Curs Diabet 1

7/29/2019 Curs Diabet 1

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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)
http://www.eatlas.idf.org/http://www.eatlas.idf.org/


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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


11/197McKinlay J et al. Lancet. 2000;356:757,761.

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



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Curba hiperbolica a relatiei dintre


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IS x CF





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IS x CF

Bonora E et al. Diabetes Care, 2002; 26 (7): 1153-1141



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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




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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



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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.



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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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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


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


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


Slide 11 of 48


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Blood glucose

Glucose uptake

Insensitivity to insulin in

ttype 2 diabetes

Glucose uptakeGlycolysis


Glucose uptake



Slide 12 of 48


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Blood glucoseConverted to triglycerides

Effect of insulin resistance in

ttype 2 diabetes

Glucose uptakeGlycolysis


Glucose uptake


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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126/197


127/197

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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137/197

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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159/197

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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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)



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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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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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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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Curs Diabet 1

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