In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist

被引：5

作者：

Jones, Ben ^{[1
]}

Burade, Vinod ^{[2
]}

Akalestou, Elina ^{[3
]}

Manchanda, Yusman ^{[3
]}

Ramchunder, Zenouska ^{[3
]}

Carrat, Gaelle ^{[3
]}

Nguyen-Tu, Marie-Sophie ^{[3
]}

Marchetti, Piero ^{[4
]}

Piemonti, Lorenzo ^{[5
]}

Leclerc, Isabelle ^{[3
,6
]}

Thennati, Rajamannar ^{[2
]}

Vilsboll, Tina ^{[7
]}

Thorens, Bernard ^{[8
]}

Tomas, Alejandra ^{[3
]}

Rutter, Guy A. ^{[3
,6
,9
]}

机构：

[1] Imperial Coll London, Fac Med, Dept Metab Digest & Reprod, Sect Endocrinol & Invest Med, London, England

[2] Sun Pharmaceut Ind Ltd, High Impact Innovat Sustainable Hlth Solut, Vadodara, Gujarat, India

[3] Imperial Coll London, Fac Med, Dept Metab Digest & Reprod, Sect Cell Biol & Funct Genom, London, England

[4] Univ Pisa, Dept Clin & Expt Med, Islet Cell Lab, Pisa, Italy

[5] IRCCS Osped San Raffaele, Diabet Res Inst, Milan, Italy

[6] Univ Montreal, CRCHUM, Montreal, PQ, Canada

[7] Univ Copenhagen, Gentofte Hosp, Steno Diabet Ctr Copenhagen, Clin Metab Physiol, Copenhagen, Denmark

[8] Univ Lausanne, Ctr Integrat Genom, Lausanne, Switzerland

[9] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore

来源：

DIABETES OBESITY & METABOLISM | 2022年 / 24卷 / 11期

基金：

英国工程与自然科学研究理事会; 英国惠康基金;

关键词：

antidiabetic drug; antiobesity drug; beta-cell function; drug development; GLP-1; analogue; incretin therapy; BETA-CELLS; GLUCOSE; ASSOCIATION; EFFICACY;

D O I：

10.1111/dom.14794

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims To describe the in vitro characteristics and antidiabetic in vivo efficacy of the novel glucagon-like peptide-1 receptor agonist (GLP-1RA) GL0034. Materials and Methods Glucagon-like peptide-1 receptor (GLP-1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis and recycling were measured using HEK293 and INS-1832/3 cells expressing human GLP-1R. Insulin secretion was measured in vitro using INS-1832/3 cells, mouse islets and human islets. Chronic administration studies to evaluate weight loss and glycaemic effects were performed in db/db and diet-induced obese mice. Results Compared to the leading GLP-1RA semaglutide, GL0034 showed increased binding affinity and potency-driven bias in favour of cAMP over GLP-1R endocytosis and beta-arrestin-2 recruitment. Insulin secretory responses were similar for both ligands. GL0034 (6 nmol/kg) led to at least as much weight loss and lowering of blood glucose as did semaglutide at a higher dose (14 nmol/kg). Conclusions GL0034 is a G protein-biased agonist that shows powerful antidiabetic effects in mice, and may serve as a promising new GLP-1RA for obese patients with type 2 diabetes.

引用

页码：2090 / 2101

页数：12