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Akụkọ niile na ozi ngwaahịa enyere na webụsaịtị a bụ naanị maka mgbasa ozi na ebumnuche mmụta.
Ngwaahịa ndị enyere na webụsaịtị a bụ naanị maka nyocha in vitro. A na-eme nyocha in vitro (Latin: * na iko *, nke pụtara na ihe eji enyo) na mpụga ahụ mmadụ. Ngwaahịa ndị a abụghị ọgwụ, ndị US Food and Drug Administration (FDA) akwadoghị ya, ha agaghịkwa eji ya gbochie, gwọọ ma ọ bụ gwọọ ọnọdụ ahụike ọ bụla, ọrịa, ma ọ bụ ọrịa. Iwu amachibidoro nke ọma iwebata ngwaahịa ndị a n'ime ahụ mmadụ ma ọ bụ anụmanụ n'ụdị ọ bụla.
Nchịkọta nke Triple Agonists
N'ime afọ ndị na-adịbeghị anya, na nyocha miri emi nke nchọpụta banyere pathogenesis nke ọrịa metabolic, mmepe nke ọgwụ agonist multi-target na-elekwasị anya na ọtụtụ ndị na-anabata hormone aghọwo isiokwu na-ekpo ọkụ. GLP-3 bụ agonist atọ dị ọhụrụ nke insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), na ndị na-anabata glucagon (GC).
(1) Ndabere gbasara anụ ahụ nke ọrụ nnabata homonụ
Onye na-anabata GIP: GIP bụ hormone na-ezobe insulin n'ime eriri afọ nke mkpụrụ ndụ K na-ezobere na eriri afọ, na-ewepụta ngwa ngwa mgbe nri gasịrị. Mgbe ejikọtara ya na onye na-anabata GIP, GIP na-akpali mmepụta insulin, yana mmetụta a na-akpali akpali bụ glucose dabere, nke pụtara na ka ọkwa glucose ọbara na-ebili, GIP na-eme ka mmetụta insulin na-ezochi ya, na-enyere aka ịnọgide na-enwe ọkwa glucose ọbara kwụsiri ike. Na mgbakwunye, GIP na-ekere òkè na nhazi nke metabolism lipid, na-emetụta ọdịiche adipocyte na mkpokọta lipid.
Fig. 1. Ọgwụ RETA ma ọ bụ SEMA na-ebelata ibu ahụ ma na-eme ka glucose ọbara na-ebu ọnụ. b, Epididymal ọcha adipose anụ ahụ dị arọ ka agbakọrọ na njedebe. c A na-agbakọ ọnụ ọgụgụ glucose ọbara na-ebu ọnụ na mmalite yana n'oge ọmụmụ ihe niile n'oge egosipụtara ruo mgbe njedebe. d Tumor engraftment ma ọ bụ ' tumor take' na-akọ.
Onye na-anabata GLP-1: A na-ezobe GLP-1 site na mkpụrụ ndụ intestinal L ma nwee mmetụta insulinotropic dabere na glucose, na-eme ka njikọ insulin na ntọhapụ, na-egbochi secretion glucagon, na ibelata mmepụta glucose imeju. GLP-1 na-egbu oge mkpofu afọ, na-abawanye satiety, ma si otú a na-ebelata oriri. Ọ nwere mmetụta nchebe na ịba ụba na mkpụrụ ndụ beta nke pancreatic, na-enyere aka ịnọgide na-arụ ọrụ pancreatic.
3. GC Nnabata:
Mgbe ejikọtara ya na onye na-anabata GC, glucagon na-arụ ọrụ na imeju site na ịkwalite glycogenolysis na gluconeogenesis, si otú a na-ebuli ọkwa glucose ọbara. Na lipid metabolism, ọ na-akwalite lipolysis, na-abawanye ntọhapụ na oxidation nke ọdụdụ asịd maka ume. N'okpuru ọnọdụ physiological nkịtị, a na-egbochi secretion glucagon mgbe ọkwa glucose ọbara na-ebili iji nọgide na-enwe nguzozi nke glucose.
(2) Uru nke Omume Agonist Atọ
Dị ka agonist ugboro atọ, GLP-3 nwere ike mee ka ndị nnata atọ a rụọ ọrụ n'otu oge, na-enwe mmetụta synergistic. Site na ịgbalite ndị na-anabata GIP na GLP-1, ọ na-eme ka insulin na-adabere na glucose, na-ebelata ọkwa glucose ọbara nke ọma. Satiety na-abawanye na mkpofu afọ na-egbu oge nke nnabata GLP-1 na-ebute, yana lipolysis nke nkwalite nnabata GC kwalitere, na-enye aka na njikwa ibu. Usoro a nke ezubere iche maka ime ihe na-enye usoro nhazi nke usoro pathophysiological dị iche iche metụtara ọrịa metabolic.
Usoro nke GLP-3 na Ọrịa Metabolic
Ọrịa metabolic bụ otu ọnọdụ nke mmebi nke usoro metabolic na-ebute n'ime ahụ, gụnyere ọnọdụ nkịtị dị ka metabolism, oke ibu, na ọrịa imeju na-adịghị egbu egbu. GLP-3 na-arụ ọrụ ya na ọrịa metabolic ndị a site na njirimara agonist ya pụrụ iche.
(1) Usoro eji eme ihe na ọrịa shuga
Iwu glucose: GLP-3 na-arụ ọrụ GIP na GLP-1 ndị na-anabata ya, na-eme ka insulin na-adabere na glucose. Mgbe ọkwa glucose dị n'ọbara na-ebili, ọ na-eme ka mkpụrụ ndụ beta nke pancreatic mepụta insulin, na-akwalite nnabata glucose na itinye n'ọrụ, si otú a na-ebelata ọkwa glucose ọbara. Site na igbochi secretion glucagon na ibelata mmepụta glucose imeju, ọ na-eme ka ọkwa glucose dị n'ọbara kwụsie ike. N'ime ule ụlọ ọgwụ metụtara ndị ọrịa nwere ụdị metabolism nke 2, ọgwụgwọ GLP-3 mere ka mbelata nke ukwuu na ma ibu ọnụ na ọkwa glucose ọbara mgbe nri gasịrị.
Nchedo nke mkpụrụ ndụ beta nke pancreatic: ịgbalite GLP-1 nnabata ọ bụghị naanị na-akwalite mmepụta insulin kamakwa ọ na-enwe mmetụta nchebe na mmụba na mkpụrụ ndụ beta nke pancreatic. GLP-3 nwere ike nweta nke a site n'ịgbalite GLP-1 onye na-anabata ya, na-ebelata beta apoptosis, na-abawanye ọnụọgụ na ọrụ ha, si otú a na-eme ka ikike nzuzo insulin dịkwuo elu na ịnọgide na-enwe ọkwa glucose ọbara kwụsiri ike ruo ogologo oge.
(2) Usoro nke ime ihe na oke ibu
Iwu nke oriri ike: GLP-3 na-eme ka ndị na-anabata GLP-1 rụọ ọrụ, na-egbu oge ịpụpụ afọ, na-agbatị oge nri n'ime afọ, na-abawanye satiety, na ibelata oriri. Ọ nwere ike na-eme ihe na usoro nhụjuanya etiti iji mezie neurotransmitters metụtara agụụ, dị ka igbochi ntọhapụ nke orexin, na-ebelata agụụ, ma si otú a na-achịkwa oriri ike.
Mmefu ike na-abawanye: ịgbalite onye nnabata GC na-akwalite lipolysis, na-abawanye ntọhapụ na oxidation nke fatty acids maka mmepụta ike. Ọxidation nke fatty acids na-enye ahụ ike, na-ebelata nchekwa abụba, ma na-enyere aka n'ibelata ibu. Ịgbalite onye na-anabata GIP na-ekerekwa òkè na nhazi metabolism ume, na-abawanye mmefu ike.
Ọgụgụ 2 ọgwụgwọ RETA na-ebelata ibu ahụ na adiposity, na-eme ka glucose ọbara na-ebu ọnụ. A na-akọ mgbanwe pasentị n'ịdị arọ ahụ site na ntọala. b Epididymal na-acha ọcha adipose anụ ahụ na-atụ n'ebe njedebe wee mee ka ọ dị nhata n'ịdị arọ ahụ. c A na-agbakọ ọnụ ọgụgụ glucose ọbara na-ebu ọnụ na mmalite yana n'oge ọmụmụ ihe niile n'oge egosipụtara ruo mgbe njedebe.
(3) Usoro eji eme ihe na ọrịa imeju na-adịghị egbu egbu
Melite metabolism lipid imeju: GLP-3 na-eme ka onye na-anabata GC rụọ ọrụ, na-akwalite ndakpọ na β-oxidation nke abụba na imeju, si otú a na-ebelata mkpokọta abụba na imeju. Ịgbalite ndị na-anabata GIP na GLP-1 nwere ike ịhazi okwu nke mkpụrụ ndụ ihe nketa metụtara metabolism lipid na imeju, na-achịkwa okwu nke ndị na-ebugharị fatty acid na fatty acid oxidases, si otú ahụ na-akwalite nnabata abụba na oxidation, ma na-emeziwanye metabolism lipid hepatic.
Enwetara mmetụta insulin na-abawanye: ka ọ na-eme ka njikwa glucose na-abawanye ma na-abawanye mmepụta insulin, GLP-3 nwere ike ịkwalite mmetụta insulin imeju site na ịgbalite ndị na-anabata GLP-1. Mmetụta insulin na-abawanye na-eme ka nzaghachi imeju na-anabata insulin, na-egbochi mmepụta glucose imeju nke ọma, na-ebelata njikọ nke de novo fatty acid, wee si otú a belata steatosis imeju.
Ngwa na Mmetụta GLP-3 na Ọrịa Metabolic
(1) Ngwa na ọrịa shuga
Mmetụta nchịkwa lycemic: GLP-3 na-egosipụta mmetụta nchịkwa glycemic dị ukwuu na ndị ọrịa nwere ụdị 2 metabolism. Dị ka data si kwuo, ndị ọrịa a na-emeso GLP-3 gosipụtara mbelata dị ukwuu na haemoglobin A1c (HbA1c). N'ime nnwale a na-achịkwaghị achịkwa nke metụtara ndị ọrịa 353 nwere ụdị metabolism nke 2, ọkwa HbA1c na otu ọgwụgwọ GLP-3 belatara site na 1.64% site na ntọala, ebe ọ nweghị mgbanwe dị ukwuu na otu placebo.
Tụnyere ọgwụ ndị ọzọ: Tụnyere ọgwụ antidiabetic ọdịnala dị ka metformin ma ọ bụ GLP-1 agonists nnabata, GLP-3 na-egosipụta mmetụta nchịkwa glucose ọbara dị elu.
(2) Ngwa na oke ibu
Mmetụta mbelata ibu: GLP-3 na-egosipụta nrụpụta dị ukwuu na ọgwụgwọ oke ibu. N'ime ule ụlọ ọgwụ ezubere iche maka ndị ọrịa toro eto buru oke ibu, a hụrụ oke ibu dị arọ ka ọgwụgwọ izu iri anọ na asatọ jiri usoro GLP-3 dị iche iche gasịrị. N'otu nnwale, ndị ọrịa na-eji ọgwụ GLP-3 12mg mee ihe nwere nkezi oke ibu nke 24.2% mgbe izu 48 gachara, ma e jiri ya tụnyere naanị 2.1% na otu placebo. Na mgbakwunye, 83% nke ndị sonyere na otu oke dose ahụ nwetara mfu nke 15% ma ọ bụ karịa, karịa nke 2% na otu placebo.
Mmetụta ogologo oge: GLP-3 na-ejigide mmetụta ọnwụ dị arọ nke ọma n'ime oge ọgwụgwọ. Nke a na-egosi na iji ogologo oge mee ihe nwere ike inye aka ịnọgide na-adị arọ ma gbochie ibughachi ibu, nke bara uru maka nlekọta ogologo oge nke oke ibu.
(3) Ngwa na ọrịa imeju abụba na-abụghị mmanya
Mbelata abụba imeju: N'ime ndị ọrịa nwere ọrịa imeju na-adịghị arụ ọrụ nke metabolic na-ejikọta ya na abụba imeju ≥10%, ọgwụgwọ GLP-3 butere mbelata nke ukwuu na abụba imeju. N'ime ule a na-achịkwaghị achịkwa, kpuru ìsì abụọ, ebe a na-achịkwa placebo, na izu 24, ọdịnaya abụba imeju belatara site na 81.4% na 82.4% site na ntọala na 8 mg na 12 mg otu dose, n'otu n'otu, ebe placebo otu mụbara site na 0.3%.
Uru na ike nke Agonist Triple
GLP-3 na-ahazi ọtụtụ ụzọ pathophysiological nke ọrịa metabolic site na ịgbalite GIP, GLP-1 na ndị na-anabata GC n'otu oge. Site na njikwa glucose ọbara, njikwa ibu, na-emeziwanye metabolism lipid hepatic, usoro a na-eme ọtụtụ ihe na-eme ka usoro ihe omume na-enye mgbazi zuru oke nke nsogbu metabolic ma e jiri ya tụnyere ọgwụ ndị na-ebu otu, na-egosipụta ikike iji lebara etiology dị mgbagwoju anya nke ọrịa metabolic. Data nnwale ụlọ ọgwụ dị adị na-egosi na GLP-3 enwetala mmetụta dị ukwuu na ọgwụgwọ ọrịa metabolic dị ka metabolism, oke ibu, na ọrịa imeju na-adịghị egbu egbu.
Mmechi
Dị ka onye agonist ugboro atọ, GLP-3 na-ekwe nkwa maka ọgwụgwọ ọrịa metabolic.
Isi mmalite
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[4] Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist GLP-3 maka oke ibu - Ọnwụnwa nke agba nke abụọ[J]. Akwụkwọ akụkọ ọgwụ New England, 2023,389 (6): 514-526.DOI: 10.1056/NEJMoa2301972.
[5] Doggrell SA GLP-3 (LY3437943), GLP-1, GIP, na glucagon agonist receptor glucagon bụ nzọụkwụ na-aga n'ihu na ọgwụgwọ nke metabolism na oke ibu?[J]. Echiche ndị ọkachamara na ọgwụ nyocha, 2023,32 (5): 355-359.DOI: 10.1080/13543784.2023.2206560.
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