Selectivity of peptide ligands for the human incretin receptors expressed in HEK-293 cells

Al-Sabah, Suleiman; Al-Fulaij, Munya A.; Ahmed, H.A.

doi:10.1016/j.ejphar.2014.08.019

Cited by 20 publications

(26 citation statements)

References 31 publications

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“…Notably, although the GIPR antagonist Pro3GIP has been consistently shown to be specific for the GIPR, the GLP-1R antagonist Ex 9–39 has been reported to possibly bind both the GLP-1R and GIPR (Gault et al, 2003). Recent studies suggest that Ex 9–39 concentrations of 1 µM and greater (that are higher than those used in our study) result in a loss of incretin receptor subtype selectivity (Al-Sabah et al, 2014). Nevertheless, a possibility exists that the reduction in cAMP production induced by the addition of 100 nM Ex 9–39 to 1 nM twincretin solution may not be due solely to the inhibition of GLP-1R binding.…”

Section: Discussionmentioning

confidence: 56%

Novel GLP-1R/GIPR co-agonist “twincretin” is neuroprotective in cell and rodent models of mild traumatic brain injury

Tamargo

Bader

et al. 2017

Experimental Neurology

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Several single incretin receptor agonists that are approved for the treatment of type 2 diabetes mellitus (T2DM) have been shown to be neuroprotective in cell and animal models of neurodegeneration. Recently, a synthetic dual incretin receptor agonist, nicknamed “twincretin,” was shown to improve upon the metabolic benefits of single receptor agonists in mouse and monkey models of T2DM. In the current study, the neuroprotective effects of twincretin are probed in cell and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in toddlers, teenagers and the elderly. Twincretin is herein shown to have activity at two different receptors, dose-dependently increase levels of intermediates in the neurotrophic CREB pathway and enhance viability of human neuroblastoma cells exposed to toxic concentrations of glutamate and hydrogen peroxide, insults mimicking the inflammatory conditions in the brain post-mTBI. Additionally, twincretin is shown to improve upon the neurotrophic effects of single incretin receptor agonists in these same cells. Finally, a clinically translatable dose of twincretin, when administered post-mTBI, is shown to fully restore the visual and spatial memory deficits induced by mTBI, as evaluated in a mouse model of weight drop close head injury. These results establish twincretin as a novel neuroprotective agent and suggest that it may improve upon the effects of the single incretin receptor agonists via dual agonism.

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Section: Discussionmentioning

confidence: 56%

Novel GLP-1R/GIPR co-agonist “twincretin” is neuroprotective in cell and rodent models of mild traumatic brain injury

Tamargo

Bader

et al. 2017

Experimental Neurology

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“…In our eight PBH participants, GIP levels were reduced by 15% ( p <0.01) during Ex-9 infusion, which could have contributed to improved glucose homeostasis via further reduction of the incretin effect. Indeed, Ex-9 was shown in one study involving cultured human embryonic kidney (HEK)-293 cells to block activity both at the GLP-1r and, to a lesser degree, the GIP receptor [44]. Ex-9 may also exert indirect influences on the alpha cell: glucagon secretion is suppressed in the presence of GLP-1, thus GLP-1r blockade may disinhibit GLP-1-mediated suppression of glucagon in patients with PBH.…”

Section: Discussionmentioning

confidence: 99%

Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia

et al. 2016

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Aims/hypothesis Post-bariatric hypoglycaemia (PBH) is a rare, but severe, metabolic disorder arising months to years after bariatric surgery. It is characterised by symptomatic postprandial hypoglycaemia, with inappropriately elevated insulin concentrations. The relative contribution of exaggerated incretin hormone signalling to dysregulated insulin secretion and symptomatic hypoglycaemia is a subject of ongoing inquiry. This study was designed to test the hypothesis that PBH and associated symptoms are primarily mediated by glucagon-like peptide-1 (GLP-1). Methods We conducted a double-blinded crossover study wherein eight participants with confirmed PBH were assigned in random order to intravenous infusion of the GLP-1 receptor (GLP-1r) antagonist, exendin (9-39) (Ex-9), or placebo during an OGTT on two separate days at the Stanford University Clinical and Translational Research Unit. Metabolic, symptomatic and pharmacokinetic variables were evaluated. Results were compared with a cohort of BMI- and glucose-matched non-surgical controls (NSCs). Results Infusion of Ex-9 decreased the time to peak glucose and rate of glucose decline during OGTT, and raised the postprandial nadir by over 70%, normalising it relative to NSCs and preventing hypoglycaemia in all PBH participants. Insulin AUC and secretion rate decreased by 57% and 71% respectively, and peak postprandial insulin was normalised relative to NSCs. Autonomic and neuroglycopenic symptoms were significantly reduced during Ex-9 infusion. Conclusions/interpretation GLP-1r blockade prevented hypoglycaemia in 100% of individuals, normalised beta cell function and reversed neuroglycopenic symptoms, supporting the conclusion that GLP-1 plays a primary role in mediating hyperinsulinaemic hypoglycaemia in PBH. Competitive antagonism at the GLP-1r merits consideration as a therapeutic strategy.

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“…Normalization of glucose concentrations has been shown to somewhat reactivate insulinotropic effects of GIP in subjects with type 2 diabetes; however, GIP might be the mediator of more insulin secretion occurring at high glucose concentrations, as shown in Figure S2C (Appendix S1). There are limitations to the interpretation of experiments using exendin [9‐39], as this agent may not fully block GLP‐1 receptors in all compartments of the organism, whereas it may have some effects on GIP receptors as well, although at much lower affinity . It also introduces a complex intervention; for example, altering gastric emptying, which may change the whole time course of events after meal ingestion .…”

Section: Discussionmentioning

confidence: 99%

Addition of a dipeptidyl peptidase‐4 inhibitor, sitagliptin, to ongoing therapy with the glucagon‐like peptide‐1 receptor agonist liraglutide: A randomized controlled trial in patients with type 2 diabetes

Nauck

Kahle

Баранов

et al. 2016

Diabetes Obesity Metabolism

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Sitagliptin, in patients already treated with a GLP-1 receptor agonist (liraglutide), increased intact GLP-1 and GIP concentrations, but with marginal, non-significant effects on glycaemic control. GLP-1 receptors have probably been maximally stimulated by liraglutide. Our findings do not support combination treatment with GLP-1 receptor agonists and DPP-4 inhibitors, but longer-term trials are needed to support clinical recommendations.

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Selectivity of peptide ligands for the human incretin receptors expressed in HEK-293 cells

Cited by 20 publications

References 31 publications

Novel GLP-1R/GIPR co-agonist “twincretin” is neuroprotective in cell and rodent models of mild traumatic brain injury

Novel GLP-1R/GIPR co-agonist “twincretin” is neuroprotective in cell and rodent models of mild traumatic brain injury

Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia

Addition of a dipeptidyl peptidase‐4 inhibitor, sitagliptin, to ongoing therapy with the glucagon‐like peptide‐1 receptor agonist liraglutide: A randomized controlled trial in patients with type 2 diabetes

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