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

2008 diabetulzaharat
Primacauzadeorbire
Primacauzadeinsuficientarenalasiboalarenalacarenecesita

dializasitransplant
Primacauzadeamputatie
24orimaifrecventebolilecoronariene&strokesladiabeticifata

denediabetici
15aniscurtareasperanteideviatafatadenediabetici
A6acauzadedecesdintretoatebolile
The Centers for Disease Control and Prevention, USA

Proiectiiglobalealeepidemieidediabet:
20072030(milioane)

Source: Diabetes Atlas 3rd Edition. www.eatlas.idf.org.

Mortalitateadiabeticilorestedublafatade
nediabetici
Ratio2.5

Ratio2.2

Ratio2.1

35

32.0

30

MortalityRate
(Deathsper
1000
patientyears)

26.9

26.9

25
20

Control
Diabetes

15.5

15
10.8

12.5

10
5
0

10,025 61

6629 279
(PatientNumbers)

631

24

Paris
Helsinki
Whitehall
ProspectiveStudy PolicemenStudy
Study
Balkau.Lancet 1997;350:1680.

Diabetulzaharatdetip2cauzamajorade
mortalitate
Fifth leading cause of death after infections,
CVD, cancer, and accidents

Excess mortality
attributable to diabetes (%)

10
8.8

8.6

Men
Women

8
7
6.0

6.1

6.9

6.6
5.1

5.4
4.8

4
3

3.4
2.2

2.5

2
1
0

Africa

Americas

Eastern
Mediterranean

Europe

Southeast
Asia

Western
Pacific

Roglic G, et al. Diabetes Care 2005;28:21305

Rata relativa a mortalitatii functie

de varsta

Creterea numruluidedecesedatorit diabetului

140

Accident vascular cerebral

Boal Cardiovascular
Cancer
Diabet

130
120
110
100
90
80
70
60
1980

1982

1984

1986

1988

1990

1992

1994

1996

Anul
McKinlay J et al. Lancet. 2000;356:757,761.

SupravieuireapostIM lafemeileibrbaiidiabetici
estemultmaimicdectlanon diabetici
Diabetici
Non-diabetici

100

Brbai

90
80
70

n=1628

60
50
40

n=228

% supravieuitorilor

% supravieuitorilor

100

Femei

90
80
70

n=568

60
50
40

0 10 20 30 40 50 60

n=15
6

0 10 20 30 40 50 60

Luni Post-IM
Sprafka et al. Diabetes Care. 1991; 14: 537-543.

Risculcoronarianesteechivalentpentrudiabeticiipentru
nediabeticiicuunIMinantecedente
Incidena IM fatal i non-fatal de-a lungul a 7 ani de urmrire
ntr-o cohort finlandez
P < 0.001
P < 0.001

Incidena n

50%

45.0%

40%
P < 0.001

30%
20%

20.2%

18.8%

10%

3.5%

0%
Cu IM

Fr IM

Fr Diabet

Cu IM

Fr IM

Cu Diabet
Haffner SM et al, N Engl J Med 1998;339:229-234

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
nlturriiglucozeidinsnge
intrriiglucozeincelule
glicogenezei
eliberriiglucozeidindepozite
glicogenolizei
gluconeogenezei
lipolizeiicetogenezei
catabolismuluiproteic

Hormonidecontrareglare
Efectnet:cretereaglicemiei
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

Insulinosecreianormal,bifazic
prima

Plasma insulin (pm

400

A
doua
faz

faz

300

200

100

0
0

20

40

60
Time (min)

Adapted from Pratley RE, Weyer C. Diabetologia 2001; 44: 92945.

80

100

120

Rolulcentralalcanalelor
Katp ininsulinosecretie

InchidereacanaluluiKATP prinlegareaunei
moleculedeATPlaunuldincele4situsuridepe
SUR1

Semnificaiafiziologic
acelulelorbeta
Celulapancreaticfuncioneaz
caunsenzorenergetic

Glucokinaza

Metabolismul
glucozei

ATP

Declanarea
insulinosecreiei

200

oral
intravenous

90
70

z
50

z
30
z

10

z
-10
-30
0

15 30 45 60 75 90
TIME(min)

INSULIN (mU/L)

GLUCOSE (mg/100ml)

Secretiadeinsulinadupaadmglucozeiintraduodenalsi
intravenos

150

100
50

z
zz

0z

15

30 45 60
TIME (min)

75

90

Gut factors termed incretins

McIntyre et al 1964

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

Cideaciunealeinsulinei lanivelul CMN

insulina

Rc.Insul.
IRS

MAPK

migrare,prolif.cel.
mus.netede

Pi3 Kinaza

sintezeimatriciale

NO,vasodilatatie

Ef.aterogenic

Ef.antiATS
scazut

IncazurideIRsau
insulinodefic.

crescu
t

KingGL,1999

DZtip2 deficitulinsulinosecreiei
postprandiale
800
insulinosecretie (pmol/min)

Persoane nediabetice
DZ tip 2
600

400

200

0
6 am

10 am

2 pm

6 pm

10 pm

2 am

6 am

timp
PolonskyKSetal.NEnglJMed1996;334:777783

Masacel indinamica
proliferare

neogeneza

hypertrofie

apoptoza

Masacel

atrofie

AckermannAM,GannonM.J.Molec.Endocrin.2007;38:193206.

DZ2 oproblemadeechilibru
Non-Diabetic State

PERIPHERAL INSULIN

-CELL MASS

RESISTANCE

& FUNCTION

Diabetic State
S
MA S
L
L
E
-C
TION
C
N
U
&F

SULI
N
I
L
RA
I PH E
R
E
P
NCE
A
T
S
I
R ES

Chris Rhodes Ph.D.

PNRI, Seattle, WA.

ISxCFdefinescariafunctionalacaredetermina
homeostaziaglucidica

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.

Curbahiperbolicaarelatieidintre
ISxCF

IR

IS

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.

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/m2
ceicareaurudedegradulIcuDZ
grupurietnicecurisccrescut
femeilecareaunscutcopiicugreutateapeste4,5kg
femeilecareauavutdiabetgestaional
hipertensivii
ceicuHDL 35mg/dli/sautrigliceride250mg/dl
ceicuGBMsaucuSTGlatestrianterioare

Criteriile pentru diagnosticul

Diabetului zaharat

simptome clasicedediabet+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,
diagnosticultrebuieconfirmatprinrepetareaglicemieiplasmaticepenemncatentro
altzi.

Criteriideinterpretareaglicemieibazale
70110mg/dl normal
110125mg/dl glicemiebazalmodificat
126mg/dl diabetzaharatprobabil;confirmarea
sefacedupadouadozare labolnavulasimptomatic

DarNormalpredominperioadapostprandial
Legenda:
stare postprandial;
stare postabsorptiv;
a jeun

Mic dejun

Prnz

Cin

0.00am

4.00am

Mic dejun

MonnierL.EurJClinInvest2000;30 (Suppl2):311.

CriteriideinterpretareaTTGO
Glicemienplasmavenoas
Diabetzaharat
bazal
la2hdupglucoz
Scdereatoleraneilaglucoz
bazal
la2hdupglucoz

Normal
bazal
la2hdupglucoz

126mg/dl(7mmol/l)
200mg/dl(11,1mmol/l)

< 126mg/dl(7mmol/l)
140mg/dl(7,8mmol/l)i
< 200mg/dl(11,1mmol/l)

< 110mg/dl(7mmol/l)
< 140mg/dl(7,8mmol/l)

Valoridiagnosticepentrudiabetzaharatialte categoriide
hiperglicemie
Sngeintegral
venos

capilar

Plasmavenoas
mg/dl(mmol/l)

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)

100 (5,6)i
<110(<6,1)

100(5,6) i
<110(<6,1)

110( 6,1) i
<126(<7,0)

Glicemiebazalmodificat
Penemncate

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

Diagnosis and types

Curriculum Module II-1
Slide 15 of 48

Pathogenesis of type 1 diabetes

Patogenezadiabetuluizaharattip1
Trigger

Genetic

Immunological
abnormalities

Beta-cell
mass

Clinical
diabetes
Pre-diabetes

Honeymoon
Chronic
phase

Time (months - years)

Slides current until 2008

Factoriiderisc implicainpatologia
diabetuluizaharattip2
vrst (ani)
20

Normal

30
Gene

Insulino-rezisten

Ambient
40

Deficienta de secretie
a insulinei

Diabetogene
primare
secundare
Gene legate de diabet

50
Obezitate
Diet
Activitate fizic 60

Diabet tip II
Modified from Kahn R. Diabetes. 1994;43:1066-1084.

Peste80%dintrepacientiicareevolueazasprediabet
zaharatdetip2suntinsulinorezistenti
Insulin sensitive;
low insulin secretion (16%)

Insulin resistant;
low insulin secretion (54%)
Insulin sensitive;
good insulin
secretion (1%)

83%

Insulin resistant;
good insulin secretion
(29%)
Haffner SM, et al. Circulation 2000; 101:975980.

Semnedeinsulinorezistenta

Obezitatea
abdominala

Acanthosis
nigricans

Diagnosis and types

Insulin deficiency in
type 1 diabetes

Curriculum Module II-1

Slide 9 of 48

Glucose uptake
Glycogenolysis
Gluconeogenesis (amino acids)
Ketone production (fatty acids)

Blood glucose

Glucose uptake
Protein degradation amino acids
Triglyceride degradation fatty acids
Slides current until 2008

Diagnosis and types

Effect of insulin resistance in

type 2 diabetes

Curriculum Module II-1

Slide 12 of 48

Glucose uptake
Glycolysis
Gluconeogenesis (amino acids)

Blood glucose

Converted to triglycerides

Glucose uptake
Protein degradation amino acids
Glucose uptake
Slides current until 2008

Patofiziologiadiabetuluizaharat
detip2

Impaired insulin secretion

Hyperglycemia
Unsuppressed glucose production
Impaired insulin action

Decreased glucose uptake

Impaired insulin action

InsulinosecreianDZ tip2 amputareafazei

precoce

insulinosecreie (pmol/min)

800

FrDZ2
DZ2

600

400

200

0
6 am

10 am

2 pm

6 pm

10 pm

2 am

6 am

Timp
PolonskyKSetal.NEnglJMed1996;334:777783

DeclinulfuncieibetacelularenDZ tip2
100

75

-Cell
function
(%)

50

IGT

25

Postprandial
Hyperglycemia

Type 2
Diabetes
Phase I

Type 2
Diabetes
Phase II

Type 2 Diabetes
Phase III

0
-12

-10

-6

-2

10

14

Diagnosis
Years from diagnosis
Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS.
Lebovitz H. Diabetes Rev 1999;7:139153.
Holman RR. Diabetes Res Clin Pract 1998;40(suppl):S21-S25.

Numeroifactoricontribuieladeclinulprogresival
funcieicelulei pancreatice
Hiperglicemie
(glicotoxicitatea)
Insulinorezisten

Glicarea
proteinelor

Celula

Lipotoxicitate
(creterea AGL, Tg)

Efectulincretinicesteredus
inDZtip2

Cumsecombinainsulinorezistentasidisfunctiacelulara
ingenezadiabetuluizaharatdetip2?
Normal

IGT*

Type 2 diabetes

Insulin
resistance

Increased insulin
resistance

Insulin
secretion

Hyperinsulinemia,
then -cell failure

Postprandial
glucose

Abnormal
glucose tolerance

Fasting
glucose

Hyperglycemia
*IGT = impaired glucose tolerance

Adapted from Type 2 Diabetes BASICS. International Diabetes Center (IDC), Minneapolis, 2000.

Pierdereamasei celulareinistorianaturalaaDZ2

PrentkiM.,NolanCJ.J.Clin.Invest.2006;116:18021812.

InsulinorezistentasiinsulinodeficientainDZ2
Insulin
Resistance
Ins
ul
in

Ac
tio

-cell
Type 2
Diabetes Dysfunction

Insulin
Concentration

y
-cell FailureH

ia
m
e
ca
y
gl
r
pe

Insulin
Resistance
Euglycaemia
Normal

IGT obesity

Diagnosis of
type 2 diabetes

Progression of
type 2 diabetes

DeFronzo R et al. Diabetes Care 1992;15:318-68

EtiopatogeniaDZ2

Factorigenetici transmiterepoligenic
Rezistencrescutlaaciuneainsulinei
Hiperinsulinismfuncional
Deficiennsecreiainsulinic hiperglicemiepersistent
Tulburriinsulinosecretorii
caracteruluipulsatoralinsulinei
dispariiafazeiprecocearspunsuluiinsulinic
ntrziereasecreieideinsulin
Scdereaabsolut asecreieiinsulinice
DZ2insulinonecesitant

Patogenezadiabetuluizaharatdetip2

Boalapoligenica
Hiperinsulinemia
Malnutritiefetala formariicelulelorbeta
Copilcugreutatemicalanastere
thriftygene
7%scadereaceluilelorbeta/an

Epidemiologia i riscul CV n diabet

Riscpentruochi,
rinichi,nervi
Diabet

STG

RiscCV

Limitaglicemieinormale

DisglicemiaesteunfactorderiscprogresivpentruevenimenteCV

GersteinH.2003

SindromulMetabolic:Operspectiva
istorica
1988: Syndrome X
Insulin
Insulin
Resistance
Resistance

Glucose
Glucose Hyperinsulinemia TG
Hyperinsulinemia TG
Intolerance
Intolerance

Hypertension

HDL-C
HDL-C Hypertension

Coronary
Coronary Heart
Heart Disease
Disease
Reaven G. Diabetes 1988;37:1565-1607.

SindromulMetabolic:Perspectivaactuala
Body
Body Size
Size

BMI
BMI

Central
Central Adiposity
Adiposity

Insulin
Insulin Resistance
Resistance

Hyperinsulinemia
Hyperinsulinemia
Glucose
Uric
Uric Acid
Acid Dyslipidemia Hemodynamic Novel
Novel Risk
Risk
Glucose
Dyslipidemia
Hemodynamic
Metabolism
Factors
Metabolism
Factors
Metabolism Metabolism
Glucose
intolerance

Uric acid
Urinary
uric acid
clearance

TG
SNS activity CRP
PP lipemia
Na retention PAI-1
HDL-C
Fibrinogen
Hypertension
PHLA
Small, dense LDL

Coronary
Coronary Heart
Heart Disease
Disease
Adapted from Reaven G. Drugs 1999;58(suppl):19-20 with permission from WolthersKluwer Health.

Definitiialesindromuluimetabolic
WHOa

EGIRb

NCEPc

IDFd

Insulinresistance
&/or FPG

Insulinresistance
(hyperinsulinaemia

FPG

Centralobesity

Plus2ormoreof
Centralobesity

Centralobesity

Centralobesity

FPGe

BP

BP

BP

BPe,f

TG, HDLC

TG, HDLCf

TG

TGf

HDLC

HDLCf

Microalbuminuria

a:WorldHealthOrganisation;b:EuropeanGroupforthestudyof Insulinresistance;
c:NationalCholesterolEducationProgram;d:InternationalDiabetesFederation
e:ordiagnosisofdiabetesorhypertensionasapplicable;f:and/ortreatment
EschwegeE.DiabetesMetab2003;29:6S1927;InternationalDiabetesFederation

SindromulmetaboliccresterisculdeBCVsiDZ2

High
LDL-C

Metabolic
Syndrome
Type 2
Diabetes

Coronary Heart Disease

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults. JAMA 2001;285:2486-2497.

DZtip2estevarfulicebergului
Type 2 Diabetes Mellitus

Stage III

Stage II

Macroangiopathy

Microangiopathy
Postprandial
plasma glucose
Glucose production
Glucose transport
Insulin secretory deficiency

Impaired
glucose
tolerance

Stage I
Normal
glucose
tolerance

Lipogenesis
Obesity
Waist/hip ratio

Atherogenesis
Hyperinsulinemia
Insulin
resistance

Diabetes Genes

TG
HDL
HTN

Beck-Nielsen H, Groop LC. J Clin Invest. 1994;94:17141721.

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

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

<200(<5,2)

200250(5,26,5)

>250(>6,5)

<150(<1,7)

150200(1,72,2)

>200(>2,2)

<25,4
<24,0

25,027,0
24,026,0

>27,0
>26,0

Glicemia(autodeterminare)
penemncate/preprandial
postprandial[mg/dl(mmol/l)]

Colesterolserictotal
mg/dl(mmol/l)

Trigliceride
mg/dl(mmol/l)

Indexmas corporal(kg/m2)
B
F

ObiectivelemanagementuluiDZ
Mentinereasauobtinereauneistarigeneralebune,auneicalitati
optimeavietii
Disparitiasauameliorareasimptomelordehiperglicemie
Atingereatintelorcontroluluimetabolicfarariscuri
RealizareauneiHbA1c<6,5
NormalizareaTAlahipertensivi
Normalizareatablouluilipidic
PrevenireacomplicatiilorDZ
Prelungireadurateidesupravietuirepinalamedianediabeticilor,
inconditiibune

Tratamentulnonfarmacologic:terapiadietetica
(introducere)

Glucide

Metabolismulbazal

Lipide

Efortfizic

Proteine

TEF

Echilibrulenergetic

Tratamentulnonfarmacologic:terapiedietetica
(introducere)
Macronutrieni(trofinecalorigene)
glucide
proteine
Surse de energie
lipide
Micronutrieni(trofinenecalorigene)
vitamine liposolubile
hidrosolubile
minerale macroelemente
microelemente
Apa(hidratare)

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

+550

14

57

29

Femeicarealpteaz
(primele6luni)

Caracterelemacronutrienilor
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

Caracteristicilealimentelor
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.

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?
Pentru 1.600 kcal.

1 porie

1 uncie

Pentru 2.200 kcal.

Pentru 2.800 kcal.

Indexulglicemicalalimentelor

138
Glucoza
126
Mierea
115Cornflakes
100%Glucoz

100%Pinealb
Pineintegral
Piuredecartofi
9199%Muesli
Biscuii

Exempledeindex
glicemic

Piuredecartofi
Morcovi
8090%Cornflakes
Miere

Cartofi
8090%Banane
Zaharoz

Pineintegral
7079%Orez
Cartofi

7079%Chipsuri

Pinealb
Banane
6069%Muesli
Biscuii
Patiserie
Spaghetefierte5min
5059%Chipsuri
Zaharoz

Macaroane
6069%Spaghetefierte15min
Sucdeportocale

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

Repartiianutrimentelorpemese
Glucide cu index
glicemic mic

Glucide cu index
glicemic mare

Mic dejun

Da

Prnz

Cina

Lipide

Proteine

Moderat

Moderat
(colesterol
alimentar)

Da

Da

Moderat
(dup o mas
bogat n fibre)

Cantitate
redus

Da

Moderat

Nu

Da
(acizi grai
polinesaturai)

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
ncondiiilecreteriinecesaruluienergetic(sarcin,lactaie,
afeciuniintercurente)
Cntarul instrumentindispensabilpersoaneicuDZ!

Etapelealctuiriiuneidiete
Precizareacaracteristicilorgeneralealedietei
Calcululaportuluicaloric
Distribuiacaloriilorpeceletreiprincipiienergeticeia
macronutrienilorngrame.
Alegereaalimentelor
Distribuiaprincipiilorenergeticepenumruldemese
Pregtireacorectaalimentelor(regulidegastrotehnie)
INDIVIDUALIZAREADIETEI!

Tratamentuldieteticndiabetulzaharattip2

Monitorizeaz
glicemia i
medicaie

Schimb
stilul de via

Restrnge caloriile
pentru normalizarea
greutii

Controlul glicemic

Crete preocuparea
de selecie a
alimentelor

Crete
activitatea fizic
Modific cant.
de grsimi
ingerat

Respect orarul
meselor

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 evitareaconsumuluiunuianumitaliment,chiarnaltnutritiv, zi
dupzi,pentruperioadelungidetimp.

Recomandrinutriionale(OMS)

Lipide
lipidesaturate
lipidemononesaturate
lipidepolinesaturate
colesterol
Glucide
Proteine
NaCl

30%
710%
1015%
10%
< 300mg/zi
5055%
1520%
< 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,24porii/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.

Tratamentuldiabetuluizaharattip2
Aportul alimentar
de glucide

Insulinorezisten

Disfuncie
-celular
(secreia de
glucagon)

Inhibitori de
-Glucozidaz

TZD

Metformin

Insulinodeficien

Declin cronic
-celular

Sulfonilureice

Meglitinide

Hiperglicemie progresia bolii

Dup DeFronzoRA.BrJDiabetesVascDis. 2003;3(suppl1):S24S40

DezvoltareaDZdetip2:
IGT

Diabet

Complicatii

Glicemia postprandiala

Glicemia -jeune
120

Functia cel. pancreatice

(%)

Glucoza
plasmatica
(mg/dL)

Factori
predispozanti
Obezitate

Rezistenta la insulina

100

Nivelul insulinei
20

10

10

20

30

Ani

Preventie primara

IGT: imapired glucose tolerance (Toleranta Alterata la Glucoza)

International Diabetes Centre, Minneapolis, USA

Preventie secundara

Preventie tertiara

Ceesteexact?
disfunctia celulara
sau
Disfunctia progresiva a celulei

Reducerea masei
celulare

sau

ambele

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

TerapiicurenteinDZdetip2
CumactioneazadiferiteleADOincontrolulglicemiei
celule beta-pancreatice
Sulfoniluree
Meglitinide
incretine

ficat

stimuleaza eliberarea
de insulina

muschi

ameliorarea
hiperglicemiei
PPAR (tiazolidindione
sau glitazone)
Biguanide
Insulina

Gut

PPAR (tiazolidindione
sau glitazone)
Biguanide
Insulina
stimuleaza preluarea de glucoza

inhiba productia de glucoza

inhibitori de alfa-glicozidaza
intarzie eliberarea glucozei in sange

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.

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
Metformin
productie hepatica
de glucoza redusa

preluare crescuta de
glucoza in muschi
Reducerea insulinorezistentei
Reducerea glucozei
plasmatice

Mecanismul exact de actiune este necunoscut

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.

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
MecanismdeactiunePrimar: reduc productia hepatica
de glucoza
Secundar: cresc aportul periferic
Eficacitatea depinde de glucoza
de
Prezenta insulinei
Dozaj
Efectesecundare
Risculmajor

1-2 ori pe zi cu mancare

greata, anorexie, diaree
acidoza lactica

Adaptat dupa Kirpichnikov D et al Ann Intern Med 2002;137(1):2533; DeFronzo RA Ann Intern Med 1999;131:281303; Glucophage/
Glucophage XR prescribing information, Bristol-Myers Squibb, April 2003; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed.
Malden, MA: Blackwell Publishing, 2004.

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
Mecanism de actiune
Eficacitatea depinde de

crescsensibilitateatesuturilorlainsulina
prezentainsulinei

Dozaj

odatasaudedouaoripezi

Efecte secundare

cresteriingreutate,edeme,anemie

Risc major

ICC;nevoiademonitorizareaenzimelorhepatice

Adapted from Actos prescribing information, Takeda Pharmaceuticals, December 2003; Avandia prescribing 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.

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 expresia
genica in
adipocite

modifica preluarea AG
si lipoliza

Agonist

modifica AG
liberi

Muschi
scheletic

modifica factorii de
insulino-senzitivitate (ex., adiponectina)

PPAR
tesut
adipos

modifica expresia/actiunea
factorilor de insulino-rezistenta
(ex., resistina/TNF)

adipocite mici,
insulino-senzitive
modifica adipozitatea
viscerala
PPAR = Peroxisome Proliferator-Activated Receptor Gamma
Adaptat dupa Moller DE Nature 2001;414:821828.

Modifica
actiunea
insulinei

Ficat

FamiliaPPAR
Ligand

Receptor

Leukotrienes
Fibrates

Prostaglandins
Thiazolidinediones

Fatty Acids

PPAR

PPAR

PPAR /
HDL Reverse
Cholesterol Trans
Fat Oxidation

Effect

Vascular Effects

Fat Oxidation

Fat
Differentiation/
Redistribution

Adapted from Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669.

Glucose
Metabolism

BeneficiilefiziologicealeagonistilorPPAR

PPAR agonist

stocare mai eficienta a AGL

Mai putini AGL in

Pancreas

Muschi

Ficat

imbunatateste
functia -cel

imbunatateste actiunea
insulinei
creste captarea glucozei

descreste
productia de
glucoza

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

cresc eliberarea de insulina

Eficacitatea depinde de

functionalitatea celulelor beta

Dozare

o data sau de doua ori pe zi

Efecte secundare

crestere in greutate

Riscul principal

hipoglicemie

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; Glynase prescribing information, Pharmacia Corporation, April 2002; Glucotrol prescribing information,
Pfizer, 2000; Glucotrol XL prescribing information, Pfizer, 2003.

TerapiicurenteinDZdetip2
Sulfonilureele:MecanismdeActiune
Glucoza
KATP

Sulfoniluree: situl
de actiune
VDCC

Ca2+

celula beta pancreatica

Metabolism

K+

ATP
ADP

Proinsulina

Generare

Insulina
K=potasiu; ATP=adenozina trifosfat; ADP=adenozina fosfat; VDCC= canal Ca2+voltaj-dependent
Adaptat dupa Siconolfi-Baez L et al Diabetes Care 1990;13(suppl 3):28.

SuIfonilureele moddeaciunepancreatic

Sulfoniluree

Canale KATP
nchise

glucoz

K+
Ca2+

Depolarizare

Secreie de
insulin
Influx de
Ca2+
Ashcroft, Gribble, Diabetologia (1999) 42: 903-919

Sulfamida
hipoglicemiant

Alte denumiri T 1/2 Durata

comerciale
(ore) de
aciune
SulfonilureicedingeneraiaI
Tolbutamid
Orinaze
7
610
Clorpropamid
Diabinese
35
2472
SulfonilureicedingeneraiaII
Glibenclamid
Maninil, Daonil
Glibenclamid
Euglucon
5
1216
micronizat
Maninil1,75;3,5

Glipizid
Minidiab

6
1214
Glucotrol
GlipizidGITS

GlucotrolXL

Gliclazida

Diamicron
Diaprel,Predian

GliclazidMR

Gliquidona
Glimepirida*

Eliminare Risc
urinar
hipo
(%)

5003000
100500

100
9095

+++
++++

2,515

50

++++

70

6070

5
80

+
+

1,7510,5

540
2,520

10

612

DiaprelMR30

Glurenorm
Amaryl

Dozazilnic
(mg)

40320
30120

2
7

57
1012

1590
36

* 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

cresc eliberarea de insulina

Eficacitateadepindede

functionalitatea celulelor beta

Dozare

de 2-4 ori pe zi,cu alimente

Efectesecundare

crestere in greutate

Risculprincipal

Hipoglicemii

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; Starlix prescribing information, Novartis
Pharmaceuticals, December 2000; DeFronzo RA Ann Intern Med 1999;131:281303.

Definitiaincretinelor

Hormoniintestinalicarecrescsecretiadeinsulina
stimulatadeglucoza

In cret in

Intestine

Secretion

Insulin

Creutzfeldt. Diabetologia. 1985;28:565.

ActiuneaGLP1
Glucose

L cell

Enterocyte

Hypothalamus:
Appetite

GLP-1

Pancreas:
Insulin
Glucagon

Stomach:
Motility

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

DP

Inhibitor
DPP-4

P4

GLP-1 inactiv

RothenbergPetal.Diabetes2000;49(suppl1):A39.

Agentifarmacologicinoi
Drug Class,
Research Name
DPP-IV Inhibitors
LAF237
MK-0431
BMS477118
GLP-1 Receptor
Agonists
Mimetics
Exendin-4
Analogues
NN2211
CJC-1131
ZP10
Albugon

Generic Name

Manufacturer

Status

Vildagliptin
Sitagliptin
Saxagliptin

Novartis
Merck
BMS

Phase 3
Phase 3
Phase 3

Exenatide

Amylin/Lilly

FDA-approved

Liraglutide
Not determined
Not determined
Not determined

Novo Nordisk
ConjuChem
Sanofi-Aventis
Human Genome
Sciences

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

intarzie absorbtia carbohidratilor

Eficacitateadepinde de

functionalitatea celulelor beta

Dozare

de trei ori pe zi la inceputul

meselor

Efectesecundare

balonari, disconfort abdominal,

diaree, flatulenta

Risculprincipal

Cresteri ale enzimelor hepatice

(rare)

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; Glyset prescribing information, Bayer Corporation, July 2003.

TerapiicurenteinDZdetip2
Inhibitoriidealfaglicozidaza:MecanismdeActiune
inhibitor de alfa-glucozidaza

inhibitiafazeifinaleadigestieiCH
la nivelulmarginiiinperieintestinale
intarzie absorbtia carbohidratilor

intarzie eliberarea glucozei in circulatie, permitand celulelor beta

sa elibereze insulina corespunzator eliberarii glucozei
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.

Glucobay acioneaznonsistemicpentruantrzia
absorbiacarbohidrailor
Fr
Glucobay

Cu
Glucobay
Stomac

Absorbia
carbohidrailor

Partea
superioar a
intestinului
subire
Carbohidrai

Partea
inferioar a
intestinului
subire

Absorbia
carbohidrailor

AvantajelesidezavantajeleADO

Clasa
Sulfonilureice

Meglitinide

Biguanide

Avantaje
Cresc secretia de insulina
(diabetic normo sau
subponderal)
Pret scazut
Cresc secretia de insulina
(diabetic normo sau
subponderal)
Scad glicemia postprandiala
Mai putine hipoglicemii decit
sulfonilureicele
Nu determina hipoglicemie in
monoterapie
Nu determina crestere in
greutate
Efect potential benefic asupra
profilului lipidic
Amelioreaza utilizarea insulinei
(la obezi)

Dezavantaje
Hipoglicemie
Crestere in
greutate
Necesita doze
zilnice multiple
Scumpe

Efecte secundare
gastro-intestinale
Contraindicate in
afectiuni frecvente
la virstnici:
insuficienta renala,
insuficienta
cardiaca

AvantajelesidezavantajeleADO(continuare)
Clasa
Avantaje
Inhibitori de
Nu determina hipoglicemie in
alfa-glucozidaza monoterapie
Nu determina crestere in
greutate
Absorbtie sistemica redusa
Scad glicemia postprandiala

Tiazolidindione Amelioreaza utilizarea

insulinei (la obezi)
Efect pozitiv asupra
trigliceridelor si HDL
u determina hipoglicemie in
monoterapie

Dezavantaje
Efecte secundare
gastrointestinale
Necesita multiple
doze zilnice
Determina o
scadere mai mica a
HbA1c decit alte
clase de
medicamente
Crestere in
greutate
Crestere a LDL
Necesita o
monitorizare
frecventa a
functiei hepatice
Scumpe

Diferenteintreterapiilecurente
Efecteterapeuticesilimitari
Clasa

Efect
terapeutic
primar

Limitari

Sulfonyluree

HbA1c

Hipoglicemie, cresteri in greutate

Meglitinide

PPG

Hipoglicemie, cresteri in greutate

Biguanide (metformin)

HbA1c

efecte adverse GI, acidoza lactica (rar)

PPARs

HbA1c

cresteri in greutate, edeme, anemie,

potential pentru toxicitate hepatica

inhibitori de alfaglucosidaza

PPG

efecte adverse GI

Insulina

HbA1c

adiminstrare injectabila, hipoglicemie,

cresteri in greutate

Analogi GLP-1

HbA1c

administrare injectabila, experienta limitata

Inhibitori DPP-4

HbA1c

experienta limitata

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.

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 alfaglucozidaza

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.

inteleHbA1c pentrucontrolulglicemic
Normal

HbA1c < 6%

Controlat
Europa 6.5%
USA 7%

Necontrolat
Europa > 6.5%
USA > 7%

NiveleleHbA1c artrebuis fiectmaiaproapeposibildecele normale

Nivelulint minimal:<7%
Niveleleint aleHbA1c sunt<6.5%nEuropai<7%nUSA1,2

1. International Diabetes Federation. Diabet Med 1999;16:71630

2. American Diabetes Association. Diabetes Care 2005;28(Suppl 1):S436

NiveleleHbA1clacare
seiniiaz orisemodific tratamentul
Normal

< 6%

Controlat

<7.0%

Necontrolat

7%

Seiniiaz ori
modific tratamentul
laniveleHbA1c 7%

Nathan DM, et al. Diabetologia 2006;49:171121

Alegereaagentuluiterapeutic
Normal

HbA1c < 6%

Diabet necontrolat

< 7.5%

SEADAUG UNAGENT
cupotenialmairedusde
scdereaglicemieioricu
debutmailentalaciunii

> 8.5%

SEADAUG UNAGENT
cuefectmaiputernicdescdere
aglicemieisauseiniiaz terapia
combinat

Nathan DM, et al. Diabetologia 2006;49:171121

2006:Managementactiviintroducereaprecoceainsulinei
bazale
HbA1c 7%

OSV+MET
MET + SU

MET+ Insulina
Bazala

MET + TZD

MET + Insulina

MET + SU +

MET + SU

MET + TZD +

Intensificat

Insulina Bazala

+ TZD

Insulina Bazala

HbA1c 7%

HbA1c 7%

Insulina Intensificat +
MET + TZD

Modificat dupa Nathan DM, et al. Diabetologia 2006;49:171121

3treptepentrumeninereacontrolului
Percepiaurgeneideatratamaieficientimairepede
TREAPTA 1
terapia iniial

TREAPTA 2
dup 23 luni se adaug
al doilea agent

TREAPTA 3
dup 23 luni se
ajusteaz tratam.

Insulina este cea mai

eficace

Optimizare stil viata

(HbA1c 12%)
Metformin
(HbA1c 1.5%)

HbA1c
7%

Insulina bazala
(HbA1c 1.52.5%)
Sulfonilureice
(HbA1c 1.5%)

HbA1c
7%

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

Adaptat dupa Nathan DM, et al. Diabetologia 2006;49:171121

Optimizareastiluluideviata+metformin
reprezintaprimatreaptaatratamentului
DIAGNOSTIC

Optimizare stil viata+ metformin

NU

HbA1c 7%

DA

TREAPTA1

TREAPTA 1:
Se initiaza metformin + OSV pentru a scurta durata
perioadelor in care pacientii sunt necontrolati.
Dupa 23 luni, daca nivelele HbA1c sunt inca 7%,
se trece la TREAPTA 2

Adaptat dupa Nathan DM, et al. Diabetologia 2006;49:171121

Insulinabazalaramanecelmaieficienttratmentdupa
insuficientaprimuluiagentoral
DIAGNOSTIC

TREAPTA 1

OSV + metformin
Nu

HbA1c 7%

DA

TREAPTA 2
Adaugarea de insulina bazala
cel mai eficient
NU

HbA1c 7%

DA

ORI
NU

Adaugare sulfonilureic
ORI
cel mai ieftin
HbA1c 7%

DA

NU

Adaugare glitazona
nu hipoglicemie
HbA1c 7%

DA

TREAPTA 2:
Nu este un consens privind alegerea agentului secund dupa metformin;
se alege insulina basala (optiune noua), SU ori TZD
Nivelele HbA1c vor influenta alegerea agentului; insulina bazala va fi luata
in consideratie la nivele > 8.5%
Dupa 23 luni, daca nivelele HbA1c sunt 7%, se trece la TREAPTA 3
Adaptat dupa Nathan DM, et al. Diabetologia 2006;49:171121

Insulinoterapiaestedeobiceinecesara
DIAGNOSTIC

TREAPTA 1

OSV + metformin
HbA1c 7%

Nu

Da

TREAPTA 2
Adaugarea de insulina bazalacel mai eficien
Nu

HbA1c 7%

Da

Intensificarea insulinoter
Nu

Adaugare sulfoniluree
cel mai ieftin

ORI

HbA1c 7%

HbA1c 7%

Nu

Adauga glitazone
Da

Adaugare glitazone
nu hypoglicemie

ORI
Da

Nu

Adauga insulina bazala

Nu

HbA1c 7%

Da

Adauga sulfoniluree

HbA1c 7%

Da

TREAPTA 3

Adauga insulina basala ori

intensificarea insulinoterapiei
Insulinoterapie intensiva + metformin glitazone
Se verifica HbA1c la 3 luni pana cand HbA1c <7% si apoi cel putin odata la 6 luni
Adaptat dupa Nathan DM, et al. Diabetologia 2006;49:171121

Structurauneitrepte
Modul
Educatie
Stil de viata

Monitorizare,
Evaluare
Metformin
Terapia orala plus insulina
Terapia orala combinata

Monoterapia orala

N.Hancu, 2008

Principaleleetapendezvoltareainsulinoterapiei

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
zaharattip1isubiecisntoi
N=8 Subieci sntoi

N=24 DZ1
Regular Human Insulin

480

Humalog

400
320

pmol/L

240
160
80
0
07:00

12:00

18:00

24:00

06:00 h

Momentul zilei
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

Efectele insulinei in cadrul regimurilor de

tratament cu multi-injectii

Lebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004

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
EfectredusasupraameliorriiHbA1c comparativcu
insulinaregular
Riscredusdehipoglicemie

Caracteristicileanalogilordeinsulincu
aciunerapid
Disociazrapidnmonomerinesutuls.c.
Variabilitatemaimicaabsorbieidelaloculde
injectare
Variabilitatemaimicinter iintraindividual
Profilimunogenicsimilarcualinsulineiumane
Comparativcudozeechivalentedeinsulinregular:
determinoconcentraiemaximdubl
timpulncareseatingeconc.max.ede2Xmaimic

Tratamentulbazalboluscuanalogide
insulin
Insulinemia plasmatic (U/mL)

75

mic dejun

prnzul

cina

Aspart, Aspart,
Lispro Lispro,
sau
sau
Glulisine Glulisine

50

Aspart,
Lispro,
sau
Glulisine

Glargine

25

sau

Detemir
4:00

8:00

12:00

16:00

timp

20:00

24:00

4:00

8:00

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

Initiereainsulinoterapiei titrareainsulineibazale

Polonsky KS et al. N Engl J Med. 1988;318:1231-1239

Initiereainsulinoterapiei titrareabolusurilorprandiale

Polonsky KS et al. N Engl J Med. 1988;318:1231-1239

InsulinoterapianDZtip2
Analog Bazal
sau NPH + ADO

Bazal Plus
R + Bazal
+ Big / TZD

Bazal Plus Plus

R + R + Bazal
+ Big / TZD

1 Injecie

2 Injecii

3 Injecii
Bazal / Bolus
R + R + R + Bazal
+ Big / TZD

4 Injecii

Pre Mix 1/zi

Mix 30/70 or 50/50
+ Big / TZD

Pre Mix 2/zi

Mix 30/70: 50/50
25/75
+ Big / TZD

Pre Mix 3/zi

+
Big / TZD

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

Cetoacidoza diabetic
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

Triadacetoacidozeidiabetice
Acidoz
metabolic

Hiperglicemie

acidoza lactic
acidoza uremic
acidoza hipercloremic
acidoza drog-indus

diabet zaharat
HHS
STG
hiperglicemia de stres

Cetoacidoza
diabetic

Cetoz
cetoza alcoolic
cetoza de foame
Kitabchi AE i colab, 2001

Cetoacidoza diabetic
Mecanisme implicate n geneza comei ceto-acidozice
Insuficien absolut
sau relativ de insulin

Lipoliz

Proteoliz

Hiperproducie de
corpi cetonici

Acidoz metabolic
Pierdere de ap, K+
PO-4, baze tampon

Accelerarea glicogenolizei i
neoglucogenozei

Eliberarea de alanin
i ali aminoacizi
Hiperglicemie i
glicozurie

Creterea ureei

Poliurie osmotic

Deshidratare

COM

Colaps

Aritmie

Hiperosmolaritate

Sete
Polidispsie

Cetoacidozadiabetic
CETOACIDOZA DIABETIC
Moderat
Glicemia (mg/dl)
pH arterial
RA (mEq/l)
cc urinari
cc serici
Osmolalitatea seric
Gaura anionic
Starea de contien
Deficite
hidric
Na+
ClK+
PO4

> 250 mg/dl

7,25 - 7,30
15 20
+
+
variabil
> 14
vigil

Avansat (precom)
> 250 mg/dl
7,00 - 7,24
10 - 15
+
+
variabil
> 14
vigil/astenic

Sever (com)
> 250 mg/dl
< 7,00
< 10
+
+
variabil
> 14
obnubilat/rar com

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
POTASIU
GLUCOZ (GIK)
Terapie adiional
(antibioterapie, O2, etc)
Bicarbonat
Fosfat

Kahn CR, 2000

Terapiaderehidratarelapacieniicucetoacidoz
diabetic
SFnprimele4ore
SGla glicemie 250mg/dl
Ora
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

Volum
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
HCO3 >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 +HCO3 )=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

Crete
vulnerabilitatea
la episoadele viitoare

Scade rspunsul
fiziologic la
hipoglicemie

Scade vigilena in
recunoaterea
hipoglicemiei

Cryer PE. Diabetes 1992; 41: 255260

100

Sweating and/or tremor

50

Patients (%)

0
100
Severe hypoglycaemia without warning

50

0
0-9

10-19

20-29

30-39

40

Duration of diabetes (years)

Frier BM, Fisher BM. Hypoglycaemia in Clinical Diabetes 1999; 121

Perros P, Dearz IJ. Hypoglycaemia in Clinical Diabetes 1999; 201

Factoriderisc
DZ1:

DZ2

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

Varsta
Bolicardiovasculare
Insuficientarenala
Reducereaconsumuluide
alimente
Consumdealcool
Medicamenteconcomitente

Diagnosticdiferential
COMA HIPO

COMA HIPER

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

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
sorbitol-dehidrogenaz

fructoz

osmolaritatea intracelular
mioinozitolul intracelular
potenialul redox intracelular

Stressuloxidativ

Radicaliioxizi:oxigenulatomic,H2O2,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

heparansulfatului

sinteza de Tx plachetar

prostaciclinei

Fibrinogenul

proteinei C

Fact. von Wilebrandt

trombomodulinei

Factorii VII, VIII, X

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 Anual
diagnosticului

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/1,73m2)
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
numruluidehipoglicemiinejustificateinecesarului
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

Patologie capilar
Alterarea coagulrii
Alterarea proprietilor
reologice ale sngelui
Glicozilarea proteinelor

Fructoza
Acumularea de sorbitol

Peroxidarea lipidelor

Atrofie
axonal

Alterarea proceselor
axoplasmatice

Glucoza endoneural

I
E

fluxul sanguin n
vasa nervorum

Disfuncie axoglial

Leziuni
funcionale
sau/i
structurale ale
neuronilor
Demielinizare
segmentar

Tipurimajoredeneuropatie clasificare
funciedeetiologie
1. Neuropatie asociat cu afeciuni metabolice
2.
3.
4.
5.
6.

Polineuropatii asociate cu expunerea la substane

toxice exogene
Polineuropatii asociate cu infecii
Polineuropatii asociate bolilor sistemice
Polineuropatia ischemic
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
Factorimetabolici
metabolici (Hiperglicemia)
Factori
(Hiperglicemia)
10x103

Factor vascular
Neuropatia
Neuropatiadureroasa
algica

Denst 8
fibre
nervoase
6

Hiperglicemia
Neuropatia
hiperglicemica
neuropatia
Hiperalgezia
Alodinia
Hipoestezia
partiala
Neuropatia
posttratament

2-5
Debutul
DZ
Debutul
DZ

Neuropatia
nedurer
Neuropatia
nedureroasa
Pierderea sensibilitatii
Ataxia
Insuficienta autonomica severa

Punct
Fact. fizici
de iresi chimici
versibilitate

5-10
Asimptomatic
Asimptomatic
Ani

Factori
neurotrofici defectivi

10-15
Simptomatic
Simptomatic

>15
Avansat
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
microangiopatie

macroangiopatie
scleroza Monckeberg

traumatism

Picior diabetic
infecie

osteoartropatia

polineuropatie

modificri structurale

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
Cresterea presiunii pe picior
Ulceratie plantara in zonele
de maxima presiune
Boulton AJM et al. Neuropathic Diabetic Foot Ulcers. N Engl J Med 2004;351:48-55

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

Punct de intrare pentru

microorganisme

Ulcere infectate

Vinik AI et al. Diabetic Autonomic Neuropathy. Semin Neurol 2003;23(4):365-372.

Kempler P (ed). Neuropathies. Nerve dysfunction of diabetic and other origin. 1996

Fluxsangvincutanatdeficitar
Pierderea tonusului simpatic din cauza neuropatiei

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.

Tulburari ale perfuziei

Deschiderea shunt-urilor a-v
+
vasodilatatie periferica

Crestere substantiala a
debitului
Cresterea nivelului de oxigen in
vene
leziuni aparent ischemice in ciuda
prezentei pulsurilor palpabile
cresterea temperaturii cutanate in
extremitati distal
distensie venoasa evidenta
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 plantar
- edem neuropatic, picioarele sunt calde
- la membrele inferioare, in principal la planta si gamba
- lichid interstitial in exces

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.

Scleroza Monckeberg a mediei

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
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
Tahicardie cu ritm stabil

Vasculare
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
Accidente anestezice

Fenomenul non-dipping

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, 011,03

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

negativ

AV clino/orto

pozitiv

Testare anuala

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

Frecvena
simptomelor
Ocazional
Frecvent
(Aproape) continuu

absente
0
0
0

Intensitatea simptomelor
redus
moderat
1,00
1,33
1,66

2,00
2,33
2,66

sever
3,00
3,33
3,66

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

ABCsofcoronaryprevention
A

Aspirin
ACE inhibition
A1C control

Beta-blockade
Blood pressure control

Cholesterol management

Diet
Dont smoke

Exercise
Adapted from Cohen JD. Lancet. 2001;357:972-3.

Strategiapreventionala2009
0

140

0
3

Nefumator

5
140

Portii de fructe sau vegetale zilnic

5
3
0

Colesterolul total < 5 mmol/l (190 mg/zi)

Mers 3 km zilnic sau orice activitate moderata 30

min/zi
TA sub 140 mmHg sistolica

LDL colesterol < 3 mmol/l (130 mg/l)

Evitarea supraponderii si diabetului

Triadaexplorariiglicemice
FPG
Fasting Glucose

PPG

Glucose
TRIADE

HbA1c

Postprandial
glucose

ComponentelecresteriiHbA1c
Uncontrolled Diabetes HbA1c 8%
Basal hyperglycaemia
contributes ~2%

Plasma glucose (mg/dL)

300

Post-prandial
hyperglycaemia
contributes HbA1c ~1%
Post-prandial
hyperglycaemia
Fasting
hyperglycaemia

200

100

Normal
HbA1c ~5%

0
6

12

18
Time of day (h)

B=breakfast; L=lunch; D=dinner.

Adapted from Riddle MC. Diabetes Care. 1990;13:676-686.

24

StudiulDCCT:complicatiimicrovascularein
functiedenivelulHbA1c
Risk of retinopathy progression vs. mean HbA1c
Mean HbA1c = 11%
Progression rate
per 100 patient-years

24

10%
9%

20
16
12

8%

8
4

7%

0
1

DCCT study time (y)

DCCT Group. Diabetes 1995;44:96883.

StudiulDCCT:controlulglicemiccutratamentconventional
siintensivcuinsulina
Intensive group:

0.45

Mean HbA1c 7.1%

Mean blood glucose 8.6 mmol/l

Density estimate

0.40
0.35

Conventional group:

0.30

Mean HbA1c 9.0%

Mean blood glucose 12.8 mmol/l

0.25
0.20
0.15
0.10
0.05
0.00
5

DCCT Group. Diabetes 1995;44:96883.

10

11

12

Glycosylated haemoglobin (%)

13

14

ControlulglicemicinstudiulEDIC(de
urmarireasubiectilordinDCCT)
Conventional group

12

Intensive group

HbA1c %

10

6
p<0.001 p<0.001 p<0.001 p=0.002 p=0.04 p=0.08

DCCT
Closeout

4
EDIC year

EDIC Group. Diabetes Care 1999;22:99111.

p=0.04

p=0.58

p=0.83

Reducerereasustinutaarisculuidecomplicatii
croniceprinameliorareainitialaacontrolului
glicemic studiulEDIC
Conventional group

0.5

Cumulative incidence

Intensive group
0.4
0.3
0.2
0.1
0

EDIC study time (y)

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

Apolipoprotein

Triglyceride

Cholesteryl ester

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

Trigliceride

(mg/dl)

(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

ParticuleleLDLmiciidense

Seasociazcuunrisccoronariantriplu

Aterogenicitatealoresteatribuit:
1. AfinitiilormairedusepentrureceptorulLDL:auo
remanencrescutncirculaie
2. Abilitiilordeaptrundemairepedenperetelearterial
3. Susceptibilitiilorcrescutelaoxidare
4. Adereneilormaicrescutefadeproteoglicaniidin
peretelearterial

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

HiperTGsecoreleaz cuconcentraiicrescutede LDL

miciidense
100
90
70

40

tant
e/flo

mar

Frecvena 60
Cumulativ 50

L DL

80

m
L
LD

ns
e
d
ic/

Fenotip A
Fenotip B

30
20
10
0

20 40 60 80 100 120 140 160 180 200 220 240 260 280 300

500

TG (mg/dl)
Austin M et al. Circulation. 1990;82:495-506.

HDL redus se asociaz cu concentraie crescut

de LDL mici i dense
100
90

L
LD

Frecvena 60
Cumulativ 50

ns
de
ic /
Lm

70

ar
e/f
lo
tan
t

LD

80

Fenotip A
Fenotip B

40
30
20

20

25

30

35

40

45

50

55

60

65

70

75

80

HDL-C (mg/dl)
Austin M et al. Circulation. 1990;82:495-506.

Tablouclinic
Xantoame detiperuptiv,tendinos,tuberos,palmar
Xantelasma
Arccornean
Lipemiaretinalis
Dureriabdominale,manifestridepancreatit
ManifestrialeATScerebrale,coronarieneiperiferice
Simptomeosteoarticulare(rar)

Investigaiiparaclinice
Apreciereaaspectuluiplasmeisauseruluidup24deorede
larecoltareipstrarelafrigider(+40C)
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
Statin
Sinteza hepatic*
1000 mg/zi

Colesterol din diet

~300 mg/zi700 mg/zi

Colesterol biliar
~1000 mg/zi

esuturi
extrahepatice

Intestin
Absorbie

Excreie
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
Slide 400
Correlations. 5th ed. New York: Wiley-Liss, 2002:10821115.

Inhibareaabsorbieiiproducieidecolesterolcu
ezetimib+simvastatin
Statin
Sinteza
hepatic*
~800 mg/zi

Colesterol din diet

~300 mg/zi700 mg/zi

Ezetimib

Colesterol biliar
~1000 mg/zi

esut
extrahepatic

Intestin

Absorbie
~700 mg/zi

Excreie
~700 mg/zi
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
Slide 401
Drugs. 2002;11:15871604; Hopfer U. Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss; 2002:10821115.

Efectelipidice alenormolipemiantelor
ATP III
LDL-C

HDL-C

TG

FIBRAI

5 20%

10 20%

20 50%

STATINE

18 55%

5 15%

7 30%

ClasificareagreutiinfunciedevalorileIMC (kg/m2)
Subponderal

< 18,5

Normal

18,5 - 24,9

Supraponderal

25 29,9

Obezitate gradul I

30 34,9

Obezitate gradul II

35 39,9

Obezitate gradul III

40

Obezitatea ginoida

Obezitatea androida

Mecanismul prin care adipozitatea visceral induce

multipli factori de risc
Obezitate central
AGL portal

Adipocitokine
TNF
Insulinorezisten

Creterea sintezei
de lipoproteine

Hiperlipidemie

Intolerana la glucoz

Hipertensiune
PAI-1

Ateroscleroz

Grupele de risc ale obezitii

(Hncu N 1998)
Grupa de risc

Descriere

Antropometrie
IMC 25-29 kg/m2 cu talia < 94 cm (brbai)

Risc sczut
i

Risc crescut

< 80 cm (femei)
Riscul cardiovascular
Estimat < 2 factori de risc
Cuantificat < 10%
Antropometrie
IMC 25-29 kg/m2 sau < 25 kg/m2 cu talia
94-101 cm la brbai i 80-87 cm la femei
Riscul cardiovascular
Estimat 2 factori de risc
Cuantificat 10-20%

Principalele comorbiditi ale obezitii i riscul de

morbiditate i mortalitate
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 HDLcolestero-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)

Obiectiveletratamentuluinobezitate

Hill JO 2000

IMC (kg/m2)
> 27
> 30

Co-morbiditi
Tratament
Da sau nu
Educaie privind schimbarea
stilului de via
Nu
Educaie i program de
modificare a obiceiurilor

> 30

Da

Educaie, program de modificare

a obiceiurilor i medicamente

> 35

Da sau nu

> 40

Da

Medicamente indicate; alte

intervenii agresive cum ar fi
dietele hipocalorice
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

Creterea intrrilor energetice

Noul echilibru

Echilibru

IN

OUT

IN

OUT

Mas gras
Mas slab
Dup Y.Schutz

Timp

Cerculviciosnterapiainadecvataobezitii

TRATAMENTE:
neindividualizate
neadecvate
comerciale

SLBIRE
RAPID

PACIENTUL
OBEZ

ACCENTUAREA OBEZITII
CRETEREA DISTRIBUIEI
DE TIP ABDOMINAL
MODIFICAREA
COMPOZIIEI CORPULUI
MASA GRAS
MASA SLAB

REDUCEREA ACCENTUAT
A MASEI SLABE

GREUTATE CICLIC

TULBURRI DE
COMPORTAMENT
ALIMENTAR
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