 3
9nde@s Anti-9n$lamasiF
9nde@s Anti-9n$lamasiF
Sindrom 'etaboli@
Sindrom 'etaboli@
./0T/M ,1P
&hen%$en%n
Seat Seat
9ndeC Anti in$lamasi Renda D .
9ndeC Anti in$lamasi Sedan& .-3
9ndeC Anti in$lamasi 8in&&i E 3
9nde@s Anti 9nde@s Anti- -9n$lamasi 9n$lamasi
9ndeC Anti in$lamasi Renda D .
9ndeC Anti in$lamasi Sedan& .-3
9ndeC Anti in$lamasi 8in&&i E 3
9nde@s Anti 9nde@s Anti- -9n$lamasi 9n$lamasi
9ndeC Anti in$lamasi Renda D .
9ndeC Anti in$lamasi Sedan& .-3
9ndeC Anti in$lamasi 8in&&i E 3
9nde@s Anti 9nde@s Anti- -9n$lamasi 9n$lamasi
9ndeC Anti in$lamasi Renda D .
9ndeC Anti in$lamasi Sedan& .-3
9ndeC Anti in$lamasi 8in&&i E 3
9nde@s Anti 9nde@s Anti- -9n$lamasi 9n$lamasi
9ndeC Anti in$lamasi Renda D .
9ndeC Anti in$lamasi Sedan& .-3
9ndeC Anti in$lamasi 8in&&i E 3
9nde@s Anti 9nde@s Anti- -9n$lamasi 9n$lamasi
9ndeC Anti in$lamasi Renda D .
9ndeC Anti in$lamasi Sedan& .-3
9ndeC Anti in$lamasi 8in&&i E 3
9nde@s Anti 9nde@s Anti- -9n$lamasi 9n$lamasi
Over 5ei&t Over 5ei&t
9G8 9G8
%re-(8 %re-(8
Fatty Liver Fatty Liver
G+ ,a#ren(e, 200-
The level %* hs23P and 4ree 4att5
(id in 'etS !r%u& are hi!her than
in 7on-'etS &rou#6
)n the (%ntrar5, the level %*
di&%ne(tin in 'etS !r%u& is l%#er
than in 7on-'etS !r%u&
The level %* hs23P is hi!her in 9G8 wit y#ertension than in 7GT #ith%ut h5&ertensi%n6
8%#ever, in b%th (%nditi%n the level is still hi!her than in 0%n97GT individual6 7t (an be related t%
$ild9$%derate disturban(e %* !lu(%se $etab%lis$ in the &re9diabeti(: 7GT individuals6
)n the (%ntrar5, the level %* adi&%ne(tin, $arker %* anti9in*la$$ati%n, is l%#er in 7GT #ith
h5&ertensi%n (%$&ared #ith 7GT #ith%ut h5&ertensi%n6 7t $i!ht be related t% the $etab%li(
$i(r%9envir%n$ent disturban(e that e;ist in h5&ertensi%n and 7GT individuals, %* &arti(ular the
<in*la$$ati%n $illeu= %* b%th (%nditi%ns6
9ndeC Anti in$lamasi Renda D .
9ndeC Anti in$lamasi Sedan& .- 3
9ndeC Anti in$lamasi 8in&&i E 3
Anti-9n$lammatory 9ndeC Anti-9n$lammatory 9ndeC
B / A99 Grou#
B . A99 Grou#
B - A99 Grou#
The in(re$ent %* hs23P, $arker %* in*la$$ati%n 7n a((%rdan(e #ith
the in(rease %* $etab%li( disturban(e (%$&%nent
The de(rease %* adi&%ne(tin, $arker %* anti9in*la$$ati%n in a((%rdan(e
#ith the in(rease %* $etab%li( disturban(e (%$&%nent
Alterations in cardiac energ' metaolism in t&e oese &eart( Fatt' acids and caro&'drates are t&e ke' so#rces of energ' s#ppl' for
t&e &eart( In oesit', a s3itc& in energ' metaolism occ#rs, s#c& t&at fatt' acids ecome a more prominent so#rce of acet'l 4oA for
t&e tricaro2'lic acid c'cle( FAT indicates fatt' acid transporter5 TG, triac'lgl'cerol5 P!H, p'r#%ate de&'drogenase5 "4T,
monocaro2'late carrier5 G67T, gl#cose transporter5 G8P, gl#cose-8-p&osp&ate5 S(R(, sarcoplasmic retic#l#m
Gary D. Lopaschuk. Circulation Research. +00-5*0*,11/
8RA7SLA897G %47D!L!' (6%O8(4S9S
8RA7SLA897G %47D!L!' (6%O8(4S9S
in Cardiac 4ner&y 'etabolism (A)
in Cardiac 4ner&y 'etabolism (A)
6 0%r$al Phase: in health5 individual #ith
n%r$al, health5 li*est5le, the
(%nsu$&ti%n %* *%%d #ill result in the
a&&r%&riate a$%unt %* *att5 a(ids (4),
there*%re (ir(ulatin! %* 4 is $aintain at
the <n%r$al ran!e=, (%nse>uentl5
(ardia( 4 ?9%;idati%n (in $it%(h%ndria)
is %nl5 re>uired at the $ini$al level6 The
result is n% $%rbid level %* intra(ellular
li&id a((u$ulati%n %bserved6
#
8RA7SLA897G %47D!L!' (6%O8(4S9S
8RA7SLA897G %47D!L!' (6%O8(4S9S
in Cardiac 4ner&y 'etabolism (:)
in Cardiac 4ner&y 'etabolism (:)
'6 2%$&ensat%r5 Phase: %n(e an individual
!%es be5%nd the health5 li*est5le, the
(%nditi%n #ill lead an individual t% the state
%* n%r$al #ei!ht but $etab%li(all5 %bese
(3uder$an 0), $eanin! the individual has
the $etab%li( hall$ark %* %besit56 t this
sta!e the b%d5 #ill (%n*r%nt #ith l%n!ter$
hi!h level %* (ir(ulatin! 46 This (%nditi%n
#ill lead t% the $it%(h%ndria (%$&ensati%n
b5 the in(re$ent %* (ardia( 4 ?9%;idati%n
and de(reasin! !lu(%se %;idati%n6 t this
sta!e the (ells +T7,, $ana!e t% kee& the
(ell *r%$ intra(ellular li&id a((u$ulati%n6
R#derman N, 4&is&olm !, Pi-S#n'er 9, Sc&neider S( T&e metaolicall' oese, normal-3eig&t indi%id#al re%isited( Diabetes. *::.5 ;-, 8::<-*1
3
8RA7SLA897G %47D!L!' (6%O8(4S9S
8RA7SLA897G %47D!L!' (6%O8(4S9S
in Cardiac 4ner&y 'etabolism (C)
in Cardiac 4ner&y 'etabolism (C)
26 D5s*un(ti%n Pha!e: the (%$&ensat%r5 &ha!e
#ill be $aintain *%r a l%n! ti$e t% kee& the
h%$e%stati( (%nditi%n6 8%#ever, i* the
$etab%li( hall$ark %* %besit5 &ersist, hi!her
a$%unt %* (ir(ulatin! 4 #ill be (%n*r%nted
b5 the (ells6 This (%nditi%n #ill lead t% the
d5s*unti%n %* the $it%(h%ndria b5 the
in(re$ent %* (ardia( 4 ?9%;idati%n and
!reater de(rease in !lu(%se %;idati%n6 t this
sta!e the (ells 47, t% kee& the (ell *r%$
intra(ellular li&id a((u$ulati%n, e6!: )besit5,
7nsulin 3esistant, T2DM
R#derman N, 4&is&olm !, Pi-S#n'er 9, Sc&neider S( T&e metaolicall' oese, normal-3eig&t indi%id#al re%isited( Diabetes. *::.5 ;-, 8::<-*1
0
8RA7SLA897G %47D!L!' (6%O8(4S9S 8RA7SLA897G %47D!L!' (6%O8(4S9S
in Cardiac 4ner&y 'etabolism (D) in Cardiac 4ner&y 'etabolism (D)
D6 M%rbid Phase: at this sta!e the b%d5 #ill
(%n*r%nt #ith &r%l%n! &ersistent hi!h level %*
(ir(ulatin! 46 This (%nditi%n #ill lead t% the
sta!e that the $it%(h%ndria (an n% l%n!er
$aintain h%$e%stati( (%nditi%n %* the (ell@
there*%re, (ardia( 4 ?9%;idati%n start
D1231+70G and hi!her a$%unt %*
intra(ellular li&id a((u$ulati%n 20 0)T be
&revented, and *urther deteri%rate %ther
(ellular (%$&%nents %* the (ell6
R#derman N, 4&is&olm !, Pi-S#n'er 9, Sc&neider S( T&e metaolicall' oese, normal-3eig&t indi%id#al re%isited( Diabetes. *::.5 ;-, 8::<-*1
D
#
3
0
D
Gl#cose-o2idation
FA =-o2idation
P&ase Normal 4ompensation !'sf#nction "orid
Intracell#lar 6ipid
acc#m#lation
Fatt' Acids >FA?
Normal
Hig& Persistent &ig& Prolonged &ig&
Cardiac 4ner&y 'etabolism in Obesity
4i!ure 26 di&%ne(tin and le&tin si!nalin! in the (ardi%$5%(5te6 di&%31:32 indi(ates adi&%ne(tin re(e&t%r 1:2@ 2PT91, (arnitine
&al$it%5l trans*erase 1@ 13A, e;tra(ellular si!nal9re!ulated kinase@ 8MB, hi!h $%le(ular #ei!ht@ M2D, $al%n5l92%
de(arb%;5lase
Gar5 D6 ,%&as(huk et al :2ardia( 1ner!5 Metab%lis$
in )besit56 Circ Res. 2007;101:335-347
nti 7n*la$$at%r5 7nde;C1"6D
nti 7n*la$$at%r5 7nde;C166D
nti 7n*la$$at%r5 7nde;C166D
THANK YOU
Dissection o$ a com#leC trait
at di$$erent levels o$ biolo&ical or&aniGation
7Ps, inter$ediate &hen%t5&es 2a$ussi , 'ian(hi G6 Hypertension 19DD@12:620962E
9%s 9%s
9%s
9%s
9%s
3OOD "R&SS4R& &5& 3OOD "R&SS4R& &5&
3OOD "R&SS4R& &5& 3OOD "R&SS4R& &5&
mole(ular
mole(ular
sub(ellular
sub(ellular
(ellular
(ellular
organs
organs
6!ole bod'
6!ole bod'
0andidate Genes
"!enot'pi(al e)el
Geneti( 3a(kground
*"ol'genes+
&n)ironment
&n)ironment
&n)ironment
&n)ironment
&n)ironment
)s(ar 6 2arreter%, MD@ +uFanne )&aril, MD
-
:lood %ressureH Clinical 9ntermediate %enoty#e