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ef.lucr. Dr.

Adriana Fodor

UMF Iuliu Haieganu
Centrul Clinic de Diabet, Nutriie, Boli metabolice
I. Bolile metabolice populaionale
II.Diabetul zaharat

Centrul Clinic de
Diabet, Nutriie,
Boli metabolice
Cluj-Napoca
Obiective curs
Obiective generale
nsuirea de noiuni de baz n domeniul patologiei metabolico-
nutriionale: diabet zaharat, obezitate, dislipidemii, sindrom
metabolic, hiperuricemie, nutritie
Obiective specifice cunostinte
bolile metabolice populaionale, impactul acestora, patogeneza i
evoluia acestora, posibilitile de prevenie
principii de baz ale abordrii globale a pacienilor cu diabet
zaharat: screening, diagnostic, clasificare, evaluare, tratament
noiuni generale despre complicaiile acute i cronice ale diabetului
zaharat: screening, diagnostic, evaluare, tratament
abordarea persoanelor cu obezitate, dislipidemii, sindrom metabolic,
hiperuricemie: screening, diagnostic, evaluare, tratament
terapia medical nutriional: definiie, principii
Coninutul cursului
Bolile metabolice populaionale: epidemiologie, impact medical,
social, economic
Diabetul zaharat : definiie, clasificare, etiopatogenez,
manifestri clinice, complicaii, management clinic
Hipoglicemiile
Obezitatea : definiie, clasificare, etiopatogenez, manifestri
clinice, complicaii, management clinic
Dislipidemiile : definiie, clasificare, etiopatogenez,
manifestri clinice, complicaii, management clinic
Sindromul metabolic si riscul cardiovascular: definiie, evaluare,
management clinic
Hiperuricemia: definiie, evaluare clinic i biochimic,
management clinic
Terapia medical nutriional: definiie, principii
Bibliografie
Catedra de DNBM. Diabet, Nutriie, Boli metabolice-Curs
pentru studeni, Editura Medical Universitar Iuliu
Haieganu, Cluj-Napoca, 2009
Hncu N., Roman G., Veresiu I.A. (editori). Diabetul zaharat,
nutritie, bolile metabolice- Tratat, vol 1 si 2, Editura Echinox
Cluj-Napoca, 2010
Hncu N., Roman G., Veresiu I.A. (editori). Farmacoterapia
diabetului zaharat. Editura Echinox Cluj-Napoca, 2008
Vereiu I.A., Hncu N, Roman G. (editori) Insulina i
tratamentul cu insulin. Editura Echinox Cluj-Napoca, 2004
De discutat:
Bolile metabolice populaionale
Diabetul zaharat
Bolile metabolice populaionale

DIABETUL ZAHARAT
OBEZITATEA
DISLIPIDEMIILE
SINDROMUL METABOLIC
Bolile metabolice populaionale
Noncommunicable diseases (NCDs) kill more than 36 million people each
year (63% of all deaths)
~ 80% of NCD deaths occur in low- and middle-income countries.
> 25% of deaths attributed to NCDs occur before the age of 60; 90%
of these "premature" deaths occurred in low- and middle-income
countries.
Cardiovascular diseases - most NCD deaths (48%)
Cancers (21%), respiratory diseases (12%), and diabetes (3%).
These 4 groups of diseases account for around 80% of all NCD
deaths.
They share four risk factors: tobacco use, physical inactivity, the
harmful use of alcohol and unhealthy diets.
WHO 2011
Bolile metabolice populaionale
Se definesc prin:
determinism predominant metabolico-nutriional
evoluie cronic nsoit de severe complicaii
care:
scad calitatea vieii
cresc mortalitatea la nivel populaional
Bolile metabolice populaionale - Impact
2. Impactul epidemiologic:
epidemia de obezitate
epidemia de prediabet & diabet
epidemia de patologie CV
3. Impactul economic, organizatoric, social:
costuri crescute ale ngrijirii
productivitate sczut
discriminare profesional, social
BMP Etio-Patogeneza
11
BMP Etio-Patogeneza
REACTIVITATE ABERANT LA STRES
Stil de via
(Atitudine, comportament, relaii)
Alimentaie
Activitate fizic
Consum de alcool
Fumat
Coabitarea cu stresul
Odihna, relaxare,somn
Starea de sntate / boal
Decizii zilnice
14
Stilul de via Individual

15
Reeaua social
Comunitatea
Condiii generale de mediu
Condiii socio-economice
Condiii de munc, locuit
Timp liber
Cultur, Tradiii
Asisten medical

Mediu
Ambient
Stilul de via
Factorii cu impact asupra seleciei alimentelor
Contento IR. 2011. Jones and Bartlett Publishers, 40 Tall Pine Drive, Sudbury,MA 01776
Comportamente cu
determinism biologic:
gust/plcere
foame/saietate
mecanisme cerebrale
Experiena alimentar:
condiionarea de asociere

Condiionarea psihologic:
sigurana/familiaritate
preferine alimentare
saietate

Condiionarea social:
modele
recompense
contextul social afectiv
Factori intra-personali:
percepii
atitudini
convingeri
motivaie/valori
cunotine/abiliti
norme sociale
norme culturale



Factori
inter-pesonali:
reeau social i
familial
Factori de mediu:
Ambientul fizic:
disponibilitatea alimentelor
resurse pentru micare
Ambientul social:
influene sociale
practici culturale
structuri sociale
politici
Ambientul economic:
resurse
preuri
timp
Ambientul informaional:
publicitate
educaie
media
Preferine/ factori
senzoriali-afectivi
Convingeri,
atitudini, norme
Disponibilitate,
influene
BMP Polimorfism clinico-metabolic
BMP-Triada ngrijirii Abordare n practic
Screening programe naionale
- cu ocazia diagnosticului unei boli metabolice & CV
Obiectivele abordrii n BMP
Optimizarea parametrilor clinico-metabolici i nutriionali, prin
care se realizeaz

Prevenirea i controlul complicaiilor i asociaiilor morbide, ceea
ce contribuie la

mbuntirea calitii vieii i a adaptrii familiale,
profesionale i sociale, creterea speranei de via.
Profilaxia BMP
Exposure to the four main behavioural risk factors that contribute to
NCDs - tobacco use, physical inactivity, harmful use of alcohol and
unhealthy diets - remains high worldwide and is increasing in the majority
of low- and middle-income countries- WHO 2011
RR: Diabet zaharat tip 2 (58%)
Cardiopatie ischemic (80%)
Cancer (30%)
De discutat:
Diabetul zaharat
1552 B.C.
Egipt poliuria
I secol D.C.
- Areteus prima descriere a DZ
'the melting down of flesh and limbs into urine.'
- diabetes sifon, scurgere
- mellitus miere (latin)



DZ - Scurt istoric
De discutat:

epidemiologie
definiie
clasificare
diagnostic
screening
etiopatogenie
aspecte clinice
tablou clinic,evoluie
complicaii acute
complicaii cronice
aspecte paraclinice
management clinic

Idf.org
Epidemiologie DZ
The global burden of diabetes
Diabetes is a huge and
growing problem

80% of people with diabetes live in low- and
middle-income countries
The greatest number of people with diabetes are
between 40 to 59 years of age
175 million people (46%) with diabetes are
undiagnosed
Diabetes caused 5.1 million deaths in 2013
Diabetes caused 11% of total health spending on
USA adults in 2013 .
Predicie 2005-2020 - EURODIAB (Epidemiology
and Prevention of Diabetes)
-dublarea numrului de cazuri noi de DZ1 la copii
< 5 ani
- cretere a prevalenei cazurilor la grupa de
vrsta < 15 ani, cu 70%
Patterson CC, Dahlquist GG, Gyurus E, et al. Incidence trends for
childhood type 1 diabetes in Europe during 1989-2003 and predicted new
cases 2005-2020: a multicentre prospective registration study. Lancet 2009;
373: 2027-33.
31
Impact Economic

- productivitate scazuta
- pierdere zile de munca,
- restrictie la anumite activitati,
- mortalitate si disabilitate prin diabet
32
De discutat:
epidemiologie
definiie
clasificare
diagnostic
screening
etiopatogenie
aspecte clinice
evoluie
complicaii acute
complicaii cronice
aspecte paraclinice
management clinic
Grup de boli metabolice caracterizate prin:
Hiperglicemie cronic indus de defecte n secreia i/sau
aciunea insulinei
Modificri n metabolismul lipidic i proteic
Consecine pe termen lung - apariia complicaiilor cronice:
Retinopatia
Nefropatia
Neuropatia
Cardiopatia ischemic
Arteriopatia periferic
Boala cerebrovascular
Aceste complicaii pot fi prevenite printr-un control
multifactorial, intensiv, instituit precoce.
Definiia diabetului zaharat
ADA, 2013. Diabetes Care, 36, suppl 1: S67-S74
Societi tiinifice
Federatia Internationala de Diabet www.idf.org
Asociatia Europeana pentru Studiul Diabetului EASD
(www. easd.org)
Asociatia Americana de Diabet ADA -
www.diabetes.org
Federatia Romana de Diabet, Nutritie, Boli metabolice
www.federatiaromanadiabet.ro
Societatea Romana de Diabet, Nutritie, Boli
metabolice - www.societate-diabet.ro
35
Definirea strilor glicemice:
- normoglicemie
- hiperglicemie intermediar:
glicemie bazal modificat
scderea toleranei la glucoz
- diabet zaharat
Hiperglicemia intermediar
Glicemie bazal (a jeun): 110 mg/dl 125 mg/dl
(6.1 - 6.9 mmol/l)
Glicemia bazal modificat
(Impaired Fasting Glucose - IFG)
&
2006
Glicemia 2h post TTGO: 140 mg/dl i <200 mg/dl)
(7.8 and <11.1mmol/l)
Scderea toleranei la glucoz
(Impaired Glucose Tolerance - IGT)
ADA. I. Classification and Diagnosis. Diabetes Care 2013;36(suppl 1)
Categorii la risc crescut pentru
diabetul zaharat (prediabet)
1.Glicemia bazal modificat (GBM)
2.Scderea toleranei la glucoz (STG)
3. HbA1c: 5,7-6,4%

38
Diabetul zaharat - Diagnostic
Glicemie bazal (a jeun)
126 mg/dl (7.0 mmol/l)
Sau
Glicemia 2h post TTGO
200 mg/dl (11.1 mmol/l)
Sau
Simptome de diabet i o glicemie 200 mg/dl
Sau
HbA1c 6,5%
&
2006
Retinopatia diabetica & hiperglicemia & diagn DZ
40

Diagnosticul de boal
Stratificarea riscului cardiovascular
Diagnosticul complicaiilor micro- i macrovasculare
Diagnosticul comorbiditilor
ADA, 2008. Diabetes Care, 31, suppl 1: S12-S54
Diagnosticul diabetului zaharat
Evaluarea global
De discutat:
epidemiologie
definiie
diagnostic
clasificare
etiopatogenie
screening
aspecte clinice
evoluie
complicaii acute
complicaii cronice
aspecte paraclinice
management clinic
I. DZ tip 1:
produs prin deficit absolut de insulin, ca urmare a
distruciei celulelor beta pancreatice
dou subtipuri:
autoimun
idiopatic

II. DZ tip 2:
90-95% din cazuri
consecin a unui de defect n secreia de insulin pe
fond de insulinorezistena
Etiopatogeneza: factori genetici & ctigai
Clasificarea etiopatogenetic a DZ
III. Tipuri specifice de diabet:
Defecte genetice ale celulelor beta pancreatice (MODY)
Defecte genetice ale mecanismului de aciune a insulinei
Pancreatopatii exocrine (pancreatite, tumori,
pancreatectomii, hemocromatoza)
Endocrinopatii (sindrom Cushing, feocromocitom, acromegalie)
Medicamente sau substane chimice (acid nicotinic,
glucocorticoizi, hormoni tiroidieni, agonisti adrenergici,
tiazide, alfa interferon)
Infecii (rubeola congenitala, virus citomegalic)
Sindroame genetice

IV. DZ gestaional:
apare n timpul sarcinii i este produs prin mecanismele tipului 1
sau 2
Clasificarea diabetului zaharat
EASD &
2007
Evoluia stadial
Diabetul zaharat tip 2 Screening
1.Populaia general
- evaluarea riscului de DZ* (+)
- evaluare glicemic la cei cu risc crescut
2. Populaia cu risc crescut de DZ tip 2 - anual
- glicemie bazal (snge venos/capilar)
GB 110 - < 126 mg/dl (+)
- TTGO
3. Populaia cu BCV evaluare glicemic bazal i TTGO
* FINDRISC 2001
Jaakko Tuomilehto, Department of Public Health, University of Helsinki,
Jaana Lindstrm, MFS, National Public Health Institute, Finland.
EASD &
2007
1. Age

< 45 years (0 p.)
554 years (2 p.)
5564 years (3 p.)
> 64 years (4 p.)
5. How often do you eat vegetables,
fruit or berries?

Every day (0 p.)
Not every day (1 p.)
2. Body mass index
< 25 kg/m (0p)
25 30 kg/m (1p)
30 kg/m (3p)
6. Have you ever taken
antihypertensive medication regularly?
No (0 p.)
Yes (2 p.)
3. Waist circumference measured below
the ribs (usually at the level of the
navel)
7. Have you ever been found to have
high blood glucose (eg in a health
examination, during an illness, during
pregnancy)?
No (0 p.)
Yes (5 p.)
Men Women
< 94 cm < 80 cm 0 p
94 - 102 cm 80 88 cm 3 p
> 102 cm > 88 cm 4 p
4. Do you usually have daily at least 30
minutes of physical activity at work
and/or during leisure time (including
normal daily activity)?

Yes (0 p.)
No (2 p.)
8. Have any of the members of your
immediate family or other relatives
been diagnosed with diabetes (type 1 or
type 2)?
oNo (0 p.)
oYes: grandparent, aunt, uncle or first
cousin (but no own parent, brother, sister
or child)
(3 p)
oYes: parent, brother, sister or own child
(5 p.)
Lower than
7
Low: estimated 1 in 100 will
develop disease
711 Slightly elevated:
estimated 1 in 25 will develop
diasease
1214 Moderate: estimated 1 in 6 will
develop diasease
1520 High: estimated 1 in 3 will
develop diasease
Higher than
20
Very high: estimated 1 in 2 will
develop diasease
Scor FINDRISC
EASD &
2007
Persoane aflate la risc crescut pentru DZ 2
Diabetul zaharat tip 2 Screening
Diabetul gestational
Sarcina i Hiperglicemia
Efectele majore al hiperglicemiei cronice:
- n primul trimestru al sarcinii - hiperglicemia (peste 150 mg/dl)
crete de 3 ori riscul producerii anomaliilor fetale i de 4-8 ori
riscul de avort spontan
- macrosomia - de 7 ori mai frecvent
- GB peste 90 - 95 mg/dl comparativ cu cele de 75 mg/dl,
- macrosomia - de 14 ori mai frecvent
- GB 105 mg/dl.
- malformaiile congenitale - 25 % n cazurile cu diabet zaharat
pregestaional (tip 1 sau tip 2) necontrolat glicemic (HbA1c
peste 10%).
G. Roman, N. Costin. Diabetul zaharat i Sarcina-ndrumar de practic medical. 2005
51
Mortalitatea peri-natal n DG
- rata de 2.6% (OR 2.3) n DG netratat
- Glicemia Postprandial < 140 mg/dl reducerea
MPN cu 75%.
Mortalitatea peri-natal n DZ pre-existent sarcinii
- media glicemic = 100 mg/dl MPN 4 %
- media glicemic = 100150 mg/dl MPN 15 %
- media glicemic = >150 mg/dl MPN 24 %
Continua cretere a MPN la glicemii > 100 mg/dl

Sarcina i Hiperglicemia
Moshe Hod M., Yogev Y. Goals of Metabolic Management of Gestational Diabetes.
Diabetes Care, 2007, 30
Screening-ul DG - Persoane cu risc crescut
Istorie familial de diabet sau obezitate
Suprapondere sau obezitate pre-sarcin
Exces ponderal rapid n primele 6 luni
Vrst mai mare a mamei (peste 35 ani)
Multiparitate
GBM sau STG sau Diabet Gestaional n antecedente
Etnie cu risc crescut pentru diabet gestaional
Macrosomie & hipotrofie fetal n sarcina curent / antecedente
Mortalitate fetal n antecedente
Ovar polichistic
53
n cazul gravidelor cu factori de risc prezeni,
cu risc crescut, screening se aplic la prima
vizita prenatal (nainte de sptmna 24-a)
n cazul unui rezultat negativ, se repet n
sptmnile 24 28;
n cazul gravidelor cu ris moderat, screeningul
se face n sptmnile 24 28 de sarcin;
Screening-ul DG
Diagnostic
Testul de screening i diagnostic trebuie efectuat
dimineaa, dup o perioad de 814 ore de repaus
digestiv i consum minimum de 150 g hidrai de carbon n
zilele precedente;
Diagnosticul se face prin determinarea glicemiei
plasmatice n cadrul TTGO cu 75 g glucoz i este
pozitiv la cel putin o valoare peste :

ADA, 2013. Diabetes Care, 36, suppl 1: S67-S74
De discutat:

epidemiologie
definiie
clasificare
diagnostic
screening
etiopatogenie
aspecte clinice
evoluie
complicaii acute
complicaii cronice
aspecte paraclinice
management clinic
Patogeneza DZ tip 1 autoimun
Boal autoimun cu etiologie multifactorial - Interaciune
factori genetici + factori mediu
Minim / absent secreie de insulin prin distrucia
autoimun selectiv a celulelor pancreatice.
Markerii auto-imuni atc anti-insulari
IAA atc anti-insulina
IA-2/ICA-512 (tirozin-fosfataza)
Atc anti-GAD (decarboxilaza ac glutamic)
antitransportor de Zn (ZnT8)
Asociere cu alte boli autoimune
Patogeneza DZ 1- Predispoziia genetic
Asociere puternic cu HLA DQA, DQB, DRB
Risc de transmitere familial: Risc crescut pentru rudele de
gradul 1 ale pacienilor cu DZ (36% comparativ cu 0.21%
n populaia general european).
2-3% pe linie matern,
5-6% pe linie patern,
30% dac ambii prini au diabet
Rata de concordan la gemenii monozigoi (30-50%)
Susceptibilitatea genetic nu e suficient pentru
a face boala.
~ 80 90% din pacieni cu DZ1 nu au rude cu
DZ1
Peste 50% din gemenii monozigoi nu fac boala
10% din persoanele susceptibile HLA fac boala
Variaia sezonier i geografic a incidenei
Asocierea cu infecii virale

Patogeneza DZ - Factori de mediu
Istoria natural a DZ tip 1
Autoanticorpi anti
antigene insulare - rol ?


Susceptibilitate Pierderea toleranei
genetic imunologice
(DR3 - DQ2, DR4 - DQ8)


Infiltrarea insulelor pancreatice:
macrofage, linfocite T CD4+, CD8+
(insulit)

Distrucia autoimun
a celulelor
???
Mecanisme patofiziologice
Dou etape la persoanele susceptibile genetic:
1. Declanarea procesului autoimun duce la apariia unuia sau mai
multor autoanticorpi i la distrugerea treptat a celulelor
2. Pierderea funciei secretorii a celulelor manifestat prin
dispariia primei faze de secreie a insulinei, reducerea
peptidului C, scderea toleranei la glucoz, iar n final
hiperglicemia.
Inducerea procesului autoimun insular la persoane susceptibile
genetic i apariia autoanticorpilor mpotriva antigenelor
insulare pot preceda debutul clinic cu luni de zile sau chiar ani.
Autoanticorpii-rol ? importan !
Dg. alte forme de diabet
Prevenia bolii !!! -preced debutul clinic cu luni sau ani
de zile.
Autoanticorpi multipli n 6-12 luni dup primul
Autonticorpii tranzitori, unul singur rar (haplotip
protectiv HLA DR15 DQ6).
Istoria natural a DZ 2
Insulino-rezisten Disfuncie -celular
Susceptibilitatea genetic, obezitatea, sedentarismul
Ficat
Producia
hepatic a
glucozei


Muchi i esut
adipos
Utilizrii
glucozei prin
mecanisme
dependente de
insulin
Reducerea secreiei -
celulare de insulin



Imposibilitatea celulelor
beta de a compensa IR
Patogeneza DZ tip 2 - Mecanisme
Reducerea utilizrii glucozei n
muchi i tes. adipos
Creterea produciei hepatice
de glucoz
glucotoxicitate lipotoxicitate
Insulino rezisten
Disfuncie -celular
Hiperglicemie
Creterea lipolizei i a
fluxului de AGL
Creterea AGL
Necesar crescut de insulin
Obezitate
abdominal
Patogeneza DZ tip 2
69
Adipozitate
intra-abdominal
Obezitate IR DZ 2

Sindrom metabolic
cardiovascular
Patogeneza DZ tip 2
70
71
HOMA=homeostasis model assessment.
UKPDS Group. Diabetes 1995;44:124958.
Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S215.
Declinul funciei -celulare
evoluia progresiv a DZ 2

-
c
e
l
l

f
u
n
c
t
i
o
n

(
%

o
f

n
o
r
m
a
l

b
y

H
O
M
A
)

Time (years)
0
20
40
60
80
100
10 8 6 4 2
0
2
4
6
Time of diagnosis
?
Pancreatic function
= 50% of normal
72
Celula beta insulinosecreia dependent de glucoz
Sensor" glucoz
Activarea Glut 2 la o
glicemie de 90 mg/dl
nchiderea canalelor de
K+ - ATP dependente,
Deschiderea canalelor
de Ca2+ dependente
de voltaj
1
2
Declansarea
depolarizarii
3
4
5
Influxul de Ca2+ i
exocitoza insulinei
73

Pierderea primei faze de secreie a insulinei
74
Glicemie
(mg/dl)
50
100
150
200
250
300
350
0
50
100
150
200
250
-10
-5
0
5 10 15
20
25
30
Ani DZ
Adaptat dup Bergenstal RM, et al. Diabetes mellitus, carbohydrate metabolism and lipid disorders.
In Endocrinology. 4th ed. 2001.
Funcie
relativ
(%)
Glic. bazal
Obezitate STG
DZ 2 Hiperglicemie
Insulino-rezisten
Glic.
Postprandial
Insulino-secretie
Diagnostic
clinic
Fiziopatologia DZ 2 - Evoluie
126
200
75
Obezitate abdominal
Insulino-rezisten
Cauze genetice, Alim. Hipercaloric, Sedentarism
Muscle Liver Arteries Other
mechanisms
Blood
Blood glucose
-cell
Dyslipidemia:
TG
HDL
Small & dense
LDL
Chol/HDL ratio
apo B
PP HLP
Pro-Thrombotic
Pro-Inflammatory
State:
PAI-1
t-PA
FVII, F XII
Fibrinogen
HBP
LVH
CHF
-cell failure
Ins. Ins.
Genetic, acquired causes
G & L toxicity
Stiffness
Endothelial
Dysfunction
Atherothrombotic
Arterial disease
CVD
T2 DM
Modified after H. Yki-Jarvinen.
Textbook of diabetes, JC Pickup&G. Williams (eds),2003
Alb-uria
Sindromul cardio-metabolic
Adipose T
FFA