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Novel glucagon-like peptide-1 analogue exhibits potency-driven G-protein biased agonism with promising effects on diabetes and diabetic dry eye syndrome.

ABSTRACT: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are considered as effective treatments for type 2 diabetes. Here, we describe the in vitro characteristics and in vivo anti-diabetic efficacies of a novel GLP-1RA, termed SM102. The in vitro functions of SM102, including GLP-1R kinetic binding parameter, cAMP activation, endocytosis and recycling, were all evaluated using the INS-1 832/13 cells expressing human GLP-1R. Chronic efficacies study was performed to evaluate the effects of SM102 on the glycemic benefits, body weight loss and other diabetic complications in db/db mice. As a result, SM102 exhibited enhanced binding affinity and potency-driven bias in favor of cAMP over GLP-1R endocytosis and β-Arrestin 2 recruitment, as well as comparable insulin secretory response compared with Semaglutide. In addition, chronic treatment of SM102 led to more promising therapeutical effects on hyperglycemia, weight control and insulin resistance as well as dry eye syndrome (DES) than Semaglutide. Furthermore, SM102 could ameliorate diabetic DES via improving antioxidant properties, inflammatory factors and inhibiting MAPKs pathway in diabetic mice. In conclusion, SM102 is a G protein-biased agonist serving as a promising new GLP-1RA for treating diabetes and diabetic complications.

SUBMITTER: Hao Y

PROVIDER: S-EPMC8975272 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Novel glucagon-like peptide-1 analogue exhibits potency-driven G-protein biased agonism with promising effects on diabetes and diabetic dry eye syndrome.

Hao Yongna Y Wei Min M Zhang Ning N Zhang Xinying X

Bioengineered 20220301 3

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are considered as effective treatments for type 2 diabetes. Here, we describe the in vitro characteristics and in vivo anti-diabetic efficacies of a novel GLP-1RA, termed SM102. The in vitro functions of SM102, including GLP-1R kinetic binding parameter, cAMP activation, endocytosis and recycling, were all evaluated using the INS-1 832/13 cells expressing human GLP-1R. Chronic efficacies study was performed to evaluate the ...[more]

PMID: 35184645

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Project description:ObjectiveTreatment with glucagon receptor antagonists (GRAs) reduces blood glucose but causes dyslipidemia and accumulation of fat in the liver. We investigated the acute and chronic effects of glucagon on lipid metabolism in mice.MethodsChronic effects of glucagon receptor signaling on lipid metabolism were studied using oral lipid tolerance tests (OLTTs) in overnight fasted glucagon receptor knockout (Gcgr-/-) mice, and in C57Bl/6JRj mice treated with a glucagon receptor antibody (GCGR Ab) or a long-acting glucagon analogue (GCGA) for eight weeks. Following treatment, liver tissue was harvested for RNA-sequencing and triglyceride measurements. Acute effects were studied in C57Bl/6JRj mice treated with a GRA or GCGA 1 h or immediately before OLTTs, respectively. Direct effects of glucagon on hepatic lipolysis were studied using isolated perfused mouse liver preparations. To investigate potential effects of GCGA and GRA on gastric emptying, paracetamol was, in separate experiments, administered immediately before OLTTs.ResultsPlasma triglyceride concentrations increased 2-fold in Gcgr-/- mice compared to their wild-type littermates during the OLTT (P = 0.001). Chronic treatment with GCGR Ab increased, whereas GCGA treatment decreased, plasma triglyceride concentrations during OLTTs (P < 0.05). Genes involved in lipid metabolism were upregulated upon GCGR Ab treatment while GCGA treatment had opposite effects. Acute GRA and GCGA treatment, respectively, increased (P = 0.02) and decreased (P = 0.003) plasma triglyceride concentrations during OLTTs. Glucagon stimulated hepatic lipolysis, evident by an increase in free fatty acid concentrations in the effluent from perfused mouse livers. In line with this, GCGR Ab treatment increased, while GCGA treatment decreased, liver triglyceride concentrations. The effects of glucagon appeared independent of changes in gastric emptying of paracetamol.ConclusionsGlucagon receptor signaling regulates triglyceride metabolism, both chronically and acutely, in mice. These data expand glucagon´s biological role and implicate that intact glucagon signaling is important for lipid metabolism. Glucagon agonism may have beneficial effects on hepatic and peripheral triglyceride metabolism.

Project description:The European Commission has recently proposed draft criteria for the identification of endocrine disrupting chemicals (EDCs) that pose a significant hazard to humans or the environment. Identifying and characterizing toxic hazards based on the manner by which adverse effects are produced rather than on the nature of those adverse effects departs from traditional practice and requires a proper interpretation of the evidence regarding the chemical's ability to produce physiological effect(s) via a specific mode of action (MoA). The ability of any chemical to produce a physiological effect depends on its pharmacokinetics and the potency by which it acts via the various MoAs that can lead to the particular effect. A chemical's potency for a specific MoA-its mechanistic potency-is determined by two properties: (1) its affinity for the functional components that comprise the MoA, i.e., its specific receptors, enzymes, transporters, transcriptional elements, etc., and (2) its ability to alter the functional state of those components (activity). Using the agonist MoA via estrogen receptor alpha, we illustrate an empirical method for determining a human-relevant potency threshold (HRPT), defined as the minimum level of mechanistic potency necessary for a chemical to be able to act via a particular MoA in humans. One important use for an HRPT is to distinguish between chemicals that may be capable of, versus those likely to be incapable of, producing adverse effects in humans via the specified MoA. The method involves comparing chemicals that have different ERα agonist potencies with the ability of those chemicals to produce ERα-mediated agonist responses in human clinical trials. Based on this approach, we propose an HRPT for ERα agonism of 1E-04 relative to the potency of the endogenous estrogenic hormone 17β-estradiol or the pharmaceutical estrogen, 17α-ethinylestradiol. This approach provides a practical way to address Hazard Identification according to the draft criteria for identification of EDCs recently proposed by the European Commission.

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Novel glucagon-like peptide-1 analogue exhibits potency-driven G-protein biased agonism with promising effects on diabetes and diabetic dry eye syndrome.

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Novel glucagon-like peptide-1 analogue exhibits potency-driven G-protein biased agonism with promising effects on diabetes and diabetic dry eye syndrome.

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