CHUYfeN oi: Hpl NGH| KHKT CAC TJNH VUNG DUVeN HAI BAC BQ LAN THJS NHAT
TUTINCRETIN TCh DPP-4 INHIBITORS VA GLP-1 ANALOGS
Ho^ng Dang Mich'
Nam 1902. Bayliss va Starling dua ra dan chung ming nh^y rugt c6 chiia mgt hormone kich thich tilt exocrin cua luy. Tuy nhien vi?c udng c^c chat chilt xuat tir mang nhiy rugt dl dilu tri dai Ihko dudng type 1 d5 thit bgi.
Tdi nkm 1932, La Barre dat ten Incretin cho mgt hormone chiet xuat tir ming nhay rugt cua dudng lieu hoa tren c6 tac dung ha dudng huylt. Chat nay dugc de nghi dl dieu tri dai thao dudng (DTD).
Nhung nam 1939 - 1940, dua vao cac nghien ciiu, Leow va cgng sir ket Iuan su tdn tai cua Incretin con la mpt cau hoi. Trong khoang 30 nkm sau do, khong cd mpt nghien Cliu nao ve Incretin dugc thuc hien.
Cac nghien ciiu sau nay cho thay Incretin khong tu kich thich tiet nhieu Insulin hon ma bang each lam cho tiet Insulin dugc kich thich tang them bdi ndng dp Glucose.
Cac thu6c nhu Sulphonylureas va meglitinides kich thich t3ng liet Insulin vi co tang nong dp glucose trong mau. Do vay co tac dung khdng mong muon la ha dudng huyet. Cac thu6c giong nhu Incretin kh6ng tac dung nhu vay.
Incretin con irc che tiet Glucagon mpt hormone lam tang glucose mau bdi Glucagon kich thich gan san xuit Glucose. Mat khac Incretin con lam cham tdng xuit da diy (cham rong da day-delays stomach emptying). Vi vay, su hap thu Glucose dupc trai deu theo thdi gian, khong lam tang nhanh dudng mau.
Sir thieu hut hay sir tang thanh thai Incretin khdng phai la ylu t6 benh sinh trong DTD type 2.
Nhang dac diem cua Incretin:
Tang giai phap Insulin tir te bao p t\i>
dio Laugerhans sau biia an.
- Lim cham chuyen chat dinh dudng vao h? tuan hoin bing cich lam cham t6ng xuit thiic an tir da day.
- LTC che giii phong Glucagon tir tl bao a cua tuy dio Langerhans.
Bj bat hoat bdi men dipeptidyl peptidase -4 (DPP-4). D^c diem nay dugc ling dung trong DTD type 2.
Tdi nim 1970, gastric inhibitory peptide (GIP) dupc tach chiet vi dinh chuoi tir mang nhay rupt. Nim 1973, GIP dupc dat ten 1^ la glucose - dependent insulinotropic hormone sau khi Brown va Dupre chimg minh dugc GIP kich thich tiet Insulin. Tuy nhien nhung nghien ciiu ban dau da khdng cong bo dugc tac dung ciia no trong dieu tri DTD.
Mpt peptide tien glucagon da dugc xic dinh vao nam 1982 bdi Lund va cgng sir.
Tiep do, gen quy dinh lien Glucagon ngudi da duoc xac djnh vio nim 1983 bdi G.Bell vi cpng sir. Vi, chuoi tien Glucagon ngirdi dugc khang dinh. Nhimg cdn phan tu glucagon like peptide-1 (GLP-I) toin bp da khdng thay tac dung dieu chinh miic Insulin.
Chi CO mpt chudi GLP-1 dac hieu da dupc- thay cd tic dung hudng Insulin, do la GLP -1;
(7-36). No dupc bit hoat nhanh chdng bdi;
mgt men co ten li dipeptidyl peptidase 4j (DPP-4) vdi nua ddi sfing trong huylt tuang li 1 -2 phut. Ca GIP cung nhu GLP-1 bi bilj hoat nhanh chdng bdi men DPP - 4. -
GLP-1 vi GIP li 2 dai dien chinh cu£;
Incretin (nhom hormone da day rugt). GLP-i
* Benfi vien Viel Tiep Hai Plidng
Y HQC VlgT NAM T H A N G 5 - Sd'oAC BlgT/2013
la san pham ciia mgt gen tien glucagon.
Ngu6n cung cap chinh cua GLP-1 la te bao ngi tilt tir rugt tiet GLP-1 nhu mpt hormone tieu hda. Dang hoat dpng sinh hpc cua GLP-1 li: GLP-1 (7-37) va GLP-1 (7-36) NH2. Dd li nhiing sin pham tir su chia tich cOa phin tli tiln Glucagon (Proglucagon).
Co che tac dung cua GLP-1 vi GIP trong viec ha dudng huyet rat don gian so vdi cic honnone khac. Chung dugc tiet bdi cac te bao ngi tilt nam d bieu md rugt non (epitheUum). Khi nong dp glucose tang trong dirdng tieu hda, cu the li trong cic ong nhd (lumen) 0 bieu mo rupt, no co tic dung nay CO de dieu tiet hormone.
Cac hormone tren vao he tuan hoan tdi mo dich la te bao P tuyen tuy. Sir kich thich tl bao p tuyen tuy gay tang them s6 lupng Insulin tuong iing de chuyen hoa Glucose.
Co nhieu dieu thu vi khi phat trien hirdng dieu tri DTD dua tren Incretin. Co che can bin cua DTD type 2 la de khang Insulin.
Do la sir giam nhay cim cua mo doi vdi Insulin va roi dan tdi giam tiet Insulin. Trong DTD type 2 cdn hay thay tinh trang khiem khuydt tilt Insulin, dac biet khi benh cing lau thi giam tiet Insulin cang ro. Do vay co rat nhieu ly do de nght rang dieu tri dua vao Incretin, nhit li GLP-1 co the dem lai nhieu
\(ji ich.
Nhieu benh nhan DTD type 2 da dupc thiy suy giim tilt Insulin trong biia in.
Ngudi ta ciing thiy GLP-1 giim tilt vi dip ling kem ciia tl bio p tuyin tuy doi voi GIP.
Tuy nhien, trong DTD type 2 thi GIP jlthSng dilu chinh su tilt Insulin phu thupc jGlucose ngay ca khi nong dp Insulin dudi miic sinh ly. Bdi vay sir giim tiet li do sir tdn
¥ chiic nang cua te bio 3» dac biet sau bua an. Mat khac, GLP-1 vin la ylu t6 hudng
Insulih trong DTD type 2. Dilu dd dan tdi nghien ciru hudng hoat hda thu thi ciia GLP-
1 vdi nhieu vien cinh cii thi?n s\r tilt Insulin.
Sir tiet GLP-1 tir te bio bieu m6 rupt non phu thugc vao sir cd mat cua chit dinh dudng d gian bio cua cac te bao rugt. Nhiing tic nhan giy ra hoac kich thich tiet GLP-1 la cac chat dinh dudng nhu Carbonhydrate, Protein vi Lipid. Khi vio he tuan hoan thi niia ddi song ciia GLP-1 li khoing 2 phut vi bi phan buy nhanh chdng bdi men dipeptidyl peptidase-4 (DPP-4), GLP-1 li hormone co kha nang chong tang dudng huyet bao gdm kich thich tiet Insulin phu thugc vao Glucose, trong khi do no lie che tiet Glucagon. Hoat dpng phu thupc vao Glucose nhu vay la rat dac biet bdi vi khi nong dp Glucose mau trong gidi ban binh thudng thi no khong kich thich tilt Insulin. Do vay kh6ng gay tac dung ha dudng huyet. GLP-1 dudng nhu phuc hdi sir nhay cam cua Glucose doi vdi te bio p tuy dao bdi CO che cd lien quan tdi su tang GLUT2 va Glucokinase. GLP-1 cung dugc biet la yeu to iic che qui trinh apoptosis cua te bao p tuy dio vi kich thich ting sinh va tang biet hda ddi vdi tl bio p. Hon nua, GLP-1 con lie chl su tilt dich va co bdp da day. Dieu niy ngan cin vi keo dii su hap thu Carbonhydrate va tham gia vio hieu iing chan an.
Cac chirc nang sinh ly hpc cua GLP-1 bao gom:
- Giam tilt Glucagon tir tuyin tuy.
- Tang do nhay cam ciia Insulin.
Tang khoi tl tao P vi xuat 16 (expression) gen Insulin.
- LTC chl tilt acid da diy va lam cham rong da day.
- Lam giam them in bdi su thda man trong nao bp.
- Thuc diy su nhay cam ciia Insulin.
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CHUYgN pg: Hpl NGH| KHKT CAC TINH VUNG PUVfeN HAI BAC Bp LAN THIJf NH^T
GLP-1 CO mgt thu thi dac higu (specific receptor), thu thi niy li protein dupc ma hda bdi mpt gen nim trong Chromosome vi con la mgt thinh vien trong hp receptor ciia Glucagon. Thy thi niy (GLP~1R) dupc xuit 16 trong ll bio p tyy dio. Khi GLP-IR dupc hoat h6a se kich thich adenyl cyclase dan tdi kit qua tang tong hpp vi giii phdng Insulin.
Do vay GLP-IR dupc cho li myc tieu tilm ning dk dieu tri DTD.
GLP-1 R ciing dupc xuit 16 d nSo tai noi lien quan tdi viec kiem soat sir ngon mieng. Ngudi ta thiy sir tang xuit 16 GLP-1 R d nSo chupt da lam cai thi?n tri nhd vi khi nang bat chudc.
GLP-1 (7-36) c6 su bit tien trong dilu tri DTD type 2 vi no phii diing dudng tmyen dudi da lien tuc. Do vay nhieu chat tuong tu co thdi gian tac dung keo dai, cd hoat dpng hudng Insulin duac phat trien nhu Exenatide, Liraglutide dk duoc thdng qua va sir dung d My.
Bit tien Idn nhat ciia chit tuong tu GLP- 1(GLP-1 analogs) li chung bugc phii diing dudng tiem dudi da.
Cac nghien ciiu khac theo hudng bat boat men hoa giang GLP-1, GIP da dupc phat trien, Nhd vay cic chat iic che men dipeptidyl peptidase~4 (DPP-4 inhibitors) ra ddi vi sir dung de ding theo dudng udng.
Tir nam 2005 co hai nhom thuoc dua tren co che hoat dgng cua Incretin dugc de nghi sir dung de lam giam mirc dudng huylt trong DTD type 2.
- Mgt nhom thuoc bat chudc Incretin
(Incretin mimetic)- cac GLP-1 analogs cotac dyng ting cudng va kdo dai hoat dgng cua thu thi GLP-1 (Exenatide). Nhiing phan tii niy dupc thilt kl dl khong bi men DPP-4 thoii giing nhanh.
Mpt nhom co tic dung tang cudng Increrin (Sitagliptin) bang cich irc che men GPP-4 (exenatide)- cac DPP-4 inhibitors.
Exenatide tiem dudi da 02 lan/ngay lam giam dudng huyet vi ting miic Insulin, dac biet trong liic in. Do cd tinh phu thugc vio Glucose nen thuoc nay kh6ng gay ha dudng huyet.
Sitagliptin udng ngiy 1 lan lam tang iugng Incretin hoat dpng dan tdi hoat dpng keo dii ciia Increrin. Trong dd GLP-1 dupc cho Ii CO che nen tang cho cac hieu ling kiem soit dudng miu.
Cac thudc tren cd mpt so tic dung phu hay gap nhu dau bung, chay mui, viem dudng hd hap tren, dau dau, budn ndn, non mua. Cac tac dung phu khac it gap nhu la;
ngiia da, ban dat, dau bung.
Ca GLP-1 analogs vi DPP-4 inhibitors deu dang dupc diing ket hpp vdi cic thuoc kiem soit dudng mau khac nhu
sulphonylureas, metformin, thiazonidinediones, insulin theo cic phac do
dupc nghien ciiu vi danh gia chat che.
Cac DPP-4 inhibitors vi GLP-1 analogs CO uu diem khi dieu tri cho benh nhan DTD suy than khdng phii ngung thudc, chi can dieu chinh lieu lugng. Day la uu diem nhat ciia cac thuoc tren.
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