Glucagon-based therapy: Past, present and future

Patil, Mohan; Deshmukh, Nitin; Patel, Mahesh; Sangle, Ganesh V.

doi:10.1016/j.peptides.2020.170296

Cited by 28 publications

(39 citation statements)

References 103 publications

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“…The addition of GLP-1 receptor agonism to glucagon receptor agonism improves lipid metabolism and hepatic steatosis when compared with GLP-1 receptor agonism alone in rodents (Day et al, 2009). In fact, a GLP-1 receptor agonist and a glucagon receptor/GLP-1 receptor coagonist administered via injection are being evaluated for the indication of NASH in a clinical trial (Knudsen and Lau, 2019;Patil et al, 2020). Considering the stimulation of glucagon and GLP-1 by GPR40 full agonists, orally available SCO-267 may be an attractive strategy to treat NASH.…”

Section: Discussionmentioning

confidence: 99%

The GPR40 Full Agonist SCO-267 Improves Liver Parameters in a Mouse Model of Nonalcoholic Fatty Liver Disease without Affecting Glucose or Body Weight

Ookawara¹,

Matsuda²,

Watanabe³

et al. 2020

J Pharmacol Exp Ther

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Full agonism of G-protein-coupled receptor 40 (GPR40)/free fatty acid 1 receptor improves glycemic control in diabetic rodents. However, the effects of GPR40 full agonism on liver parameters are largely unknown. In the present study, we examined the effects of a GPR40 full agonist, SCO-267, on liver parameters in a nondiabetic mouse model with early-stage nonalcoholic fatty liver disease (NAFLD). SCO-267 was orally administered to mice, which were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), a mouse model for NAFLD. An oral dose of SCO-267 increased levels of circulating glucagon and glucagon-like peptide-1 in CDAHFD-fed mice. In a chronic-dose experiment, effects of SCO-267 were compared with those of a dipeptidyl peptidase-4 inhibitor (alogliptin) and a sodium glucose cotransporter 2 inhibitor (dapagliflozin). SCO-267 decreased liver triglyceride content, weight, collagen content, and plasma alanine aminotransferase (ALT) levels without affecting food intake or glucose levels in CDAHFD-fed mice. Furthermore, SCO-267 decreased levels of liver thiobarbituric acid reactive substances (TBARS), markers of oxidative stress. Alogliptin and dapagliflozin had no effect on liver weight or levels of triglyceride, collagen, plasma ALT, and liver TBARS. SCO-267 elevated mRNA levels of molecules with roles in mitochondrial function and b-oxidation while inhibiting those with roles in lipogenesis, inflammation, reactive oxygen species generation, and fibrosis in the liver, all of which were less evident with alogliptin and dapagliflozin. This is the first study to show that the GPR40 full agonist SCO-267 improves liver parameters without affecting glucose or body weight in a mouse model of NAFLD. SIGNIFICANCE STATEMENT Full agonism of GPR40/free fatty acid 1 receptor signaling stimulates islet and gut hormone secretions. The present study is the first to show the treatment effects of GPR40 full agonism on liver parameters in a mouse model for nonalcoholic fatty liver disease.

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Section: Discussionmentioning

confidence: 99%

The GPR40 Full Agonist SCO-267 Improves Liver Parameters in a Mouse Model of Nonalcoholic Fatty Liver Disease without Affecting Glucose or Body Weight

Ookawara¹,

Matsuda²,

Watanabe³

et al. 2020

J Pharmacol Exp Ther

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“…Its main action consists in a counter-regulatory effect toward insulin, inducing hepatic glycogenolysis and gluconeogenesis by targeting the class B GPCR glucagon receptor (GCGR) ( Herr, 2012 ). The use of native glucagon in the therapeutic approach to hypoglycaemia is not easily practicable ( Patil et al, 2020 ) for its very low stability in physiological formulations and its consequent high tendency to aggregate in few hours, after reconstitution ( Hӧvelmann et al, 2018 ). Thus, the development of new analogues/agonists of the native glucagon peptide is necessary in treatment of hypoglycaemia.…”

Section: Diabetes Obesity Short Bowel Syndrome and Hyperinsulinemia The Proglucagon Legacymentioning

confidence: 99%

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Cabri

Cantelmi

Corbisiero

et al. 2021

Front. Mol. Biosci.

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Targeting protein-protein interactions (PPIs) has been recently recognized as an emerging therapeutic approach for several diseases. Up today, more than half a million PPI dysregulations have been found to be involved in pathological events. The dynamic nature of these processes and the involvement of large protein surfaces discouraged anyway the scientific community in considering them promising therapeutic targets. More recently peptide drugs received renewed attention since drug discovery has offered a broad range of structural diverse sequences, moving from traditionally endogenous peptides to sequences possessing improved pharmaceutical profiles. About 70 peptides are currently on the marked but several others are in clinical development. In this review we want to report the update on these novel APIs, focusing our attention on the molecules in clinical development, representing the direct consequence of the drug discovery process of the last 10 years. The comprehensive collection will be classified in function of the structural characteristics (native, analogous, heterologous) and on the basis of the therapeutic targets. The mechanism of interference on PPI will also be reported to offer useful information for novel peptide design.

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“…Chronic administration of GLP-1/GCGR dual agonist leads to a more pronounced improvement in plasma metabolic parameters (insulin, leptin, and adiponectin) compared to GLP-1R agonist alone. 99 Oxyntomodulin, JNJ-64565111, and MEDI-0382 100 , 101 are examples of some agents being developed in this emerging class with some encouraging results being reported with MEDI-0382 recently. 102 …”

Section: Therapies Targeting the Glucagon Receptormentioning

confidence: 99%

“…Weight gain, elevated hepatic enzymes, increase in low-density-lipoprotein-C (LDL-C) levels and liver fat content, rise in systolic blood pressure, and α-cell hyperplasia are some of the concerns reported with GRA use. 105 , 106 Efforts are underway to minimize side effects of GRAs, 107 and many agents are currently being developed from this class 101 ( Table 2 ).…”

Section: Therapies Targeting the Glucagon Receptormentioning

confidence: 99%

Therapeutics for type-2 diabetes mellitus: a glance at the recent inclusions and novel agents under development for use in clinical practice

Shah

Abdalla

Deshmukh

et al. 2021

Therapeutic Advances in Endocrinology

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Diabetes mellitus (DM) is a chronic, progressive, and multifaceted illness resulting in significant physical and psychological detriment to patients. As of 2019, 463 million people are estimated to be living with DM worldwide, out of which 90% have type-2 diabetes mellitus (T2DM). Over the years, significant progress has been made in identifying the risk factors for developing T2DM, understanding its pathophysiology and uncovering various metabolic pathways implicated in the disease process. This has culminated in the implementation of robust prevention programmes and the development of effective pharmacological agents, which have had a favourable impact on the management of T2DM in recent times. Despite these advances, the incidence and prevalence of T2DM continue to rise. Continuing research in improving efficacy, potency, delivery and reducing the adverse effect profile of currently available formulations is required to keep pace with this growing health challenge. Moreover, new metabolic pathways need to be targeted to produce novel pharmacotherapy to restore glucose homeostasis and address metabolic sequelae in patients with T2DM. We searched PubMed, MEDLINE, and Google Scholar databases for recently included agents and novel medication under development for treatment of T2DM. We discuss the pathophysiology of T2DM and review how the emerging anti-diabetic agents target the metabolic pathways involved. We also look at some of the limiting factors to developing new medication and the introduction of unique methods, including facilitating drug delivery to bypass some of these obstacles. However, despite the advances in the therapeutic options for the treatment of T2DM in recent years, the industry still lacks a curative agent.

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Glucagon-based therapy: Past, present and future

Cited by 28 publications

References 103 publications

The GPR40 Full Agonist SCO-267 Improves Liver Parameters in a Mouse Model of Nonalcoholic Fatty Liver Disease without Affecting Glucose or Body Weight

The GPR40 Full Agonist SCO-267 Improves Liver Parameters in a Mouse Model of Nonalcoholic Fatty Liver Disease without Affecting Glucose or Body Weight

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Therapeutics for type-2 diabetes mellitus: a glance at the recent inclusions and novel agents under development for use in clinical practice

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