The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets

El, Kimberley; Douros, Jonathan D.; Willard, Francis S.; Novikoff, Aaron; Sargsyan, Ashot; Pérez-Tilve, Diego; Wainscott, David B.; Yang, Bin; Chen, A. Y.; Wothe, Donald; Coupland, Callum; Tschöp, Matthias H.; Finan, Brian; D’Alessio, David A.; Sloop, Kyle W.; Müller, Timo D.; Campbell, Jonathan E.

doi:10.1038/s42255-023-00811-0

Cited by 49 publications

(15 citation statements)

References 48 publications

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“…Thus, there is particular interest in understanding the mechanisms involved in GIPR agonism. So far we know tirzepatide drives insulin secretion primarily via GIPR in human islets [ 108 ]. Moreover, GIPR signaling in the hypothalamus regulates appetite and body weight [ 53 ].…”

Section: Open Questions On Mechanism For Weight Loss: Insights From P...mentioning

confidence: 99%

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

Gutgesell,

Nogueiras,

Tschöp

et al. 2024

Diabetes Ther

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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.

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Section: Open Questions On Mechanism For Weight Loss: Insights From P...mentioning

confidence: 99%

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

Gutgesell,

Nogueiras,

Tschöp

et al. 2024

Diabetes Ther

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“…Tirzepatide is a dual GLP1 and GIP (glucose-dependent insulinotropic peptide, formerly called gastric inhibitory peptide) receptor agonist recently approved for obesity treatment in both the U.S.A. and Europe. Regarding pharmacodynamics, tirzepatide couples the activation of the GLP1-RA to the effect on the GIP receptor, which is responsible for most of the action in stimulating insulin secretion ( 122 ). The phase III SURMOUNT-1 trial studied the efficacy and safety profile of 10 or 15 mg tirzepatide in patients not affected by T2DM treated for 72 weeks, showing a significant decrease in both body weight and abdominal circumference.…”

Section: Pharmacological Treatment Of Obesitymentioning

confidence: 99%

Adipocentric origin of the common cardiometabolic complications of obesity in the young up to the very old: pathophysiology and new therapeutic opportunities

Sarzani,

Landolfo,

Di Pentima

et al. 2024

Front. Med.

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Obesity is a multifactorial chronic disease characterized by an excess of adipose tissue, affecting people of all ages. In the last 40 years, the incidence of overweight and obesity almost tripled worldwide. The accumulation of “visceral” adipose tissue increases with aging, leading to several cardio-metabolic consequences: from increased blood pressure to overt arterial hypertension, from insulin-resistance to overt type 2 diabetes mellitus (T2DM), dyslipidemia, chronic kidney disease (CKD), and obstructive sleep apnea. The increasing use of innovative drugs, namely glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2-i), is changing the management of obesity and its related cardiovascular complications significantly. These drugs, first considered only for T2DM treatment, are now used in overweight patients with visceral adiposity or obese patients, as obesity is no longer just a risk factor but a critical condition at the basis of common metabolic, cardiovascular, and renal diseases. An adipocentric vision and approach should become the cornerstone of visceral overweight and obesity integrated management and treatment, reducing and avoiding the onset of obesity-related multiple risk factors and their clinical complications. According to recent progress in basic and clinical research on adiposity, this narrative review aims to contribute to a novel clinical approach focusing on pathophysiological and therapeutic insights.

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“…Besides activation by its cognate hormone GIP, the GIPR is activated by pharmacological peptide agonists such as the GLP-1R/GIPR dual agonist tirzepatide. However, while there is evidence for GIPR engagement by tirzepatide in ex vivo human islets ( El et al . 2023 ), the direct engagement of GIPR by tirzepatide in vivo in humans is still debated ( Drucker & Holst 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Lipid regulation of the glucagon receptor family

Oqua,

Manchanda,

McGlone

et al. 2024

Journal of Endocrinology

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The glucagon receptor family are typical class B1 G protein-coupled receptors (GPCRs) with important roles in metabolism, including the control of pancreas, brain, and liver function. As proteins with 7 transmembrane domains, GPCRs are intimately in contact with lipid bilayers and therefore can be putatively regulated by interactions with their lipidic components, including cholesterol, sphingolipids, and other lipid species. Additionally, these receptors, as well as the agonists they bind to, can undergo lipid modifications, which can influence their binding capacity and/or elicit modified or biased signalling profiles. While the effect of lipids, and in particular cholesterol, has been widely studied for other GPCR classes, information about their role in regulating the glucagon receptor family is only beginning to emerge. Here we summarise our current knowledge on the effects of cholesterol modulation of glucagon receptor family signalling and trafficking profiles, as well as existing evidence for specific lipid–receptor binding and indirect effects of lipids via lipid modification of cognate agonists. Finally, we discuss the different methodologies that can be employed to study lipid-receptor interactions and summarise the importance of this area of investigation to increase our understanding of the biology of this family of metabolically relevant receptors.

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The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets

Cited by 49 publications

References 48 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

Adipocentric origin of the common cardiometabolic complications of obesity in the young up to the very old: pathophysiology and new therapeutic opportunities

Lipid regulation of the glucagon receptor family

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