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C ch bnh sinhi tho ng tp 2

ThS.BS. Trn Th TrungB mn Ni Tit

i hc Y Dc TP.HCM

Slide 2

c im i tho ng tp 2

T tpe 2 chim 90-95% bnh T

Kt hp khng Insulin v gim tit Insulin:

khng Insulin Bo ph (nht l bo bng/ tng m tng)

t vn ng

t nhim ceton tr khi c stress nng

Gim tit Insulin T bo beta-ty khng tit insulin b tr cho tnh

trng khng insulin.

T bo beta suy gim chc nng dn dn theo thi gian.

Slide 3

c im phn bit i tho ng tp 1 v tp 2

c im Tp 1 Tp 2

Tui khi pht Tr, thanh thiu nin Thng > 40

Biu hin khi pht t ngt Chm

Tin cn gia nh C th c T tp 1 Thng c T tp 2

C chKhng r; di truyn, t min, virus

Khng r; di truyn

Cp sinh i

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Slide 4

Nhng ri lon thng i km i tho ng tp 2

Bo ph

khng insulin

Tng insulin mu

Tng huyt p

Gai en (Acanthosis Nigerians)

Bnh l mch mu ln v nh

PCOS (hi chng bung trng a nang)

Slide 5

Cc hormone ca ty

Insulin (t bo beta tit) Kch thch thu nhn glucose vo t bo,

do vy lm gim glucose mu

Glucagon (t bo alpha tit) Kch thch phn gii glycogen v phng

thch glucose, do vy lm tng nng glucose mu

Glucagon v insulin hot ng phi hp cng nhau iu ha v duy tr nng ng mu.

Slide 6

Chc nng ca insulin

Vn chuyn glucose vo t bo, cung cp nng lng cho c th Glucose l nng lng a thch

ca hu ht t bo, l ngun nng lng duy nht cho t bo no.

No + Hng cu hp thu glucose khng cn insulin

Chuyn glucose thnh dng glycogen d tr ti c v gan

Chuyn glucose d tha thnh dng m

Ngn nga phn gii protein

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Slide 7

Tc dng ca insulin

Michael Stumvoll et al,Pathogenesis of Type 2 Diabetes, Type 2 Diabetes Principles and Practice (2008)

Slide 8

Ngi khng i tho ng

Insulin

Tu

C

Glucose

Tun hon

Glucose v Insulin

Carbohydrate

M

Slide 9

Bnh nhn i tho ng tp 2

Insulin

Tu

C

Glucose

Tun hon

Glucose v Insulin

Carbohydrate

M

Ri lon chc nng t bo beta tu v khng insulin

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Slide 10

Gen Mi trng

C ch bnh sinh i tho ng tp 2

Suy t bo beta khng insulin

i tho ng tp 2

Slide 11

Vai tr yu t di truyn

Tn sut i tho ng theo sc dn ti M: Caucasians: 2-4 %

African-American 4-6%

Mexican-American: 10-15%

Pima Indians: 35%

Yu t gia nh > Bo ph + gii + thi quen vn ng.

Tn sut T tng nhanh nhng ngi/vng c chuyn i li sng sang phng ty nhanh. t vn ng

Bo ph vng bng

Slide 12

Vai tr yu t di truyn

Sinh i: Gen chim 60-90% kh nng b T

Sinh i cng trng 70-90% ng b T

Khc trng: 15-25%

Nguy c tng theo thi gian sng.

Tin cn gia nh (trc h) c i tho ng = Nguy c 40%.

C cha + m cng b i tho ng = nguy c b i tho ng l 70%.

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khng Insulin v ri lon chc nng t bo b

khngInsulin

Yu t c a, bo ph, li sng t vn ng

Bnh i tho ng type 2

IRRi lon chc nng t bo bb

Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):313.

Slide 14

Cc yu t nguy c T tp 2

1. Cn nng

2. Phn b m

3. t vn ng

4. Tin s gia nh

5. Chng tc, sc dn

6. Tui

7. Tin i tho ng

8. Tin cn i tho ng thai k (n)

www.mayoclinic.com

Slide 15

khng insulin

Ri lon quan trng trong i tho ng tp 2

Gim p ng sinh hc (ca cc m) vi insulin

Yu t d bo i tho ng tp 2 mnh

Lin quan cht vi bo ph

1American Diabetes Association. Diabetes Care 1998; 21:310314.

2Beck-Nielsen H & Groop LC. J Clin Invest 1994; 94:17141721. 3Bloomgarden ZT. Clin Ther 1998; 20:216231.

4Haffner SM, et al. Circulation 2000; 101:975980. 5Boden G. Diabetes 1997; 46:310.

Insulinresistance

Glucose output Glucose uptake Glucose uptake

Hyperglycemia

Liver Muscle Adiposetissue

IR

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Slide 16

Vai tr ca khng insulin

khngInsulin

Tng huyt p

T Type 2

RL tiusi huyt

RL lipid mu

TG, LDL

HDL

RL chc nngT bo ni mc Hin tng vim

X va ng mch

Bo bng

Adapted from the ADA. Diabetes Care. 1998;21:310-314;Pradhan AD et al. JAMA. 2001;286:327-334.

Slide 17

khng insulin:Yu t Di truyn v Mc phi

khng insulin = Phi hp Di truyn + Mc phi:

Bo ph

Thi quen n ung

t tp vn ng

Tnh trng bnh i tho ng (tp 2) xut hin cng lm xu thm tnh trng khng insulin:

Tng nng FFA (acid bo t do)

Tng ng huyt

=> C th o ngc (ci thin nhng khng bnh thng hon ton) nu kim sot tt ng huyt.(10% n 75% theo cc nghin cu)

Di truyn(gen)

Slide 18

C ch khng insulin

Ba khu c th lin quan: Th th insulin

Nhng thnh phn ca th th (IRS-1, IRS-2)

B phn vn chuyn glucose [phosphatidylinositol-3-kinase (PI-3-kinase) v glucose transporter isoform (Glut-4)]

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Slide 19

C ch khng insulin

Gim s lng th th insulin mng t bo:

Ngi bo ph v ngi ri lon dung np glucose (do tng insulin mu).

Bnh nhn i tho ng bo ph v khng bo ph.

Cn gim < 10-20% so vi bnh thng mi nh hng n nhy cm insulin.

Slide 20

khng insulin:Yu t Di truyn

Nhng gen c kh nng lin quan khng insulin:

insulin receptor, Glut-4, glycogen synthase, PI-3-

kinase

C ch a gen phc tp:

Vai tr ca tng gen n l rt hn ch

C s cng hng nu kt

hp nhiu gen, km vi yu t mi trng hoc yu t khc nh tng FFA

Nhng gen lin quan n bnh sinh i tho ng tp 2

Slide 21

o lng khng insulin

C nhiu phng php:

Ly mu lin tc o insulin/glucose1

Tiu chun vng nhng km thc hnh, khng p dng

rng ri c

o insulin/glucose mt ln2

n gin, t mt mu mu lc i (o insulin v glucose)

D p dng cho s lng ln

1Bergman RN, et al. Eur J Clin Invest 2002; 32 (Suppl. 3):3545.

2Matthew s DR, et al. Diabetologia 1985; 28:412419.

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Slide 22

o lng khng insulin

Vng eo l mt chs lm sng tt phn nh khng insulin.-Nam > 90 cm-N > 80 cm

Slide 23

Ri lon chc nng t bo beta

Ri lon quan trng trong i tho ng tp 2

Gim kh nng bi tit insulin ca t bo beta ty p ng vi tnh trng ng huyt cao

b

b

b

b

DeFronzo RA, et al. Diabetes Care 1992; 15:318354.

Slide 24

Ri lon chc nng bi tit insulin bnh nhn i tho ng tp 2

Gim nh tit sm v mun bnh nhn i tho ng tp 2 khi lm nghim php kp glucose cc mc 7.5, 10 v 15 mmol/L.

Vivian Fonseca and Jennifer John-Kalarickal. Type 2 Diabetes Mellitus: Epidemiology, Genetics, Pathogenesis, and Clinical Manifestations. Principles of Diabetes Mellitus 2nd (2010)

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Slide 25

Suy chc nng t bo beta xy ra trc khi bnh i tho ng c chn on

Time from diagnosis (years)

Up to 50% loss

100

80

60

40

b-c

ell

fun

cti

on

(%

)

20

0

Diagnosis

-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 1 2 3 4 5 6

Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21S25.

Slide 26

Thay i chc nng t bo beta

Marc Prentki and Christopher J. Nolan.Islet b cell failure in type 2 diabetes. J. Clin. Invest. 116:18021812 (2006)

Slide 27

C ch suy t bo beta

Tng glucose ko di

Tng bi tit insulin b tr1,2

Tng nng FFA

Ng c glucose(Glucotoxicity)2

Ty

Ng c m (Lipotoxicity)3

Ri lon chc nng t bo b

1Boden G & Shulman GI. Eur J Clin Invest 2002; 32:1423.

2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:522.

3Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20S27.

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Slide 28

Nhng thay i trong bi tit insulin bnh nhn i tho ng tp 2

Gim kh nng tit insulin

Gim nhy ca t bo beta vi glucose

Mt pha tit insulin sm vi glucose

Tng phng thch proinsulin

Mt nhp iu bi tit bnh thng

Thay i hnh thi hc (gim khi lng t bo beta; lng ng amyloid)

Slide 29

khng insulin v Suy t bo beta

Slide 30

Chc nng t bo beta v khng insulin

ng cong biu

din mi lin h

gia chc nng

t bo beta v

nhy insulin trn

nhng nhm i

tng khc nhau.T2DM: i tho ng

tp 2; IGT: Ri lon dung

np glucose; NGT: Dung

np glucose bnh

thng

Michael Stumvoll et al,Pathogenesis of Type 2 Diabetes, Type 2 Diabetes Principles and Practice (2008)

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Slide 31

Normal

Din tin t nhin ca bnh i tho ng tp 2

Impaired glucose

tolerance

Type 2 diabetes

Fasting plasma glucoseInsulin sensitivityInsulin secretion

Insulin sensitive

Normal insulin secretion

Normoglycaemia

Hyperglycaemia

-cell exhaustion

Insulin resistance

Late type 2 diabetes

complications

Adapted from Bailey CJ et al. Int J Clin Pract 2004;58:867876. Groop LC. Diabetes Obes Metab 1999;1 (Suppl. 1):S1S7.

Insulin resistance

Slide 32

o lng Chc nng t bo b

nh gi chnh xc chc nng t bo b: phc tp, kh p dng lm sng

nh gi bng m hnh HOMA (Homeostasis model assessment) l cch n gin c tnh chc nng t bo b2

i khi dng t l (Proinsulin:insulin) nh gi s ri lon chc nng t bo b1

1Matthew s DR, et al. Diabetologia 1985; 28:412419.

2Bergman RN, et al. Eur J Clin Invest 2002; 32 (Suppl. 3):3545.

Slide 33 Garber A. J Am Osteopath Assoc 2011;111:S20-S30

Chc nng t bo beta vTc dng ca GLP-1

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Slide 34

Sn xut glucose t gan (HGO)

Khi nhn i qua m, glucose mu c duy tr ch yu do glucose t gan (90%) vi tc khong 1.8-2.2 mg/kg/pht.

Bnh nhn i tho ng, mc ng huyt i tng quan vi HGO.

Yu t tng thm HGO:

khng insulin ca gan

Thiu insulin tng i

Tng nng glucagon mu

Tng nng tin cht tn to glucose

Tng nng acid bo t do (FFA)

Slide 35

C ch tng glucose mu i

No hp thu phn ln glucose khi i (50-60%).

C ch ng gp tiu th 15-20% glucose lng lc i.

Tng ng huyt lc i ch yu c ngun gc do tng sn xut glucose t gan.

Slide 36

C ch tng glucose mu sau n

Sau n, glucose mu c hp thu vo:

Gan: th u < 10%, tng cng 20-35%.

Phn ln cc m ngoi bin (50-60% c)

Yu t ng gp vo tng ng huyt sau n:

Tng lng cung glucose: t thc n v t gan

Gim thu nhn glucose vo c (do khng insulin)

Gim thu nhn glucose vo gan gim

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Slide 37

Gen v Phng nga i tho ng

T tp 2 l c th phng nga:

Duy tr cn nng ph hp

Hot ng th lc

Pht hin gen s lm sng t c ch sinh bnh

iu tr phng nga tp trung vo nhm nguy c cao

Liu xt nghim gen c gip ngn nga bnh?

Hiu bit c dn n thay i hnh vi ?

Slide 38

Gen v Phng nga i tho ng

Thch thc v kh khn bao gm:

Gi tr tin on thp

Din gii v s dng thng tin nguy c?

Kh khn din t kt qu phn tch (a) gen

C th dn n khng hong tinh thn

Phn bit i x trong bo him v tuyn dng

Tnh bo mt v th phi

Tc ng th trng xt nghim gen

Slide 39

Nhng ri lon/ch iu tr trong bnh i tho ng tp 2

PPAR-gamma (bit ha t bo m)

IRS1 (th th insulin)

Glucagon synthase

TCF7L2 (tng hp glucagon)

Glucagon

GLP-1 (kch thch tit insulin)

DPP-IV (thoi ging GLP-1)

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Slide 40

Nhng ro cn trong t mc tiu kim sot ng huyt

Khng t c mc tiu khc phc nhng c ch sinh bnh!

Slide 41

Lm th no ci thin vic iu tr v t kt qu tt ?

Nhm n khc phc nhng ri lon trong c ch sinh bnh, trong bao gm tnh trng khng insulin.

Del Prato S, et al. Int J Clin Pract 2005; 59:13451355.

Slide 42

Gen Mi trng

C ch bnh sinh i tho ng tp 2

Suy t bo beta khng insulin

i tho ng tp 2

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Slide 43

Gen Mi trng

C ch bnh sinh i tho ng tp 2

Suy t bo beta khng insulin

i tho ng tp 2

Tm sot gen, xp loi nguy c-Xc nh c ch ri lon-Bin php phng nga

-Hng dn iu tr-C th ha iu tr

Slide 44

Gen Mi trng

C ch bnh sinh i tho ng tp 2

Suy t bo beta khng insulin

i tho ng tp 2

Li sng-Bo ph

-Vn ng-Ch n

Slide 45

Gen Mi trng

C ch bnh sinh i tho ng tp 2

Suy t bo beta khng insulin

i tho ng tp 2

Thay i li sng:-Bo ph-Vn ng-Ch nThuc:-PPAR (TZD)

-Metformin

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Slide 46

Gen Mi trng

C ch bnh sinh i tho ng tp 2

khng insulin

i tho ng tp 2

Suy t bo beta

Li sng-Bo ph-Vn ng

-Ch n

Thuc-SU, glinides-GLP-1

-DDP-IV-Insulin

Slide 47

Kt lun

C ch bnh sinh i tho ng tp 2:

Ri lon bi tit insulin + Ri lon tc dng insulin

Ri lon chc nng t bo beta+ khng insulin

Yu t di truyn + yu t mi trng (li sng)

khng insulin xy ra cc m: gan, c, m.

Tng ng huyt v FFA cng lm tng khng insulin.

Bnh i tho ng (ch) xut hin khi chc nng t bo beta suy gim.