GLP-15 mg

▎ Ọdịdị GLP-1

Isi mmalite: PubChem

Usoro: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-lys (Aeea-Aeea-γ-glu-octadecanedioic)-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH Ụdị mkpụrụ ndụ: C 187H 291N 45O59 Ibu molekụla: 4114 g/mol Nọmba CAS: 910463-68-2 PubChem CID: 56843331 Ụdị okwu: Rybelsus; Ozempic; Wegovy

▎ Nchọpụta GLP-1

Kedu ihe ndabere nyocha nke GLP-1?

GLP-1 bụ ihe analog nke glucagon dị ka peptide-1 (GLP-1), nke klaasị GLP-1 ọgwụ agonist nnabata. GLP-1 bụ homonụ na-apụta n'okike nke mkpụrụ ndụ eriri afọ na-ezobe mgbe o richara nri, nke na-akwalite mmepụta insulin ma na-egbochi secretion glucagon iji mezie ọkwa glucose ọbara. Mmepe nke GLP-1 sitere na nyocha miri emi banyere ọrụ physiological nke GLP-1. GLP-1 nwere obere ndụ ọkara ndụ n'ime ahụ, ihe dị ka nkeji 1-2, ebe ọ na-adị mfe iweda ya site na dipeptidyl peptidase-4 (DPP-4) enzymes n'ime ahụ. Iji merie njedebe a, ndị ọkà mmụta sayensị gbanwere nhazi nke GLP-1, na-ewebata amino acid dị iche iche ma na-agbakwụnye otu nchebe iji kwalite nguzogide ya na enzymes DPP-4, si otú ahụ na-agbatị ogologo oge ọrụ ya n'ime ahụ ^[1] . Na nhazi nke GLP-1, alanine nọ n'ọnọdụ 8 na-anọchi anya α-aminoisobutyric acid (Aib), nke ọ bụghị nanị na-eme ka nkwụsi ike nke ọgwụ ahụ dịkwuo mma kamakwa na-eme ka ike ejikọta ya na ndị na-anabata GLP-1 ^[2] . A na-agbakwunye eriri acid fatty acid pụrụ iche na C-terminus nke GLP-1, nke jikọtara ya na lysine residue site na γ-glutamine, na-agbatịkwu ọkara ndụ ọgwụ ahụ ma kwe ka a gbanye ya otu ugboro n'izu ma ọ bụ were ọnụ ya otu ugboro n'ụbọchị ^[1] . Emepụtara GLP-1 na mbụ dabere na nyocha na mgbanwe nke GLP-1 eke, na-achọ ịnye ọgwụgwọ dị irè maka ndị ọrịa nwere ụdị ọrịa shuga 2 ^{[1, 2]} . Site na njikarịcha nhazi ndị a, GLP-1 abụghị naanị na-ejigide ọrụ physiological nke GLP-1 kamakwa ọ na-eme ka akụrụngwa ọgwụ ya dịkwuo mma, na-aghọ agonist GLP-1 na-eme ogologo oge nke uru ụlọ ọgwụ dị mkpa. Mmepe nke GLP-1 bụ nnukwu mmeri, na-eweta nhọrọ ọgwụgwọ ọhụrụ maka ndị ọrịa nwere ụdị ọrịa shuga 2. Site n'ịkwalite nhazi nke GLP-1 eke, ọ na-emeri njedebe nke ọkara ndụ ya dị mkpụmkpụ ma na-eme ka nkwụsi ike nke ọgwụ na ogologo oge na-arụ ọrụ.

 

Kedu ihe bụ usoro nke GLP-1?

GLP-1 bụ glucagon na-arụ ọrụ ogologo oge dị ka peptide-1 (GLP-1) agonist nnabata, a na-enwetakwa usoro ya site na akụkụ ndị a:

Usoro nchịkwa glucose ọbara:

GLP-1 bụ GLP-1 agonist nnabata (GLP-1RA). Usoro ya bụ isi bụ igbochi agụụ nri site na igbochi agụụ, ibelata mmasị maka nri nwere nnukwu abụba, yana imezi ebe nri hypothalamic iji belata oriri. Ọ na-abawanye satiety, na-egbu oge ịwụfu afọ, ma na-ebelata motility eriri afọ, si otú ahụ na-enweta ọnwụ. Mbelata ibu a na-eme ka mmetụta insulin dịkwuo elu ma na-enyere aka ịhazi ọkwa glucose ọbara ^[3] . GLP-1 na-ebute mbelata ibu n'ime òké site na ụzọ akwara kesara ekesa. Nnyocha na-egosi na ọ na-arụ ọrụ na ụbụrụ ụbụrụ, septal nucleus, na hypothalamus mana ọ naghị agafe ihe mgbochi ụbụrụ ọbara. Kama, ọ na-emekọrịta ihe na ụbụrụ site na akụkụ okirikiri na mpaghara ventricular-proximal. GLP-1 na-arụ ọrụ c-Fos na mpaghara ụbụrụ iri, gụnyere mpaghara azụ azụ echere ozugbo na mpaghara nke abụọ dị ka akụkụ parabrachial nucleus na-enweghị mmekọrịta GLP-1R kpọmkwem. Nyocha akpaaka na-atụ aro ka ịgbalite gụnyere akwara parabrachial nucleus neurons na-achịkwa nkwụsị nri, si otú a na-achịkwa glucose ọbara ^[4] .

Usoro nke eriri afọ:

GLP-1 na-arụ ọrụ na ndị na-anabata GLP-1 na eriri afọ, na-eji ụzọ irighiri akwara na-emezigharị motility eriri afọ. Ọ na-egbochi mkpụkọ antral, na-akwado pyloric sphincter esemokwu, na-agbatịkwa nri nri afọ, na-egbu oge ntinye duodenal na igbochi spikes ọbara postprandial, na-eduga n'ọkwa kwụsiri ike ^[5] . Na mgbakwunye, GLP-1 na-emetụta ndị na-anabata GLP-1 etiti, ọkachasị na hypothalamic arcuate na paraventricular nuclei. Ọ na-egbochi ihe ndị na-akpali agụụ mmekọahụ dị ka neuropeptide Y (NPY) na protein metụtara agouti (AgRP), ebe ọ na-eme ka neurons proopiomelanocortin (POMC) na-arụ ọrụ iji kwalite ihe nzuzo nke alpha-melanocyte na-akpali akpali (α-MSH ⁾ . Omume ndị a na-ebute afọ ojuju, na-ebelata agụụ, na ibelata oriri nri, na-enyere aka ịchịkwa ibu na imeziwanye njikwa glucose ọbara n'ụzọ na-apụtaghị ìhè.

Nchekwa obi:

GLP-1 na-akwalite ntọhapụ nke nitric oxide (NO) na vasodilator ndị ọzọ sitere na sel endothelial vaskụla, na-eme ka vasodilation na ọbara eruba. Ọ na-egbochikwa mbufụt na nrụgide oxidative, na-ebelata mmebi endothelial na ihe ize ndụ nke atherosclerosis. Site n'ịkwụsị agụụ na iri nri, ọ na-enyere aka ịbelata ibu, na-eme ka ọrịa shuga dịkwuo mma, na-ebelata triglycerides na cholesterol cholesterol dị ala (LDL-C), ma na-ebuli cholesterol dị elu nke lipoprotein (HDL-C). Ọzọkwa, ọ nwere ike ịba uru ọbara mgbali elu site n'ịgbanwe hemodynamics renal na ọrụ neuroendocrine, na-ebelata ihe ize ndụ ọbara mgbali elu na ibelata ihe ize ndụ ọrịa obi ^[6]. .

 

 

GLP-1 na ụkpụrụ ntụgharị nke WAT na ntụgharị BAT yana ịgbalite BAT.

Isi mmalite: PubMed ^[13]

Nnwale isi na nyocha

N'ihe banyere nhazi usoro kemịkalụ na njikarịcha ya, n'oge imewe nke GLP-1, a nakweere usoro ngbanwe nke njikọta na albumin iji gbatịa ogologo oge nke ọgwụ ahụ. Site na ikpebi nchikota kacha mma nke fatty acids na linkers, a na-abawanye ikike ijikọ albumin ka ọ na-ejigide nrụpụta ya na onye na-anabata GLP-1 (GLP-1R) (Knudsen LB, 2019).

N'ihe gbasara ngwa ọgwụ, GLP-1 nwere mmetụta mbelata ibu dị elu. GLP-1 bụ glucagon-dị ka peptide-1 receptor agonist (GLP-1 RA) nwere ogologo oge mkpochapụ ọkara ndụ, na-enye ohere ịgba ntụtụ subcutaneous kwa izu. Mmetụta ọnwụ ya dị ịrịba ama. N'ime ndị ọrịa nwere ụdị ọrịa shuga 2 (T2DM), injection subcutaneous kwa izu nke GLP-1 yiri ka ọ dị irè maka mbelata ibu karịa GLP-1RA ndị ọzọ kwa izu. N'ime ule nyocha nke usoro nke II maka ndị ọrịa buru ibu na-enweghị T2DM, injection subcutaneous nke GLP-1 otu ugboro kwa ụbọchị dị irè maka oke ibu karịa placebo na otu ugboro kwa ụbọchị 3.0mg liraglutide. Mbelata arọ nke GLP-1 kpatara n'ọmụmụ ihe a karịrị ọkọlọtọ maka ọgwụ mgbochi oke ibu nke European Medicines Agency (EMA) na US Food and Drug Administration (FDA) setịpụrụ, na-enweghị nsogbu nchekwa, na-egosi na ntụtụ nke GLP-1 otu ugboro kwa ụbọchị nwere ike ịbụ ọgwụ na-efunahụ ibu n'ọdịnihu ^. .

GLP-1 nwere ike imeziwanye ọrụ obi ma jiri ya mee ihe maka ọgwụgwọ ọrịa obi. A mara ọkwa nsonaazụ nke ule STEP-HFpEF, nke nnukwu ọgwụ antidiabetic glucagon-dị ka peptide 1 agonist GLP-1 mere ka akara ngosi nke nkụda obi dịkwuo mma site n'ichekwa ejection fraction (HFpEF) ma belata N-terminal pro-B-ụdị natriuretic peptide (NT-proBNP) ọkwa. Ọmụmụ ihe ahụ nwalere mmetụta nke nnukwu ọgwụgwọ GLP-1 na trabeculae aka nri mmadụ dịpụrụ adịpụ wee chọpụta na GLP-1 mụbara esemokwu nke trabeculae mmadụ ihe karịrị ugboro atọ n'ụzọ dabere na dose, na-enweghị ịbawanye ọchịchọ nke arrhythmias. Mmetụta a nwere ike ịbụ n'ihi mmụba nke sarcoplasmic reticulum Ca2+. Ọgwụ GLP-1 dị elu na ndị ọrịa nkụda obi nwere ike imeziwanye ọrụ atrial wee si otú a belata mgbaàmà ^[8] .

A na-amụ GLP-1 maka ọgwụgwọ steatohepatitis na-adịghị egbu egbu (NASH). Nhazi ezi uche ya enyela nnukwu onyinye n'ịkwalite njikwa glucose ọbara, ịdị arọ, ọbara mgbali elu, lipids, ọrụ β-cell, na usoro obi obi na ndị ọrịa nwere ụdị ọrịa shuga 2. Ọzọkwa, mmepe nke usoro ọnụ nke GLP-1 nwere ike inye ndị ọrịa uru ọzọ n'ihe gbasara nnabata ọgwụgwọ ^[9] .

Ọdịiche dị na Mmetụta Mbelata Arọ nke GLP-1 Gburugburu Ndị Mmadụ

Mmetụta mbelata ibu na ndị okenye nwere ọrịa obi, oke ibu ma ọ bụ oke ibu na-enweghị ọrịa shuga: 

N'ime ule SELECT cardiovascular, GLP-1 belatara nnukwu ihe omume obi na-adịghị mma (MACE) site na 20% na ndị okenye 17,604 nwere ọrịa obi, oke ibu ma ọ bụ oke ibu, na enweghị ọrịa shuga ^[10] . N'ime nyocha a akọwapụtara nke ọma, ndị nyocha nyochara nsonaazụ GLP-1 na ịdị arọ, nsonaazụ anthropometric, nchekwa, na nnabata site na ntinye ihe nrịbama ahụ (BMI). Ndị ọrịa na-anata GLP-1 nwere mbelata ịdị arọ karịa izu 65, na-adịgide ruo afọ 4. N'ime izu 208, GLP-1 mere ka mbelata ịdị arọ nke ukwuu (-10.2%), okirikiri ukwu (-7.7 cm), na oke n'úkwù na ịdị elu (-6.9%) ma e jiri ya tụnyere placebo (-1.5%, -1.3 cm, na -1.0%, n'otu n'otu; ntụnyere niile bụ ọnụ ọgụgụ dị ịrịba ama. Ejikọtara GLP-1 na obere ihe ọjọọ dị njọ maka ụdị BMI nke ọ bụla (<30, 30 ka <35, 35 ka <40, na ≥40 kg/m²), GLP-1 nwere obere ihe omume ọjọọ dị njọ (ihe omume kwa 100 mmadụ-afọ: 43.23, 45.70, na 65. 50.48, 49.66, 52.73 na 60.85 maka placebo).

Mmetụta mbelata ibu na ndị oke ibu ma ọ bụ buru oke ibu na-enweghị ọrịa shuga:  

Nyochaa nhazi nyochara ịdị irè na nchekwa nke GLP-1 na ndị buru ibu ma ọ bụ ndị buru ibu na-enweghị ọrịa shuga ^[11] . Nyochaa a rụpụtara nsonaazụ sitere na ọtụtụ nnwale ụlọ ọgwụ, na-egosipụta mmetụta GLP-1 na mbelata ibu, paramita metabolic, yana nsonaazụ ahụike zuru oke. Nchọpụta egosiputara na GLP-1 jikọtara ya na nnukwu mbelata ibu yana mmụba na metrik ahụike metụtara oke ibu, na-atụ aro ike ya dị ka nhọrọ ọgwụgwọ bara uru maka ndị ọrịa buru ibu. 

Mmetụta Mbelata arọ na ndị ọrịa na-abụghị ọrịa shuga (ihe akaebe sitere na ọtụtụ RCT): 

Nnwale anọ a na-achịkwa (RCT) nke metụtara ndị ọrịa nwere oke ibu nke 96-105 n'arọ kwa izu 2.4 mg subcutaneous GLP-1 gbakwunyere usoro ndụ ndụ (ndụmọdụ, nri, mmega ahụ) maka ọnwụ ^[12] . Otu RCT n'ime ndị ọrịa na-abụghị ndị ọrịa mamịrị (N = 1,961) kọrọ na mbelata dị arọ nke 15% (15 n'arọ) vs. 2% (3 n'arọ) na placebo mgbe izu 68 gasịrị (ọnụ ọgụgụ dị ịrịba ama). Ọnụ ọgụgụ nke ndị ọrịa na-enweta ≥5% ọnwụ ọnwụ bụ 86% vs. 32% (ọnụọgụ achọrọ iji gwọọ [NNT] = 2), na ≥10% ọnwụ ọnwụ bụ 69% vs. 12% (NNT = 2). Mbelata ịdị arọ gbagoro na ~ 60 izu. Ihe omume ọjọọ nke eriri afọ (AEs) mere na 74% vs. 48% (ọnụọgụ achọrọ iji merụọ [NNH] = 3). Nkwụsị n'ihi AEs bụ 7% vs. 3% (NNH = 25). Achọpụtara nsonaazụ ndị yiri ya na RCT ọzọ na ntinye aka na ndụ siri ike (N = 611): GLP-1 kpalitere 16% (17 kg) vs. 6% (6 kg). N'ime nyocha dose-nyocha RCT na ndị ọrịa na-abụghị ndị ọrịa mamịrị (N = 1,210), kwa izu 2.4 mg GLP-1, 1.0 mg GLP-1, ma ọ bụ placebo wepụtara pụtara mfu nke 10%, 7%, na 3% mgbe izu 68 gasịrị. Oke na-enweta ≥5% ọnwụ dị arọ bụ 69% (2.4 mg), 57% (1.0 mg), na 29% (placebo). Maka 2.4 mg vs. 1.0 mg, NNT = 9. Profaịlụ AE yiri n'ofe doses. Na mmezi arọ RCT (N = 803), ndị na-abụghị ndị na-arịa ọrịa shuga na-anata 2.4 mg GLP-1 kwa izu maka izu 20, wee bụrụ ndị a na-ahazi ka ha gaa n'ihu GLP-1 ma ọ bụ gbanwee na placebo. Mgbe izu 48 gachara, ndị ọrụ GLP-1 gara n'ihu tụfuru 8% vs. ndị ọrụ placebo na-enweta 7%. 

Na nchịkọta, GLP-1 bụ agonist nnabata GLP-1 nwere uru ngwa ọtụtụ ngalaba. Na ọgwụgwọ ọrịa shuga, ọ na-ejikọ ndị na-anabata GLP-1 iji kwalite insulin secretion na igbochi ntọhapụ glucagon, na-achịkwa ọkwa glucose ọbara nke ọma ma na-enye nhọrọ ọgwụgwọ dị mkpa maka ndị ọrịa nwere ụdị ọrịa shuga 2. N'ihe banyere ọgwụgwọ oke ibu, GLP-1 nwere ike belata oriri ume nke ukwuu site na usoro dị ka mbelata agụụ nke etiti na igbu oge na-egbu oge, na-enyere ndị ọrịa buru ibu aka ifelata ma melite ọnọdụ metabolic ha. Na mgbakwunye, GLP-1 na-egosi atụmanya ngwa nwere ike na mgbochi na ọgwụgwọ nke ọrịa obi, yana nkwalite ya nke ihe ize ndụ nke obi na-enye ụzọ ọhụrụ iji belata ihe omume nke obi. Mwepụta nke GLP-1 abụghị naanị na-eme ka usoro ọgwụgwọ maka ọrịa ndị metụtara ya dịkwuo mma kamakwa na-ewetakwa olileanya ọhụrụ maka ịkwalite ogo ndụ na ahụike nke ndị ọrịa.

 

Banyere Onye dere ya

Ihe niile a kpọtụrụ aha n'elu bụ Cocer Peptides na-enyocha, dezie ma chịkọta ya.

Onye ode akwụkwọ akụkọ sayensị

Hegner P bụ onye nyocha na Mahadum Regensburg. Ọrụ ya gụnyere Chemistry, Cardiovascular System, na Cardiology. Na Chemistry, ọ na-enyocha mmeghachi omume jikọtara na ahụike obi. N'ime usoro ọmụmụ Cardiovascular, ọ na-enyocha obi na ọrụ arịa, na-achọ nghọta ọgwụgwọ. Nnyocha nke Cardiology ya na-elekwasị anya na mgbochi ọrịa obi, nchọpụta, na ọgwụgwọ.

Enyemaka Hegner dị oke mkpa. Nghọta kemịkalụ ya akwalitela mmepe ọgwụ obi ọhụrụ. Ọrụ ya na usoro obi na arịa emewo ka nghọta nke ọrịa obi. Na ụlọ ọgwụ, nchọpụta ya emeela ka nlekọta ọrịa obi dịkwuo mma, na-ebuli ụkpụrụ nlekọta ndị ọrịa. N'ozuzu, ụzọ dị iche iche nke Hegner na-eme ka nkà mmụta ọgwụ na-eme ka obi dịkwuo mma, na-enye olileanya maka mbelata ibu ọrịa na nsonaazụ ndị ọrịa ka mma. Edepụtara Hegner P na ntụnye aka [8].

▎ Okwu ndị dị mkpa

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[2] Ma H, Huang W, Wang X, et al. Nghọta ihe arụrụ arụ na ịgbalite GLP-1R site na obere agonist molecule[J]. Nnyocha cell, 2020,30 (12): 1140-1142.DOI:10.1038/s41422-020-0384-8.

[3] Kim HS, Jung C H. Oral GLP-1, Glucagon nke mbụ ingestible-dị ka Peptide-1 Nnabata Agonist: Ọ nwere ike ịbụ ihe anwansi maka ụdị ọrịa shuga 2?[J]. Akwụkwọ akụkọ International nke Science Molecular, 2021,22(18).DOI:10.3390/ijms22189936.

[4] Gabery S, Salinas CG, Paulsen SJ, et al. GLP-1 na-ebelata ibu ahụ n'ime òké site n'okporo ụzọ akwara na-ekesa[J]. Jci Insight, 2020,5 (6).DOI:10.1172/jci.inight.133429.

[5] Katsurada K, Yada T. Mmetụta akwara nke gut- na ụbụrụ sitere na glucagon-dị ka peptide-1 na onye na-anabata ya [J]. Akwụkwọ akụkọ nyocha ọrịa shuga, 2016,7: 64-69.DOI: 10.1111 / jdi.12464.

[6] Ryan DH, Lingvay I, Colhoun HM, et al. Mmetụta GLP-1 na nsonaazụ obi na ndị nwere oke ibu ma ọ bụ oke ibu (SELECT) echiche na imewe[J]. Akwụkwọ akụkọ obi America, 2020,229:61-69.DOI:10.1016/j.ahj.2020.07.008.

[7] Christou GA, Katiki N, Blundell J, et al. GLP-1 dị ka ọgwụ mgbochi oke ibu na-ekwe nkwa[J]. Nlebanya oke ibu, 2019,20(6):805-815.DOI:10.1111/obr.12839.

[8] Hegner P, Seitz S, Schopka S, et al. GLP-1 na-akwalite ọrụ nkwekọrịta na atrium mmadụ dịpụrụ adịpụ. Akwụkwọ akụkọ obi European, 2024,45.DOI:10.1093/eurheartj/ehae666.3729.

[9] Knudsen LB, Lau J. Nchọpụta na mmepe nke Liraglutide na GLP-1[J]. Ihu ihu na Endocrinology, 2019,10.DOI:10.3389/fendo.2019.00155.

[10] Ryan DH, Lingvay I, Deanfield J, et al. Mmetụta ọnwụ ogologo oge nke GLP-1 na oke ibu na-enweghị ọrịa shuga na nnwale SELECT[J]. Ọgwụ okike, 2024,30 (7): 2049-2057.DOI: 10.1038/s41591-024-02996-7.

[11] Alanazi M, Alshahrani JA, Aljaberi AS, et al. Mmetụta GLP-1 n'ime ndị mmadụ nwere oke ibu ma ọ bụ oke ibu na-enweghị ọrịa shuga[J]. Akwụkwọ akụkọ Cureus nke sayensị ahụike, 2024,16 (8).DOI:10.7759/cureus.67889.

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[13] Papakonstantinou I, Tsioufis K, Katsi V. Ntụkwasị obi na Mechanism nke Action nke GLP-1[J]. Okwu ndị dị ugbu a na usoro ihe ọmụmụ ihe, 2024,46(12):14514-14541.DOI:10.3390/cimb46120872.

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.