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CursdeDiabetsiBolimetabolice

U.M.F.Gr.T.Popa Iasi
FacultateadeMedicina
SpecializareaMedicinagenerala
AnulV
Diabetzaharatsibolimetabolice
Designulcursului
Importantaproblemei
Backgroundfiziopatologic
Definitiadiabetuluizaharatsiaaltorcategoriideintoleranta la
glucoza
Diagnosticuldiabetuluizaharat(DZ)
Tipuriledediabetzaharat:definitie,etiopatogeneza,istorie
naturala
Tratamentuldiabetuluizaharat
ComplicatiileacutespecificealeDZ
ComplicatiilecronicealeDZ
Obezitatea
Dislipidemiile
Hiperuricemiile
Sd.metabolic
Primacauzadeorbire
Primacauzadeinsuficientarenalasiboalarenalacarenecesita
dializasitransplant
Primacauzadeamputatie
24orimaifrecventebolilecoronariene&strokesladiabeticifata
denediabetici
15aniscurtareasperanteideviatafatadenediabetici
A6acauzadedecesdintretoatebolile
2008 diabetulzaharat
The Centers for Disease Control and Prevention, USA
Source: Diabetes Atlas 3rd Edition. www.eatlas.idf.org.
Proiectiiglobalealeepidemieidediabet:
20072030(milioane)
Mortalitateadiabeticilorestedublafatade
nediabetici
0
5
10
15
20
25
30
35
Control
Diabetes
10,025 61 6629 279 631 24
(PatientNumbers)
Ratio2.5 Ratio2.2 Ratio2.1
10.8
26.9
12.5
26.9
15.5
32.0
Whitehall
Study
MortalityRate
Paris
ProspectiveStudy
Helsinki
PolicemenStudy
(Deathsper
1000
patientyears)
Balkau.Lancet 1997;350:1680.
Diabetulzaharatdetip2cauzamajorade
mortalitate
3.4
5.4
6.6
6.1
6.0
2.2
4.8
6.9
5.1
8.8
8.6
2.5
0
1
2
3
4
5
6
7
8
9
10
E
x
c
e
s
s


m
o
r
t
a
l
i
t
y


a
t
t
r
i
b
u
t
a
b
l
e

t
o

d
i
a
b
e
t
e
s

(
%
)
Africa Americas Eastern
Mediterranean
Europe Southeast
Asia
Western
Pacific
Men
Women
Roglic G, et al. Diabetes Care 2005;28:21305
Fifth leading cause of death after infections,
CVD, cancer, and accidents
McKinlay J et al. Lancet. 2000;356:757,761.
Creterea numruluidedecesedatorit diabetului
R
a
t
a

r
e
l
a
t
i
v
a

a

m
o
r
t
a
l
i
t
a
t
i
i

f
u
n
c
t
i
e

d
e

v
a
r
s
t
a
Anul
140
1980
Accident vascular cerebral
Boal Cardiovascular
Cancer
Diabet
130
120
110
100
90
80
70
60
1982 1984 1986 1988 1990 1992 1994 1996
SupravieuireapostIM lafemeileibrbaiidiabetici
estemultmaimicdectlanon diabetici
Sprafka et al. Diabetes Care. 1991; 14: 537-543.
100
90
80
70
60
50
40
0 10 20 30 40 50 60
100
90
80
70
60
50
40
0 10 20 30 40 50 60
Luni Post-IM
Brbai
Femei
Diabetici
Non-diabetici
%

s
u
p
r
a
v
i
e

u
i
t
o
r
i
l
o
r
%

s
u
p
r
a
v
i
e

u
i
t
o
r
i
l
o
r
n=228
n=1628
n=15
6
n=568
Risculcoronarianesteechivalentpentrudiabeticiipentru
nediabeticiicuunIMinantecedente
Incidena IM fatal i non-fatal de-a lungul a 7 ani de urmrire
ntr-o cohort finlandez
18.8%
3.5%
45.0%
20.2%
0%
10%
20%
30%
40%
50%
Cu IM Fr IM Cu IM Fr IM
I
n
c
i
d
e
n

n

P < 0.001
P < 0.001
P < 0.001
Haffner SM et al, N Engl J Med 1998;339:229-234
Cu Diabet Fr Diabet
Diabetzaharatsibolimetabolice
Designulcursului
Importantaproblemei
Backgroundfiziopatologic
Definitiadiabetuluizaharatsiaaltorcategoriideintoleranta la
glucoza
Diagnosticuldiabetuluizaharat(DZ)
Tipuriledediabetzaharat:definitie,etiopatogeneza,istorie
naturala
Tratamentuldiabetuluizaharat
ComplicatiileacutespecificealeDZ
ComplicatiilecronicealeDZ
Obezitatea
Dislipidemiile
Hiperuricemiile
Sd.metabolic
NicolaePaulescu
18691931
Savantulromancarea
descoperitinsulinasiadescris
efecteleacesteia
Efecteleglucometabolicealeinsulinei
Controlulhormonalalglicemiei
Insulina
Efectnet:scdereaglicemiei
Hormonidecontrareglare
Efectnet:cretereaglicemiei
nlturriiglucozeidinsnge
intrriiglucozeincelule
glicogenezei
eliberriiglucozeidindepozite
glicogenolizei
gluconeogenezei
lipolizeiicetogenezei
catabolismuluiproteic
nlturriiglucozeidinsnge
intrriiglucozeincelule
glicogenezei
eliberriiglucozeidindepozite
glicogenolizei
gluconeogenezei
lipolizeiicetogenezei
catabolismuluiproteic
Pancreasulendocrin noiunideanatomiei
fiziologie
InsuleleLangerhans
800.000 1.500.000
1 2%dinmasa
pancreatictotal
Celule:A,B,C,D
Formareainsulinei
Preproinsulina
Proinsulina
Insulina
Structurainsulinei
Insulinosecreiafiziologic profil24ore
Adapted from Pratley RE, Weyer C. Diabetologia 2001; 44: 92945.
0
100
200
300
400
0 20 40 60 80 100 120
Time (min)
P
l
a
s
m
a

i
n
s
u
l
i
n

(
p
m
prima
faz
A
doua
faz
Insulinosecreianormal,bifazic
Rolulcentralalcanalelor
Rolulcentralalcanalelor
K
K
atp atp
ininsulinosecretie
ininsulinosecretie
InchidereacanaluluiK
InchidereacanaluluiK
ATP ATP
prinlegareaunei
prinlegareaunei
moleculedeATPlaunuldincele4situsuridepe
moleculedeATPlaunuldincele4situsuridepe
SUR1
SUR1
Semnificaiafiziologic
acelulelorbeta
Celulapancreaticfuncioneaz
caunsenzorenergetic
Glucokinaza Metabolismul
glucozei
ATP
Declanarea
insulinosecreiei

-30
-10
10
30
50
70
90
0 15 30 45 60 75 90
TIME (min)

0
50
100
150
200
0 15 30 45 60 75 90
TIME (min)
McIntyre et al 1964

G
L
U
C
O
S
E

(
m
g
/
1
0
0
m
l
)

I
N
S
U
L
I
N

(
m
U
/
L
)
oral
intravenous
Secretiadeinsulinadupaadmglucozeiintraduodenalsi
intravenos
Gut factors termed incretins
ActiuneainsulinotropaaGLP1siGIPasupra
celbetapancreatice
K.Mussig et al Diabetologia 2010 ,53(11),2289
Receptoruldeinsulina
Legareainsulineilareceptorulspecific
cudeclansareareactiilorintracelulare
Principaleletesuturitintaaleinsulinei
Posibileledefectecauzatoaredeinsulinorezisten
Laniveldeprereceptor
Insulinanormal
Degradareacrescutainsulinei
Prezenansngeaantagonitilorhormonali
Laniveldereceptor
Scdereanumruluidereceptori
Receptorianormali
Alterareaunorfunciialereceptorului
(activitiitirozinkinazei,autofosforilareareceptorului)
Lanivelpostreceptor
Alterrialesistemuluiefectorilor(transportoriideglucoz)
Defectealeenzimelori.c.implicatenmetab.intermediare
insulina
Rc.Insul.
IRS
Pi3 Kinaza
MAPK
NO,vasodilatatie
Ef.antiATS
migrare,prolif.cel.
mus.netede
sintezeimatriciale
Ef.aterogenic
scazut
IncazurideIRsau
insulinodefic.
crescu
t
KingGL,1999
Cideaciunealeinsulinei lanivelul CMN
DZtip2 deficitulinsulinosecreiei
postprandiale
timp
6 am 10 am 2 pm 6 pm 10 pm 2 am 6 am
800
600
400
200
i
n
s
u
l
i
n
o
s
e
c
r
e
t
i
e
(
p
m
o
l
/
m
i
n
)
0
DZ tip 2
Persoane nediabetice
PolonskyKSetal.NEnglJMed1996;334:777783
Masacel
proliferare
neogeneza
hypertrofie
atrofie
apoptoza
Masacel indinamica
AckermannAM,GannonM.J.Molec.Endocrin.2007;38:193206.
Chris Rhodes Ph.D.
PNRI, Seattle, WA.
DZ2 oproblemadeechilibru
PERIPHERAL INSULIN
RESISTANCE
-CELL MASS
& FUNCTION
Non-Diabetic State
P
E
R
IP
H
E
R
A
L
IN
S
U
L
IN
R
E
S
IS
T
A
N
C
E

-
C
E
L
L
M
A
S
S
&
F
U
N
C
T
IO
N
Diabetic State
NGT : Normal glucose tolerance - IS : Insulin Sensitivity - CF : Cell function
Adapted from Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP et al. Quantification of the relationship between
insulin sensitivity and beta cell function in human subjects. Evidence for a hyperbolic function. Diabetes 1993, 42: 1663-72. Bergman RN, Ader M. Huecking K, Van Citters G. Accurate
assessment of beta-cell function: the hyperbolic correction. Diabetes 2002, 51 Suppl. 1: S212-20. Bergman RN. Pathogenesis and prediction of diabetes mellitus: lessons from
integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
ISxCFdefinescariafunctionalacaredetermina
homeostaziaglucidica
Curbahiperbolicaarelatieidintre
ISxCF
NGT : Normal glucose tolerance - IS : Insulin Sensitivity - CF : Cell function
Adapted from Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP et al. Quantification of the relationship between
insulin sensitivity and beta cell function in human subjects. Evidence for a hyperbolic function. Diabetes 1993, 42: 1663-72. Bergman RN, Ader M. Huecking K, Van Citters G. Accurate
assessment of beta-cell function: the hyperbolic correction. Diabetes 2002, 51 Suppl. 1: S212-20. Bergman RN. Pathogenesis and prediction of diabetes mellitus: lessons from
integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
IR
IS
Curbahiperbolicaarelatieidintre
ISxCF
NGT : Normal glucose tolerance IR: Insulin Resistance - CF : Cell function
Adapted from Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP et al. Quantification of the relationship between
insulin sensitivity and beta cell function in human subjects. Evidence for a hyperbolic function. Diabetes 1993, 42: 1663-72. Bergman RN, Ader M. Huecking K, Van Citters G. Accurate
assessment of beta-cell function: the hyperbolic correction. Diabetes 2002, 51 Suppl. 1: S212-20. Bergman RN. Pathogenesis and prediction of diabetes mellitus: lessons from
integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
Curbahiperbolicaarelatieidintre
ISxCF
NGT : Normal glucose tolerance IR: no Insulin Resistance (i.e. normal insulin sensitivity) - CF : Cell
function
Adapted from Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP et al. Quantification of the relationship between
insulin sensitivity and beta cell function in human subjects. Evidence for a hyperbolic function. Diabetes 1993, 42: 1663-72. Bergman RN, Ader M. Huecking K, Van Citters G. Accurate
assessment of beta-cell function: the hyperbolic correction. Diabetes 2002, 51 Suppl. 1: S212-20. Bergman RN. Pathogenesis and prediction of diabetes mellitus: lessons from
integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
CurbahiperbolicaarelatieidintreISxCFlanormali
siDZ2
Adapted from Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP et al. Quantification of the relationship between
insulin sensitivity and beta cell function in human subjects. Evidence for a hyperbolic function. Diabetes 1993, 42: 1663-72. Bergman RN, Ader M. Huecking K, Van Citters G. Accurate
assessment of beta-cell function: the hyperbolic correction. Diabetes 2002, 51 Suppl. 1: S212-20. Bergman RN. Pathogenesis and prediction of diabetes mellitus: lessons from integrative
physiology. Mt Sinai J Med. 2002, 69: 280-90.
Curbahiperbolicaarelatieidintre
ISxCF
NGT : Normal glucose tolerance IFG/IGT: Impaired Fasting Glucose/Impaired Glucose Tolerance T2M:
Type 2 Diabetes Mellitus
Adapted from Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP et al. Quantification of the relationship between
insulin sensitivity and beta cell function in human subjects. Evidence for a hyperbolic function. Diabetes 1993, 42: 1663-72. Bergman RN, Ader M. Huecking K, Van Citters G. Accurate
assessment of beta-cell function: the hyperbolic correction. Diabetes 2002, 51 Suppl. 1: S212-20. Bergman RN. Pathogenesis and prediction of diabetes mellitus: lessons from
integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
90%dintreDZ2:IRandSndr.Metabolic
Adapted from International Diabetes Center (IDC), Minneapolis, MinnesotaAdapted from Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard
JC, Palmer JP et al. Quantification of the relationship between insulin sensitivity and beta cell function in human subjects. Evidence for a hyperbolic function. Diabetes 1993, 42: 1663-72. Bergman
RN, Ader M. Huecking K, Van Citters G. Accurate assessment of beta-cell function: the hyperbolic correction. Diabetes 2002, 51 Suppl. 1: S212-20. Bergman RN. Pathogenesis and prediction of
diabetes mellitus: lessons from integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
Diabetzaharatsibolimetabolice
Designulcursului
Importantaproblemei
Backgroundfiziopatologic
Definitiadiabetuluizaharatsiaaltorcategoriideintoleranta la
glucoza
Diagnosticuldiabetuluizaharat(DZ)
Tipuriledediabetzaharat:definitie,etiopatogeneza,istorie
naturala
Tratamentuldiabetuluizaharat
ComplicatiileacutespecificealeDZ
ComplicatiilecronicealeDZ
Obezitatea
Dislipidemiile
Hiperuricemiile
Sd.metabolic
Diagnosticuldiabetuluizaharat
Labolnavsimptomatic
cusimptometipicedediabetzaharat
cusemneatipicesauaunorcomplicatii(acutesaucronice)
Labolnavasimptomatic
intimplator
bilantalstariidesanatate
incadrulunuiscreening
.populational
.pegrupuriderisc
DiagnosticulclinicalDZ
Poliurie
Polidipsie
Polifagie
Scdereponderal
Astenie
IndicaiilescreeninguluipentruDZlasubiecii
asimptomaticicuajutorulglicemieibazale
Toisubieciicuvrsta 45ani;sevarepetalaintervalede3ani
Testareasevafacelavrstesub45aniisevarepetalaintervale
maiscurtela:
persoanecuIMC 27kg/m
2
ceicareaurudedegradulIcuDZ
grupurietnicecurisccrescut
femeilecareaunscutcopiicugreutateapeste4,5kg
femeilecareauavutdiabetgestaional
hipertensivii
ceicuHDL 35mg/dli/sautrigliceride250mg/dl
ceicuGBMsaucuSTGlatestrianterioare
Criteriile pentru diagnosticul
Diabetului zaharat
simptome clasice de diabet + glicemie plasmatic ntmpltoare 200mg/dl
(11,1mmol/l)
simptomele clasice de diabet includ poliuria, polidipsia, polifagia i scderea
inexplicabilngreutate;
glicemiantmpltoaresereferlarecoltarefrrelaiecuultimulprnz.
Sau
glicemieplasmatic penemncate 126mg/dl(7,0mmol/l);
starea pe nemncate (fasting sau jeun) este definit la minim 8 ore de la ultima
ingestiecaloric.
Sau
glicemie plasmatic 200mg/dl (11,1 mmol/l) la 2 ore de la ingestia de
glucozncadrulunuitestdetoleranlaglucoz(TTGO);
testulseexecututiliznd75gdeglucozdizolvaten300mlap.
n absena unei hiperglicemii cu semne acute de decompensare metabolic,
diagnosticul trebuie confirmat prin repetarea glicemiei plasmatice pe nemncate ntro
altzi.
Criteriideinterpretareaglicemieibazale
70110mg/dl normal
110125mg/dl glicemiebazalmodificat
126mg/dl diabetzaharatprobabil;confirmarea
sefacedupadouadozare labolnavulasimptomatic
Mic dejun Prnz Cin 0.00am 4.00am Mic dejun
MonnierL.EurJClinInvest2000;30 (Suppl2):311.
DarNormalpredominperioadapostprandial
Legenda:
stare postprandial;
stare postabsorptiv;
a jeun
CriteriideinterpretareaTTGO
Glicemienplasmavenoas
Diabetzaharat
bazal
la2hdupglucoz
126mg/dl(7mmol/l)
200mg/dl(11,1mmol/l)
Scdereatoleraneilaglucoz
bazal
la2hdupglucoz
< 126mg/dl(7mmol/l)
140mg/dl(7,8mmol/l)i
< 200mg/dl(11,1mmol/l)
Normal
bazal
la2hdupglucoz
< 110mg/dl(7mmol/l)
< 140mg/dl(7,8mmol/l)
Valoridiagnosticepentrudiabetzaharatialte categoriide
hiperglicemie
Sngeintegral
Plasmavenoas
mg/dl(mmol/l)
venos capilar
mg/dl(mmol/l)
Diabetzaharat
Penemncatesau
La2oredupglucoz
110(6,1)
180(10,9)
110(6,1)
200(11,1)
126(7,0)
200(11,1)
Scdereatoleraneilaglucoz
Penemncatei
La2oredupglucoz
<110(<6,1) i
120(6,7)
<110(<6,1)i
140(7,8)
<126(<7,0)i
140(7,8)
Glicemiebazalmodificat
Penemncate 100 (5,6)i
<110(<6,1)
100(5,6) i
<110(<6,1)
110( 6,1) i
<126(<7,0)
Hemoglobinaglicat unposibilviitorcriteriude
diagnostic
Evalueazcontrolulpetermenlungaldiabetului(46spt.)
memoriediabeticdelungdurat
Subfraciuni:A1a,A1b,A1c
Valorinormale:HbA1=8%
HbA1c=46%
DeterminareaHbA1c cromatografic
colorimetric
radioimunologic
Glicozilareaneenzimaticaproteinelor
Proporionalcu conc.glucozeidinsg.
duratamenineriiei
Glucoz+Protein+BazSchiff+ProdusAmadori
AGE (advancedglycationendproducts)
stabili
seacumuleazcaatare(RD,ND, mbtrnire)
aulocusurispecificedeaciune
potfiidentificaindiferitestructuridatorit
fluorescenei lorcaracteristice
CorelaiintrevalorileA1ciglicemie
A1c (%) Medianivelelorglicemice
6 135 mg/dl(7,5mmol/l)
7170mg/dl(9,5mmol/l)
8205mg/dl(11,5mmol/l)
9240mg/dl(13,5mmol/l)
10275mg/dl(15,5mmol/l)
11310mg/dl(17,5mmol/l)
12345mg/dl(19,5mmol/l)
ADA.Testsofglycemiaindiabetes.
DiabetesCare2003;26(Suppl1):S106S108.
Diabetzaharatsibolimetabolice
Designulcursului
Importantaproblemei
Backgroundfiziopatologic
Definitiadiabetuluizaharatsiaaltorcategoriideintoleranta la
glucoza
Diagnosticuldiabetuluizaharat(DZ)
Tipuriledediabetzaharat:definitie,etiopatogeneza,istorie
naturala
Tratamentuldiabetuluizaharat
ComplicatiileacutespecificealeDZ
ComplicatiilecronicealeDZ
Obezitatea
Dislipidemiile
Hiperuricemiile
Sd.metabolic
Clasificareadiabetuluizaharat
Tip1 (distruciacelulelorbetacareconducedeobiceilainsulinodeficiena absolut)
autoimun
idiopatic
Tip 2 (datorat predominant insulinorezistenei cu relativ insulinodeficien
pnladefectpredominantdesecreiecusaufrinsulinorezisten)
Altetipurispecifice
defectegeneticealefuncieiceluleibeta
defectegeneticealeaciuniiinsulinei
bolialepancreasuluiexocrin
endocrinopatii
indusdeadministrareademedicamentesauchimice
infecii
formeraredediabetmediatimun
altesindroamegeneticecaresepotasociacudiabetul
Diabetulgestaional
Patogenezadiabetuluizaharatdetip1
Autoimunitate
Progresiadistructieibetacelulare
Insuficientafunctieibetacelulare
Dependentadeinsulinaexogena
Riscdecetoacidoza
EtiopatogeniaDZ1autoimun
Predispoziiegenetic
Factordemediu(viral,toxic,alimentar)
Activareautoimuninsulit
Scdereacapacitiisecretoare;afectareafazeisecretorii
iniiale,darinsulinemiaplasmaticestenormal
Diabetclinicmanifest;insulinemieplasmaticsczut,
hiperglicemie,aparsimptomele
Apariiacomplicaiilor
Slides current until 2008
Diagnosis and types
Curriculum Module II-1
Slide 15 of 48
Beta-cell
mass
Pathogenesis of type 1 diabetes
Time (months - years)
Trigger
Genetic
Pre-diabetes
Honeymoon
Chronic
phase
Clinical
diabetes
Immunological
abnormalities
Patogenezadiabetuluizaharattip1
Modified from Kahn R. Diabetes. 1994;43:1066-1084.
60
50
40
30
20
Gene Gene Ambient Ambient
Diabetogene
primare
secundare
Gene legate de diabet
Normal
Deficienta de secretie
a insulinei
Insulino-rezisten
Diabet tip II Diabet tip II
Obezitate
Diet
Activitate fizic
vrst (ani)
Factoriiderisc implicainpatologia
diabetuluizaharattip2
Factoriiderisc implicainpatologia
diabetuluizaharattip2
Peste80%dintrepacientiicareevolueazasprediabet
zaharatdetip2suntinsulinorezistenti
Insulin resistant;
low insulin secretion (54%)
Insulin resistant;
good insulin secretion
(29%)
Insulin sensitive;
good insulin
secretion (1%)
Insulin sensitive;
low insulin secretion (16%)
83%
83%
Haffner SM, et al. Circulation 2000; 101:975980.
Semnedeinsulinorezistenta
Obezitatea
abdominala
Acanthosis
nigricans
Slides current until 2008
Diagnosis and types
Curriculum Module II-1
Slide 9 of 48
Glucose uptake
Glycogenolysis
Gluconeogenesis (amino acids)
Ketone production (fatty acids)
Glucose uptake
Protein degradation amino acids
Blood glucose
Insulin deficiency in
type 1 diabetes
Triglyceride degradation fatty acids
Slides current until 2008
Diagnosis and types
Curriculum Module II-1
Slide 12 of 48
Blood glucose
Converted to triglycerides
Effect of insulin resistance in
t
type 2 diabetes
Glucose uptake
Glycolysis
Gluconeogenesis (amino acids)
Glucose uptake
Protein degradation amino acids
Glucose uptake
Patofiziologiadiabetuluizaharat
detip2
Decreased glucose uptake
Impaired insulin action
Unsuppressed glucose production
Impaired insulin action
Hyperglycemia
Impaired insulin secretion
InsulinosecreianDZ tip2 amputareafazei
precoce
Timp
6 am 10 am 2 pm 6 pm 10 pm 2 am 6 am
800
600
400
200
i
n
s
u
l
i
n
o
s
e
c
r
e

i
e
(
p
m
o
l
/
m
i
n
)
0
DZ2
FrDZ2
PolonskyKSetal.NEnglJMed1996;334:777783
Lebovitz H. Diabetes Rev 1999;7:139153.
Holman RR. Diabetes Res Clin Pract 1998;40(suppl):S21-S25.
-Cell
function
(%)
Postprandial
Hyperglycemia
IGT Type 2
Diabetes
Phase I
Type 2
Diabetes
Phase II
Type 2 Diabetes
Phase III
25
100
75
0
50
-12 -10 -6 -2 0 2 6 10 14
Years from diagnosis
Diagnosis
Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS.
DeclinulfuncieibetacelularenDZ tip2
Numeroifactoricontribuieladeclinulprogresival
funcieicelulei pancreatice
Celula
Hiperglicemie
(glicotoxicitatea)
Insulinorezisten
Lipotoxicitate
(creterea AGL, Tg)
Glicarea
proteinelor
Efectulincretinicesteredus
inDZtip2
Cumsecombinainsulinorezistentasidisfunctiacelulara
ingenezadiabetuluizaharatdetip2?
Abnormal
glucose tolerance
Hyperinsulinemia,
then -cell failure
Normal IGT* Type 2 diabetes
Post-
prandial
glucose
Insulin
resistance
Increased insulin
resistance
Fasting
glucose
Hyperglycemia
Insulin
secretion
*IGT = impaired glucose tolerance
Adapted from Type 2 Diabetes BASICS. International Diabetes Center (IDC), Minneapolis, 2000.
PrentkiM.,NolanCJ.J.Clin.Invest.2006;116:18021812.
Pierdereamasei celulareinistorianaturalaaDZ2
Insulin
Resistance
Type 2
Diabetes
-cell
Dysfunction
Insulin
Resistance
H
y
p
e
r
g
l
y
c
a
e
m
i
a
Insulin
Concentration
I
n
s
u
l
i
n

A
c
t
i
o
n
Euglycaemia
-cell Failure
Normal IGT obesity Diagnosis of
type 2 diabetes
Progression of
type 2 diabetes
DeFronzo R et al. Diabetes Care 1992;15:318-68
InsulinorezistentasiinsulinodeficientainDZ2
EtiopatogeniaDZ2
Factorigenetici transmiterepoligenic
Rezistencrescutlaaciuneainsulinei
Hiperinsulinismfuncional
Deficiennsecreiainsulinic hiperglicemiepersistent
Tulburriinsulinosecretorii
caracteruluipulsatoralinsulinei
dispariiafazeiprecocearspunsuluiinsulinic
ntrziereasecreieideinsulin
Scdereaabsolut asecreieiinsulinice
DZ2insulinonecesitant
Patogenezadiabetuluizaharatdetip2
Boalapoligenica
Hiperinsulinemia
Malnutritiefetala formariicelulelorbeta
Copilcugreutatemicalanastere
thriftygene
7%scadereaceluilelorbeta/an
Diabet
STG
Limitaglicemieinormale
Riscpentruochi,
rinichi,nervi
RiscCV
DisglicemiaesteunfactorderiscprogresivpentruevenimenteCV
GersteinH.2003
Epidemiologia i riscul CV n diabet
SindromulMetabolic:Operspectiva
istorica
Reaven G. Diabetes 1988;37:1565-1607.
Insulin
Resistance
Insulin Insulin
Resistance Resistance
Glucose
Intolerance
Glucose Glucose
Intolerance Intolerance
Hyperinsulinemia
Hyperinsulinemia Hyperinsulinemia
^ TG
^ ^ TG TG
+ HDL-C
+ HDL-C
Hypertension
Hypertension
1988: Syndrome X 1988: Syndrome X
Coronary Heart Disease
Coronary Heart Disease Coronary Heart Disease
SindromulMetabolic:Perspectivaactuala
Adapted from Reaven G. Drugs 1999;58(suppl):19-20 with permission from WolthersKluwer Health.
Body Size
^ BMI
^ Central Adiposity
Body Size Body Size
^ ^ BMI BMI
^ ^ Central Adiposity Central Adiposity
Glucose
Metabolism
Glucose Glucose
Metabolism Metabolism
Uric Acid
Metabolism
Uric Acid Uric Acid
Metabolism Metabolism
Dyslipidemia
Dyslipidemia Dyslipidemia
Hemodynamic
Hemodynamic
Novel Risk
Factors
Novel Risk
Factors
Insulin Resistance
Insulin Resistance Insulin Resistance
Hyperinsulinemia
Hyperinsulinemia Hyperinsulinemia
+ +
^ ^ TG TG
^ ^ PP lipemia PP lipemia
+ + HDL HDL- -C C
+ + PHLA PHLA
Small, dense LDL Small, dense LDL
Glucose Glucose
intolerance intolerance
^ ^ Uric acid Uric acid
+ + Urinary Urinary
uric acid uric acid
clearance clearance
^ ^ SNS activity SNS activity
^ ^ Na retention Na retention
Hypertension Hypertension
^ ^ CRP CRP
^ ^ PAI PAI- -1 1
^ ^ Fibrinogen Fibrinogen
Coronary Heart Disease
Coronary Heart Disease Coronary Heart Disease
Definitiialesindromuluimetabolic
WHO
a
EGIR
b
NCEP
c
IDF
d
Insulinresistance
&/orqFPG
Insulinresistance
(hyperinsulinaemia
qFPG Centralobesity
Plus2ormoreof
Centralobesity Centralobesity Centralobesity qFPG
e
qBP qBP qBP qBP
e,f
qTG,+HDLC qTG,+HDLC
f
qTG qTG
f
Microalbuminuria +HDLC +HDLC
f
a:WorldHealthOrganisation;b:EuropeanGroupforthestudyof Insulinresistance;
c:NationalCholesterolEducationProgram;d:InternationalDiabetesFederation
e:ordiagnosisofdiabetesorhypertensionasapplicable;f:and/ortreatment
EschwegeE.DiabetesMetab2003;29:6S1927;InternationalDiabetesFederation
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults. JAMA 2001;285:2486-2497.
SindromulmetaboliccresterisculdeBCVsiDZ2
Coronary Heart Disease
Coronary Heart Disease
Type 2
Type 2
Diabetes
Diabetes
High
High
LDL
LDL
-
-
C
C
Metabolic
Metabolic
Syndrome
Syndrome
DZtip2estevarfulicebergului
Beck-Nielsen H, Groop LC. J Clin Invest. 1994;94:17141721.
Type 2 Diabetes Mellitus
Stage III
Stage II
Impaired
glucose
tolerance
Stage I
Normal
glucose
tolerance
Macroangiopathy Microangiopathy
Postprandial
plasma glucose
Glucose production
Glucose transport
Insulin secretory deficiency
Atherogenesis
Hyperinsulinemia
Insulin
resistance
Diabetes Genes
Lipogenesis
Obesity
Waist/hip ratio
TG
HDL
HTN
Diabetzaharatsibolimetabolice
Designulcursului
Importantaproblemei
Backgroundfiziopatologic
Definitiadiabetuluizaharatsiaaltorcategoriideintoleranta la
glucoza
Diagnosticuldiabetuluizaharat(DZ)
Tipuriledediabetzaharat:definitie,etiopatogeneza,istorie
naturala
Tratamentuldiabetuluizaharat
ComplicatiileacutespecificealeDZ
ComplicatiilecronicealeDZ
Obezitatea
Dislipidemiile
Hiperuricemiile
Sd.metabolic
Obiectivebiomedicalepentrucontroluldiabetului zaharat
Bun Lalimit Precar
Glicemia(autodeterminare)
penemncate/preprandial
postprandial[mg/dl(mmol/l)]
80110(4,46,1)
100145(5,58,0)
111140(6,27,8)
146180(8,110,0)
>140(>7,8)
>180(>10,0)
HbA1c(%)
<6,5 6,57,5 >7,5
HbA1(%)
<8,00 8,09,5 >9,5
Colesterolserictotal
mg/dl(mmol/l)
<200(<5,2) 200250(5,26,5) >250(>6,5)
Trigliceride
mg/dl(mmol/l)
<150(<1,7) 150200(1,72,2) >200(>2,2)
Indexmas corporal(kg/m
2
)
B
F
<25,4
<24,0
25,027,0
24,026,0
>27,0
>26,0
ObiectivelemanagementuluiDZ
Mentinereasauobtinereauneistarigeneralebune,auneicalitati
optimeavietii
Disparitiasauameliorareasimptomelordehiperglicemie
Atingereatintelorcontroluluimetabolicfarariscuri
RealizareauneiHbA1c<6,5
NormalizareaTAlahipertensivi
Normalizareatablouluilipidic
PrevenireacomplicatiilorDZ
Prelungireadurateidesupravietuirepinalamedianediabeticilor,
inconditiibune
Tratamentulnonfarmacologic:terapiadietetica
(introducere)
Glucide
Lipide
Proteine
Metabolismulbazal
Efortfizic
TEF
Echilibrulenergetic
Tratamentulnonfarmacologic:terapiedietetica
(introducere)
Macronutrieni(trofinecalorigene)
glucide
proteine
lipide
Micronutrieni(trofinenecalorigene)
vitamine liposolubile
hidrosolubile
minerale macroelemente
microelemente
Apa(hidratare)
Surse de energie
Recomandrinutriionale(introducere)
CANTITATIVE pentrupopulaiasntoasexiststandarde,repere
pentrucategoriideindivizinfunciedevrst,sexiactivitatefizic.
CALITATIVE
nfunciederepartiianutrimentelornraiaenergetic
incontdeanumitecaracteristicipentrufiecarecategoriede
nutrimentenergetic
proporiaPanimale/vegetale
proporiaacizigraisaturai/mononesaturai/polinesaturai
indexulglicemicalalimentelor(putereahiperglicemiant)
Necesarulcalorici deprincipiialimentareladiferitevrste
Vrsta Greutate
Necesarcaloric
(kcal/zi)
Necesarde
proteine(%)
Necesarde
glucide(%)
Necesarde
lipide(%)
< 1an 7,3 820
1 3ani 13,4 1300 15 55 30
4 6ani 20,2 1830 14 54 31
7 9ani 28,1 2190 13 55 32
Biei 10 12ani 36,9 2600 13 55 32
Biei 13 15ani 49,9 2490 13 58 32
Biei 16 19ani 54,4 2310 13 58 30
Brbaiaduli
(activitatemedie)
65,0 2900 13 58 30
Femeiadulte
(activitatemedie)
55,0 2200 13 58 30
Femeigravide
(ultimile5luni)
+350 15 57 28
Femeicarealpteaz
(primele6luni)
+550 14 57 29
Proteine Glucide Lipide
Saietate
Suprimarea senzaiei de foame
Aport energetic (kcal/g)
% din aportul energetic zilnic
Capacitatea de depozitare
Ci metabolice spre alte compartimente
Autoreglarea (capacitatea de stimulare a
oxidrii n cazul aportului excesiv)
+++
+++
4
+

+
+++
++
+++
4
++
+
+
++

9
+++
+++
0
0
Caracterelemacronutrienilor
DENSITATEENERGETIC
procentajuldekcalpentru100gdealiment
determinantesenialalsaietii
esteinversproporionalcuvolumulalimentelor
cuctunalimentestemaisracnlipidedensitateasa energetic este mai
mic
DENSITATENUTRIIONAL
coninutul n nutrimente nonenergetice (sau de proteine) pentru 100 kcal de
aliment
pentrufiecareporiede100kcalestepreferabilcadensitateanutriionalsfie
nalt
un aliment avnd o densitate nutriional optim pentru un nutriment dat va
conineomarecantitatedinacelnutrimentiunslabaportdelipide.
Caracteristicilealimentelor
Echivalenealimentarecantitativepentruoporie
Alimentele Echivalenelecantitativepentruoporie
Pine,cereale,orez,paste
finoase,mmlig
1feliedepine,can*cereale,orezsaupaste
finoase(fierte),1biscuit
Legume,zarzavaturi,cartofi canvegetaleproaspetesaufierte,1can
legumefrunzefierte,canzarzavaturifierte,
cansucderoii,1cartofmijlociu
Fructe 1fructmediu(mr,banan,portocal),
grapefruit,cansuc,canciree,1feliemedie
depepene,1ciorchinemijlociudestrugure
Carne,pete,fasoleboabe,oui
fructeoleaginoase
100gcarnegtit,1ou,canleguminoase
uscatefierte
Lapte,iaurt,brnz 1candelaptesauiaurt,canbrnzdevac,
50gtelemea
Grsimi,uleiuriidulciuri 1linguri*ulei,margarin,untsauzahr
Cteporiidinfiecareetajalpiramidei
artrebuisconsumaizilnic?
1 porie 1 uncie
Pentru 1.600 kcal. Pentru 2.200 kcal. Pentru 2.800 kcal.
Indexulglicemicalalimentelor
138 Glucoza
126 Mierea
115Cornflakes
100%Glucoz 100%Pinealb
Pineintegral
Piuredecartofi
9199%Muesli
Biscuii
Piuredecartofi
Morcovi
8090%Cornflakes
Miere
Cartofi
8090%Banane
Zaharoz
Pineintegral
7079%Orez
Cartofi
7079%Chipsuri
Pinealb
Banane
6069%Muesli
Biscuii
Patiserie
Macaroane
6069%Spaghetefierte15min
Sucdeportocale
Spaghetefierte5min
5059%Chipsuri
Zaharoz
Mere,portocale
5059%Iaurt
ngheat
Mazreuscat
Mazreuscat
4049%Portocale
Sucdeportocale
Spaghetefierte5min
4049%Piersici
Lapte
Piersici
3039%ngheat
Mere
Lapte,iaurt
3039%Fructoz
2029%Fasolepsti
Fructoz
1019%Arahide
Soia
1019%Arahide
Soia
Exempledeindex
glicemic
Repartiianutrimentelorpemese
Glucide cu index
glicemic mic
Glucide cu index
glicemic mare
Lipide Proteine
Mic dejun
Prnz
Cina
Da
Da
Moderat
Moderat
Moderat
(dup o mas
bogat n fibre)
Nu
Moderat
(colesterol
alimentar)
Cantitate
redus
Da
(acizi grai
polinesaturai)
Da
Da
Da
ChevallierL,2003
Regulinalctuireauneidiete
Dietaprescrisnutrebuiesfienociv:
saducnutrimenteleplasticeienergeticencantitiadecvate;
valoarenutriionalbun.
Modificriprudentealeobiceiuriloralimentare:
obiceiurideterminateprininterogatoriulalimentar;
evitareaproduceriifrustraiilorinutile.
Rezultatecontrolateperiodic.
Prescripiidieteticeposibile
Prescripiapozitivatuturoralimentelorindispensabilei
echivalenelelor
lassubiectuluiposibilitateadealeadaptalagusturileiobiceiurilesale
Prescriereanntregimeaunuiregimpersonalizat
pornetedelaprescripiilemedicale
inecontdedateleipreferinelepacientului
necesitoperioadlungdetimpiprogramecomputerizate
Tratamentuldieteticndiabetulzaharat
Respectareaetapeloralctuiriiuneidiete
Atenie distribuirea caloriilor pe cele 3 principii energetice i
pemese
Suplimentareacuvitamineimineraleestenecesardoarla
pacieniiceurmeazunregimhipocaloricperioadelungide
timp
n condiiile creterii necesarului energetic (sarcin, lactaie,
afeciuniintercurente)
Cntarul instrumentindispensabilpersoaneicuDZ!
Etapelealctuiriiuneidiete
Precizareacaracteristicilorgeneralealedietei
Calcululaportuluicaloric
Distribuiacaloriilorpeceletreiprincipiienergeticeia
macronutrienilorngrame.
Alegereaalimentelor
Distribuiaprincipiilorenergeticepenumruldemese
Pregtireacorectaalimentelor(regulidegastrotehnie)
INDIVIDUALIZAREADIETEI!
Tratamentuldieteticndiabetulzaharattip2
Monitorizeaz
glicemia i
medicaie
Crete
activitatea fizic
Controlul glicemic
Modific cant.
de grsimi
ingerat
Respect orarul
meselor
Crete preocuparea
de selecie a
alimentelor
Restrnge caloriile
pentru normalizarea
greutii
Schimb
stilul de via
Alimentaiasntoas 5criterii
Adecvat alimentele consumate s aduc nutrieni eseniali, fibre i
energie n cantiti suficiente pentru meninerea sntii i a greutii
corpului.
Echilibrat nu trebuie s prevaleze un nutriment sau aliment n
defavoareaaltuia(respectareaproporiilor).
Controlat caloric se refer la aportul energetic care trebuie s
corespund nevoilor metabolice; astfel se asigur controlul greutii
corporale.
Moderat atenielaposibileexcesealimentareprecumsarea,grsimile,
zahrulsaualtcomponentpesteanumitelimite.
moderaie,nuabstinen!
Variat evitarea consumului unui anumit aliment, chiar nalt nutritiv, zi
dupzi,pentruperioadelungidetimp.
Recomandrinutriionale(OMS)
Lipide 30%
lipidesaturate 710%
lipidemononesaturate 1015%
lipidepolinesaturate 10%
colesterol < 300mg/zi
Glucide 5055%
Proteine 1520%
NaCl < 5g/zi
Recomandri nutriionale(AHA)
Pine, cereale, orez, paste finoase, mmlig, 611 porii/zi; aceste alimente ofer
glucidecomplexe,fibrealimentare,riboflavin,tiamin,niacin,fier,proteine,magneziuialinutrieni;
Legume,zarzavaturi,cartofi,35porii/zi;acestealimenteconinfibre,vitaminaA,vitaminaC,
folai,potasiuimagneziu.Serecomandafifolosite,decteoriesteposibil,proaspeteicrude.
Fructe, 24 porii/zi; suntosursbogatdefibre,vitaminaA,vitaminaCipotasiu.Serecomanda
ficonsumate,pectesteposibil,crudeiproaspete.
Carne,pete,fasoleboabe,ouifructeoleaginoase,23porii/zi;acestealimentesunt
bogate n proteine, fosfor, vitamina B6, vitamina B12, zinc, magneziu, fier, niacin i tiamin. Se
recomandconsumuldecarnedepui,curcan,carneslabdeporcsaudevitipete.
Lapte,iaurt,brnz,23porii/zi;acesteproduseauavantajuldeafibogatencalciu,riboflavin,
proteine,vitaminaB12,iarcndsuntfortificateinvitaminaDiA.
Grsimi,uleiuriidulciuri,moderat, zahruligrsimeasuntbogatecaloricdar,nacelaitimp,
suntsracennutrimente,ceeacejustificlimitareaconsumuluilor.
Dup DeFronzoRA.BrJDiabetesVascDis. 2003;3(suppl1):S24S40
Hiperglicemie progresia bolii
Sulfonilureice
Meglitinide
Insulino-
rezisten
Disfuncie
-celular
(secreia de
glucagon)
Aportul alimentar
de glucide
Inhibitori de
-Glucozidaz
TZD
Metformin
Declin cronic
-celular
Insulino-
deficien
? ?
Tratamentuldiabetuluizaharattip2
Factori
predispozanti
Obezitate
IGT Diabet Complicatii
DezvoltareaDZdetip2:
IGT: imapired glucose tolerance (Toleranta Alterata la Glucoza)
International Diabetes Centre, Minneapolis, USA
Ani
20 10 0 10 20 30
Glicemia postprandiala
Glicemia -jeune
Rezistenta la insulina
Nivelul insulinei
120
100
G
l
u
c
o
z
a

p
l
a
s
m
a
t
i
c
a

(
m
g
/
d
L
)
F
u
n
c
t
i
a

c
e
l
.

-
p
a
n
c
r
e
a
t
i
c
e

(
%
)
Preventie primara Preventie secundara Preventie tertiara
Ceesteexact?
disfunctia -
celulara
Reducerea masei
celulare
Disfunctia progresiva a celulei
ambele
sau
sau
DZ tip 2 afeciune progresiv
n evoluie, majoritatea
persoanelor cu diabet vor
necesita insulin pentru
obinerea controlului
glicemic optim!
Caracteristicidezirabilealemedicaiei
antihiperglicemiceorale
Controlglicemicdurabil
Frriscdehipoglicemie
Aciunibeneficeasuprametabolismuluilipidic
Tolerabilitatebuniprofildesiguran
Regimsimpludedozare
UtillaunnumrmaredepacienicuDZ2
Reducereamorbiditii/mortalitiicardiovasculareimicrovasculare
PPAR=peroxisome proliferator-activated receptor agonist
Adaptat dupa Williams G, Pickup JC, eds. Handbook of Diabetes, 3rd ed. Malden, MA: Blackwell Publishing, 2004; DeFronzo RA Ann Intern Med
1999;131:281303; Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:14271483.
TerapiicurenteinDZdetip2
CumactioneazadiferiteleADOincontrolulglicemiei
celule beta-pancreatice
ameliorarea
hiperglicemiei
Sulfoniluree
Meglitinide
incretine
stimuleaza eliberarea
de insulina
Gut
inhibitori de alfa-glicozidaza
intarzie eliberarea glucozei in sange
muschi ficat
PPAR (tiazolidindione
sau glitazone)
Biguanide
Insulina
inhiba productia de glucoza
PPAR (tiazolidindione
sau glitazone)
Biguanide
Insulina
stimuleaza preluarea de glucoza
NoitinteterapeuticepentruDZ2
Nature 414, 821 - 827 (2001)
Tratamentulcuantidiabeticeorale
Medicamentecarescadrezistenalainsulin
biguanide
thiazolidinedione
Medicamentecarecrescsecreiapancreaticdeinsulin
sulfonilureice
reglatoriprandialiaiglicemiei
incretine
Medicamentecarescadabsorbiaintestinaldeglucoz
inhibitoridealfaglucozidaz
Medicamentecarescadrezistenalainsulin
Biguanidele
Mecanismdeaciune
Efecteadverse
Contraindicaii
Preparate:
fenformin
metformin:Meguan,Siofor,Metfogamma,Metformin
(1cp=500mg,850mg;dozamaxim=2550mg)
buformin:SilubinRetard
(1cp=100mg;dozamaxim=300mg)
TerapiicurenteinDZdetip2
Biguanidele (Metforminul):Mecanismde Actiune
Adaptat dupa DeFronzo RA Ann Intern Med 1999;131:281303; Kirpichnikov D et al Ann Intern Med 2002;137(1):2533; Williams G, Pickup JC,
eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004; Hundal RS et al Diabetes 2000;49(12):20632069.
Metformin
preluare crescuta de
glucoza in muschi
Reducerea insulino-
rezistentei
productie hepatica
de glucoza redusa
Mecanismul exact de actiune este necunoscut
Reducerea glucozei
plasmatice
Mecanismeleaciuniiantihiperglicemiceametforminului
Scderea produciei hepatice de glucoz prin diminuarea glicogenolizei i a
gluconeogenezei
Stimulareacaptriimusculareaglucozeimediatdeinsulin
Cretereautilizriisplanhniceaglucozei
Scderea absorbiei intestinale a glucozei Inhibiia lipolizei i scderea
nivelelordeacizigrailiberi,urmatdeameliorareacicluluiRandle
Mecanismelecelularearfi:
Creterealegriiinsulineidereceptori
Stimulareaactivitiitirozinkinazeiareceptorilorinsulinici
Amplificarea transportului celular al glucozei prin activarea transportului
GLUT4
Cretereaactivitiiglicogensintetazei
TerapiicurenteinDZdetip2
Biguanide(Metformin):Caracteristicigenerale
Mecanismdeactiune
Eficacitatea depinde
de
Dozaj
Efectesecundare
Risculmajor
Adaptat dupa Kirpichnikov D et al Ann Intern Med 2002;137(1):2533; DeFronzo RA Ann Intern Med 1999;131:281303; Glucophage/
Glucophage XRprescribing information, Bristol-Myers Squibb, April 2003; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed.
Malden, MA: Blackwell Publishing, 2004.
Primar: reduc productia hepatica
de glucoza
Secundar: cresc aportul periferic
de glucoza
Prezenta insulinei
1-2 ori pe zi cu mancare
greata, anorexie, diaree
acidoza lactica
Contraindicaiilemetforminuluinterapia persoanelorcu
diabetzaharattip2
Insuficienrenal:creatininaseric 1.4mg/dllafemeisau
1.5mg/dllabrbai
Insuficiencardiaccongestivcarenecesitfarmacoterapie
Hepatopatiicronicecutransaminazecedepescde3ori
valoareasuperioaranormalului
Bolnaviipeste80anidacclearanceulscadesub70ml/min
Sarcinailactaia
Diabetulzaharattip1
Persoaneledependentedealcoolsaucuconsumexcesivde
alcool
Traumatismesevere,infeciisistemice,oc
DeficitdevitaminaB12
Tiazolidindionele
ActivatoriaiPPAR
Crescinsulinosensibilitatealaniveladipocitarihepatic
Efectepemetabolismulglucidicilipidic
Efecteasupraadipogenezeiihomeostazieienergetice
Implicareninflamaieiaterotromboz
TerapiicurenteinDZdetip2
Agonistii PPAR :Caracteristicigenerale
crescsensibilitateatesuturilorlainsulina
prezentainsulinei
odatasaudedouaoripezi
cresteriingreutate,edeme,anemie
ICC;nevoiademonitorizareaenzimelorhepatice
Adapted from Actosprescribing information, Takeda Pharmaceuticals, December 2003; Avandiaprescribing information, GlaxoSmithKline,
May 2004; DeFronzo RA Ann Intern Med 1999;131:281303; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell
Publishing, 2004.
Mecanism de actiune
Eficacitatea depinde de
Dozaj
Efecte secundare
Risc major
Tiazolidindionele(glitazonele)
Mecanismdeaciune:PPAR (peroxisomeproliferator activated
receptors)
Efecteadverse
Preparate:
troglitazona
pioglitazona(Actos)
(1cp=15;30;45mg)
rosiglitazona(Avandia)(1cp=4mg;dozamaxim=8mg)
TerapiicurenteinDZdetip2
PPAR Agonistii:Mecanismde Actiune
modifica factorii de
insulino-senzitivitate (ex., adiponectina)
modifica expresia/actiunea
factorilor de insulino-rezistenta
(ex., resistina/TNF)
tesut
adipos
Agonist
PPAR
modifica preluarea AG
si lipoliza
modifica AG
liberi
adipocite mici,
insulino-senzitive
modifica adipozitatea
viscerala
modifica expresia
genica in
adipocite
Modifica
actiunea
insulinei
PPAR = Peroxisome Proliferator-Activated Receptor Gamma
Adaptat dupa Moller DE Nature 2001;414:821828.
Ficat
Muschi
scheletic
FamiliaPPAR
PPAR /
Adapted from Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669.
Ligand
Effect
Receptor
Leukotrienes
Fibrates
Prostaglandins
Thiazolidinediones
Fatty Acids
Glucose
Metabolism
Vascular Effects Fat
Differentiation/
Redistribution
PPAR
Fat Oxidation
PPAR
HDL Reverse
Cholesterol Trans
Fat Oxidation
PPAR agonist
stocare mai eficienta a AGL
Mai putini AGL in
Pancreas
imbunatateste
functia -cel
Muschi
imbunatateste actiunea
insulinei
creste captarea glucozei
Ficat
descreste
productia de
glucoza
BeneficiilefiziologicealeagonistilorPPAR
TZD+PPAR
incelulaadipoasa
Stocaj mai eficient a AGL in adipocite
nivelul circulator al AGL
imbunatatesc metabolismul glucidic
in ficat si muschi
protectie -celulara de efectele
toxice ale AGL
reduce suprasarcinape
pancreas
TerapiicurenteinDZdetip2
Sulfonilureele:Caracteristicigenerale
Mecanism de actiune
Eficacitatea depinde de
Dozare
Efecte secundare
Riscul principal
Adaptat dupa Siconolfi-Baez L et al Diabetes Care 1990;13(suppl 3):28; Riddle MC Am Fam Physician 1999;60(9):26132620; DeFronzo RA
Ann Intern Med 1999;131:281303; Glynaseprescribing information, Pharmacia Corporation, April 2002; Glucotrolprescribing information,
Pfizer, 2000; Glucotrol XLprescribing information, Pfizer, 2003.
cresc eliberarea de insulina
functionalitatea celulelor beta
o data sau de doua ori pe zi
crestere in greutate
hipoglicemie
TerapiicurenteinDZdetip2
Sulfonilureele:MecanismdeActiune
K=potasiu; ATP=adenozina trifosfat; ADP=adenozina fosfat; VDCC= canal Ca
2+
voltaj-dependent
Adaptat dupa Siconolfi-Baez L et al Diabetes Care 1990;13(suppl 3):28.
Sulfoniluree: situl
de actiune
VDCC
Proinsulina
Ca
2+
celula beta pancreatica
Glucoza
Metabolism
ATP
ADP
Insulina
Generare
K
+
K
ATP

Secreie de
insulin
Depolarizare
Canale K
ATP
nchise
K
+
Ashcroft, Gribble, Diabetologia (1999) 42: 903-919
Sulfoniluree
Influx de
Ca
2+
q
Ca
2+
glucoz
SuIfonilureele
SuIfonilureele

moddeac
moddeac

iunepancreatic
iunepancreatic
Sulfamida
hipoglicemiant
Alte denumiri
comerciale
T 1/2
(ore)
Durata
de
aciune
Dozazilnic
(mg)
Eliminare
urinar
(%)
Risc
hipo
SulfonilureicedingeneraiaI
Tolbutamid Orinaze 7 610 5003000 100 +++
Clorpropamid Diabinese 35 2472 100500 9095 ++++
SulfonilureicedingeneraiaII
Glibenclamid
Glibenclamid
micronizat
Maninil, Daonil
Euglucon
Maninil1,75;3,5
5

1216

2,515
1,7510,5
50 ++++
Glipizid

GlipizidGITS
Minidiab
Glucotrol
GlucotrolXL
6 1214
540
2,520
70 +
Gliclazida

GliclazidMR
Diamicron
Diaprel,Predian
DiaprelMR30
10 612
40320
30120
6070 +
Gliquidona Glurenorm 2 57 1590 5 +
Glimepirida* Amaryl 7 1012 36 80 +
* Considerat de unii autori prima sulfamid hipoglicemiant de generaia a treia dat fiind
existenaunorefecteperiferice(scdereglicemiccuminimcretereainsulinemiei).
Reglatoriiprandialiaiglicemiei
Acelaimecanismdeaciunecaalsulfonilureicelor
Duratscurtdeaciune
Rischipoglicemicredus
Omasodoz,niciomasniciodoz
Preparate: Repaglinida(NovoNorm;0,5 1 2mg)
Nateglinida(Starlix)
TerapiicurenteinDZdetip2
Meglitinide:Caracteristicigenerale
Mecanismdeactiune
Eficacitateadepindede
Dozare
Efectesecundare
Risculprincipal
Adaptat dupa Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004; Riddle MC Am Fam
Physician 1999;60(9):26132620; Del Prato S et al Diabetes Care 2003;26(7):20752080; Starlixprescribing information, Novartis
Pharmaceuticals, December 2000; DeFronzo RA Ann Intern Med 1999;131:281303.
cresc eliberarea de insulina
functionalitatea celulelor beta
de 2-4 ori pe zi,cu alimente
crestere in greutate
Hipoglicemii
Definitiaincretinelor
Hormoniintestinalicarecrescsecretiadeinsulina
stimulatadeglucoza
In

cret

in
Intestine Secretion Insulin
Creutzfeldt. Diabetologia. 1985;28:565.
ActiuneaGLP1
L cell
GLP-1
Glucose Glucose
Enterocyte Enterocyte
Pancreas: Pancreas:
Insulin Insulin
Glucagon Glucagon
Stomach: Stomach:
Motility Motility
Hypothalamus: Hypothalamus:
Appetite Appetite
GLP1indiabet
AgonistidereceptoriGLP1(mimetics)
Posedacaracteristicifiziologicesiactivitatebiologicanativa
casiGLP1darrezistentladegradareadecatreDPPIV
Exenatide(exendin4) Byetta
AnalogiideGLP1
Duratadeviatacrescutaprinmodificareamoleculeicasafie
rezistentsladegradareadecatreDPPIV
Liraglutide Victoza
Drucker. Diabetes Care. 2003;26:2929.
Dungan. Clin Diabetes. 2005;23:56.
EfectelecreteriiconcentraieiplasmaticeaGLP1
Russell-Jones D. Br J Diabetes Vasc Dis 2010;10:21-30.
TerapiacuGLP1:
Mimeazafiziologia
Source: Kieffer & Habener (1999): Endocrine Reviews 20: 876-913
EfecteleadministrriiGLP1lapersoanecuDZtip2
Irwin N et al. Br J Diabetes Vasc Dis 2009;9:44-52.
Metodedecretereainsulinosecreiei
Irwin N et al.
Br J Diabetes Vasc Dis
2009;9:44-52.
EfecteleSUiGLP1asupracelulelorpancreatice
Irwin N et al. Br J Diabetes Vasc Dis 2009;9:44-52.
InhibitoriiDPP4
Aport
alimentar
Eliberare
de GLP-1
GLP-1 biologic activ
Inhibitor
DPP-4
GLP-1 inactiv
D
P
P
-
4
RothenbergPetal.Diabetes2000;49(suppl1):A39.
Agentifarmacologicinoi
Drug Class,
Research Name
Generic Name Manufacturer Status
DPP-IV Inhibitors
LAF237
MK-0431
BMS477118
Vildagliptin
Sitagliptin
Saxagliptin
Novartis
Merck
BMS
Phase 3
Phase 3
Phase 3
GLP-1 Receptor
Agonists
Mimetics
Exendin-4
Analogues
NN2211
CJC-1131
ZP10
Albugon
Exenatide
Liraglutide
Not determined
Not determined
Not determined
Amylin/Lilly
Novo Nordisk
ConjuChem
Sanofi-Aventis
Human Genome
Sciences
FDA-approved
Phase 2
Phase 2
Phase 2
Phase 2
Medicamentecarescadabsorbiaintestinalde
glucoz
Inhibitoriidealfaglucozidaz
Mecanismdeaciune
Efecteadverse
Preparate
acarboza(Glucobay,1cp=50;100mg;dozamaxim=300mg)
miglitolul
TerapiicurenteinDZdetip2
Inhibitoriidealfaglicozidaza:CaracteristiciGenerale
Mecanismdeactiune
Eficacitateadepinde de
Dozare
Efectesecundare
Risculprincipal
Adaptat dupa Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:14271483; DeFronzo RA Ann
Intern Med 1999;131:281303; Glysetprescribing information, Bayer Corporation, July 2003.
intarzie absorbtia carbohidratilor
functionalitatea celulelor beta
de trei ori pe zi la inceputul
meselor
balonari, disconfort abdominal,
diaree, flatulenta
Cresteri ale enzimelor hepatice
(rare)
TerapiicurenteinDZdetip2
Inhibitoriidealfaglicozidaza:MecanismdeActiune
inhibitiafazeifinaleadigestieiCH
la nivelulmarginiiinperieintestinale
Adaptat dupa DeFronzo RA Ann Intern Med 1999;131:281303; Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia:
Saunders, 2003:14271483.
intarzie absorbtia carbohidratilor
intarzie eliberarea glucozei in circulatie, permitand celulelor beta
sa elibereze insulina corespunzator eliberarii glucozei
inhibitor de alfa-glucozidaza
Glucobay

acioneaznonsistemicpentruantrzia
absorbiacarbohidrailor
Partea
superioar a
intestinului
subire
Partea
inferioar a
intestinului
subire
Fr
Glucobay

Absorbia
carbohidrailor
Carbohidrai
Stomac
Cu
Glucobay

Absorbia
carbohidrailor
AvantajelesidezavantajeleADO
Clasa Avantaje Dezavantaje
Sulfonilureice Cresc secretia de insulina
(diabetic normo sau
subponderal)
Pret scazut
Hipoglicemie
Crestere in
greutate
Meglitinide Cresc secretia de insulina
(diabetic normo sau
subponderal)
Scad glicemia postprandiala
Mai putine hipoglicemii decit
sulfonilureicele
Necesita doze
zilnice multiple
Scumpe
Biguanide Nu determina hipoglicemie in
monoterapie
Nu determina crestere in
greutate
Efect potential benefic asupra
profilului lipidic
Amelioreaza utilizarea insulinei
(la obezi)
Efecte secundare
gastro-intestinale
Contraindicate in
afectiuni frecvente
la virstnici:
insuficienta renala,
insuficienta
cardiaca
AvantajelesidezavantajeleADO(continuare)
Clasa Avantaje Dezavantaje
Inhibitori de
alfa-glucozidaza
Nu determina hipoglicemie in
monoterapie
Nu determina crestere in
greutate
Absorbtie sistemica redusa
Scad glicemia postprandiala
Efecte secundare
gastrointestinale
Necesita multiple
doze zilnice
Determina o
scadere mai mica a
HbA1c decit alte
clase de
medicamente
Tiazolidindione Amelioreaza utilizarea
insulinei (la obezi)
Efect pozitiv asupra
trigliceridelor si HDL
u determina hipoglicemie in
monoterapie
Crestere in
greutate
Crestere a LDL
Necesita o
monitorizare
frecventa a
functiei hepatice
Scumpe
Diferenteintreterapiilecurente
Efecteterapeuticesilimitari
Adaptat dupa DeFronzo RA Ann Intern Med 1999;131:281303; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA:
Blackwell Publishing, 2004; Holz GG, Chepurny OG Curr Med Chem 2003;10(22):24712483; Meneilly GS Diabetes Care 2003;26(10):
28352841; Ahrn B et al Diabetes Care 2002;25(5):869875; Moller DE Nature 2001;414:821828.
Clasa
Efect
terapeutic
primar Limitari
Sulfonyluree + HbA
1c
Hipoglicemie, cresteri in greutate
Meglitinide + PPG Hipoglicemie, cresteri in greutate
Biguanide (metformin) + HbA
1c
efecte adverse GI, acidoza lactica (rar)
PPARs + HbA
1c
cresteri in greutate, edeme, anemie,
potential pentru toxicitate hepatica
inhibitori de alfa-
glucosidaza
+ PPG efecte adverse GI
Insulina + HbA
1c
adiminstrare injectabila, hipoglicemie,
cresteri in greutate
Analogi GLP-1 + HbA
1c
administrare injectabila, experienta limitata
Inhibitori DPP-4 + HbA
1c
experienta limitata
Diferenteintreterapiilecurente
EfectulpeCelulaBeta
Clasa Efectul pe celula beta
Sulfoniluree Stimularea secretiei de insulina;
Epuizarea celulei beta la expunerea pe termen lung
Meglitinide Stimularea secretiei de insulina;
Epuizarea celulei beta la expunerea pe termen
Biguanide (metformin) Fara efecte directe
Agonisti PPAR Efecte indirecte prin imbunatatirea insulino-senzitivitatii;
Evidente ale imbunatatirii functiei beta-celulare
inhibitori alfa-
glucozidaza
Dau timp celulei beta sa augmenteze eliberarea de
glucoza;
Fara efecte directe
Terapiile recente:
Analogi GLP-1 Prezervare si restaurare a functiei (date animale)
DPP-4 Inhibitori Prezervare si restaurare a functiei (date animale)
Adaptat dupa Buchanan TA et al Diabetes 2002;51:27962803; Ovalle F, Bell DS Diabetes Obes Metab 2002;4(1):5659; Wolffenbuttel BH,
Landgraf R Diabetes Care 1999;22(3):463467; DeFronzo RA Ann Intern Med 1999;131:281303; Ahrn B Curr Diab Rep 2003;3:365372;
Drucker DJ Expert Opin Invest Drugs 2003;12(1):87100; Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia:
Saunders, 2003:14271483; Skrumsager BK et al J Clin Pharmacol 2003;43(11):12441256.
Sumarsi Concluzii
DZdetip2estecaracterizatprin:
elibereareasiproductiadeficitaradeinsulina (disfunctiabetacelulara)
pierdereasensibilitatiilaactiuneainsulinei (insulino rezistenta)
eliberareainexcesaglucagonului(hiperproductiehepaticadeglucoza)
Fiecareclasaactioneazaprintrunmecanismunicdeactiunepentru
imbunatatireahiperglicemiei
Acestemecanismedeactiunedeterminaaparitiaaltorefecte:
Efectesecundare
Efectepeprofilullipidic
Efectepefondulbolii (ex.,efectepefunctiabetacelulara)
Optiunileterapeuticetrebuiesaiainconsiderarenevoilereale alefiecarui
pacientinparte
Adaptat dupa DeFronzo RA Ann Intern Med 1999;131:281303; Inzucchi SE JAMA 2002;287(3):360372; Doebber TW et al Biochem
Biophys Res Comm 2004;318:323328; Holz GG, Chepurny OG Curr Med Chem 2003;10(22):24712483.
n2006, ADAiEASDauelaborat
primulConsensInternaionalprivind
managementulhiperglicemiei.
inteleHbA
1c
pentrucontrolulglicemic
NiveleleHbA
1c
artrebuis fiectmaiaproapeposibildecele normale
Nivelulint minimal:<7%
Niveleleint aleHbA
1c
sunt<6.5%nEuropai<7%nUSA
1,2
1. International Diabetes Federation. Diabet Med 1999;16:71630
2. American Diabetes Association. Diabetes Care 2005;28(Suppl 1):S436
Normal Controlat Necontrolat
HbA
1c
< 6%
Europa 6.5%
USA 7%
Europa > 6.5%
USA > 7%
NiveleleHbA1clacare
seiniiaz orisemodific tratamentul
Nathan DM, et al. Diabetologia 2006;49:171121
Normal Controlat Necontrolat
< 6% <7.0% 7%
Seiniiaz ori
modific tratamentul
laniveleHbA
1c
7%
Alegereaagentuluiterapeutic
Normal Diabet necontrolat
HbA
1c
< 6% < 7.5% > 8.5%
SEADAUG UNAGENT
cupotenialmairedusde
scdereaglicemieioricu
debutmailentalaciunii
SEADAUG UNAGENT
cuefectmaiputernicdescdere
aglicemieisauseiniiaz terapia
combinat
Nathan DM, et al. Diabetologia 2006;49:171121
2006:Managementactiviintroducereaprecoceainsulinei
bazale
Modificat dupa Nathan DM, et al. Diabetologia 2006;49:171121
HbA
1c
7%
HbA
1c
7%
HbA
1c
7%
OSV+MET
MET+ Insulina
Bazala
MET + SU
MET + TZD
MET + Insulina
Intensificat
MET + SU +
Insulina Bazala
MET + SU
+ TZD
MET + TZD +
Insulina Bazala
Insulina Intensificat +
MET + TZD
3treptepentrumeninereacontrolului
Adaptat dupa Nathan DM, et al. Diabetologia 2006;49:171121
Percepiaurgeneideatratamaieficientimairepede
Optimizare stil viata
(HbA
1c
12%)
Metformin
(HbA
1c
1.5%)
TREAPTA 1
terapia iniial
TREAPTA 2
dup 23 luni se adaug
al doilea agent
TREAPTA 3
dup 23 luni se
ajusteaz tratam.
Insulina bazala
(HbA
1c
1.52.5%)
Sulfonilureice
(HbA
1c
1.5%)
Tiazolidindione
(HbA1c 0.51.4%)
Se incepe ( intensifica)
insulino terapia
Se adauga al treilea
agent oral daca este
cost-eficient
DZ tip 2 este o boal progresiv
Adugarea medicaiei este regula pentru a menine intele terapeutice
HbA
1c
7%
HbA
1c
7%
Insulina este cea mai
eficace
Optimizareastiluluideviata+metformin
reprezintaprimatreaptaatratamentului
DIAGNOSTIC
Optimizare stil viata+ metformin
HbA
1c
7% NU DA TREAPTA1
Adaptat dupa Nathan DM, et al. Diabetologia 2006;49:171121
TREAPTA 1:
Se initiaza metformin + OSV pentru a scurta durata
perioadelor in care pacientii sunt necontrolati.
Dupa 23 luni, daca nivelele HbA
1c
sunt inca 7%,
se trece la TREAPTA 2
Insulinabazalaramanecelmaieficienttratmentdupa
insuficientaprimuluiagentoral
DIAGNOSTIC
OSV + metformin
HbA
1c
7% Nu DA
Adaugarea de insulina bazala
cel mai eficient
Adaugare sulfonilureic
cel mai ieftin
Adaugare glitazona
nu hipoglicemie
HbA
1c
7% HbA
1c
7% HbA
1c
7% NU
DA
NU DA NU DA
TREAPTA 1
TREAPTA 2
ORI
ORI
Adaptat dupa Nathan DM, et al. Diabetologia 2006;49:171121
TREAPTA 2:
Nu este un consens privind alegerea agentului secund dupa metformin;
se alege insulina basala (optiune noua), SU ori TZD
Nivelele HbA
1c
vor influenta alegerea agentului; insulina bazala va fi luata
in consideratie la nivele > 8.5%
Dupa 23 luni, daca nivelele HbA
1c
sunt 7%, se trece la TREAPTA 3
Insulinoterapiaestedeobiceinecesara
DIAGNOSTIC
OSV + metformin
HbA
1c
7% Nu Da
Adaugarea de insulina bazala-
cel mai eficien
Adaugare sulfoniluree
cel mai ieftin
Adaugare glitazone
nu hypoglicemie
HbA
1c
7% HbA
1c
7% HbA
1c
7% Nu
Da
Nu Da Nu Da
Adauga glitazone Intensificarea insulinoter Adauga insulina bazala Adauga sulfoniluree
HbA
1c
7% HbA
1c
7% Nu Da Nu Da
Insulinoterapie intensiva + metformin glitazone
Adauga insulina basala ori
intensificarea insulinoterapiei
TREAPTA 1
TREAPTA 2
TREAPTA 3
ORI
ORI
Adaptat dupa Nathan DM, et al. Diabetologia 2006;49:171121
Se verifica HbA
1c
la 3 luni pana cand HbA
1c
<7% si apoi cel putin odata la 6 luni
Monoterapia orala
Terapia orala combinata
Terapia orala plus insulina
Structurauneitrepte
Educatie
Metformin
Stil de viata
Monitorizare,
Evaluare
Modul
N.Hancu, 2008
P
P
rincipaleleetape
rincipaleleetape

ndezvoltareainsulinoterapiei
ndezvoltareainsulinoterapiei
Descoperirea insulinei (1921)
Insuline "clasice" (convenionale) (1922)
Insuline cu aciune prelungit (1936)
Insuline NPH (1950)
Insuline nalt purificate (monocomponent) (1978)
Insuline umane (1982)
Analogi de insulin (1996)
Clasificareainsulinelor
Dupprovenien animale
detipuman
Dupduratadeaciune
cuaciune ultrarapid(analogi)
cuduratscurtdeaciune
cuaciuneintermediar
cuduratlungdeaciune
insulinepremixate
Lebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004
Preparatedeinsulin
Cuaciunerapid(ultrarapida analogideinsulin):
Ins.aspart(NovoRapid)
Ins.lispro(Humalog)
Ins.glulisine(Apidra)
Insulineumanecuaciunescurt:
ActrapidHM
HumulinR
InsumanRapid
Cuaciuneintermediar (insulineNPH):
InsulatardHM
HumulinN
InsumanBazal
Cuaciunelung (lente):
MonotardHM
HumulinL
Analogideinsulincuaciunelung:
Ins.glargine(Lantus)
Insdetemir(Levemir)
Insulinepremixate:
MixtardHM10 50
HumulinM1 5
InsumanComb25;InsumanComb50
Analogipremixai:
NovoMix30
HumalogMix25,HumalogMix50
Schemedeinsulinoterapie
Convenional
Intensificat
Insulinoterapia intensificat
Insulineprandiale
Insulinebazale
Insulinemiaplasmaticlapersoanecudiabet
Insulinemiaplasmaticlapersoanecudiabet
zaharattip1
zaharattip1

isubiec
isubiec

isnto
isnto

i
i
Momentul zilei
pmol/L
N=24 DZ1
Regular Human Insulin
Humalog
480
400
320
240
160
80
0
07:00
06:00 h 24:00 18:00
12:00
N=8 Subieci sntoi
Ciofetta M et al. Diabetes Care 1999;22(5):795-800.
Efectele insulinei in cadrul regimurilor de
tratament conventionale
Lebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004
Lebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004
Efectele insulinei in cadrul regimurilor de
tratament cu multi-injectii
Efectele insulinei in cadrul regimurilor de tratament
cu multi-injectii
Lebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004
Analogiideinsulincuaciunerapid
Insulineprandiale
Maieficientedectinsulinaregularnreducerea
hiperglicemieipostprandiale
Prin hiperglicemieipostprandiale efectmaibun
dectinsulinaregularasuprareduceriicomplicaiilor
DZ
EfectredusasupraameliorriiHbA
1c
comparativcu
insulinaregular
Riscredusdehipoglicemie
Caracteristicileanalogilordeinsulincu
aciunerapid
Disociazrapidnmonomerinesutuls.c.
Variabilitatemaimicaabsorbieidelaloculde
injectare
Variabilitatemaimicinter iintraindividual
Profilimunogenicsimilarcualinsulineiumane
Comparativcudozeechivalentedeinsulinregular:
determinoconcentraiemaximdubl
timpulncareseatingeconc.max.ede2Xmaimic
4:00
25
50
75
8:00 12:00 16:00 20:00 24:00 4:00
mic dejun prnzul cina
8:00
Glargine
sau
Detemir
timp
Aspart,
Lispro
sau
Glulisine
Aspart,
Lispro,
sau
Glulisine
Aspart,
Lispro,
sau
Glulisine
Tratamentulbazalboluscuanalogide
insulin
I
n
s
u
l
i
n
e
m
i
a

p
l
a
s
m
a
t
i
c

U
/
m
L
)

Limiteleinsulinelor umane
Administrats.c.ajungelaunmaximdeabiadup2
orenecesarinjectareacuminimum30min.
naintedemas
Duratadeaciuneestede46orehiperinsulinemie
postprandial hipoglicemie
Concentraiideinsulinnsngeleperifericmaimari
dectnsngeleportal
Administrateodatpezi,insulineleintermediarei
lentenuasigurinsulinemiebazaleficient24deore
Hiperglicemiilematinale
Subinsulinizarea
FenomenulSomogyi
Fenomenuldezori(Dawnphenomenon)
Administrareainsulinei
Ciledeadministrare
Dispozitiveledeadministrare
Autocontroluliajustareadozelor
Pompadeinsulin
Indicaiileinsulinoterapiei
Prima
pompade
insulina
IndicatiileinsulinoterapieiinDZ2
Insulinoterapiedefinitiva
DZtip1(LADA)
DZtip2lacaremedicatiaoralainasocieresiladozesuficiente
nuinducecontrolulglicemicpropus
Complicatiicroniceevolutive
Insuficienteleseveredeorgan
Insulinoterapietemporara
Afectiuniacute:IMA,infectiicudiferitelocalizari
Interventiichirurgicale(pre,intra sipostoperator)
Sarcina
Comahiperglicemicahiperosmolara
Scopurileinsulinoterapiei temporare
Restabilireapromptaechilibruluiglicemic
Anihilareaglucotoxicitii
Rereglareametabolicapacientului
IndicaiileinsulinoterapieinDZ tip2
Meninereadezechilibruluiglicemic,nciudadozelormaximede
agenioralicombinai
Complicatiicroniceevolutive
Decompensareageneratdeevenimenteintercurente(infecii,
traumatismeacutesaualtestressuri)
Managementulperioperator
Sarcinailactaia
Hepatopatiii/saunefropatii
AlergiasaualtereaciiadverseserioaselaADO
Hiperglicemiiimportantelamomentulnregistrrii
IMA
Pentruconservareamaseibetacelulare
Boulton AJM, 2000
Hncu i colab, 2001
Insulinoterapianueste:
oameninare
consecinalipseidecomplianapacientului
tratamentdeultimintenie
Insulinoterapiaeste:
terapiaindicatpacienilorcuDZtip2dacseare
nvedere:
glucotoxicitateailipotoxicitatea
insuficientaproducereainsulineiendogene
contraindicaiilaADO
Levy P, 2004
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239
Initiereainsulinoterapiei titrareainsulineibazale
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239
Initiereainsulinoterapiei titrareabolusurilorprandiale
InsulinoterapianDZtip2
Analog Bazal
sau NPH + ADO
Pre Mix 1/zi
Mix 30/70 or 50/50
+ Big / TZD
1 Injecie
Bazal Plus
R + Bazal
+ Big / TZD
Pre Mix 2/zi
Mix 30/70: 50/50
25/75
+ Big / TZD
2 Injecii
Bazal Plus Plus
R + R + Bazal
+ Big / TZD
Pre Mix 3/zi
+
Big / TZD
3 Injecii
Bazal / Bolus
R + R + R + Bazal
+ Big / TZD
4 Injecii
Efectelesecundarealeinsulinoterapiei
Hipoglicemia
Cretereangreutate
Lipodistrofia
Abceselelaloculinjeciei
Alergialainsulin
Produciadeanticorpilapreparateleinsulinice
Neuropatiadureroas (temporar)
Scdereaacuitiivizuale (temporar)
Monitorizareaglicemica
continuaprinCGMS
(ContinuousGlucose
MonitoringSystem)
Monitorizareaglicemica
continuaprinCGMS
(ContinuousGlucose
MonitoringSystem)
Tratamentuldiabetuluizaharat
DZesteoboalcronic
Obiectivulprincipal:meninereaparametrilorclinicii
biochimicispecificictmaiaproapedenormal
Tratamentultrebuieprivitnperspectivasperaneidevia
PreveniaprimaraDZtip1
Promovareaalimentriicopiluluilasn
Evitareabolilorinfecioasecupotenialdiabetogen
Evitareasubstanelortoxicepancreatotrope
Msurifarmacologice
PreveniaprimaraDZtip2
Controlulgreutii
Promovareaactivitiifizice
Dietebogatenfibreisracengrsimi
Msurifarmacologice
Preveniasecundar prevenireaapariiei
complicaiilor
Diagnosticprecoce
Controlulglicemiei(HbA1c)
Tratamentulfactorilorderiscvascular
(obezitate,dislipidemie,
hipertensiune)
Evitareafumatului
Detectareacomplicaiilorcronicen
stadiulsubclinic
Preveniateriar
Tratamentulactivalcomplicaiilor
cronice
Evitareacomplicriicomplicaiilor
Diabetzaharatsibolimetabolice
Designulcursului
Importantaproblemei
Backgroundfiziopatologic
Definitiadiabetuluizaharatsiaaltorcategoriideintoleranta la
glucoza
Diagnosticuldiabetuluizaharat(DZ)
Tipuriledediabetzaharat:definitie,etiopatogeneza,istorie
naturala
Tratamentuldiabetuluizaharat
ComplicatiileacutespecificealeDZ
ComplicatiilecronicealeDZ
Obezitatea
Dislipidemiile
Hiperuricemiile
Sd.metabolic
ComplicaiileDZ
Acute
comele hiperglicemice cetoacidozic
hiperosmolar
lactacidemic
hipoglicemic
infeciile
Cronice
microangiopatice
macroangiopatice
neuropatice
Urgenelehiperglicemicendiabetulzaharat
CETOACIDOZADIABETIC
STAREAHIPERGLICEMICHIPEROSMOLAR
elementecomune: insulinodeficiena
hiperglicemia deshidratare
Cetoacidozadiabetic insulinodeficienabsolut+ hormonilordestres
cetoz,acidoz
Stareahiperglicemichiperosmolar
insulinodeficienrelativ
hiperosmolaritate
frcetoz,fracidoz
Cauze:
Insulinodeficiena absolut
- ntreruperea insulinoterapiei
- cetoacidoz inaugural (20%)
Insulinodeficiena relativ
- afeciuni intercurente/coexistente:
infecioase (pneumonii, infecii urinare, sepsis)
accidente vasculare cerebral
infarctul miocardic acut
pancreatita acut
embolia pulmonar
ocluzia intestinal, tromboza a. mezenterice
gangrena diabetic
- endocrinopatii: tireotoxicoza, sindromul Cushing, acromegalia
- iatrogen (corticoizi, simpatomimetice)
- sarcin, stres
Cetoacidoza diabetic
Cetoacidoza
diabetic
Hiperglicemie
Acidoz
metabolic
Cetoz
diabet zaharat
HHS
STG
hiperglicemia de stres
acidoza lactic
acidoza uremic
acidoza hipercloremic
acidoza drog-indus
cetoza alcoolic
cetoza de foame
Triadacetoacidozeidiabetice
Kitabchi AE i colab, 2001
Lipoliz
Hiperproducie de
corpi cetonici
Acidoz metabolic
Pierdere de ap, K
+
PO
-
4
, baze tampon
Proteoliz
Eliberarea de alanin
i ali aminoacizi
Creterea ureei
Insuficien absolut
sau relativ de insulin
Accelerarea glicogenolizei i
neoglucogenozei
Hiperglicemie i
glicozurie
Poliurie osmotic
Deshidratare
Hiperosmolaritate
Sete
Polidispsie Aritmie Colaps
COM
Cetoacidoza diabetic
Mecanisme implicate n geneza comei ceto-acidozice
Cetoacidozadiabetic
CETOACIDOZA DIABETIC
Moderat Avansat (precom) Sever (com)
Glicemia (mg/dl)
pH arterial
RA (mEq/l)
cc urinari
cc serici
Osmolalitatea seric
Gaura anionic
Starea de contien
> 250 mg/dl
7,25 - 7,30
15 20
+
+
variabil
> 14
vigil
> 250 mg/dl
7,00 - 7,24
10 - 15
+
+
variabil
> 14
vigil/astenic
> 250 mg/dl
< 7,00
< 10
+
+
variabil
> 14
obnubilat/rar com
Deficite
hidric
Na
+
Cl
-
K
+
PO
4
10% din greutate = 6 8 litri
7-10 mEq/kg = 350 700 mEq/l
3-5 mEq/kg = 200 700 mEq/l
3-5 mEq/kg = 210 770 mEq/l
5-7 mEq/kg = 350 500 mEq/l
CETOACIDOZADIABETICESTEOURGEN
MAJOR!
Cetoacidozadiabeticpoateucidedar
moarteapoatefiprevenit prin:
Diagnosticprecoce
Monitorizare
Aplicareaghidurilorterapeutice
Tratamentulurgenelorhiperglicemice
HIDRATARE
INSULIN
GLUCOZ (GIK)
POTASIU
Terapie adiional
(antibioterapie, O
2
, etc)
Bicarbonat
Fosfat
Kahn CR, 2000
Terapiaderehidratarelapacieniicucetoacidoz
diabetic
SFnprimele4ore
SGla glicemie 250mg/dl
Ora Volum
Prima h 1h
A 2-a or
A 3-a or
A 4-a or
A 5-a or
Total primele 5 ore
Orele 6-12
1litru
1l
500 ml - 1l
500 ml 1l
500 ml 1l
3,5 5l
250 500 ml/h
Joslins Diabetes Mellitus, 2005
Terapiacuinsulin
Iniial610Uinsulinrapidiv(sau0,1U/kg)
Seevalueazglicemialafiecareor
Scdereaglicemieicu10%dinvaloareainiial(70
mg/or)
Lipsderspunsmriredozadeinsulin
Scderepreabrusc0,05U/kg/or
Terapiacupotasiu
Semonitorizeazla12ore
K
+
< 3,5mmol/lseadministreaz40 mmol/h(diureza
prezent)
K
+
=3,54,5mmol/lseadministreaz20mmol/h
K
+
=4,55,5mmol/lseadministreaz10mmol/h
K
+
> 5,5mmol/l sentrerupeadministrareaK
+
Alteterapii
bicarbonatul cupruden
lapH< 6,9 7
Glicemia< 250mg/dl soluieGIK
lapacieniicuhiperosmolaritate:soluiihipoosmolare,
heparin
TA<100mmHgdup2oredeperfuzie soluiicoloidale
Sondagastric,sondurinar
Tratamentulcetoacidozei
complicaiiiefecteadverse
Hipoglicemia(glicemie 50mg/dl) monitorizareglicemie,dozemicide
insulin,soluiiGIK;
Hipokalemia(K
+
3mEq/l) monitorizareecg,laboratordinornor;
Alcalozametabolic;acidozaparadoxalaalcr utilizareprudenta
bicarbonatului;
Insuficienacardiaccongestiv monitorizarefluide,diurez,dispnee,
raluripulmonare,msurarePVC;
Recurenedecetoacidoz insuficienatratamentuluiinsulinic;
Edemcerebral evitatprininsulinoterapiendozemici,prudennadm.
bicarbonatuluiiasol.hipotone;
Altecomplicaii AVC,IMA,nefropatieacuttubulointerstiial,colaps,
tromboembolii,aspiraiadeconinutdigestiv,sindromdedetresrespir.,
infecii.
Comahiperosmolar
Definiie
Osmolaritateplasmatic>350mOsm/l
Glicemie>600mg/dl
pH>7,25
HCO
3
>15mEq/l
Semnededeshidrataremasiv
Frecven
10%dincomelediabeticehiperglicemice
Formulenecesare
Osmolaritateaplasmatic:
2[Na
+
(mEq/l)+K
+
(mEq/l)]+glicemia(mmol/l)+ureea
(mmol/l)
Gauraanionic:
(Na
+
+K
+
) (Cl

+HCO
3

)=16
Fiziopatologie
Tablouclinic
Teren
Factorpredispozant
ASC alteraresistemosmoreglare
Debut
Etapapremonitorie
Factordeclanant
deshidratarehiperton pierdericutanateipulmonare
pierderidigestive
pierderirenale
hiperglicemiemarcat
Metabolismulhidroelectrolitic
Metabolismulapei
deshidratareglobalcuhipertonie
deshidratarepredominantintracelular
rarcolaps
Metabolismulsodiului
Na
natriuria (< 20 mEq/24h )
Metabolismulpotasiului
deficit: 400 1000mEq
prinpoliurieosmotic
hiperaldosteronism
Alteinvestigaii
Rxtoracic
Ecografieabdominal
CT
RMN
ECG
Diagnosticpozitiv
Hiperosmolaritateaplasmatic
Hiperglicemie
Semneleuneideshidratriprofunde
Semneneurologice
AbsenarespiraieiKussmaul
Absenamirosuluiacetonemicalrespiraiei
AbsenaCCurinari
Diagnosticdiferenial
Comadiabeticcetoacidozic
Lipsesc: respiraiaKussmaul
mirosuldeacetonalexpirului
CCurinari
Comalactacidemic
Comelecerebraleprimitive
Complicaii
Complicaiilegatededeshidratare
trombozevenoase
arteriale
CID
hTAsevercolaps
necroztubular IRA
Complicaiilegatedetulburrileelectrolitice
hipopotasemia
hipernatremia
Complicaiinervoase
hemoragiicerebrale
edemulcerebral
Tratament
Reechilibrarehidroelectrolitic
soluiiutilizate
cantitate
ritmdeadministrare monitorizaredebiturinar
PVC
DacTA:SF,HHC,sol.macromoleculare,snge,plasm
Insulinoterapia
Soluiidepotasiu
Heparina
Antibiotice
Tratamentulfactorilorprecipitani
Dializaextrarenal
Regulilejoculuimetabolic
1. Menine glicemialaovaloarectmaiconstant
2. Asigur,pentrusituaiiledeurgen,osursde
energie(glicogenul)carespoatfirapidfolosit
pentrufugsaulupt
3. Nuirosinimic,frezervedecombustibil(grsimii
proteine)nperioadeledebunstare
4. Foloseteoricetertippentruameninerezervele
proteice
Cahill GF. Diabetes 1971; 20: 785-799
Factoriiglucoreglatori
Hormoni glucagon
adrenalina
STH
cortizol
Neurotransmitori
Substraturisauintermediarimetabolici
glucoza
AGneesterificai
Valorilenormalealeglicemiei:
In plasm:
A jeun: < 100 mg/dl ( 5,6 mmol/l)
La 2 ore post-prandial: < 140 mg/dl (7,8 mmol/l)
In snge capilar:
A jeun: 70-90 mg/dl (4,0-5,0 mmol/l)
La 2 ore post-prandial:70-135 mg/dl (4,0-7,5 mmol/l)
Hipoglicemie: glucoza plasmatica < 50 mg/dl(2.8 mmol/l)
Hipoglicemiile
Definiiescdereavalorilorglicemieisub60mg/dlnplasma
venoas(sub50mg/dlnsngelevenostotal)
Prevalen
Clasificare uoare
medii
severe
CauzeexcesdeinsulinsaudeADOsecretagoge
scdereaaportuluiglucidic
efortfizicexcesiv
consumuldealcool
ComahipoglicemicRegulatreimilor
1 din 3 pacieni are o com hipoglicemic la un
momentdatnvia
1din3dintreacetia(10%dintotal)aavutocom
nultimulan
1 din 3 dintre acetia (23% din total) are o
perturbare sever a activitii zilnice prin come
hipoglicemicerecurente
Gale EAM. Diabetes 1985; 934-937
Frecvenaiimpactulclinical
hipoglicemiilor
PacieniicuDZ1cuunbuncontrolglicemic
numeroaseepisoadedehipoglicemiiasimptomatice
glicemii<5060mg/dl 10%dintimp
2hipoglicemiisimptomatice/sptmn
ohipoglicemiesever/ an
24%dindeceselepacienilorcuDZ1 determinatede
hipoglicemie
DatemaipuinepentruDZ2 riscde10Xmaimic
Factorideriscpentruhipoglicemia
diabeticilor
Excesdeinsulin(sauADOsecretagoge)
Aportalimentarinsuficientdeglucide
Scdereaproducieiendogenedeglucoz(alcool)
Cretereautilizriiglucozei(efortfizic)
Cretereasensibilitiilainsulin
Scdereaclearanceuluideinsulin(IRC)
Mecanismeledeaprarempotrivahipoglicemiei
scdereasecreieideinsulin
cretereasecreieipancreaticedeglucagon
stimularesimpatic secreieidecatecolamine
cretereasecreieidecortizolih.decretere
Simptome
periferice
centrale
Cazuriparticulare
hipoglicemiilenecontientizate
hipoglicemiilenocturne
Hipoglicemiilenocturne
Aparla10 56%dintrediabetici
Suntasimptomaticen2570%dincazuri
Potdurapnla6ore
Momentulapariieidepindede
regimuldeinsulin
orameseidesear
Tattersall RB. Hypoglycaemia in Clinical Diabetes 1999; 58-62
Pragurileglicemice
~83mg/dl secreiadeinsulin
~68mg/dl secreiadeglucagoniadrenalin
~67mg/dl secreiadeSTH
~58mg/dl secreiadecortizol
~54mg/dl aparsimptomeledehipoglicemie
~49mg/dl aparedisfunciacognitiv
Manifestriclinicedehipoglicemie
Simptome adrenergice Simptome de
neuroglicopenie
Transpiraii profuze Somnolen, confuzie
Palpitaii Dificulti de concentrare, de
coordonare i de vorbire
Tremurturi Tulburri de comportament
Foame Convulsii, com agitat
Diagnosticulhipoglicemiei
Simptomeisemnenespecificenecesar
documentareaniveluluiglicemicsczut
TriadaWhipple: simptomecompatibilecuhipoglicemia
concentraiaglucozeinplasm
dispariiasimptomelordupcenivelul
glicemieiestereaduslanormal
Stadializareahipoglicemiilor
Usoare( 60 mg/dl mg/dl)
Clinic- aparitia simptomelor de alarma:transpiratii,
palpitatii, tremor,foame exagerata
Medii( 60-50 mg/dl):
Clinic- semne de neuroglicopenie:vertij, somnolenta,
confuzie,tulburari de vorbire,tulburari de comportament
Severe(glicemie <25 mg%): convulsii,coma
Morbiditileasociatehipoglicemiei
Creier efectepsihice
efecteneurologice
Cordischemiemiocardic,infarct
aritmii
Ochi hemoragiivitreene
agravarearetinopatiei
Altele accidente(inclusivrutiere)
hipotermie
Complicaiilehipoglicemiilor
Accidentvascularcerebral
Infarctdemiocard
Tulburrifuncionalecerebraleminore
Encefalopatiaposthipoglicemic
Hemoragiiretinienemasive
Decerebrare
Tratamentulhipoglicemiilor
Tratamentpreventiv educaiapacientuluidiabetic
Tratamentcurativ
hipoglicemiileuoareimedii
gluciderapid +lentabsorbabile

hipoglicemiilesevere
glucozi.v.
glucagon
gluciderapid +lentabsorbabile
PACIENT
CONSTIENT:
-GLUCOZA ORALA 20-30 g
-ZAHAR
PACIENT COMATOS:
-SG 33 % 30-50 mL I.V.
-GLUCAGON I.M.,S.C.
VERIFICA GLICEMIA PESTE 15-20 MIN
COMA:
I.V. SG 10 %
SPITALIZARE
PACIENT CONSTIENT:
STABILIREA CAUZEI,
RE-EDUCARE
Fiziopatologiacontrareglriiglicemicela
diabetici
Absenascderiiconcentraieideinsulin
Disparerspunsulsecretornglucagon
Scaderspunsulsecretornadrenalin
Cerculviciosalhipoglicemieirepetate
Hipoglicemia
Scade rspunsul
fiziologic la
hipoglicemie
Scade vigilena in
recunoaterea
hipoglicemiei
Crete
vulnerabilitatea
la episoadele viitoare
Cryer PE. Diabetes 1992; 41: 255260
Severe hypoglycaemia without warning
0
50
100
Sweating and/or tremor
0
50
100
30-39 0-9 10-19 20-29 40
Duration of diabetes (years)
P
a
t
i
e
n
t
s

(
%
)
Frier BM, Fisher BM. Hypoglycaemia in Clinical Diabetes 1999; 121
Perros P, Dearz IJ. Hypoglycaemia in Clinical Diabetes 1999; 201
Factoriderisc
DZ1:
Doza inadecvata de insulina,
sulfonilureice
Aport insuficient de glucide,
nerespectarea orarului meselor
Efort fizic
Tulburari de absorbtie (
gastropareza, diaree neuropata)
Consum de alcool;
Unele medicamente
Boli endocrine concomitente
Insuficienta renala, neuropatia
autonoma
DZ2
Varsta
Bolicardiovasculare
Insuficientarenala
Reducereaconsumuluide
alimente
Consumdealcool
Medicamenteconcomitente
Diagnosticdiferential
COMA HIPO
Se instaleaza brusc
Precedata de semne autonome
si/sau neuroglicopenice
Ex. clinic:
-coma agitata, convulsii
- tegumente umede
- tahicardie, hipertensiune
- Respiratie superficiala tip
Cheyne-Stookes,fara acetona
- ROT vii, Babinski bilateral
Biologic: glicemie < 60
mg/dl,absenta acidozei I
glicozuriei
COMA HIPER
Se instaleaza pe parcursul mai
multor ore sau zile
Polidipsie, poliurie, polifagie,
scadere ponderala
Ex. clinic:
- Semne de deshidratare:tegumente
si mucoase uscate,hipotonie,
hipotensiune, ROT diminuate
- Dispnee Kssmaull, halena de
acetona
Biologic:hiperglicemie, acidoza
marcata, cetonurie, glicozurie
Infeciile
Frecventeladiabeticuldezechilibrat
Predispoziiactreinfeciiexplicatprinmodificri
legatedehiperglicemie:
mobilizriiichemotactismuluileucocitar
capacitiifagocitareapolimorfonuclearelor
capacitiibactericideapolimorfonuclearelor
funciilormonocitare
Infeciiputernicasociatediabetului (quasispecifice),severe,dar
foarterare:
mucormicozele
otitaexternmalign
pielonefritaemfizematoas
colecistitaemfizematoas
Infeciipostterapeutice:
abceseinsulinice (rare),infeciiasociatetransplantuluirenal,
dializeiperitoneale,hemodializei
InfeciinespecificeasociateDZ:
infeciiurinare:cistite,pielonefrite,abceserenale/perirenale
infeciirespiratorii
infeciicutanate,mucoase,aleesutuluicelulars.c.
altele:fasceitanecrozant,gangrenaFournieraorganelorgenitale
Diabetzaharatsibolimetabolice
Designulcursului
Importantaproblemei
Backgroundfiziopatologic
Definitiadiabetuluizaharatsiaaltorcategoriideintoleranta la
glucoza
Diagnosticuldiabetuluizaharat(DZ)
Tipuriledediabetzaharat:definitie,etiopatogeneza,istorie
naturala
Tratamentuldiabetuluizaharat
ComplicatiileacutespecificealeDZ
ComplicatiilecronicealeDZ
Obezitatea
Dislipidemiile
Hiperuricemiile
Sd.metabolic
Complicatiicronicealediabetuluizaharat
Microvascularespecifice:
Retinopatiadiabetica
Nefropatiadiabetica
Neuropatiadiabetica
Macrovasculare:aterosclerozacudiverse
localizari(cerebrale,coronariene,periferice)
Mixte:picioruldiabetic
Etiopatogenezacomplicatiilorcroniceale
diabetuluizaharat
Factoriimplicati:
Predispozitiagenetica
Duratadeevolutieadiabetului
Controlulmetabolic
Mecanismepatogenice:
Glicozilareaproteinelor
Activareacaiipoliol
Crestereaproduceriideradicaliactivi(stressoxidativ)
Modificarihemoreologice
Glicozilareaneenzimaticaproteinelor
Proporionalcu conc.glucozeidinsg.
duratamenineriiei
Glucoz+Protein+BazSchiff+ProdusAmadori
AGE (advancedglycationendproducts)
stabili
seacumuleazcaatare(RD,ND, mbtrnire)
aulocusurispecificedeaciune
potfiidentificaindiferitestructuridatorit
fluorescenei lorcaracteristice
Glicozilareaproteinelor structurale(vase,nervi,ficat,piele)
plasmatice
Glicozilarealipoproteinelor catabolismulLDL
catabolismulHDL
AGE sintezaIL1 proliferareaFb,CMN,cel.mezangiale,
endoteliale procesedegenerative
sintezaproteoglicanilorpurttoridesarcinielectrice
efectenegativeasuprafen.deatracie/respingere
intermolecular
Proteineleglicate maisusceptibilelastressuloxidativ
Glicozilareaenzimaticaproteinelor
Glicozilareaproteoglicanilor(vase,nervi,MBG)
Glicozilareacolagenului
piele:ngroare,tulburritroficecutanate
gingii:parodontopatie
muchiitendoane:cheiroartropatie
mobilitiiarticulare
inim:cardiomiopatie
nervi
cristalin
ficat
Caleapoliol
Glucoza extracelular
glucoza intracelular
aldoz-reductaz
sorbitol osmolaritatea intracelular
sorbitol-dehidrogenaz mioinozitolul intracelular
fructoz potenialul redox intracelular
Stressuloxidativ
Radicaliioxizi:oxigenulatomic,H
2
O
2
,radicalulhidroxid
Substaneleantioxidanteprimare:
proceseenzimatice:SOD,catalaz,Seglutationperoxidaz
proceseneenzimatice:
antioxidaniliposolubili:vit.E,A
antioxidanihidrosolubili:vit.C,glutationul,aciduluric
prot.plasmaticeantioxidante:transferina,ceruloplasmina
Substaneleantioxidantesecundare:
refacereaADNoxidat:NAD,vit.B12,folat,endonucleaze
refacerealipideloroxidate:fosfolipaz
refacereaproteineloroxidate:enzimeleproteolitice
Ladiabetici: substaneleoxidante
capacitateaantioxidant
Hiperglicemie autooxidareaglucozei formareaderadicali
liberiOH

altereazaciziinucleici,lipide,proteine
PeroxidareaLDLfavorizeazATS
Oxidarealipidelor circulante
dinmbr.celulare
dinteacademielin
Modificrihemoreologiceihemostatice
Rolimportantnapariiacomplicaiilormacrovasculare
Factorii procoagulani Factorii antitrombotici
Hiperreactivitate plachetar
sinteza de Tx plachetar
Fibrinogenul
Fact. von Wilebrandt
Factorii VII, VIII, X
heparansulfatului
prostaciclinei
proteinei C
trombomodulinei
fibrinolizei
Clasificarearetinopatieidiabetice
RDneproliferativa:microanevrisme,exudate
dure,microhemoragii
Controloftalmologicla1an
RDcuinteresare maculara:maculopatieischemicasau
edematoasacu/faraleziunidefond
controlFOla34luni
RDpreproliferativa:exudatemoi,hemoragii
ControlFOla23luni
RDproliferativa:neovase
ControlFOla23luni
Boalaoculara avansata:dezlipirederetina,rubeosisiridis,
glaucomneovascular
Screeningulretinopatieidiabetice
TIPUL
DIABETULUI
PRIMUL EX.
FO
EXAMINARE
DE RUTINA
DZ 1 3-5 ani de la
diagnostic
Anual
DZ 2 La momentul
diagnosticului
Anual
GRAVIDA
DIABETICA
Preconception
al si in timpul
primului
trimestru
In functie de
rezultatul la
prima
examinare
Retinafotocoagulata
Istorianaturalanefropatieidiabetice
nDZ1: evoluiaND:binedefinit
Mogensen:5stadii
nDZ2: evoluiaND:maipuinbinecaracterizat
Momentuldebutului?
Alifactori(HTA,vrstaetc.)
Mortalitatecardiovascularcrescut
StadializareaND
Ceamaisimplclasificare 3stadii:
NDincipient(microalbuminurie) 515ani
NDpatent(macroalbuminurie) 510ani
boalrenalterminal 36ani
DZ1:Mogensen,1983 clasificaren5stadii
(revizuitn1999in2000)
StadiulI hiperfuncieihipertrofierenal
AparedeladiagnosticareaDZ
Reversibilcuunbuncontrolglicemic
cu2050%aRFG(>150ml/min/1,73m
2
)
Dupechilibraremetabolic:50%FGsenormalizeaz
50%hiperfiltrareglomerular

microalbuminurie
Microalbuminurietranzitorie ndezechilibruglicemic,efortfizic
excesiv,diethiperproteic
Modificristructurale: dimensiunilorrinichiloriaglomerulilor
TAnormal
StadiulII silenios,normoalbuminuric
Aparenprimii5anideladiagnosticareaDZ
3050%trecnstadiulIIIdup57anideladebutulbolii
PBR:ngroareaMBglomerulare
expansiunemezangial
RFGsemeninecrescut(cu2050%)
REUAnormal
TAnormal
StadiulIII nefropatiadiabeticincipient
Aparedup615anideladebutulDZ
ProgresieopritsauncetinitprincontrolulglicemieiialTA
Microalbuminuriepersistent(30300mg/24ore) predicie
pentruapariiaproteinuriei
RFGeste,dar cu35ml/min/an
TAnormalsauuor ( cu3mmHg/an)
Modificrilemorfopatologiceseaccentueaz+obstrucii
glomerulare
StadiulIV nefropatiadiabeticpatentsauclinic
manifest
Aparedup1525anideladebutulDZ
Proteinurieclinic(albuminurie>300mg/24ore)
FG progresiv(cu812ml/min/an)
3substadii: precoce(FG>130ml/min)
intermediar(FG<100ml/min)
avansat(FG<70ml/min)
HTA( cu5mmHg/an)
Morfopatologic:sclerozglomerularprogresiv
distrucietreptatamaseirenale
ControlulglicemieiialTAncetineteprogresiaafectrii
renale
StadiulV insuficienarenalcronicterminal
Aparedup2530anideevoluieaDZ
Proteinuriavariabil
Eliminareadeureeurinar<10g/24ore
FG<10ml/min
TAconstant
Morfopatologic:ocluziialeglomerulilorileziuni
importantealeacestora
RoluldiagnosticuluiclinicndepistareaprecoceaND
Valori aleTA:ameeli,cefalee,acufene,fosfene
Edeme
Sughi
apetitului,greuri,vrsturi
diurezei,urinicolorate,tulburi,
cudepozitgros
Halenauremic
Anemie:paloare,asteniefizic
Semnedeinsuficiencardiac
Prezena altor complicaii ale diabetului: retinopatie,
macroangiopatie,neuropatie
numrului de hipoglicemii nejustificate i necesarului
deinsulin
Screeningulpentrumicroalbuminurie
Serecomandasefaceanual,ncepnddela:
pubertatesaudup5anideladebutulDZ1
diagnosticareaDZ2,dupcesarealizat
echilibrulglicemicisaexclusproteinuriaclinic
Min.3determinrindecursde36luni
microalbuminuriepersistent2din3determinri
ntre20200g/min
Evoluiantimpafiltratuluiglomerulariaeliminrii
urinaredealbumin
SemnificaiaclinicaEUP
DZ1 elementdeprediciepentruNDpatent
DZ2 markeralapariieiND
predictorindependentalevenimentelorcardio
vasculare
afectarevascularextins
corelaiecufactorulvonWillebrand
corelaiecuhiperhomocisteinemia
Factorii patogeniciaineuropatiei diabeticeirelaiiledintre
ei
Factori genetici/imunologici
H
I
P
E
R
G
L
I
C
E
M
I
E
Patologie capilar
Alterarea coagulrii fluxul sanguin n
vasa nervorum
Alterarea proprietilor
reologice ale sngelui
Atrofie
axonal
Glicozilarea proteinelor
Glucoza endoneural
Fructoza
Acumularea de sorbitol
Peroxidarea lipidelor
Alterarea proceselor
axoplasmatice
Disfuncie axoglial Demielinizare
segmentar
Leziuni
funcionale
sau/i
structurale ale
neuronilor
Tipurimajoredeneuropatie clasificare
funciedeetiologie
1. Neuropatie asociat cu afeciuni metabolice
2. Polineuropatii asociate cu expunerea la substane
toxice exogene
3. Polineuropatii asociate cu infecii
4. Polineuropatii asociate bolilor sistemice
5. Polineuropatia ischemic
6. Polineuropatia alergic
Kempler P, 1997
Neuropatieasociatcuafeciunimetabolice
neuropatiediabetic
alcoolic
uremic
polineuropatiadinsarcin
distrofia polineuropatiadin:
deficitdevit.B
malabsorbie
disproteinemie
sindromparaneoplazic
Kempler P, 1997
Clasificareaneuropatieidiabetice
Neuropatiasubclinic
Neuropatiaclinic
Periferic
Vegetativ(autonom)
Clasificareasistadializareaneuropatieidiabetice
ADA:ConsensusSanAntonio
Neuropatiasubclinica
Testedeelectrodiagnosticanormale
1.vitezadeconducerenervoasascazuta
2.amplitudinescazutaapotentialuluideactiuneevocatmuscular sau
nervos
Testarecantitativasenzorialaanormala
1.vibratorie/tactila
2.termalacald/rece
3.altele
Testealefunctieiautonomeanormale
1.aritmiesinusalascazuta(ratavariatieifrecventeicardiace)
2.functiesudomotoriescazuta
3.latentapupilaracrescuta
Neuropatiaclinica
Neuropatiadifuza
1.polineuropatiesenzorialasimotoriesimetricadistala
a.neuropatiaprimitivaafibrelormici
b.neuropatiaprimitivaafibrelormari
c.mixt
2.neuropatiaautonoma
a.functiepupilaraanormala
b.disfunctieautonomasudomotorie
c.neuropatieautonomagenitourinara
d.neuropatiaautonomagastrointestinala
e.neuropatiaautonomacardiovasculara
f.hipoglicemianeconstientizata
Stadializareaneuropatiei(dupaDYCK)

stadiul0(frneuropatie):niciunsimptomimai
puin de 2 anomalii la teste (incluznd funciile
autonome);
stadiul I (neuropatie asimptomatic): nici un
simptom dar 2 sau mai multe anomalii la testarea
funcional;
stadiulII(neuropatiesimptomatic):simptomede
gradmici2saumaimulteanomaliifuncionale:
stadiul III (neuropatie invalidant): simptome
invalidantei2saumaimulteanomaliifuncionale.
Istorianaturalaapolineuropatieidiabetice
Factori metabolici (Hiperglicemia)
10x10
3
Factor vascular
Neuropatia algica
Denst 8 Hiperglicemia
fibre neuropatia Neuropatia nedurer
nervoase Hiperalgezia Pierderea sensibilitatii
6 Alodinia Ataxia
Hipoestezia Insuficienta autonomica severa
partiala
4 Neuropatia
posttratament Fact. fizici
si chimici
2 Factori
neurotrofici defectivi
2-5 5-10 10-15 >15
Debutul DZ Asimptomatic Simptomatic Avansat
Ani
Factori metabolici (Hiperglicemia)
Neuropatia dureroasa
Neuropatia
hiperglicemica
Neuropatia nedureroasa
Punct
de ire-
versibilitate
Debutul DZ Asimptomatic Simptomatic
Avansat
Polineuropatiadistalsimetric
Ceamaifrecvent
Tulburridesensibilitate(hiperesteziesauhiposensibilitate)
Membreleinferioare
Evoluiecentripet
Disestezie
Anesteziedureroas
Agravarenocturn
Semnededisfuncievegetativ
Pieleuscat/aspectpseudoinflamator
Sensibilitateavibratorie/proprioceptiv
Atrofieihipotoniemuscular
Neuropatiadiabeticacut
Rar,darcaracteristicDZ
Instalareacut
Dureriintensenmembreleinferioare
Caexieneuropat
Insomnie
Depresie
Impoten
Neuropatiadiabetichiposenzitiv
Lipsescacuzelesubiective
Scdere/dispariieasensibilitiidureroas,termic,vibratorie
Alterarevariabilafunciilorvegetative
VCN
Riscdeleziunicutanate
Evaluarecantitativ:determinareapraguluideelectropercepie
Neuropatiamotorieproximalamembrelor
inferioare
Rar
Amiotrofii
Poliradiculopatiadiabetic
Instalareacut/subacut
Topireamuchilor
Mononeuropatiile
Celmaifrecvent:
nerviicranieni
Cubital
Sciaticpopliteuextern
Neuropatiiletruncale
Rare
Instalareacutsauprogresiv
Durereabdominalsautruncalunilateral
T3 T12
Neuropatia distala dureroasa
MichiganSensoryNeuropathyInventory
MSNI
cuantificareasimptomelor
largtestativalidat
chestionarcu15ntrebri
minim4rspunsuripozitivecoreleazcuneuropatia
cuantificabillaex.clinic
Rspunsulpozitivestenotatcu1punctlantrebrile:1 3,5
6,89,11 12,1415
Rspunsulnegativlantrebrile7i13estenotatcu1punct
ntrebarea4sereferlacirculaiasanguin,iarntrebarea10
laasteniageneralinusuntinclusenscorulfinal
MichiganSensoryNeuropathyInventory
MSNI
1.Vsimiipicioarelesaumembreleinferioarengeneralamorite?1Da 0Nu
2.Aiavutvreodatdurerisubformdearsurlamembreleinferioare?1Da 0Nu
3.Vsimiipicioarelesensibilelaatingere?1Da 0Nu
4.Aveticrampemuscularelanivelulpicioarelor?1Da 0Nu
5.Aiavutsenzaiedenepturlanivelulpicioarelor?1Da 0Nu
6.Simiidurerelaatingereacuplapuma?1Da0Nu
7. Ladu sunteicapabilsfaceidiferenantreapacaldicearece?0Da 1Nu
8.Aiavutvreoranlanivelulpicioarelor?1Da 0Nu
9.Mediculdvs.vaspuscaaveineuropatiediabetic?1Da 0Nu
10.Vsimiislbitnceamaimareparteatimpului?1Da 0Nu
11.Simptomelesenrutescnoaptea?1Da 0Nu
12.Vdorpicioareleatuncicndmergei?1Da 0Nu
13.Vsimiipicioarelecndmergei?0Da 1Nu
14.Pieleadelanivelulpicioareloresteuscatiarecrpturi?1Da 0Nu
15. Aisuferitvreodatvreoamputaie?1Da 0Nu
Total:______
13maximum)
MichiganDiabeticNeuropathyScore MDNS
Abordareacantitativaexaminriiclinice
neurologice
FolositnstudiuldecontinuarealDCCT
Validat
Aplicatpe8000pacieni
MichiganDiabeticNeuropathyScore MDNS
Testareapercepieivibratorii,dureroaseitactile
Diapazon,ac,monofilament
Scor:
Percepiesenzitiv:
810normal scor0
1 7reducereapercepiei scor1
absenapercepiei scor2
Reflexeosteotendinoase:
normale scor0
reduse scor1
absente scor2
Tonusmuscular:
Normal scor0
Moderatredusscor1
Sczutscor2
Foartesczutscor3
2 anormal
Sensibilitateatermic
Tratamentulneuropatieiperiferice
Echilibraremetabolicriguroas
AINS,analgeziceopioidecuaciunecentral
Tranchilizanteminore
Carbamazepina,Gabapentin
Antidepresivetriciclice
TENS,electroacupunctura
Capsaicina
Vitaminoterapia,benfotiamina,acidulalfalipoic
IonizrialemembrelorinferioarecuXilin1%ivit.B1
Balneofizioterapia(mofete,bicarbogazoase,ionizri)
Piciordiabetic infecia,ulceraiai/saudistrucia
esuturilorprofunde,asociatcuanomaliineurologiceicu
boalvascularperifericndiferitegradelanivelul
membrelorinferioare.
Boalvascularperiferic prezenasemnelor
clinicecaabsenapulsuluilapedioase,istoricdeclaudicaie
intermitent,durereanrepausi/sauanomaliilainvestigarea
vascularnoninvazivindicndalterareacirculaiei.
ConsenculInternaionalprivindPiciorulDiabetic,1999
Factorietiologicinpatogeniapicioruluidiabetic
Picior diabetic
macroangiopatie
microangiopatie
traumatism
infecie
polineuropatie
modificri structurale
scleroza Monckeberg
osteoartropatia
Kempler P (ed). Neuropathies. Nerve dysfunction of diabetic and other origin. 1996
Combinatie de :
- Lipsa senzatiiilor
- Limitarea mobilitatii articulare
- Disfunctie autonoma-->piele uscata
- Cresteri repetate de presiune
Formarea de callus
Boulton AJM et al. Neuropathic Diabetic Foot Ulcers. N Engl J Med 2004;351:48-55
Cresterea presiunii pe picior
Ulceratie plantara in zonele
de maxima presiune
Disfunctiasudomotorie
afectarea inervatiei simpatice a glandelor sudoripare cutanate
autosimpatectomie
reducerea / absenta transpiratiei - anhidroza
in principal la membrele inferioare
piele uscata poate duce la formarea de fisuri
Kempler P (ed). Neuropathies. Nerve dysfunction of diabetic and other origin. 1996
Punct de intrare pentru
microorganisme
Ulcere infectate
Vinik AI et al. Diabetic Autonomic Neuropathy. Semin Neurol 2003;23(4):365-372.
Fluxsangvincutanatdeficitar
sunturile a-v deschise; devierea
fluxului sqnguin de la piele
reducerea in amplitudine a
vasomotricitatii in diabetul zaharat
contractia ritmica a arteriolelor si
arterelor mici este perturbata
flux sangvin deficitar in circulatia
capilara
raspuns incetinit la rece, apucare si
caldura
Vinik AI et al. Diabetic Autonomic Neuropathy. Semin Neurol 2003;23(4):365-372.
Pierderea tonusului simpatic din cauza neuropatiei
Tulburari ale perfuziei
Cresterea nivelului de oxigen in
vene
leziuni aparent ischemice in ciuda
prezentei pulsurilor palpabile
cresterea temperaturii cutanate in
extremitati distal
distensie venoasa evidenta
Deschiderea shunt-urilor a-v
+
vasodilatatie periferica
Crestere substantiala a
debitului
Vinik AI et al. Dermal Neurovascular Dysfunction in Type 2 Diabetes. Diabetes Care 2001;24:1468-1475.
Consecintele hemodinamice ale vasodilatatiei arteriale si
cresterii sunturilor arterio-venoase
edem neuropatic
osteoporoza
scleroza Monckeberg
Kempler P (ed). Neuropathies. Nerve dysfunction of diabetic and other origin. 1996
- edem neuropatic, picioarele sunt calde
- la membrele inferioare, in principal la planta si gamba
- lichid interstitial in exces
Edem plantar
Probleme:
- Scaderea densitatii retelei capilare la locul leziunii
- Lichidul interstitial in exces va distanta capilarele intre ele
Rezultate:
Mai putin oxigen, nutrienti si o mai mica
indepartare a metabolitilor pe gram de tesut in
jurul leziunii
Davidson JK. The Diabetic Foot. In: Clinical Diabetes Mellitus, a problem-oriented approach. 1991.
Osteoartropatia neuropatica
Fiziopatologia afectarii neuropatice a oaselor si
articulatiilor
2 teorii
Teoria neurotraumatica Teoria neurovasculara
In absenta feed-back-ului normal
protector senzitiv, traumatisme
mecanice repetate duc la distructie
articulara progresiva
Denervatie simpatica ce duce la
vasodilatatie si hiperemie, care la
randul lor stimuleaza resorbtia
osoasa
Jones EA et al. Neuropathic Osteoarthropathy: Diagnostic Dilemmas and Differential Diagnosis. RadioGraphics 2000;20:S279-S293.
calcificarea degenerativa a tunicii
medii a arterelor mari si mijlocii
de obicei vasele extremitatilor
de obicei este benigna si subclinica
in cazuri avansate de scleroza Mockenberg a mediei, vasele pot deveni rigide si
isi pierd elasticitatea
in forma sa pura, acest proces nu conduce la ingustarea lumenului si nu apar
fenomene ischemice si embolice de ateroscleroza
totusi, in unele cazuri se suprapune ateroscleroza cu placi de fibroza ale intimei
Scleroza Monckeberg a mediei
Alberti KGMM et al. Autonomic Neuropathy. In: International Textbook of Diabetes Mellitus. 1997.
Osteoartropatianeuropatica PiciorCharcot
Osteoartropatianeuropatica PiciorCharcot
Osteoartropatianeuropatica PiciorCharcot
Osteoartropatianeuropatica PiciorCharcot
Tratament
Preventia ulcerelor la nivelul piciorului
Preventia ulcerelor la nivelul piciorului
Neuropatiaautonoma Manifestariclinice
Manifestaripupilare
Diminuareaadaptariilaintuneric
SemnArgyllRobertson
Manifestarimetabolice
Hipoglicemiineconstientizate
Manifestaricardiovasculare
Tahicardia,intolerentalaefort
Denervareacardiaca
Hipotensiuneaortostatica
Manifestarineurovasculare
Hiperhidroza
Anhidrozaplantara
Hipersudoratiagustativa
Manifestarigastrointestinale
Incetinireagoliriigastrice
Gastroparesisdiabeticorum
Diaree
constipatie
Manifestarigenitourinare
Disfunctieerectila
Vezicaneurogena
Tulburaridereglarecardiovasculara
neurogena
Tablouclinic:
vertijortostaticnesistematizatsauoscilant
evenimentesincopaleortostatice(negruinfataochilor)
sausimptomepresincopale(tremuraturiinfataochilor)
senzatiedetensiunesaudureribilateralealecenturilor
scapularesicervicale(coathangerpain)
asteniegeneralasioboseala
senzatiederecelaextremitati
insindromultahicardieposturala(STOP)inplustahicardie
subiectivadependentadeortostatism
Neuropatiacardiovascular
Manifestrilecardiovascularealeneuropatiei
Cardiace Vasculare
Tahicardie cu ritm stabil Hipotensiune ortostatic
Infarct miocardic nedureros Tulburri circulatorii cerebrale
intervalului QTc (>400 ms) Tulburri circulatorii ale
extremitilor
Tulburri de ritm Edeme ale membrelor
inferioare
Moarte subit Fenomenul non-dipping
Accidente anestezice
Neuropatiaautonomacardiaca metodedediagnostic
testelereflexelorcardiovasculare
dupaEwingsiClarck
Metoda Parametrul testat Normal
(0 pct)
La limita
(1 pct)
Anormal
(2 pct)
Investigarea functiei parasimpatice
Inspir profund si
expir
Variatia bataie cu bataie
(batai/min)
15 11 - 14 10
Manevra Valsalva Coeficient Valsalva ( rap. Intre
AV max si AV min in 15 sec la p
aer 40 mm Hg)
1,21 1,11
1,20
1,10
Trecerea din clino
in ortostatism
Rap intre AV max la a 15 bataie
si AV minima la a 30 bataie
1,04 1, 01-
1,03
1,00
Investigarea functiei simpatice
Trecere din clino
in ortostatism
Scaderea TA sistolice <10 11 - 29 30
Testul handgrip Cresterea TA diastolice > 16 11- 15 10
Hipotensiuneortostatica:masurareapresiuniisanguine
dupapatruminutedeclinostatismsi3minutede
ortostatism;rezultatpatologicincazul:
scaderiiTAsistolicecuminim20mmHgsau
scaderiiTAdiastolicecuminim10mmHgintimpulcelor3
minutedeortostatism
Sindromtahicardieposturala (STOP): masurarea
frecventeicardiacedupa4minutedeclinostatismsipeste
5minutedeortostatism,rezultatpatologicincazul
cresteriifrecventeicardiacelapeste120/min,respectivla
ocresterecuminim30/minfataderepaustimpdeminim
50%dintimpulmasurat
MonitorizareacontinuaambulatorieaTA
(ABPM)
Predictormaisensibilalriscului
cardiovascularcamasurareaindividualaa
TA
Fenomenulnondipper absentascaderii
normalenocturneaTAcu1015%fatade
ceadiurna(disfunctiesimpatica)
Parametricesecoreleazacuafectarea
organelortinta:
MediaTAmasurate
CrestereaTAmediinocturne
VariabilitateaTAmasurataindecursde30
secunde
Pressureload(nrvalorilorTAmari/nr
masuratorilorTA)
Ecocardiografia
CAN semnprecocedeDVSlapacientiiasimptomatici
DisfunctiaVSprezentala60%dinpacientiicuCANsila10%din pacientiifara
neuropatie
Disfunctiadiastolica:scadereavitezeideumplerediastolica,scaderearaportului
E/A
Disfunctiasistolica:alungireaperioadeidepreejectie,scadereatimpuluideejectie
aVS
ScintigramacuMIBG
MIBG analogstructuralde
guanetidinaceparticipalacaptarea
NElanivelulneuronilorsimpatici
postganglionari
Alterareainervatieisimpatice
adrenergiceimplicindregiunea
posterioarasiinferioaraaVS
Screeningulneuropatieiautonomecardiace
American Diabetes Association Standard of Medical Care in
Diabetes, 2007:
Screeningul CAN trebuie realizat in momentul diagnosticului DZ 2 si
la 5 ani de la diagnosticul DZ1. Testele electrofiziologice sint rareori
necesare.
CAN este cea mai studiata si mai importanta forma de NA. CAN este
sugerata de tahicardia de repaus, hipotensiunea ortostatica ( scaderea
cu mai mult de 20 mmHg a TAS la trecerea in clinostatism), precum si
de alte manifestari ale neuropatiei autonome: pupilare, sudomotorii,
gastrointestinale si genitourinare.
Screeningulneuropatieiautonomecardiace
Semne/simptome
Variabilitatea AV
AV bataie cu bataie Manevra Valsalva AV clino/orto
negativ
Testare anuala
pozitiv
Alte teste
Tulburarineurogenegastrointestinalede
motilitate
Tablouclinic
senzatiede plin precoce
greata
voma
senzatiedepresiuneabdominala
constipatie
diaree
pierdereingreutate
Manifestariclinicealeneuropatiei
digestive
Tulburarialemotilitatiiesofagiene
Tulburarialemotilitatiigastrice gastropatiadiabetica
Tulburarialemotilitatiiintetinale:
Contipatia
Diareea
Incontinentafecala
Tulburarialemotilitatiiveziculeibiliare litiazabiliaraveziculara
Tulburarialemotilitatiiesofagiene
Contractiideamplitudinescazuta
Scadereavelocitatii
Intirzereatranzituluiesofagian
Reducerea/absentaperistalticii
primare
Peristalticatertiara
ScadereatonusuluiSEI
Gastropatiadiabetica manifestariclinice
Gastroplegia
Dilatareacutaastomacului
Factorifavorizanti:stres,afectiuniintercurente,interventiichirurgicale,
administrareaatropinei
Sdrocluzivinalt
Radiografiaabdominalasimpla:stomacdilatatcunivelelichidiene
Tratament:aspiratiegastrica,alimentatieparenterala
Diagnostic
confirmareauneigoliriincompleteastomaculuisi/sau
timpuluidetrecereprelungit(gastropareze,
pseudoobstructiicronice)
Diagnosticsuplimentar
radiografieabdominalapegol
tranzitbaritatcuimaginitardivesauscintigrafiedegolire
astomaculuicuTc99m
Diagnosticdiferential
indusmedicamentos caefectsecundaranticolinergic
intrealtelelaantidepresiveletriciclice
obstructiemecanica atractuluigastrointestinal
AnomaliialemotilitatiigastricelapacientiicuDZ
Determinatedeafectareapredominanta
inervatieiparasimpatice
Anomaliialecontractiilorgastrice:
Scadereaamplitudiniicontractiilor
regiuniifundice
Scadereaamplitudiniicontractiilor
regiuniiantrale
Scadereafrecventeicontractiilorregiunii
antrale
Spasmpiloric
Perioadedecontractiicufrecventainalta
nepropagate
Gastropatiadiabetica manifestariclinice
Secoreleazaslabcugradul
intirzieriievacuariigastrice
Asimptomatica
Anorexie,satietateprecoce,
senzatiedeplenitudine
postprandiala
Greata,varsaturi(cualimente
vechi)
Controlglicemicprecar(DZ
instabil)
Gastropatiadiabetica diagnosticdiferential
Acuta
Medicamente(opiacee,
anticolinergice,levoDOPA,Ca
blocanti,octreotid,alcool)
Tulburarielectroliticesimetabolice
(hiperglicemia,hipoK,hipoMg)
Infectiivirale
Ileuspostoperator
Afectiunicritice
Cronica
DZ
Dispepsiafunctionala
Chirurgicala(vagotonia)
BRGE
Acalazia
Afectiunisistemice:LES,scleroza
sistemice,dermato/polimiozita
Afectiuniendocrine(
hipo/hipertiroidia,b.Addison)
Insuficientahepatica,IRC
Afectiunineuromusculare(AVC,b.
Parkinson)
Anorexianervoasa
Neoplazii
infectiaHIV
Gastropatiadiabetica exploraridelaborator
Scintigramagastrica
TesterespiratoriicuH,laculoza,C13
acoctanoic
Manometriagastroduodenala
RMN
Evaluarepsihologica
EGG
Tulburarialemotilitatiiintestinale
Constipatia
Diareea
Incontinentafecala
Tulburarialemotilitatiiintestinale constipatia
Manifestarefrecventaa
neuropatieiautonomedigestive
(60%)
Complicatii:ulceratii,perforare,
megacolon
Alterareareflexuluigastrocolic
Tulburarialemotilitatiiintestinale constipatia
Controlglicemic
Excludereahipotiroidiei,deshidratarii,
tulburarilorhidroelectrolitice
Istoricmedicatie
Tuseurectal,vaginal
Examenulscaunuluipentruhemoragii
oculte(3scaune) prezent:HLG,Fe,
TIBG,rectosigmoidoscopie,clisma
baritata,colonoscopie
Manometrieanorectalapentruevaluarea
tonusuluisfincteriansiareflexului
inhibitoranalptdiferentiereadisfunctiei
rectosigmoidienedehipomotilitatea
colonului
Evaluareatimpuluidetranzit markeri
radioopaci
Tulburarialemotilitatiiintestinale
diareea
Tulburarialemotilitatiiintestinale
diareea
Istoric excludereaintoleranteilalactoza,intoleranteimedicamentoase
(biguanide,inh. glucozidaza),altecauzeiatrogene
Istoric calatorii prezentatulburarilordetranzitlamembriifamiliei
Consumdealcool
APP pancreatita,LBV
Ex.coproparazitologic
Testcudxylozapentruexcludereasdrdemalabsorbtie(testscreening)
Steatoree Rgabdominalasimpla calcificaripancreatice prezente:teste
functionale
Suspiciunedeboalaceliaca Acspecifici(Acantigliadina,gluten,reticulina).
dietaglutenfreeEDS/biopsieintestinala
ExcludereaboliiCrohn tranzitbaritat
VitB12,concac.Folic
TestrespiratorcuH/testSchilling dgexacerbariiactivitatiifloreiintestinale
Hemoragiioculte prezente:EDS,colonoscopie
Tulburarivezicaleneurogene
Clasificare
tulburarialeveziciiprinleziune(I)situatedeasupraconului
medular:
tablouclinic:incotinenta,necesitateimperioasadeaurina,
polakiurie
mecanismepatologice(posibileformemixte):
hiperreflexiadetrusorului:farareziduu,fluxuretralsi
sfincterecorecte;faracomplicatii
disinergiesfincteriana/detrusor:reziduunormalsau
crescut;fluxuretralcumictiunesacadata;complicatii:
presiunepedetrusorcrescuta stagnare insuficienta
renala(mairapidadecitlaareflexiadedetrusor)
Tulburarialeveziciiinleziunialeconuluimedular,ale
coziidecalsi/saualeinervatieiperiferice:
tablouclinic:inceputgreoial
mictiunii,incontinentafarasenzatiede
presiuneavezicii
cauza:areflexiadetrusorului;reziduuvezical
incantitatemare,fluxuretralfractionat
Complicatii:supradilatare,stazaIRC
Tulburarineurogenealefunctieisexuale
masculine
Etiologie:mielopatii,sindromdecon/coadadecal,leziunide
plexsacrat,neuropatii(inspecialindiabetzaharat),boli
sistemicecuparticipareasistemuluinervosautonom,
leziunialehipotalamusului,efectemedicamentoase
nedorite
Tablouclinic
libidoredus
tulburarideerectie(erectiaspontana mentinuta=indiciu
detulburarepsihogena)
ejaculareretrogada
Tulburarialesudoratiei
Clasificaresietiologie
hiperhidrozaprimara
hiperhidrozasecundara
hipo/anhidroza
Tablouclinic
hiposauanhidroza
regional(etajulsuperior,accentuatelaextremitatisau
trunchi)respectivgeneralizatsauhiperhidroza:local
(facial,axilar,palmar,plantar),respectivgeneralizat
Sumar al manifestarilor de disfunctie autonoma in
diabet
Sudomotor
- transpiratie gustativa: inervatie aberanta a glandelor
sudoripare faciale
- anhidrosis-hyperhidrosis: degenarare preferentiala a
fibrelor lungi din membrele inferioare
Vasomotor
- afectarea fibrelor vasoconstrictive simpatice cu rasunet
pe vasoconstrictie/vasodilatatie
Pedal edema
Davidson JK. Diabetic Autonomic Neuropathy. In: Clinical Diabetes Mellitus, 1991
Metodeterapeuticenpolineuropatiadiabetic
Mecanismpatogenic
Inhibitoriidealdozreductaz
Acidlinolenic
Antioxidani acidlipoic,vitaminaE
VasodilatatoareinhibitoriACE,analogideprostaciclin
Factoridecreterenervoas(NGF)
Aminoguanidine
Simptomatice
Antiinflamatoriinesteroidiene
Antidepresivetriciclice
Anticonvulsivante
Mexiletin
Tramadol
Capsaicinlocal
Efectealetratamentuluicuacidlipoic
Agentantioxidant;
Normalizareavitezeideconducerenervoas;
fluxuluisanguinlanivelulvasanervorum;
niveluluiglutationului.
Reducereaperoxidriilipideloresutuluineural.
Nagamatsuicolab.,1995;Nickandericolab.,1996.
Amelioreazdeficituldeneuropeptide(NPY)
Garretticolab.,1997
Crete preluareaiutilizareaglucozeilanivelulmiocardului;
debitulcardiac;
preluareaglucozeilanivelneural;
ratametabolismului;
coninutulnmioinozitol.
Strodter,1995;Low,1997;Cotter,1998.
ScadeactivitateafactoruluidetranscripieNFkB induceexpresiagenelorendotelinei
1iafactoruluitisular.
Bierhausicolab.,1997
mbunteteinsulinosensibilitatea.
Jacobicolab.,1995,1996
Confirmrialeeficieneiterapeuticeaaciduluilipoic
NSS:NeuropathySymptom Score(sauTSS) evaluareasimptomatologiei
NIS: Neuropathy Impairment Score evaluarea deficitului neurologic
sensibilitateatermic,tactil,dureroas,vibratorie,reflexeosteotendinoase.
NDS: Neuropathy Disability Score evaluarea deficitului neurologic, mai ales n
scopepidemiologic.
HPAL: Hamburg Pain Adjective List chestionar ce cuprinde 37 de adjective
pentruadescriedurerea.
QST:Quantitative SensoryTesting
Frecvena
simptomelor
Intensitatea simptomelor
absente redus moderat sever
Ocazional
Frecvent
(Aproape) continuu
0 1,00 2,00 3,00
0 1,33 2,33 3,33
0 1,66 2,66 3,66
Adapted from Cohen JD. Lancet. 2001;357:972-3.
B
Beta-blockade
Blood pressure control
A
Aspirin
ACE inhibition
A1C control
C
Cholesterol management
D
Diet
Dont smoke
E
Exercise
ABCsofcoronaryprevention
Strategiapreventionala2009
0 3 5 140 5 3 0
0
Nefumator
3
Mers 3 km zilnic sau orice activitate moderata 30
min/zi
5
Portii de fructe sau vegetale zilnic
140
TA sub 140 mmHg sistolica
5
Colesterolul total < 5 mmol/l (190 mg/zi)
3
LDL colesterol < 3 mmol/l (130 mg/l)
0
Evitarea supraponderii si diabetului
PPG
Postprandial
glucose
FPG
Fasting Glucose
HbA
1c
Glucose
TRIADE
Triadaexplorariiglicemice
Post-prandial
hyperglycaemia
Post-prandial
hyperglycaemia
contributes HbA
1c
~1%
B=breakfast; L=lunch; D=dinner.
Adapted from Riddle MC. Diabetes Care. 1990;13:676-686.
P
l
a
s
m
a

g
l
u
c
o
s
e

(
m
g
/
d
L
)
300
200
100
0
Time of day (h)
6 12 18 24 6
Uncontrolled Diabetes HbA
1c
8%
Fasting
hyperglycaemia
Basal hyperglycaemia
contributes ~2%

B

L

D
Normal
HbA
1c
~5%
ComponentelecresteriiHbA1c
DCCT Group. Diabetes 1995;44:96883.
24
20
16
12
8
4
0
1 2 3 4 5 6 7 8 9
Mean HbA
1c
= 11%
10%
9%
8%
7%
DCCT study time (y)
P
r
o
g
r
e
s
s
i
o
n

r
a
t
e

p
e
r

1
0
0

p
a
t
i
e
n
t
-
y
e
a
r
s
Risk of retinopathy progression vs. mean HbA
1c
StudiulDCCT:complicatiimicrovascularein
functiedenivelulHbA
1c
0.05
0.00
0.15
0.10
0.45
0.20
D
e
n
s
i
t
y

e
s
t
i
m
a
t
e
0.25
0.30
0.35
0.40
5 6 7 8 9 10 11 12 13 14
Glycosylated haemoglobin (%)
Intensive group:
Mean HbA
1c
7.1%
Mean blood glucose 8.6 mmol/l
Conventional group:
Mean HbA
1c
9.0%
Mean blood glucose 12.8 mmol/l
StudiulDCCT:controlulglicemiccutratamentconventional
siintensivcuinsulina
DCCT Group. Diabetes 1995;44:96883.
Conventional group
Intensive group
12
10
8
6
DCCT
Closeout
1 2 3 4 5 6 7 8
p<0.001 p<0.001 p<0.001 p=0.002 p=0.04 p=0.08 p=0.04 p=0.58 p=0.83
EDIC year
H
b
A
1
c
%
ControlulglicemicinstudiulEDIC(de
urmarireasubiectilordinDCCT)
EDIC Group. Diabetes Care 1999;22:99111.
EDIC study time (y)
0 1 2 3 4 5 6 7
0
0.1
0.2
0.3
0.4
0.5
C
u
m
u
l
a
t
i
v
e

i
n
c
i
d
e
n
c
e
Conventional group
Intensive group
Reducerereasustinutaarisculuidecomplicatii
croniceprinameliorareainitialaacontrolului
glicemic studiulEDIC
DCCT/EDIC Group. JAMA 2002;287:2563.
Diabetzaharatsibolimetabolice
Designulcursului
Importantaproblemei
Backgroundfiziopatologic
Definitiadiabetuluizaharatsiaaltorcategoriideintoleranta la
glucoza
Diagnosticuldiabetuluizaharat(DZ)
Tipuriledediabetzaharat:definitie,etiopatogeneza,istorie
naturala
Tratamentuldiabetuluizaharat
ComplicatiileacutespecificealeDZ
ComplicatiilecronicealeDZ
Obezitatea
Dislipidemiile
Hiperuricemiile
Sd.metabolic
Dislipidemiile
Definireatermenilor
Dislipidemii
Hiperlipidemii
Valorilenormale
colesterolserictotal<190mg/dl(<5mmol/l)
triglicerideserice<180mg/dl(<2mmol/l)
colesterol HDL>40mg/dl(>1mmol/l)
colesterol LDL<115mg/dl(<3mmol/l)
Obiectiveleterapeutice
Importanadislipidemiilor
Impactulepidemiologic
bolipopulaionale
nRomnia:55%dinpopulaiantre20i60ani
Impactulbiologic:risccardiovascular
riscdepancreatitacut
Impactuleconomic
Lipoproteinele
Asocierimoleculare dintrediferitecomponentelipidicesanguine
(TG,colesterol,fosfolipide,AG)iproteinelecirculante
Constituitedin:
parteatransportat:AGesterificaisubformdeTGiesteri
decolesterol
transportorul:apoproteine
Rolulapoproteinelor:
structural
funcional:legareadereceptori
activareasauinhibareaunorenzime
(LPL,LCAT)
StructuraLipoproteinelor
Free cholesterol
Phospholipid
Triglyceride
Cholesteryl ester
Apolipoprotein
Clasemajorelipoproteice
Chilomicronii 90%TG
VLDL 60%TG,12%colesterol
IDL formetranzitorii;30%colesterol,40%TG
LDL 60%colesterol
fenotipA
fenotipB
fenotipintermediar
HDL
Clasificareadislipidemiilor(Frederickson)
TipulIchilomicronemiebazal
TipulIIa hiper LDL
TipulIIb hiper LDLihiper VLDL
TipulIII cuIDLncondiiibazale
TipulIV hiperVLDL
TipulVchilomicronemiebazal+ hiper VLDL
TipulVI hiper HDL
Clasificareadislipidemiilor
(AsociaiaEuropeandeateroscleroz)
Forma de dislipidemie Colesterol
(mg/dl)
Trigliceride
(mg/dl)
Hipercolesterolemie
- de grani
- moderat
- sever
190-249
250-300
> 300
< 180
< 180
< 180
Hipertrigliceridemie
- moderat
- sever
< 190
< 190
180-400
> 400
Hiperlipidemie mixt
- moderat
- sever
190-300
> 300
180-400
> 400
Etiopatogeniadislipidemiilor
Factorigenetici
defectcromozomialmonogenic (ex.HLPtipIIa)
defectcromozomial poligenic
Factorictigai
exceselealimentare
abuzuldealcool
fumatul
sedentarismul
stressul
obezitatea
diverseboli:DZdezechilibrat,hipotiroidismul,sdr.
Nefrotic,colestaza
unelemedicamente:corticoizii,contraceptiveleorale
Mecanismepatogenetice
Cretereasintezeisauproducieilipoproteice
diethipercaloric,hiperlipidic,hipercolesterolic,
bogatnglucidesimple fluxuldeAGLspreficat
VLDL IDLiLDL
Diminuareacatabolismuluilipoproteic
activitiiLPL hiperchilomicronemiei/sau VLDL
absenareceptorilorLDLsauactivitiilor LDL
anomaliialeApoE IDLnumaisuntrecunoscutede
receptoriiLDLhiperlipidemiamixtsever
Combinareamaimultorfactoriimecanismedeproducere
Subfractiile LDL
Lamarche B, et al. Diabetes Med. 1999; 25:199-211.
Tribble DL, et al. Atherosclerosis. 1992; 93:189-199.
Anber V, et al., Atherosclerosis. 1996; 124: 261-271
ParticuleleLDLmiciidense
Seasociazcuunrisccoronariantriplu
Aterogenicitatealoresteatribuit:
1. AfinitiilormairedusepentrureceptorulLDL:auo
remanencrescutncirculaie
2. Abilitiilordeaptrundemairepedenperetelearterial
3. Susceptibilitiilorcrescutelaoxidare
4. Adereneilormaicrescutefadeproteoglicaniidin
peretelearterial
Austin M et al. Circulation. 1990;82:495-506.
0
10
20
30
40
50
60
70
80
90
100
20 40 60 80 100120140160180200220240260280300 500
Fenotip A
Fenotip B
Frecvena
Cumulativ
%
TG (mg/dl)
HiperTGsecoreleaz cuconcentraiicrescutede LDL
miciidense
L
D
L
m
i
c
/
d
e
n
s
L
D
L
m
a
r
e
/
f
l
o
t
a
n
t
Austin M et al. Circulation. 1990;82:495-506.
20 25 30 35 40 45 50 55 60 65 70 75 80
Fenotip A
Fenotip B
Frecvena
Cumulativ
%
HDL-C (mg/dl)
100
90
80
70
60
50
40
30
20
HDL redus se asociaz cu concentraie crescut
de LDL mici i dense
L
D
L
m
i
c
/
d
e
n
s
L
D
L
m
a
r
e
/
f
l
o
t
a
n
t
Tablouclinic
Xantoame detiperuptiv,tendinos,tuberos,palmar
Xantelasma
Arccornean
Lipemiaretinalis
Dureriabdominale,manifestridepancreatit
ManifestrialeATScerebrale,coronarieneiperiferice
Simptomeosteoarticulare(rar)
Investigaiiparaclinice
Apreciereaaspectuluiplasmeisauseruluidup24deorede
larecoltareipstrarelafrigider(+4
0
C)
DozareacolesteroluluitotaliaTG
DozareaHDLcolesterolului
CalcululLDLcolesterolului(formulaluiFriedwald):
LDLcol=colesteroltotal HDLcol TG/5(mg/dl)
LDLcol=colesteroltotal HDLcol TG/2,2(mmol/l)
Condiie:TG<400mg/dl
Altemetode(electroforeza,ultracentrifugarea,dozarea
apoproteinelor)
Depistareadislipidemiilor
Ideal:screeningsistematiclantreagapopulaiecuvrsta>20
ani
Practic:lagrupelecurisccrescut
Grupelecurisccrescutlacareserecomand
depistareadislipidemiilor
1. Bolnavicubolicardiovasculareaterosclerotice
2. Persoanecufactoriderisccardiovascular
3. Persoanecuarccorneansauxantomatoz
4. RudeledegradulIalepersoanelordelapunctele1i2
Dislipidemiileaterogene
Hipercolesterolemiedegrani(190249mg/dl)
Hipertrigliceridemie>180mg/dl
ScdereacolesteroluluiHDL<40mg/dllabrbai
<50mg/dlla femei
ModificareaLDLcaredevinmiciidense
Dislipidemiilesecundare
Hipercolesterolemii hipotiroidie,colestaz,sindromnefrotic,
sarcin,medicaiecutiazideiprogesteron
Hipertrigliceridemie DZnecontrolat,sindromnefrotic,
insuficienrenalcronic,paraproteinemie
Hiperlipidemiemixt DZnecontrolat,sindromnefrotic,
medicaiecutiazide,corticosteroizi,progestageni
Managementuldislipidemiilor
Stabilireaobiectivelor
Optimizareastiluluidevia
dietahipolipidic
exerciiulfizic
Tratamentulmedicamentos
Principiiledieteihipolipidice
Adaptareaaportuluicaloricnfunciedenecesitiigreutatea
corporal
Reducereaaportuluicaloricprovenitdinlipide<30%
Scderealipidelorsaturatela1/3dintotalullipidelor
Lipidelemononesaturateicelepolinesaturate(formacis)vor
reprezentabazaaportuluilipidic(cte1/3)
Scdereaaportuluidecolesterol<300mg/zi
Cretereaaportuluideglucidecomplexe(5055%)
Fibrelealimentare 2030g/zi
Glucidelesimple 10%dinnecesarulcaloric
Alcoolulvafisuspendatsaumultlimitat
Evitareafumatului
Dietatrebuienegociat cupacientul
Controlla3luni
Scadecolesterolulcu1020%
Exerciiulfizic
Scadetrigliceridele
CreteHDLcolesterolul
Tratamentulmedicamentos
Rezinele(Colestiramina)
Mecanismdeaciune
blocheazcircuitulenterohepaticalacizilorbiliari
activeaztransformareacolesteroluluinacizibiliari
stimuleazcaptareaLDLpecaleareceptorilorLDL
Efectesecundare disconfortabdominal,constipaie,diaree,
cretereaTG, absorbieialtormedicamente
Contraindicaii obstruciebiliarcomplet,ulcerpeptic,
sarcin
Monitorizare leucocite
Acidulnicotiniciderivaii(Acipimox)
Mecanismdeaciune
inhibeliberareaAGdindepozite
sintezaisecreiadeVLDL
Efectesecundare prurit,greuri,congestiafeei,vrsturi
Contraindicaii insuficienhepatic,infarctmiocardicrecent,
cardiopatiecongestiv,gut,sarcin,ulcergastric
Monitorizare glicemie,testefuncionalehepatice, aciduric
Uleiuldepete
ConineAGpolinesaturaiomega3
InhibsintezaisecreiadeVLDL
Fibraii
Mecanismdeaciune
PPAR exprimareageneiLPL
exprimareageneiApoAIiApoAII
diminuareageneiApoC
activeazLPL
stimuleazcatabolismulLDLiVLDL
inhiblipolizaTGdinadipocite
concentraiaLDLmiciidense
HDLdevolumcrescut
hiperlipemiapostprandial
fibrinogenul efectantitrombogen
Statinele
Mecanismdeaciune
inhibHMGCoAreductaza,decisintezacolesterolului
sintezareceptorilorLDL,decicatabolizareaacestuia
procentuldeLDLmiciidense
oxidabilitateaLDL
fibrinogenul,Lp(a),PAI1efectefavorabilepesistemuldecoagulare
fibrinoliz
Efectesecundare flatulen, enzimelorhepaticeimusculare,erupii
Contraindicaiibolihepaticeactive,sarcin,alptare
Monitorizare testefuncionalehepatice,creatinkinaza
Preparate rosuvastatin,atorvastatin,simvastatin,pravastatin,lovastatin,
fluvastatin
Indicaiideutilizareaclaselordehipolipemiante
Tipul de hiperlipidemie Prima alegere Alternativ
Hipercolesterolemie Statine Rezine, acid
nicotinic, fibrai
Hipertrigliceridemie Fibrai Acid nicotinic, ulei
de pete
Hiperlipidemie mixt Fibrai, statine Acid nicotinic
Asocieri medicamentoase recomandate
Colestiramin + statine
Fibrai + statine
Statineleinhibdoarproduciadecolesterol
Slide 400
Cifrele (mg/zi) corespund unei diete vestice tipice
*i esut extrahepatic
Adaptare dup Champe PC, Harvey RA. In: Biochemistry. 2nd ed. Philadelphia: Lippincott Raven; 1994:163170,205228; Glew RH. In: Devlin
TM, ed. Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728777; Rader DJ, Hobbs HH. In: Kasper DL, et
al, eds. Harrisons Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:22862298; Shepherd J. Eur Heart J Suppl. 2001;3(suppl
E):E2E5; Bays H. Expert Opin Investig Drugs. 2002;11:15871604; Hopfer U. In: Devlin TM, ed. Textbook of Biochemistry with Clinical
Correlations. 5th ed. New York: Wiley-Liss, 2002:10821115.
Statin
esuturi
extrahepatice
Colesterol din diet
Sinteza hepatic*
Excreie
1000 mg/zi
~300 mg/zi700 mg/zi
Intestin
Absorbie
Colesterol biliar
~1000 mg/zi
Inhibareaabsorbieiiproducieidecolesterolcu
ezetimib+simvastatin
Slide 401
Cifrele (mg/zi) corespund unei diete vestice tipice
*i esut extrahepatic
Adaptare dup Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott Raven; 1994:163170, 205228; Glew RH. Textbook of
Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss; 2002:728777; Rader DJ, Hobbs HH. Harrisons Principles of Internal
Medicine. 16th ed. New York: McGraw-Hill; 2005:22862298; Shepherd J. Eur Heart J Suppl. 2001;3(suppl E):E2E5; Bays H. Expert Opin Investig
Drugs. 2002;11:15871604; Hopfer U. Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss; 2002:10821115.
Statin
esut
extrahepatic
Colesterol din diet
Sinteza
hepatic*
Excreie
~800 mg/zi
~700 mg/zi
Absorbie
~700 mg/zi
~300 mg/zi700 mg/zi
Intestin
Ezetimib
Colesterol biliar
~1000 mg/zi
Efectelipidice alenormolipemiantelor
LDL-C HDL-C TG
FIBRAI +
5 20%
qq
10 20%
+++
20 50%
STATINE +++
18 55%
q
5 15%
+
7 30%
ATP III
ClasificareagreutiinfunciedevalorileIMC (kg/m
2
)
Subponder al < 18,5
Nor mal 18,5 - 24,9
Supr aponder al 25 29,9
Obezi t at e gr adul I 30 34,9
Obezi t at e gr adul I I 35 39,9
Obezi t at e gr adul I I I 40
Obezitatea ginoida
Obezitatea androida
Obezitate central
Hiperlipidemie Intolerana la glucoz Hipertensiune
Ateroscleroz
Insulinorezisten
TNF
AGL portal Adipocitokine
PAI-1
Creterea sintezei
de lipoproteine
Mecanismul prin care adipozitatea visceral induce
multipli factori de risc
Grupa de risc Descriere
Risc sczut
Antropometrie
IMC 25-29 kg/m
2
cu talia < 94 cm (brbai)
i
< 80 cm (femei)
Riscul cardiovascular
Estimat < 2 factori de risc
Cuantificat < 10%
Risc crescut
Antropometrie
IMC 25-29 kg/m
2
sau < 25 kg/m
2
cu talia
94-101 cm la brbai i 80-87 cm la femei
Riscul cardiovascular
Estimat 2 factori de risc
Cuantificat 10-20%
Grupele de risc ale obezitii
(Hncu N 1998)
Comorbiditi ce
induc morbiditate
ntr-o msur mai
mare dect
mortali-tate
Artroze
Litiaz biliar
Disfuncie vezical
Probleme psihologice (depresie, statut social sczut,
omaj, dezinserie social)
Nivelul sczut al activitii fizice
Comorbiditi ce
determin indirect
mortalitate, mai ales
prin boal
cardiovascular
Apneea obstructiv de somn i alte tipuri de
hipoventilaie nocturn
Diabetul zaharat
Dislipidemia (hipertrigliceridemie, scderea HDL-
colestero-lului, LDL mici i dense)
Hipertensiune arterial
Boala tromboembolic
Comorbiditi ce
deter-min direct
mortalitate
Boala cardio-vascular (inclusiv cardiomiopatiile)
Cancere favorizate de obezitate (cancer de colon,
uterin, ovarian, de vezic biliar)
Principalele comorbiditi ale obezitii i riscul de
morbiditate i mortalitate
Obiectiveletratamentuluinobezitate
Hill JO 2000
IMC (kg/m
2
) Co-morbiditi Tratament
> 27 Da sau nu

Educaie privind schimbarea
stilului de via
> 30 Nu Educaie i program de
modificare a obiceiurilor

> 30 Da

Educaie, program de modificare
a obiceiurilor i medicamente

> 35

Da sau nu Medicamente indicate; alte
intervenii agresive cum ar fi
dietele hipocalorice
> 40 Da Toate cele enumerate anterior i
metode chirurgicale


Obezul: persoan nemulumit de
greutatea sa corporal i cu dorina
de a slbi
Model estetic de referin
Convingerea modificrii
duratei de via
Dinamica creterii ponderale
Timp
Mas gras
Mas slab
Creterea intrrilor energetice
Echilibru
Noul echilibru
IN
IN
OUT OUT
Dup Y.Schutz
Cerculviciosnterapiainadecvataobezitii
TRATAMENTE:
neindividualizate
neadecvate
comerciale
PACIENTUL
OBEZ
ACCENTUAREA OBEZITII
CRETEREA DISTRIBUIEI
DE TIP ABDOMINAL
MODIFICAREA
COMPOZIIEI CORPULUI
MASA GRAS
MASA SLAB
SLBIRE
RAPID
REDUCEREA ACCENTUAT
A MASEI SLABE
TULBURRI DE
COMPORTAMENT
ALIMENTAR
GREUTATE CICLIC
CRETEREA INGESTIEI CALORICE
CRETEREA MASEI GRASE
INTRA-ABDOMINALE
CRETERE
PONDERAL
Explicaia recidivelor numeroase dup cura de slbire. Pierderile
energetice totale diminu dup slbire i sunt mai joase dect a
persoanelordeaceeaigreutatecarenuaufostniciodatobeze
(LecerfJM2001)
Mecanismuldeaciunealorlistatului
Alimentaialaomesteofunciecutrei
valene:
Energoplastic
Hedonic
Cultural
Analiza nutriional - NFS, 1995
Dieta,inactivitateaicretereaponderal
Strategiipentrumanagementulclinic
ProgramulTEME
Terapie
Educatie
Monitorizare
Evaluare
Condiiile6S
Structurat(TEME)
Standardizat(minim,rezonabil,optim)
Stratificat(primar,secundar,tertiar)
Specific(individualizat)
Sincronizat
Strategic(termenscurt,mediusilung)
Hincu N, Cerghizan A. Cardiovascular Risk
in Type 2 diabetes, Springer Verlag 2003