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Diabetes Mellitus
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Diabet zaharat si boli metaboliceDesign-ul cursului
Importanta problemei Background fiziopatologic Definitia diabetului zaharat si a altor categorii de intoleranta
la glucoza Diagnosticul diabetului zaharat (DZ) Tipurile de diabet zaharat: definitie, etiopatogeneza, istorie
naturala Tratamentul diabetului zaharat Complicatiile acute specifice ale DZ
Complicatiile cronice ale DZ Obezitatea Dislipidemiile Hiperuricemiile
Sd. metabolic
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Fat FrumosAdrian Paunescu
Oameni, oameni, fraii mei,Disperaii, fericiii,V-ai splat de superstiii,De demoni i dumnezei.
ns-i nu-i destul folosDac peste tot ce esteV-ai splat i de poveste,L-ai pierdut pe Ft-Frumos
Vin la voi acum plngnd,Gura-mi snger ca rana,Unde este Cosnzeana,n ce boli, pe ce pmnt?
M ridic plngnd de jos,Ca la un pierdut examen,Unde v e basmul, oameni.
Ce-ai fcut cu Ft-Frumos?
Ft-Frumos n-a existat,N-a stat nimnui n cale,Era numai visul moaleAl vreunui trist biat
Mai visai de vrei s fiiFericii cu capu-n pern,Ferii epoca modernDe rigizi i scoflcii.
Din prea mult entuziasmS nu spargei Voroneul,Dai-i voi mai mare preul,Oameni, mai rvnii la basm.
Voi, care avei copii,Nu-i lsati sub gnd satanic,S respire sterp, mecanic,Ca i cnd nu ar fi.
Dobori himera jos,Oameni, revenii n lume,Pe umana noastra culmeRegsii pe Ft-Frumos.
Ft-Frumos i toi ai lui,Fiinc unde nu-i povesteLume nu-i i om nu estei, de fapt, nimica nu-i.
El venea la noi pe josi ni l-au rpit piraii,Vamei vigileni, redai-iActele lui Ft-Frumos.
Dai-i viaa napoi,Ochii mari, micarea buzii,Ft-Frumosul din iluzii
i frumos numai prin voi.
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Prima cauza de orbire
Prima cauza de insuficienta renala si boala renala care necesita
dializa si transplant
Prima cauza de amputatie
24 ori mai frecvente bolile coronariene & strokes la diabetici fata de
nediabetici15 ani scurtarea sperantei de viata fata de nediabetici
A 6-a cauza de deces dintre toate bolile
2008 diabetul zaharat
The Centers for Disease Control and Prevention, USA
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Source: Diabetes Atlas 3rd Edition. www.eatlas.idf.org.
Proiectii globale ale epidemiei de diabet:2007-2030 (milioane)
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Diabetul zaharat:
O chemare la aciune
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~90% dintre persoanele
cu diabet zaharat de tip 2sunt supraponderale sau
obeze
World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity
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Mortalitatea diabeticilor estedubla fata de nediabetici
0
5
10
15
20
25
30
35
ControlDiabetes
10,025 61 6629 279 631 24(Patient Numbers)
Ratio 2.5 Ratio 2.2 Ratio 2.1
10.8
26.9
12.5
26.9
15.5
32.0
Whitehall
Study
Mortality Rate
Paris
Prospective Study
Helsinki
Policemen Study
(Deaths per1000
patient years)
Balkau.Lancet1997; 350: 1680.
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Diabetul zaharat de tip 2 cauza majorade mortalitate
3.4
5.4
6.66.16.0
2.2
4.8
6.9
5.1
8.88.6
2.5
0
1
23
4
5
6
7
8
9
10
Excess
mortality
attributabletodiabetes(%)
Africa Americas EasternMediterranean
Europe SoutheastAsia
WesternPacific
Men
Women
Roglic G, et al. Diabetes Care 2005;28:21305
Fifth leading cause of death after infections,CVD, cancer, and accidents
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Creterea numrului de decese datoritDiabetului
Ratarelativaamortalitatiifunctie
devarsta
Anul
140
1980
Accident vascular cerebralBoal CardiovascularCancerDiabet
130
120
110100
90
80
70
601982 1984 1986 1988 1990 1992 1994 1996
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Supravieuirea post-IM la femeile i brbaiidiabetici este mult mai mic dect la non - diabetici
Sprafka et al. Diabetes Care. 1991; 14: 537-
100
9080
70
60
50
400 10 20 30 40 50 60
100
9080
70
60
50
400 10 20 30 40 50 60
Luni Post-IM
B rba i Femei
DiabeticiNon-diabetici
%s
upravieuitorilor
%su
pravieuitori
lor
n=228
n=1628
n=156
n=568
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Incidena IM fatal i non-fatal de-a lungul a 7 ani de urmrire
ntr-o cohort finlandez
18.8%
3.5%
45.0%
20.2%
0%
10%
20%
30%
40%
50%
Cu IM Fr IM Cu IM Fr IM
Inc
idenan%
P < 0.001
P < 0.001
P < 0.001
Haffner SM et al, N Engl J Med 1998;339:229-234
Cu DiabetF r Diabet
Riscul coronarian este echivalent
pentru diabetici i pentru nediabeticii
cu un IM in antecedente
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Nicolae Paulescu1869-1931
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JJ Richard MacLeod1876-1935
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Friderick Grant Banting1891-1941
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Charles Herbert Best
1889-1978
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James Collip1892-1965
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Controlul hormonal al glicemiei
Insulina
Efect net: scderea glicemiei
Hormoni de contrareglare
Efect net: creterea glicemiei
nlturrii glucozei din sngeintrrii glucozei n celule
glicogenezeieliberrii glucozei din depozite
glicogenolizeigluconeogenezei
lipolizei i cetogenezeicatabolismului proteic
nlturrii glucozei din sngeintrrii glucozei n celule
glicogenezeieliberrii glucozei din depozite
glicogenolizeigluconeogenezei
lipolizei i cetogenezeicatabolismului proteic
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Insulinosecreia fiziologic profil 24 ore
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Pancreasul endocrin - noiuni de anatomie ifiziologie
Insulele Langerhans
800.000 1.500.000 1 2 % din masa
pancreatic total
Celule: A, B, C, D
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Adapted from Pratley RE, Weyer C. Diabetologia 2001; 44: 92945.
0
100
200
300
400
0 20 40 60 80 100 120
Time (min)
Plasmainsulin(pmol/l
primafaz
A douafaz
Insulinosecreia normal, bifazic
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ROLUL CENTRAL AL CANALELORROLUL CENTRAL AL CANALELORKKATPATP IN INSULINOSECRETIEIN INSULINOSECRETIE
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SEMNIFICAIA FIZIOLOGICA CELULELOR BETA
Celula -pancreatic funcioneazca un senzor energetic
Glucokinaza Metabolismulglucozei
ATP
Declanareainsulino-secreiei
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INCHIDEREA CANALULUI KINCHIDEREA CANALULUI KATPATP PRINPRINLEGAREA UNEI MOLECULE DE ATP LALEGAREA UNEI MOLECULE DE ATP LA
UNUL DIN CELE 4 SITUSURI DE PE SUR1UNUL DIN CELE 4 SITUSURI DE PE SUR1
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Secretia de insulina dupa adm glucozei intraduodenal
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-3 0
-1 0
1 0
3 05 0
7 0
9 0
0 1 5 3 0 4 5 6 0 7 5 9 0
T IM E (m in )
0
5 0
1 0 0
1 5 0
2 0 0
0 1 5 3 0 4 5 6 0 7 5 9 0
T IM E (m in )
McIntyre et al 1964
GLUCOSE(mg
/100ml)
INSULIN
(mU/L)
oralintravenous
Secretia de insulina dupa adm glucozei intraduodenalsi intravenos
Gut factors termed incretins
A ti i li t GLP1 i GIP
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Actiunea insulinotropa a GLP1 si GIPasupra cel beta pancreatice
K.Mussig et al Diabetologia 2010 ,53(11),2289
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Posibilele defecte cauzatoare de insulino-rezisten
La nivel de prereceptor
Insulin anormal Degradarea crescut a insulinei Prezena n snge a antagonitilor hormonali
La nivel de receptor Scderea numrului de receptori Receptori anormali Alterarea unor funcii ale receptorului
(activitii tirozinkinazei, autofosforilarea receptorului)La nivel postreceptor Alterri ale sistemului efectorilor (transportorii de glucoz) Defecte ale enzimelor i.c. implicate n metab. intermediare
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CI DE ACIUNE ALE INSULINEI LA NIVELUL CMN
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insulina
Rc. Insul.
IRS
Pi3 - Kinaza
MAPK
NO, vasodilatatie
Ef. anti ATS
migrare, prolif. cel.mus. netede
sintezei matriciale
Ef. aterogenic
scazutIn cazuri de IR sauinsulino defic.
crescut
King GL, 1999
CI DE ACIUNE ALE INSULINEI LA NIVELUL CMN
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DZ tip 2 deficitul insulinosecreieipostprandiale
timp
6 am 10 am 2 pm 6 pm 10 pm 2 am 6 am
800
600
400
200
ins
ulinosecretie(pmol/min)
0
DZ tip 2
Persoane nediabetice
Polonsky KS et al. N Engl J Med 1996; 334: 777-783
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Masa cel-
proliferare
neogeneza
hypertrofie atrofie
apoptoza
Masa cel in dinamica
Ackermann AM, Gannon M. J. Molec. Endocrin. 2007;38:193-206.
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Chris Rhodes Ph.D.PNRI, Seattle, WA.
PERIPHERAL INSULIN
RESISTANCE
-CELL MASS
& FUNCTION
Non-Diabetic State
PERIPHE
RALINS
ULIN
RESISTA
NCE
-CEL
LMASS
&FUNCT
ION
Diabetic State
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NGT : Normal glucose tolerance - IS : Insulin Sensitivity - CF : Cell functionAdapted 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: lessonsfrom integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
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NGT : Normal glucose tolerance IR: Insulin Resistance - IS : Insulin Sensitivity - CF : Cell functionAdapted 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: lessonsfrom integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
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NGT : Normal glucose tolerance - IS : Insulin Sensitivity - CF : Cell functionAdapted 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: lessonsfrom integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
Curba hiperbolica a relatiei dintre
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Curba hiperbolica a relatiei dintre
IS x CF
NGT : Normal glucose tolerance - IS : Insulin Sensitivity - CF : Cell functionAdapted 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: lessonsfrom integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
Curba hiperbolica a relatiei dintre
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Curba hiperbolica a relatiei dintre
IS x CF
Bonora E et al. Diabetes Care, 2002; 26 (7): 1153-1141
Curba hiperbolica a relatiei dintre
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Curba hiperbolica a relatiei dintre
IS x CF
NGT : Normal glucose tolerance IR: Insulin Resistance - CF : Cell functionAdapted 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: lessonsfrom integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
Curba hiperbolica a relatiei dintre
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Curba hiperbolica a relatiei dintre
IS x CF
NGT : Normal glucose tolerance IR: no Insulin Resistance (i.e. normal insulin sensitivity) - CF : CellfunctionAdapted 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: lessonsfrom integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
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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.Accurateassessment of beta-cell function: the hyperbolic correction. Diabetes 2002, 51 Suppl. 1: S212-20. Bergman RN. Pathogenesis and prediction of diabetes mellitus: lessons from integrativephysiology. Mt Sinai J Med. 2002, 69: 280-90.
Curba hiperbolica a relatiei dintre
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pIS x CF
NGT : Normal glucose tolerance IFG/IGT: Impaired Fasting Glucose/Impaired Glucose Tolerance T2M:Type 2 Diabetes MellitusAdapted 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 relationshipbetween 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: lessonsfrom integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
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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. BergmanRN, 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 ofdiabetes mellitus: lessons from integrative physiology. Mt Sinai J Med. 2002, 69: 280-90.
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Diagnosticul diabetului zaharat
La bolnav simptomatic- cu simptome tipice de diabet zaharat- cu semne atipice sau a unor complicatii (acute sau
cronice) La bolnav asimptomatic
- intimplator- bilant al starii de sanatate
- in cadrul unui screening. populational. pe grupuri de risc
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Diagnosticul clinic al DZ
Poliurie
Polidipsie Polifagie
Scdere ponderal
Astenie
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Indicaiile screening ului pentru DZ la subiecii
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Indicaiile screening-ului pentru DZ la subieciiasimptomatici cu ajutorul glicemiei bazale
Toi subiecii cu vrsta 45 ani; se va repeta la intervale de 3 ani Testarea se va face la vrste sub 45 ani i se va repeta la intervale
mai scurte la:
- persoane cu IMC 27 kg/m2
- cei care au rude de gradul I cu DZ- grupuri etnice cu risc crescut
- femeile care au nscut copii cu greutatea peste 4,5 kg
- femeile care au avut diabet gestaional
- hipertensivii
- cei cu HDL 35 mg/dl i/sau trigliceride 250 mg/dl
- cei cu GBM sau cu STG la testri anterioare
CRITERIILE PENTRU DIAGNOSTICULDIABETULUI ZAHARAT
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DIABETULUI ZAHARAT
- simptomele clasice de diabet includ poliuria, polidipsia, polifagia iscderea inexplicabil n greutate;
- glicemia ntmpltoarese refer la recoltare fr relaie cu ultimul prnz.
Sau
- starea pe nemncate (fasting sau jeun) este definit la minim 8 ore de laultima ingestie caloric.
Sau
- testul se execut utiliznd 75g de glucoz dizolvate n 300 ml ap.
n absena unei hiperglicemii cu semne acute de decompensaremetabolic, diagnosticul trebuie confirmat prin repetarea glicemiei
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Criterii de interpretare a glicemiei bazale
70-110 mg/dl normal
110-125 mg/dl glicemie bazal modificat
126 mg/dl diabet zaharatprobabil; confirmarea
se face dup a doua dozare la bolnavul asimptomatic
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Mic dejun Prnz Cin 0.00am 4.00am Mic dejun
Monnier L. Eur J Clin Invest 2000;30 (Suppl 2):3-11.
NORMAL PREDOMIN PERIOADAPOSTPRANDIAL
Legenda:
stare postprandial;
stare postabsorptiv;
a jeun
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Criterii de interpretare a TTGO
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Criterii de interpretare a TTGO
Glicemie n plasma venoas
Diabet zaharat- bazal- la 2 h dup glucoz
126 mg/dl (7 mmol/l) 200 mg/dl (11,1 mmol/l)
Scderea toleranei la glucoz- bazal- la 2 h dup glucoz
< 126 mg/dl (7 mmol/l) 140 mg/dl (7,8 mmol/l) i
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VALORI DIAGNOSTICE PENTRU DIABET ZAHARAT
I ALTE CATEGORII DE HIPERGLICEMIE
Snge integral Plasma venoasmg/dl (mmol/l)venos capilar
mg/dl (mmol/l)
Diabet zaharatPe nemncate sauLa 2 ore dup glucoz
110 ( 6,1) 180 ( 10,9)
110 ( 6,1) 200 ( 11,1)
126 ( 7,0) 200 ( 11,1)
Scderea toleranei la glucozPe nemncate iLa 2 ore dup glucoz
< 110 (
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CLASIFICAREA DIABETULUI ZAHARAT
(distrucia celulelor beta care conduce de obicei la insulinodeficiena
absolut)autoimunidiopatic
(datorat predominant insulinorezistenei cu relativ insulinodeficienpn la defect predominant de secreie cu sau fr
insulinorezisten)
defecte genetice ale funciei celulei betadefecte genetice ale aciunii insulineiboli ale pancreasului exocrin
endocrinopatiiindus de administrarea de medicamente sau chimiceinfeciiforme rare de diabet mediat imunalte sindroame genetice care se pot asocia cu diabetul
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Glicozilarea neenzimatic a proteinelor
Proporional cu - conc. glucozei din sg.
- durata meninerii ei
Glucoz + Protein Baz Schiff Produs AmadoriAGE (advanced glycation end-products)
- stabili
- se acumuleaz ca atare ( RD, ND, mbtrnire )
- au locusuri specifice de aciune
- pot fi identificai n diferite structuri datoritfluorescenei lor caracteristice
Hemoglobina glicat
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Hemoglobina glicat
Evalueaz controlul pe termen lung al diabetului (4-6 spt.)
memorie diabetic de lung durat
Subfraciuni: A1a, A1b, A1c
Valori normale: Hb A1 = 8%
HbA1c = 4-6%
Determinarea Hb A1c - cromatografic
- colorimetric
- radioimunologic
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Corelaii ntre valorile A1c i glicemie
A1c (%) Media nivelelor glicemice
6 135 mg/dl (7,5 mmol/l)
7 170 mg/dl (9,5 mmol/l)
8 205 mg/dl (11,5 mmol/l)
9 240 mg/dl (13,5 mmol/l)
10 275 mg/dl (15,5 mmol/l)
11 310 mg/dl (17,5 mmol/l)12 345 mg/dl ( 19,5 mmol/l)
ADA. Tests of glycemia in diabetes.
Diabetes Care 2003; 26 (Suppl 1): S106-S108.
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Autoimunitate Progresia distructiei beta celulare
Insuficienta functiei beta celulare Dependenta de insulina exogena Risc de ceto acidoza
Patogeneza diabetului zaharat de tip 1
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Etiopatogenia DZ 1 autoimun
Predispoziie genetic
Factor de mediu (viral, toxic, alimentar)
Activare autoimun insulit
Scderea capacitii -secretoare; afectarea fazei secretorii
iniiale, dar insulinemia plasmatic este normal
Diabet clinic manifest; insulinemie plasmatic sczut,
hiperglicemie, apar simptomele Apariia complicaiilor
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Diagnosis and typesCurriculum Module II-1
Slide 15 of 48
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Slides current until 2008
Slide 15 of 48
Beta-cellmass
Pathogenesis of type 1 diabetes
Time (months - years)
Trigger
Genetic
Pre-diabetes Honeymoon
Chronicphase
Clinicaldiabetes
Immunologicalabnormalities
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Factorii de risc implicai n patologiaFactorii de risc implicai n patologia
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Modified from Kahn R. Diabetes. 1994;43:1066-1084.
60
50
40
30
20
GeneGene AmbientAmbient
Diabetogene
primare secundare
Gene legate de diabet
Normal
Deficienta de secretie
a insulinei
Insulino-rezisten
Diabet tip IIDiabet tip II
Obezitate
Diet
Activitate fizic
vrst (ani)
p p gdiabetului zaharat tip 2
p p gdiabetului zaharat tip 2
Peste 80% dintre pacientii care evolueaza spre
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Peste 80% dintre pacientii care evolueaza sprediabet zaharat de tip 2 sunt insulino-rezistenti
Insulin resistant;low insulin secretion (54%)
Insulin resistant;good insulin secretion
(29%)
Insulin sensitive;good insulinsecretion (1%)
Insulin sensitive;
low insulin secretion (16%)
83%83%
Haffner SM, et al. Circulation 2000; 101:975980.
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ACANTHOSIS NIGRICANS
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ACANTHOSIS NIGRICANS
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Diagnosis and typesCurriculum Module II-1
Slide 8 of 48
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Insulin
Gluconeogenesis
Glycogenolysis
Glycogen synthesis
Glucose uptakeGlycogensynthesis
Blood glucose
Insulin and glucose disposal
Free fatty acid release
Diagnosis and typesCurriculum Module II-1
Slide 9 of 48
I li d fi i i
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Glucose uptake
GlycogenolysisGluconeogenesis (amino acids)
Ketone production (fatty acids)
Glucose uptakeProtein degradation amino acids
Blood glucose
Insulin deficiency intype 1 diabetes
Triglyceride degradation fatty acids
Diagnosis and typesCurriculum Module II-1
Slide 10 of 48
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Slide 10 of 48
Glucose uptake
Glycolysis
Gluconeogenesis (amino acids)
Glucose uptake
Protein degradation amino acids
Blood glucose
Insulin insensitivity in
ttype 2 diabetes
Diagnosis and typesCurriculum Module II-1
Slide 11 of 48
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Blood glucose
Glucose uptake
Insensitivity to insulin in
ttype 2 diabetes
Glucose uptakeGlycolysis
Gluconeogenesis (amino acids)
Glucose uptake
Protein degradation amino acids
Diagnosis and typesCurriculum Module II-1
Slide 12 of 48
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Blood glucoseConverted to triglycerides
Effect of insulin resistance in
ttype 2 diabetes
Glucose uptakeGlycolysis
Gluconeogenesis (amino acids)
Glucose uptake
Protein degradation amino acids
Glucose uptake
Patofiziologia diabetului zaharat
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Patofiziologia diabetului zaharatde tip 2
Decreased glucose uptake
Impaired insulin action
Unsuppressed glucose production
Impaired insulin action
Hyperglycemia
Impaired insulin secretion
INSULINOSECREIA N DZ TIP 2
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INSULINOSECREIA N DZ TIP 2
Timp
6 am 10 am 2 pm 6 pm 10 pm 2 am 6 am
800
600
400
200
in
sulinosecreie(pmol/min)
0
DZ 2
Fr DZ 2
Polonsky KS et al. N Engl J Med 1996; 334: 777-783
DECLINUL FUNCIEI BETA-CELULARE NDIABETUL ZAHARAT TIP 2
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Lebovitz H. Diabetes Rev1999;7:139153.Holman RR. Diabetes Res Clin Pract 1998;40(suppl):S21-
-Cellfunction
(%) PostprandialHyperglycemia
IGT Type 2DiabetesPhase I Type 2
DiabetesPhase II
Type 2 DiabetesPhase III25
100
75
0
50
-12 -10 -6 -2 0 2 6 10 14
Years from diagnosisDiagnosis
Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS.
DIABETUL ZAHARAT TIP 2
Numeroi factori contribuie la declinul progresiv
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al funciei celulei pancreatice
Celula
Hiperglicemie(glicotoxicitatea)
Insulinorezisten
Lipotoxicitate(creterea AGL, Tg)Glicareaproteinelor
Secreia insulinei
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Secreia insulinei
Pulsatorie
Bifazic
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Cum se combina insulino-rezistenta si disfunctia
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Cum se combina insulino-rezistenta si disfunctia-celulara in geneza diabetului zaharat de tip 2?
Abnormal
glucose tolerance
Hyperinsulinemia,then -cell failure
Normal IGT* Type 2 diabetes
Post-prandial
glucose
Insulinresistance
Increased insulinresistance
Fastingglucose Hyperglycemia
Insulinsecretion
*IGT = impaired glucose tolerance
Ada ted from T e 2 Diabetes BASICS. International Diabetes Center IDC Minnea olis
Pierderea masei celulare in istoria naturala a DZ2
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Prentki M., Nolan CJ. J.Clin. Invest. 2006; 116:1802-1812.
Pierderea masei celulare in istoria naturala a DZ2
INSULINOREZISTENTA SIINSULINODEFICIENTA IN DZ 2
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InsulinResistance
Type 2Diabetes
-cellDysfunction
InsulinResistance
Hyp
erglyc
aemia
InsulinConcentration
InsulinAction
Euglycaemia
-cell Failure
Normal IGT obesity Diagnosis oftype 2 diabetes
Progression oftype 2 diabetes
DeFronzo R et al. Diabetes Care 1992;15:31
INSULINODEFICIENTA IN DZ 2
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Etiopatogenia DZ 2
Factori genetici transmitere poligenic Rezisten crescut la aciunea insulinei Hiperinsulinism funcional Deficien n secreia insulinic hiperglicemie persistent
Tulburri insulinosecretorii- caracterului pulsator al insulinei
- dispariia fazei precoce a rspunsului insulinic
- ntrzierea secreiei de insulin Scderea absolut a secreiei insulinice DZ 2 insulinonecesitant
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Boala poligenica Hiperinsulinemia
Malnutritie fetala formarii celulelorbeta
Copil cu greutate mica la nastere
thrifty gene 7% scaderea celuilelor beta/an
Patogeneza diabetului zaharat de tip 2
9
FIZIOPATOLOGIA DIABETULUI ZAHAR
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Glucos
e(G)
Carbohydrate
Glucose
D IG ESTIV E EN ZYM ES
Insulin
(I)
I
I
I
II
I
I
I
G
G
G
G
G
G
G
GI
G
G
G
Defective
cell secretion
Excess glucose
production
Excessive
fatty acid release
insulinorezisten
Reduced glucose
uptake
TIP 2
Adipose Tissue
Liver
Pancreas
Muscle
Epidemiologia i riscul CV n diabet
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Diabet
STG
Limita glicemiei
normale
Risc pentruochi, rinichi,nervi
RiscCV
Disglicemia este un factor de risc progresiv pentru evenimente CV
Gerstein H. 2003
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PPGPostprandial
glucose
FPGFasting Glucose
HbA1c
Glucose
TRIADE
Triada explorarii glicemice
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Post-prandialhyperglycaemia
Post-prandialhyperglycaemiacontributes HbA1c ~1%
B=breakfast; L=lunch; D=dinner.Adapted from Riddle MC. Diabetes Care. 1990;13:676-686.
Pla
smaglucose(mg/dL)
300
200
100
0
Time of day (h)6 12 18 24 6
Uncontrolled Diabetes HbA1c 8%
Fastinghyperglycaemia
Basal hyperglycaemiacontributes ~2%
B L D
NormalHbA1c ~5%
Componentele cresterii HbA1c
DCCT: microvascular complicationsstratified by HbA1
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DCCT Group. Diabetes 1995;44:96883.
24
20
1612
8
4
01 2 3 4 5 6 7 8 9
Mean HbA1c = 11%10%
9%
8%
7%
DCCT study time (y)
Progressionrat
e
per100patient-years
Risk of retinopathy progression vs. mean HbA1c
stratified by HbA1c
DCCT: glycaemic control with conventional
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0.05
0.00
0.15
0.10
0.45
0.20
Densityestimate
0.25
0.30
0.35
0.40
5 6 7 8 9 10 11 12 13 14
Glycosylated haemoglobin (%)
Intensive group:
Mean HbA1c 7.1%
Mean blood glucose 8.6 mmol/l
Conventional group:
Mean HbA1c 9.0%Mean blood glucose 12.8 mmol/l
and intensive insulin treatment
DCCT Group. Diabetes 1995;44:96883.
Glycaemic control throughout EDIC
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Conventional group
Intensive group12
10
8
6
DCCTCloseout
1 2 3 4 5 6 7 8
p
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EDIC study time (y)
0 1 2 3 4 5 6 70
0.1
0.2
0.3
0.4
0.5
Cumulative
incidence
Conventional group
Intensive group
control
DCCT/EDIC Group.JAMA 2002;287:2563.
The Metabolic Syndrome:Historical
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yPerspective
Reaven G. Diabetes 1988;37:1565-1607.
InsulinInsulinResistanceResistance
InsulinInsulinResistanceResistance
GlucoseGlucose
IntoleranceIntolerance
GlucoseGlucose
IntoleranceIntolerance HyperinsulinemiaHyperinsulinemiaHyperinsulinemiaHyperinsulinemia TGTGTGTG HDL-CHDL-C Hypertension
Hypertension
1988: Syndrome X1988: Syndrome X
Coronary Heart DiseaseCoronary Heart DiseaseCoronary Heart DiseaseCoronary Heart Disease
The Metabolic Syndrome:C t P ti
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Current Perspective
Adapted from Reaven G. Drugs 1999;58(suppl):19-20 with permission from WolthersKluwer Health.
Body SizeBody SizeBMIBMI
Central AdiposityCentral Adiposity
Body SizeBody SizeBMIBMI
Central AdiposityCentral Adiposity
GlucoseGlucoseMetabolismMetabolism
GlucoseGlucoseMetabolismMetabolism
Uric AcidUric AcidMetabolismMetabolism
Uric AcidUric AcidMetabolismMetabolism DyslipidemiaDyslipidemia
DyslipidemiaDyslipidemia HemodynamicHemodynamicNovel Risk
Factors
Novel RiskFactors
Insulin ResistanceInsulin ResistanceInsulin ResistanceInsulin Resistance
HyperinsulinemiaHyperinsulinemiaHyperinsulinemiaHyperinsulinemia++
TGTG PP lipemiaPP lipemia
HDL-CHDL-C PHLAPHLASmall, dense LDLSmall, dense LDL
Glucose Glucoseintoleranceintolerance
Uric acidUric acid UrinaryUrinary
uric aciduric acidclearanceclearance
SNS activitySNS activity Na retentionNa retention
HypertensionHypertension
CRPCRP PAI-1PAI-1
FibrinogenFibrinogen
Coronary Heart DiseaseCoronary Heart DiseaseCoronary Heart DiseaseCoronary Heart Disease
Defining the metabolic syndrome
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WHOa EGIRb NCEPc IDFd
Insulinresistance&/or FPG
Insulin resistance(hyperinsulinaemia FPG Central obesity
Plus 2 or more of
Central obesity Central obesity Centralobesity
FPGe
BP BP BP BPe,f
TG, HDL-C TG, HDL-Cf TG TG
f
Microalbuminuria
HDL-C HDL-Cf
aWorld Health Organisation; bEuropean Group for the study of Insulinresistance;
cNational Cholesterol Education Program; dInternational Diabetes
Federationeor diagnosis of diabetes or hypertension as applicable; fand/or
Metabolic Syndrome Increases Risk for CHDd T 2 Di b t
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Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults.JAMA 2001;285:2486-2497.
and Type 2 Diabetes
Coronary Heart DiseaseCoronary Heart Disease
Type 2Type 2DiabetesDiabetes
HighHighLDL-CLDL-C
MetabolicMetabolicSyndromeSyndrome
Type 2 DM is the Tip of the Iceberg
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Type 2 DM is the Tip of the Iceberg
Beck-Nielsen H, Groop LC. J Clin Invest. 1994;94:17141721.
Type 2 Diabetes MellitusStage III
Stage II
Impairedglucosetolerance
Stage I
Normalglucosetolerance
Macroangiopathy MicroangiopathyPostprandial
plasma glucoseGlucose productionGlucose transport
Insulin secretory deficiency
Atherogenesis
HyperinsulinemiaInsulin
resistanceDiabetes Genes
LipogenesisObesity
Waist/hip ratio
TGHDL
HTN
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OBIECTIVE BIOMEDICALE PENTRU CONTROLULDIABETU UI ZAHARAT
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DIABETULUI ZAHARAT
Bun La limit Precar
Glicemia (autodeterminare)pe nemncate/preprandialpostprandial [mg/dl (mmol/l)]
80-110 (4,4-6,1)100-145 (5,5-8,0)
111-140 (6,2-7,8)146-180 (8,1-10,0)
> 140 (>7,8)> 180 (>10,0)
HbA1c (%)< 6,5 6,5-7,5 > 7,5
HbA1 (%) < 8,00 8,0-9,5 > 9,5
Colesterol seric totalmg/dl (mmol/l)
< 200 (< 5,2) 200-250 (5,2-6,5) > 250 (>6,5)
Trigliceridemg/dl (mmol/l)
< 150 (< 1,7) 150-200 (1,7-2,2) > 200 (> 2,2)
Index mas corporal (kg/m2)BF
< 25,4< 24,0
25,0-27,024,0-26,0
> 27,0> 26,0
OBIECTIVELE MANAGEMENTULUI DZ
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Mentinerea sau obtinerea unei stari generale bune, a uneicalitati optime a vietii
Disparitia sau ameliorarea simptomelor de hiperglicemie Atingerea tintelor controlului metabolic fara riscuri
Realizarea unei HbA1c
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ECHILIBRUL ENERGETIC
Glucide
Lipide
Proteine
Metabolismul bazal
Efort fizic
TEF
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Macronutrieni (trofine calorigene)- glucide- proteine
- lipide Micronutrieni (trofine necalorigene)
- vitamine - liposolubile- hidrosolubile
- minerale - macroelemente- microelemente
Apa (hidratare)
Surse de energie
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Apetitul, foamea isaietatea constituie trei poli opuiai necesitii fiziologice de supravieuire.
Foamea
reprezint dorina i necesitatea imperioas de a ingeraalimente, n special energetice, far discriminare.
Saietatea constituie senzaia de plenitudine sau de satisfacie,att fizic ct i psihic, dat de ingestia alimentelor.
Apetituleste o dorin pentru un anume aliment bogat ntr-ovarietate de nutrimente cum ar fi proteine, carbohidrai. Apetitulare o conotaie personal care ine de un model cultural dealimentaie
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RECOMANDRI NUTRIIONALE
CANTITATIVE pentru populaia sntoas exist standarde,repere pentru categorii de indivizi n funcie de vrst, sex i activitatefizic.
CALITATIVE
- n funcie de repartiia nutrimentelor n raia energetic
- in cont de anumite caracteristici pentru fiecare categorie denutriment energetic
- proporia P animale/vegetale
- proporia acizi grai saturai/mononesaturai/polinesaturai
- indexul glicemic al alimentelor (puterea hiperglicemiant)
NECESARUL CALORIC I DE PRINCIPIIALIMENTARE LA DIFERITE VRSTE
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ALIMENTARE LA DIFERITE VRSTEVrsta Greutate Necesar caloric
(kcal/zi)Necesar de
proteine (%)Necesar deglucide (%)
Necesar delipide (%)
1 an 7,3 820
1 3 ani 13,4 1300 15 55 30
4 6 ani 20,2 1830 14 54 31
7 9 ani 28,1 2190 13 55 32
Biei 10 12 ani 36,9 2600 13 55 32Biei 13 15 ani 49,9 2490 13 58 32
Biei 16 19 ani 54,4 2310 13 58 30
Brbai aduli(activitate medie)
65,0 2900 13 58 30
Femei adulte(activitate medie)
55,0 2200 13 58 30
Femei gravide(ultimile 5 luni)
- +350 15 57 28
Femei care alpteaz(primele 6 luni)
+550 14 57 29
CARACTERELE MACRONUTRIENILOR
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Proteine Glucide Lipide
SaietateSuprimarea senzaiei de foame
Aport energetic (kcal/g)% din aportul energetic zilnicCapacitatea de depozitareCi metabolice spre alte compartimenteAutoreglarea (capacitatea de stimulare a
oxidrii n cazul aportului excesiv)
++++++
4++
+++
+++++
4++++
++
9++++++
00
CARACTERELE MACRONUTRIENILOR
REGULI N ALCTUIREA UNEI DIETE
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DENSITATE ENERGETIC
- procentajul de kcal pentru 100 g de aliment- determinant esenial al saietii- este invers proporional cu volumul alimentelor
- cu ct un aliment este mai srac n lipide densitatea sa energetic estemai mic
DENSITATE NUTRIIONAL- coninutul n nutrimente nonenergetice (sau de proteine) pentru 100 kcal dealiment
- pentru fiecare porie de 100 kcal este preferabil ca densitatea nutriional s
fie nalt- un aliment avnd o densitate nutriional optim pentru un nutriment dat vaconine o mare cantitate din acel nutriment i un slab aport de lipide.
ECHIVALENE ALIMENTARE CANTITATIVEPENTRU O PORIE
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PENTRU O PORIEAlimentele Echivalenele cantitative pentru o porie
Pine, cereale, orez, pastefinoase, mmlig
1 felie de pine, can* cereale, orez sau pastefinoase (fierte), 1 biscuit
Legume, zarzavaturi, cartofi can vegetale proaspete sau fierte, 1 canlegume frunze fierte, can zarzavaturi fierte,
can suc de roii, 1 cartof mijlociu
Fructe 1 fruct mediu (mr, banan, portocal), grapefruit, can suc, can ciree, 1 felie
medie de pepene, 1 ciorchine mijlociu destrugure
Carne, pete, fasole boabe, ou
i fructe oleaginoase
100g carne gtit, 1 ou, can leguminoase
uscate fierteLapte, iaurt, brnz 1 can de lapte sau iaurt, can brnz de vac,
50g telemea
Grsimi, uleiuri i dulciuri 1 linguri* ulei, margarin, unt sau zahr
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Cte porii din fiecare etaj al piramidei
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Cte porii din fiecare etaj al piramideiar trebui s consumai zilnic?
1 porie 1 uncie
Pentru 1.600 kcal. Pentru 2.200 kcal. Pentru 2.800 kcal.
CONINUTUL PROTEIC AL DIVERSELOR
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Alimentul Proteine(g/100g aliment consumabil)
1. Carne ( vit, porc, pasre, pete) 15-22
2. Mezeluri ( salam, crnai, unc) 10-20
3. Brnzeturi 15-304. Lapte de vac 3,5
5. Ou 14
6. Pine 7-8
7. Paste finoase, gris, orez, fin de gru 9-128. Fasole, linte, mazre, soia (boabe uscate) 20-34
9. Nuci 17
GRUPE DE ALIMENTE
CONINUTUL DE AMINOACIZI ESENIALI
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Aminoacidg/100 g
necesarmg/kg/zi
gru Soia Cartof Orez Fasole Combinaiecereale +
leguminoase
Fenilalanin 14 4,9 4,9 4,0 5,3 5,2 5,25
Izoleucin 10,5 3,6 4,5 3,8 4,6 4,2 4,4Leucin 14 7,3 7,3 6,0 9,0 7,6 8,4
Lizin 12 3,1 6,4 4,8 3,9 7,2 5,55
Metionin +
cistin
13 1,6 1,3 1,3 2,3 1,0 1,65
Triptofan 3,5 1,2 1,3 3,8 1,5 1,0 1,25
Valin 10 4,8 4,8 1,6 6,3 4,6 5,45
CONINUTUL DE AMINOACIZI ESENIALI
CONINUTUL LIPIDIC AL DIVERSELOR GRUPE
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Tipuri de acizigrai
Carne Uleiurii alte
grsimi
Lapte iproduselactate
Leguminoaseuscate i fructe
oleaginoase
Ou Altealimente
Acizi graisaturai
39 34 20 2 2 3
Acizi graimononesaturai
35 48 8 4 2 3
Acizi graipolinesaturai 18 68 2 6 2 6
CONINUTUL LIPIDIC AL DIVERSELOR GRUPEDE ALIMENTE
Acizi grai Natura grsimiiPorc Vit Pasre Unt Ou Porumb Soia Msline
1. Acizi grai saturai
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g
- butiric 5,5
- capric 3
- lauric 2 3,5
- miristic 1,5 3 7 12
- palmitic 27 29 25 28 25 12,5 11,5 13
- stearic 13,5 21 6 13 10 2,5 4 2,5
- arahic 0,5 0,5
2. Acizi grai mono-nesaturai
- palmit oleic 3 3 8 3 1
- oleic 43,5 41 36 28,5 50 29 24,5 74
3. Acizi graipolinesaturai
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38 Glucoza
26 Mierea
15 Cornflakes100% Glucoz 100% Pine alb
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Pine integralPiure de cartofi
91-99% MuesliBiscuii
Piure de cartofiMorcovi
80-90% CornflakesMiere
Cartofi80-90% Banane
Zaharoz
Pine integral70-79% Orez
Cartofi
70-79% Chipsuri
Pine albBanane
60-69% MuesliBiscuiiPatiserie
Macaroane60-69% Spaghete fierte 15 min
Suc de portocale
Spaghete fierte 5 min50-59% Chipsuri
Zaharoz
Mere, portocale50-59% Iaurt
ngheatMazre uscat
Mazre uscat40-49% Portocale
Suc de portocale
Spaghete fierte 5 min40-49% Piersici
Lapte
Piersici30-39% ngheat
MereLapte, iaurt
30-39% Fructoz
20-29% Fasole pstiFructoz
10-19% ArahideSoia
10-19% ArahideSoia
Exemple deindex glicemic
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REPARTIIA NUTRIMENTELOR PEMESE
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MESE
Glucide cu indexglicemic mic
Glucide cu indexglicemic mare
Lipide Proteine
Mic dejun
Prnz
Cina
Da
Da
Moderat
Moderat
Moderat(dup o mas
bogat n fibre)
Nu
Moderat(colesterol
alimentar)
Cantitate redus
Da(acizi graipolinesaturai)
Da
Da
Da
Chevallier L, 2003
REGULI N ALCTUIREA UNEI DIETE
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Dieta prescris nu trebuie s fie nociv:- s aduc nutrimentele plastice i energetice n cantiti adecvate;- valoare nutriional bun.
Modificri prudente ale obiceiurilor alimentare:- obiceiuri determinate prin interogatoriul alimentar;- evitarea producerii frustraiilor inutile.
Rezultate controlate periodic.
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PRESCRIPII DIETETICE POSIBILE
Prescripia pozitiv a tuturor alimentelor indispensabile iechivalenele lor- las subiectului posibilitatea de a le adapta la gusturile i obiceiurile sale
Prescrierea n ntregime a unui regim personalizat- pornete de la prescripiile medicale
- ine cont de datele i preferinele pacientului
- necesit o perioad lung de timp i programe computerizate
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TRATAMENTUL DIETETIC NDIABETUL ZAHARAT
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Respectarea etapelor alctuirii unei diete Atenie distribuirea caloriilor pe cele 3 principii energetice i
pe mese
Suplimentarea cu vitamine i minerale este necesar doar la- pacienii ce urmeaz un regim hipocaloric perioade lungi
de timp
- n condiiile creterii necesarului energetic (sarcin,
lactaie, afeciuni intercurente)
Cntarul instrument indispensabil persoanei cu DZ!
DIABETUL ZAHARAT
ETAPELE ALCTUIRII UNEI DIETE
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Precizarea caracteristicilor generale ale dietei Calculul aportului caloric Distribuia caloriilor pe cele trei principii energetice i a
macronutrienilor n grame. Alegerea alimentelor Distribuia principiilor energetice pe numrul de mese Pregtirea corect a alimentelor (reguli de gastrotehnie)
INDIVIDUALIZAREA DIETEI!
TRATAMENTUL DIETETIC NDIABETUL ZAHARAT TIP 2
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Monitorizeazglicemia i
medicaie
Creteactivitatea fizic
Controlul glicemic
Modific cant.de grsimi
ingerat
Respect orarulmeselor
Crete preocupareade selecie a
alimentelor
Restrnge caloriilepentru normalizarea
greutii
Schimbstilul de via
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ALIMENTAIA SNTOAS 5 CRITERII
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Adecvat alimentele consumate s aduc nutrieni eseniali, fibre ienergie n cantiti suficiente pentru meninerea sntii i a greutiicorpului.
Echilibrat nu trebuie s prevaleze un nutriment sau aliment ndefavoarea altuia (respectarea proporiilor).
Controlat caloric se refer la aportul energetic care trebuie scorespund nevoilor metabolice; astfel se asigur controlul greutiicorporale.
Moderat atenie la posibile excese alimentare precum sarea, grsimile,
zahrul sau alt component peste anumite limite. moderaie, nu abstinen!
Variat evitarea consumului unui anumit aliment, chiar nalt nutritiv,zi dup zi, pentru perioade lungi de timp.
RECOMANDRI NUTRIIONALE (OMS)
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RECOMANDRI NUTRIIONALE (OMS)
Lipide 30%
- lipide saturate 7-10%
- lipide mononesaturate 10-15%- lipide polinesaturate 10%- colesterol 300 mg/zi
Glucide 50-55%
Proteine 15-20% NaCl 5 g/zi
RECOMANDRI NUTRIIONALE (AHA) Pine, cereale, orez, paste finoase, mmlig, 6-11 porii/zi;
aceste alimente ofer glucide complexe fibre alimentare riboflavin tiamin
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aceste alimente ofer glucide complexe, fibre alimentare, riboflavin, tiamin,niacin, fier, proteine, magneziu i ali nutrieni;
Legume, zarzavaturi, cartofi, 3-5 porii/zi; aceste alimente conin fibre,vitamina A, vitamina C, folai, potasiu i magneziu. Se recomand a fi folosite, de cteori este posibil, proaspete i crude.
Fructe, 2-4 porii/zi; sunt o surs bogat de fibre, vitamina A, vitamina C ipotasiu. Se recomand a fi consumate, pe ct este posibil, crude i proaspete.
Carne, pete, fasole boabe, ou i fructe oleaginoase, 2-3porii/zi; aceste alimente sunt bogate n proteine, fosfor, vitamina B6, vitaminaB12, zinc, magneziu, fier, niacin i tiamin. Se recomand consumul de carne de pui,curcan, carne slab de porc sau de vit i pete.
Lapte, iaurt, brnz, 2-3 porii/zi; aceste produse au avantajul de a fibogate n calciu, riboflavin, proteine, vitamina B12, iar cnd sunt fortificate i n
vitamina D i A. Grsimi, uleiuri i dulciuri, moderat, zahrul i grsimea sunt bogate
caloric dar, n acelai timp, sunt srace n nutrimente, ceea ce justific limitareaconsumului lor.
Valori int DZ tip 2 (IDF)
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Risc redus Riscarterial
Riscmicrovascular
HbA1c (%) 6,5 >6,5 > 7,5
Glicemia jeun/preprandialmmol/l
mg/dl
6,0
< 110
> 6,0
110
7,0
> 125Automonitorizare
jeun/preprandialmmol/l
mg/dlpostprandialmmol/lmg/dl
5,5
< 100
< 7,5 135
> 5,5
100
> 7,5 135
> 6
110
> 9,0> 160
IDF Guidelines. Diabet Med1999;16:716-30
TRATAMENTUL DIABETULUI ZAHARAT TIP 2
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Dup DeFronzo RA Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24S40
Hiperglicemie progresia bolii
Sulfonilureice
Meglitinide
Insulino-rezisten
Disfuncie-celular
(secreia deglucagon)
Aportul alimentarde glucide
Inhibitori de-Gluco zidaz
TZD
Metformin
Declin cronic-cel ular
Insulino-deficien
? ?
New Drug Targets for Type 2 Diabetes
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Nature414, 821 - 827 (2001)
DIABETUL ZAHARAT TIP 2 OPIUNI TERAPEUTICE
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OPIUNI TERAPEUTICE
insulinorezistena disfuncie -celularMetformin SulfonilureeTZDs Meglitinide
Hiperglicemie
inhibitori de insulinoterapie glucozidaz TZD?
Digestia i absorbia HC reducerea masei-celulare
tratamentul obezitii i al dislipidemiei
CARACTERISTICI DEZIRABILE ALEMEDICAIEI ANTIHIPERGLICEMICE ORALE
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Control glicemic durabil
Fr risc de hipoglicemie
Aciuni benefice asupra metabolismului lipidic Tolerabilitate bun i profil de siguran
Regim simplu de dozare
Util la un numr mare de pacieni cu DZ 2 Reducerea morbiditii/mortalitii cardiovasculare imicrovasculare
Terapia n DZ tip 2
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Tratament
nefarmacologic
ADOmonoterapie
ADOcombinaii
Insulin la culcare+/- ADO Insulinoterapie
Decompensaremetabolic acut
INSULINOREZISTENTA SIINSULINODEFICIENTA IN DZ 2
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InsulinResistance
Type 2Diabetes
-cellDysfunction
InsulinResistance
Hype
rgly
caem
ia
InsulinConcentration
InsulinAction
Euglycaemia
-cell Failure
Normal IGT obesity Diagnosis oftype 2 diabetes
Progression oftype 2 diabetes
DeFronzo R et al. Diabetes Care 1992;15:31
Type-2 Diabetes - A Question of Balance -
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Chris Rhodes Ph.D.
PNRI, Seattle, WA.
PERIPHERAL INSULIN
RESISTANCE
-CELL MASS
& FUNCTION
Non-Diabetic State
PERIPHE
RALINS
ULIN
RESISTA
NCE
-CELLM
ASS
&FUNCTIO
N
Diabetic State
The PPAR Family
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PPAR /
Adapted from Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669.
Ligand
Effect
Receptor
Leukotrienes
Fibrates
Prostaglandins
Thiazolidinediones Fatty Acids
Glucose
Metabolism
Vascular Effects Fat
Differentiation/
Redistribution
PPAR
Fat Oxidation
PPAR
HDL Reverse
Cholesterol Trans
Fat Oxidation
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Ce este exact ?
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disfunctia -celulara
Reducerea masei celulare Disfunctia progresiva acelulei
ambele
sau
sau
DZ TIP 2 AFECIUNE PROGRESIV
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n evoluie, majoritateapersoanelor cu diabet vor
necesita insulin pentruobinerea controlului
glicemic optim!
SuIfonilureele mod de aciune pancreaticSuIfonilureele mod de aciune pancreatic
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K+
Ashcroft, Gribble, Diabetologia (1999) 42: 903-919
Ca2+
Caracteristicile principalelor SU utilizate n diabetul zaharat de tip 2Compusul i anul introduceriipe pia
T (ore) Durata deaciune (ore)
Doza zilnic(mg)
Metabolii Excreia
Generaia nti
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Tolbutamid 1956
Clorpropamid - 1957
7
36-48
6-10
24-72
500-2000
100-500
Inactivi
Activi saunemodificat
Renal
Renal
Generaia a douaGliclazid 1972
Glipizid 1971
Glipizid GITS
Gliquidona
Glibenclamid 1969
Glibenclamid micronizat
8
2-4
1.3-1.5
15-20
1.5-3.3
6-12
16-24
Nivel const.dup cteva zile5-8
20-24
20-24
80-320
2.5-5
5-20
15-120
2.5-20
2.5-15
Inactivi
Inactivi
Inactivi
Inactivi
Inactivi sau slab
activiInactivi sau slabactivi
Renal 75%Bil 25%Renal 80%
Bil 20%
Renal 5%Bil 95%Renal 50%
Bil 50%
Generaia a treiaGlimepirid 1995 7 12-24 2-8
2 metabolii unul activ
Renal 60%Bil 40%
Sulfamidahipoglicemiant
Alte denumiricomerciale
T 1/2(ore)
Duratadeaciune
Doza zilnic(mg)
Eliminare urinar(%)
Rischipo
Sulfonilureice din generaia ITolbutamid Orinaze 7 6 10 500 3000 100 +++
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Tolbutamid Orinaze 7 6-10 500-3000 100 +++Clorpropamid Diabinese 35 24-72 100-500 90-95 ++++
Sulfonilureice din generaia IIGlibenclamidGlibenclamid
micronizat
Maninil, DaonilEugluconManinil 1,75; 3,5
5 12-16 2,5-151,75 10,5
50 ++++
Glipizid
Glipizid GITS
MinidiabGlucotrol
Glucotrol XL
6 12-14 5-40
2,5 - 20
70 +
Gliclazida
Gliclazid MR
DiamicronDiaprel, PredianDiaprel MR 30
10 6-12 40-32030 - 120
60-70 +
Gliquidona Glurenorm 2 5-7 15-90 5 +Glimepirida* Amaryl 7 10-12 3-6 80 +
* Considerat de unii autori prima sulfamid hipoglicemiant de generaia a treia
dat fiind existena unor efecte periferice (scdere glicemic cu minim cretere a
insulinemiei).
Scderea produciei hepatice de glucoz prin diminuarea
MECANISMELE ACIUNIIANTIHIPERGLICEMICE A METFORMINULUI
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glicogenolizei i a gluconeogenezei
Stimularea captrii musculare a glucozei mediat de insulin Creterea utilizrii splanhnice a glucozei Scderea absorbiei intestinale a glucozei Inhibiia lipolizei i
scderea nivelelor de acizi grai liberi, urmat de ameliorarea
ciclului Randle Mecanismele celulare ar fi : Creterea legrii insulinei de receptori Stimularea activitii tirozin-kinazei a receptorilor insulinici
Amplificarea transportului celular al glucozei prin activareatransportului GLUT-4 Creterea activitii glicogen sintetazei
CONTRAINDICAIILE METFORMINULUI N TERAPIAPERSOANELOR CU DIABET ZAHARAT TIP 2
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Insuficien renal: creatinina seric 1.4 mg/dl la femei
sau 1.5 mg/dl la brbai Insuficien cardiac congestiv care necesit farmacoterapie Hepatopatii cronice cu transaminaze ce depesc de 3 ori
valoarea superioar a normalului
Bolnavii peste 80 ani dac clearance-ul scade sub 70 ml/min Sarcina i lactaia Diabetul zaharat tip 1 Persoanele dependente de alcool sau cu consum excesiv de
alcool Traumatisme severe, infecii sistemice, oc Deficit de vitamina B12
TIAZOLIDINDIONELE
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Activatori ai PPAR Cresc insulinosensibilitatea la nivel adipocitar i
hepatic
Efecte pe metabolismul glucidic i lipidic Efecte asupra adipogenezei i homeostaziei energetice Implicare n inflamaie i aterotromboz
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TZD + PPARin celula adipoasa
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p
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 suprasarcinapepancreas
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Success of controllingtype 2 diabetes
Reduction in insulinresistance
Improvement in -cellfunction
(delay disease progression)
PPAR agonistBeneficiile fiziologice ale agonistilor PPAR
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g
stocare mai eficienta a AGL
Mai putini AGL in
Pancreasimbunatatestefunctia -cel
Muschi imbunatatesteactiunea insulinei creste captarea
l i
Ficatdescreste
productia deglucoza
DEFINITION OF INCRETINS
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Gut-derived factors that increase
glucose-stimulated insulin secretion
Incretin
Intestine Secretion Insulin
Creutzfeldt Diabetologia 1985;28:565
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GLP-1
GlucoseGlucose
EnterocyteEnterocyte
InsulinInsulin GlucagonGlucagon
Stomach:Stomach:
MotilityMotility
Hypothalamus:Hypothalamus:
AppetiteAppetite
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Inhibitorii DPP-4
A t
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Aport
alimentarEliberarede GLP-1
GLP-1 biologic activ
InhibitorDPP-4
GLP-1 inactiv
DPP-4
Rothenberg P et al Diabetes 2000;49(suppl 1):A39
GLP-1 therapy:Mimicking physiology
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Source: Kieffer & Habener (1999): Endocrine Reviews 20: 876-913
PHARMACOLOGIC AGENTS
Drug Class,Research Name
Generic Name Manufacturer Status
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DPP-IV InhibitorsLAF237MK-0431BMS477118
VildagliptinSitagliptinSaxagliptin
NovartisMerckBMS
Phase 3Phase 3Phase 3
GLP-1 ReceptorAgonists
MimeticsExendin-4 Analogues
NN2211CJC-1131ZP10
Albugon
Exenatide
LiraglutideNot determinedNot determined
Not determined
Amylin/Lilly
Novo NordiskConjuChemSanofi-Aventis
Human GenomeSciences
FDA-approved
Phase 2Phase 2Phase 2
Phase 2
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Lineage relationships
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Endodermal precursorPancreatic precursor
Endocrine precursors
Exocrine precursor
InsulinGlucagon
Exocrine
Ductal
Time
?
g pduring pancreatic
development
Liver
Duodenum
Jensen and Jensen, 2002.
SOURCES OF -CELLS FORTRANSPLANTATION
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Ackermann AM Gannon M J Molec Endocrin 2007;38:193 206
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AVANTAJELE SI DEZAVANTAJELE ADO
Clasa Avantaje Dezavantaje
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Clasa Avantaje Dezavantaje
Sulfonilureice Cresc secretia de insulina
(diabetic normo sau
subponderal)
Pret scazut
Hipoglicemie
Crestere in
greutate
Meglitinide Cresc secretia de insulina
(diabetic normo sau
subponderal)Scad glicemia postprandiala
Mai putine hipoglicemii decit
sulfonilureicele
Necesita doze
zilnice multiple
Scumpe
Biguanide Nu determina hipoglicemie in
monoterapie
Nu determina crestere ingreutate
Efect potential benefic asupra
profilului lipidic
Amelioreaza utilizarea insulinei
(la obezi)
Efecte secundare
gastro-intestinale
Contraindicate inafectiuni frecvente
la virstnici:
insuficienta renala,
insuficienta
cardiaca
AVANTAJELE SI DEZAVANTAJELE ADO(continuare)
Clasa Avantaje Dezavantaje
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Clasa Avantaje Dezavantaje
Inhibitori de
alfa-glucozidaza
Nu determina hipoglicemie in
monoterapie
Nu determina crestere in
greutate
Absorbtie sistemica redusa
Scad glicemia postprandiala
Efecte secundare
gastrointestinale
Necesita multiple
doze zilnice
Determina o
scadere mai mica a
HbA1c decit alteclase de
medicamente
Tiazolidindione Amelioreaza utilizarea
insulinei (la obezi)
Efect pozitiv asupra
trigliceridelor si HDLu determina hipoglicemie in
monoterapie
Crestere in
greutate
Crestere a LDL
Necesita omonitorizare
frecventa a
functiei hepatice
Scumpe
INDICATIILE INSULINOTERAPIEI in DZ2Insulinoterapie definitiva
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DZ tip 1(LADA) DZ tip 2 la care medicatia orala in asociere si la doze
suficiente nu induce controlul glicemic propus Complicatii cronice evolutive Insuficienta hepatica
Insuficienta renalaInsulinoterapie temporara Afectiuni acute: IMA, infectii cu diferite localizari Interventii chirurgicale (pre-, intra- si postoperator) Sarcina Coma hiperglicemica hiperosmolara
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Lebovitz HE Therapy for Diabetes Mellitus and Related Disorders 2004
Idealized insulin effect provided by flexiblemultiple-dose regimens
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Lebovitz HE Therapy for Diabetes Mellitus and Related Disorders 2004
Idealized insulin effect provided by flexiblemultiple-dose regimens
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Lebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004
Idealized insulin effect provided bysplit-mixed insulin regimens
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Lebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004
Idealized basal insulin effect providedby a bedtime injection
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Lebovitz HE Therapy for Diabetes Mellitus and Related Disorders 2004
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n 2006, ADA i EASD au elaborat
primul Consens Internaional privindmanagementul hiperglicemiei.
INTELE HBA1C PENTRU CONTROLULGLICEMIC
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Nivelele HbA1c ar trebui s fie ct mai aproape posibil de celenormale Nivelul int minimal: < 7%
Nivelele-int ale HbA1c sunt 6.5%
USA> 7%
NIVELELE HBA1c LA CARESE INIIAZ ORI SE MODIFICTRATAMENTUL
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Nathan DM, et al. Diabetologia 2006;49:171121
Normal Controlat Necontrolat
< 6%
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Normal Diabet necontrolat
HbA1c < 6% < 7.5% > 8.5%
SE ADAUG UN AGENT
cu potenial mai redus descdere a glicemiei ori cudebut mai lent al aciunii
SE ADAUG UN AGENT
cu efect mai puternic de scderea glicemiei sau se iniiaz
terapia combinat
Nathan DM, et al. Diabetologia 2006;49:171121
2006: MANAGEMENT ACTIV I INTRODUCEREAPRECOCE A INSULINEI BAZALE
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Modificat dupa Nathan DM, et al. Diabetologia 2006;49:171121
HbA1c 7%
HbA1c 7%
HbA1c 7%
OSV+MET
MET+ InsulinaBazala
MET + SU MET + TZD
MET + InsulinaIntensificat
MET + SU +Insulina Bazala
MET + SU+ TZD
MET + TZD +Insulina Bazala
Insulina Intensificat +MET + TZD
3 TREPTE PENTRU MENINEREA CONTROLULUIPercepia urgenei de a trata mai eficient i mai repede
TREAPTA 2
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Adaptat dupa Nathan DM, et al. Diabetologia 2006;49:171121
Optimizare stil viata(HbA
1c
12%)
Metformin(HbA1c 1.5%)
TREAPTA 1terapia iniial
TREAPTA 2dup 23 luni se adaug
al doilea agentTREAPTA 3
dup 23 luni seajusteaz tratam.
Insulina bazala(HbA
1c1.52.5%)
Sulfonilureice(HbA1c 1.5%)
Tiazolidindione(HbA1c 0.51.4%)
Se incepe ( intensifica)insulino terapia
Se adauga al treileaagent oral daca este
cost-eficient
DZ tip 2 este o boal progresivAdugarea medicaiei este regula pentru a menine intele terapeutice
HbA1c 7%
HbA1c 7%
Insulina este cea maieficace
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