Recent progress in the development of small-molecule glucagon receptor antagonists

Sammons, M. F.; Lee, Esther C.Y.

doi:10.1016/j.bmcl.2015.07.092

Cited by 41 publications

(34 citation statements)

References 24 publications

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“…For example, the GLP1R agonists exenatide (Byetta) and liraglutide (Victoza) are FDA-approved antidiabetic drugs and are able to enhance insulin secretion by stimulating cAMP production in β cells. Small molecular antagonists for glucagon receptor are under preclinical or clinical investigations for their inhibitory effects on HGP (Sammons & Lee 2015). cAMPdegrading PDEs have been suggested as antidiabetic targets (Furman & Pyne 2006).…”

Section: Strategies For Camp/pka Pathway Targetingmentioning

confidence: 99%

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Yang

2016

Journal of Molecular Endocrinology

143

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In mammals, cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is usually elicited by binding of hormones and neurotransmitters to G protein-coupled receptors (GPCRs). cAMP exerts many of its physiological effects by activating cAMPdependent protein kinase (PKA), which in turn phosphorylates and regulates the functions of downstream protein targets including ion channels, enzymes, and transcription factors. cAMP/PKA signaling pathway regulates glucose homeostasis at multiple levels including insulin and glucagon secretion, glucose uptake, glycogen synthesis and breakdown, gluconeogenesis, and neural control of glucose homeostasis. This review summarizes recent genetic and pharmacological studies concerning the regulation of glucose homeostasis by cAMP/PKA in pancreas, liver, skeletal muscle, adipose tissues, and brain. We also discuss the strategies for targeting cAMP/PKA pathway for research and potential therapeutic treatment of type 2 diabetes mellitus (T2D).

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Section: Strategies For Camp/pka Pathway Targetingmentioning

confidence: 99%

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Yang

2016

Journal of Molecular Endocrinology

143

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“…The body contains a myriad of other endogenous peptides and small proteins that regulate sleep (orexins) 6,7 , stress (CRF) 8 , metabolism (leptin) 9 , and more 2 . Furthermore, molecules that activate or inhibit receptors for these hormones 10–13 or control the levels of endogenous hormones 14,15 have successfully been translated into novel therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Discovery and characterization of smORF-encoded bioactive polypeptides

2015

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Analysis of genomes, transcriptomes, and proteomes reveals the existence of hundreds to thousands of translated, yet non-annotated short open reading frames (small ORFs or smORFs). The discovery of smORFs, and their protein products, smORF-encoded polypeptides (SEPs), reveals a fundamental gap in our knowledge of protein-coding genes. Different studies have identified central roles for smORFs in metabolism, apoptosis, and development. The discovery of these bioactive SEPs emphasizes the functional potential of this unexplored class of biomolecules. Here, we provide an overview of this emerging field and highlight the opportunities for chemical biology to answer fundamental questions about these novel genes. Such studies will provide new insights into the protein-coding potential of genomes and identify functional genes with roles in biology and disease.

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“…Following decades during which reduced insulin action was viewed as the exclusive cause of diabetes mellitus and hormonal replacement proved transformative to diabetic individuals worldwide, renewed interest in glucagon has resulted in a rediscovered appreciation of the role this hormone plays in the pathophysiology of impaired glucose homeostasis [1][2][3]. This recent excitement for glucagon antagonism as a viable therapeutic approach stems from the tantalising preclinical results suggesting that reducing glucagon action or secretion will exert potent reductions in the elevated hepatic glucose production present in both type 1 and 2 diabetes mellitus [4][5][6][7][8]. Glucagon is secreted by the pancreatic alpha cell in response to changes in the local concentration of glucose, amino acids or insulin.…”

Section: Glucagon: Hormonal Mediator Of Hepatic Metabolismmentioning

confidence: 99%

“…Pharmacological GCGR antagonism has been shown in preclinical studies to be an effective treatment for the elevated hepatic glucose output that characterises the diabetic state [5][6][7][8]. The positive results of these preclinical studies have begun to translate into clinical impact, with impressive glucose lowering with small molecule glucagon receptor antagonists in diabetic individuals [4,50].…”

Section: Glucagon Antagonismmentioning

confidence: 99%

Glucagon: acute actions on hepatic metabolism

Miller

Birnbaum

2016

Diabetologia

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Type 2 diabetes mellitus is the result of impaired systemic control of glucose homeostasis, in part through the dysregulation of the hormone glucagon. Glucagon acts on the liver to increase glucose production through alterations in hepatic metabolism, and reducing the elevated glucagon signalling in diabetic patients is an attractive strategy for the treatment of hyperglycaemia. Here we review the actions of the hormone in the liver, focusing on the acute alterations of metabolic pathways. This review summarises

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Recent progress in the development of small-molecule glucagon receptor antagonists

Cited by 41 publications

References 24 publications

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Discovery and characterization of smORF-encoded bioactive polypeptides

Glucagon: acute actions on hepatic metabolism

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