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

Ben Jones; Vinod Burade; Elina Akalestou; Yusman Manchanda; Zenouska Ramchunder; Gaëlle Carrat; Marie-Sophie Nguyen-Tu; Piero Marchetti; Lorenzo Piemonti; Isabelle Leclerc; Thennati Rajamannar; Tina Vilsboll; Bernard Thorens; Alejandra Tomas; Guy A Rutter

doi:10.1111/dom.14794

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

Ben Jones, Vinod Burade, Elina Akalestou, Yusman Manchanda, Zenouska Ramchunder, Gaëlle Carrat, Marie-Sophie Nguyen-Tu, Piero Marchetti, Lorenzo Piemonti, Isabelle Leclerc, Thennati Rajamannar, Tina Vilsboll, Bernard Thorens, Alejandra Tomas, Guy A Rutter

Abstract

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 β-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.

Original language	English
Journal	Diabetes, Obesity and Metabolism
Volume	24
Issue number	11
Pages (from-to)	2090-2101
Number of pages	12
ISSN	1462-8902
DOIs	https://doi.org/10.1111/dom.14794
Publication status	Published - Nov 2022

Keywords

Adenosine Monophosphate
Animals
Blood Glucose
Cyclic AMP/metabolism
Diabetes Mellitus, Type 2/drug therapy
Glucagon-Like Peptide-1 Receptor/agonists
HEK293 Cells
Humans
Hypoglycemic Agents/pharmacology
Insulins
Ligands
Mice
Weight Loss
beta-Arrestins/metabolism

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Jones, B., Burade, V., Akalestou, E., Manchanda, Y., Ramchunder, Z., Carrat, G., Nguyen-Tu, M-S., Marchetti, P., Piemonti, L., Leclerc, I., Rajamannar, T., Vilsboll, T., Thorens, B., Tomas, A., & Rutter, G. A. (2022). In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist. Diabetes, Obesity and Metabolism, 24(11), 2090-2101. https://doi.org/10.1111/dom.14794

Jones, B, Burade, V, Akalestou, E, Manchanda, Y, Ramchunder, Z, Carrat, G, Nguyen-Tu, M-S, Marchetti, P, Piemonti, L, Leclerc, I, Rajamannar, T, Vilsboll, T, Thorens, B, Tomas, A & Rutter, GA 2022, 'In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist', Diabetes, Obesity and Metabolism, vol. 24, no. 11, pp. 2090-2101. https://doi.org/10.1111/dom.14794

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

abstract = "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 β-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.",

keywords = "Adenosine Monophosphate, Animals, Blood Glucose, Cyclic AMP/metabolism, Diabetes Mellitus, Type 2/drug therapy, Glucagon-Like Peptide-1 Receptor/agonists, HEK293 Cells, Humans, Hypoglycemic Agents/pharmacology, Insulins, Ligands, Mice, Weight Loss, beta-Arrestins/metabolism",

author = "Ben Jones and Vinod Burade and Elina Akalestou and Yusman Manchanda and Zenouska Ramchunder and Ga{\"e}lle Carrat and Marie-Sophie Nguyen-Tu and Piero Marchetti and Lorenzo Piemonti and Isabelle Leclerc and Thennati Rajamannar and Tina Vilsboll and Bernard Thorens and Alejandra Tomas and Rutter, {Guy A}",

year = "2022",

month = nov,

doi = "10.1111/dom.14794",

language = "English",

volume = "24",

pages = "2090--2101",

journal = "Diabetes, Obesity and Metabolism",

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TY - JOUR

T1 - In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist

AU - Jones, Ben

AU - Burade, Vinod

AU - Akalestou, Elina

AU - Manchanda, Yusman

AU - Ramchunder, Zenouska

AU - Carrat, Gaëlle

AU - Nguyen-Tu, Marie-Sophie

AU - Marchetti, Piero

AU - Piemonti, Lorenzo

AU - Leclerc, Isabelle

AU - Rajamannar, Thennati

AU - Vilsboll, Tina

AU - Thorens, Bernard

AU - Tomas, Alejandra

AU - Rutter, Guy A

PY - 2022/11

Y1 - 2022/11

N2 - 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 β-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.

AB - 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 β-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.

KW - Adenosine Monophosphate

KW - Animals

KW - Blood Glucose

KW - Cyclic AMP/metabolism

KW - Diabetes Mellitus, Type 2/drug therapy

KW - Glucagon-Like Peptide-1 Receptor/agonists

KW - HEK293 Cells

KW - Humans

KW - Hypoglycemic Agents/pharmacology

KW - Insulins

KW - Ligands

KW - Mice

KW - Weight Loss

KW - beta-Arrestins/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85135039320&partnerID=8YFLogxK

U2 - 10.1111/dom.14794

DO - 10.1111/dom.14794

M3 - Journal article

C2 - 35676825

VL - 24

SP - 2090

EP - 2101

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 11

ER -

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

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