The past, present, and future physiology and pharmacology of glucagon

Capozzi, Megan E.; D’Alessio, David A.; Campbell, Jonathan E.

doi:10.1016/j.cmet.2022.10.001

Cited by 48 publications

(21 citation statements)

References 231 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These are almost all positive things for the treatment of diabetes and obesity, which makes the glucagon signaling pathway an attractive target for an anti-obesity medication despite the induction of glucose production, but only if its hyperglycemic liability can be restrained. Consistent with the observation that glucagon acts on the pancreatic β-cells to stimulate insulin secretion via the GLP-1 receptor (GLP-1R) [24][25][26][27], long-term treatment of diet-induced obese (DIO) mice with a biochemically modified water-soluble glucagon improved glucose metabolism with equal efficacy relative to treatment with exendin-4 [23].…”

Section: Introductionsupporting

confidence: 58%

Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes

Gutgesell,

Nogueiras,

Tschöp

et al. 2024

Diabetes Ther

View full text Add to dashboard Cite

The discovery of long-acting incretin receptor agonists represents a major stride forward in tackling the dual epidemic of obesity and diabetes. Here we outline the evolution of incretin-based pharmacotherapy, from exendin-4 to the discovery of the multi-incretin hormone receptor agonists that look set to be our next step toward curing diabetes and obesity. We discuss the multiagonists currently in clinical trials and the improvement in efficacy each new generation of these drugs bring. The success of these agents in preclinical models and clinical trials suggests a promising future for multiagonists in the treatment of metabolic diseases, with the most recent glucose-dependent insulinotropic peptide receptor:glucagon-like peptide 1 receptor:glucagon receptor (GIPR:GLP-1R:GCGR) triagonists rivaling the efficacy of bariatric surgery. However, further research is needed to fully understand how these therapies exert their effect on body weight and in the last section we cover open questions about the potential mechanisms of multiagonist drugs, and the understanding of how gut–brain communication can be leveraged to achieve sustained body weight loss without adverse effects.

show abstract

Section: Introductionsupporting

confidence: 58%

Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes

Gutgesell,

Nogueiras,

Tschöp

et al. 2024

Diabetes Ther

View full text Add to dashboard Cite

show abstract

“…Glucagon-mediated activation of hepatic GCGRs leads to the activation of the G s /PKA signaling cascade, which triggers the stimulation of gluconeogenesis and glycogen breakdown and ultimately results in enhanced hepatic glucose production and output. While this signaling pathway plays a key role in maintaining euglycemia under fasting conditions, elevated hepatic GCGR signaling is thought to contribute to the pathophysiology of T2D and related metabolic disorders (Capozzi et al, 2022;D'Alessio, 2011).…”

Section: A Cell Type-specific β-Arrestin Mutant Mice As Novel Toolsmentioning

confidence: 99%

β−Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives

Wess¹,

Oteng²,

Rivera‐Gonzalez³

et al. 2023

Pharmacol Rev

View full text Add to dashboard Cite

The two β-arrestins, β-arrestin-1 and -2 (systematic names: arrestin-2 and -3, respectively), are multifunctional intracellular proteins that regulate the activity of a very large number of cellular signaling pathways and physiological functions. The two proteins were discovered for their ability to disrupt signaling via G protein-coupled receptors (GPCRs) via binding to the activated receptors. However, it is now well recognized that both β-arrestins can also act as direct modulators of numerous cellular processes via either GPCR-dependent orindependent mechanisms. Recent structural, biophysical, and biochemical studies have provided novel insights into how β-arrestins bind to activated GPCRs and downstream effector proteins.Studies with β-arrestin mutant mice have identified numerous physiological and pathophysiological processes regulated by β-arrestin-1 and/or -2. Following a short summary of recent structural studies, this review will primarily focus on β-arrestin-regulated physiological functions, with particular focus on the central nervous system and the roles of β-arrestins in carcinogenesis and key metabolic processes including the maintenance of glucose and energy homeostasis. This review will also highlight potential therapeutic implications of these studies and discuss strategies that could prove useful for targeting specific β-arrestin-regulated signaling pathways for therapeutic purposes.

show abstract

“…There is some evidence suggesting that alpha‐cells maintain high intracellular ATP levels in the absence of glucose by beta‐oxidation of fatty acids 184 . In addition to glucose and fatty acids, glucagon secretion is also stimulated by amino acids and it has been proposed that their effect on glucagon secretion might be more important than that of glucose 185 . However, it is notable that whereas a fall in glucose leads to a sustained stimulation of glucagon secretion, the stimulatory effect of amino acids tends to be transient 186 …”

Section: Glucagon and The Control Of The Endocrine Pancreasmentioning

confidence: 99%

History of key regulatory peptide systems and perspectives for future research

Chen

Rehfeld

Watts

et al. 2023

J Neuroendocrinology

View full text Add to dashboard Cite

Throughout the 20th Century, regulatory peptide discovery advanced from the identification of gut hormones to the extraction and characterization of hypothalamic hypophysiotropic factors, and to the isolation and cloning of multiple brain neuropeptides. These discoveries were followed by the discovery of G‐protein‐coupled and other membrane receptors for these peptides. Subsequently, the systems physiology associated with some of these multiple regulatory peptides and receptors has been comprehensively elucidated and has led to improved therapeutics and diagnostics and their approval by the US Food and Drug Administration. In light of this wealth of information and further potential, it is truly a time of renaissance for regulatory peptides. In this perspective, we review what we have learned from the pioneers in exemplified fields of gut peptides, such as cholecystokinin, enterochromaffin‐like‐cell peptides, and glucagon, from the trailblazing studies on the key stress hormone, corticotropin‐releasing factor, as well as from more recently characterized relaxin‐family peptides and receptors. The historical viewpoints are based on our understanding of these topics in light of the earliest phases of research and on subsequent studies and the evolution of knowledge, aiming to sharpen our vision of the current state‐of‐the‐art and those studies that should be prioritized in the future.

show abstract

The past, present, and future physiology and pharmacology of glucagon

Cited by 48 publications

References 231 publications

Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes

Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes

β−Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives

History of key regulatory peptide systems and perspectives for future research

Contact Info

Product

Resources

About