New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling

Tomás, Alejandra; Jones, Ben; Leech, Colin A.

doi:10.1016/j.jmb.2019.08.009

Cited by 45 publications

(28 citation statements)

References 245 publications

(235 reference statements)

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“…Several basic and clinical studies have demonstrated that treatment with GLP-1 analogs or GLP-1R agonists greatly mitigates renal fibrosis associated with DN by inhibiting TGF-β1-activated Smad 3 and ERK1/2 [ 39 ]. Furthermore, GLP-1-activated cyclic AMP-protein kinase A is thought to increase Sirt-1 activity through phosphorylation of Sirt-1 (serine 434) [ 40 , 41 ]. We found that the oligo-FO also has an ability to enhance GLP-1R expression in AGE-stimulated NRK-52E cells, suggesting that oligo-FO may be a GLP-1R agonist.…”

Section: Discussionmentioning

confidence: 99%

Oligo-Fucoidan Improves Diabetes-Induced Renal Fibrosis via Activation of Sirt-1, GLP-1R, and Nrf2/HO-1: An In Vitro and In Vivo Study

Huang

Chou

2020

Nutrients

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Fucoidan extracted from brown algae has multiple beneficial functions. In this study, we investigated the effects of low-molecular-weight fucoidan (oligo-FO) on renal fibrosis under in vitro and in vivo diabetic conditions, and its molecular mechanisms. Advanced glycation product (AGE)-stimulated rat renal proximal tubular epithelial cells (NRK-52E) and diabetic mice induced by high-fat diet and intraperitoneal injection of streptozotocin and nicotinamide were used. Oligo-FO treatment significantly inhibited anti-high mobility group box 1 (HMGB1)/RAGE/ anti-nuclear factor-kappa B (NF-κB)/transforming growth factor-β1 (TGF-β1)/TGF-β1R/Smad 2/3/fibronectin signaling pathway and HIF-1α activation in AGE-stimulated NRK-52E cells. Conversely, the expression and activity of Sirt-1; the levels of ubiquitin-specific peptidase 22 (USP22), p-AMPK, glucagon-like peptide-1 receptor (GLP-1R), and heme oxygenase-1 (HO-1); and Nrf2 activation were remarkably increased by oligo-FO in AGE-stimulated cells. However, the above effects of oligo-FO were greatly diminished by inhibiting Sirt-1, HO-1, or GLP-1R activity. Similar changes of these pro-fibrotic genes in the kidney and a marked attenuation of renal injury and dysfunction were observed in oligo-FO-treated diabetic mice. These findings indicated that the inhibitory effects of the oligo-FO on diabetes-evoked renal fibrosis are mediated by suppressing TGF-β1-activated pro-fibrogenic processes via Sirt-1, HO-1, and GLP-1R dependence. Collectively, fucoidan-containing foods or supplements may be potential agents for ameliorating renal diseases due to excessive fibrosis.

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Section: Discussionmentioning

confidence: 99%

Oligo-Fucoidan Improves Diabetes-Induced Renal Fibrosis via Activation of Sirt-1, GLP-1R, and Nrf2/HO-1: An In Vitro and In Vivo Study

Huang

Chou

2020

Nutrients

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“…These paradoxical effects of GLP-1 signaling could be the result of species-specific biology, as well as differences in approaches and outcomes tested. Since the cardioprotective nature of GLP-1 mimetics is typically examined after long term exposure, it is also possible that GLP-1 has multiple tissue specific intracellular signaling cascades based on time of exposure or concentration (Jessen et al, 2017;Tomas et al, 2020).…”

Section: Glucagon-like Peptidementioning

confidence: 99%

Interplay Between Systemic Metabolic Cues and Autonomic Output: Connecting Cardiometabolic Function and Parasympathetic Circuits

2021

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There is consensus that the heart is innervated by both the parasympathetic and sympathetic nervous system. However, the role of the parasympathetic nervous system in controlling cardiac function has received significantly less attention than the sympathetic nervous system. New neuromodulatory strategies have renewed interest in the potential of parasympathetic (or vagal) motor output to treat cardiovascular disease and poor cardiac function. This renewed interest emphasizes a critical need to better understand how vagal motor output is generated and regulated. With clear clinical links between cardiovascular and metabolic diseases, addressing this gap in knowledge is undeniably critical to our understanding of the interaction between metabolic cues and vagal motor output, notwithstanding the classical role of the parasympathetic nervous system in regulating gastrointestinal function and energy homeostasis. For this reason, this review focuses on the central, vagal circuits involved in sensing metabolic state(s) and enacting vagal motor output to influence cardiac function. It will review our current understanding of brainstem vagal circuits and their unique position to integrate metabolic signaling into cardiac activity. This will include an overview of not only how metabolic cues alter vagal brainstem circuits, but also how vagal motor output might influence overall systemic concentrations of metabolic cues known to act on the cardiac tissue. Overall, this review proposes that the vagal brainstem circuits provide an integrative network capable of regulating and responding to metabolic cues to control cardiac function.

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“…Resistance to the insulinotropic effect of GLP-1r may potentially account for the relative reduction in the effect of exogenous GLP-1 and GLP-1 agonists in insulin-resistant obese and in type 2 diabetes 5 as well as the substantial interindividual variability in the glucose-lowering response to GLP-1r agonists. 37 A reduction in GLP-1r in the vagal nodose ganglion, 38 in β (and probably α) pancreatic cells, 10 in endothelial cells, 7 and in gastric glands 6 have been reported. In all but one of these studies, data were derived from quantitative in vitro expression of RNA, and the etiology of this was not investigated.…”

Section: Discussionmentioning

confidence: 98%

Pancreatic GLP-1r binding potential is reduced in insulin-resistant pigs

Malbert

Chauvin

Horowitz

2020

BMJ Open Diab Res Care

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IntroductionThe insulinotropic capacity of exogenous glucagon like peptide-1 (GLP-1) is reduced in type 2 diabetes and the insulin-resistant obese. We have tested the hypothesis that this response is the consequence of a reduced pancreatic GLP-1 receptor (GLP-1r) density in insulin-resistant obese animals.Research design and methodsGLP-1r density was measured in lean and insulin-resistant adult miniature pigs after the administration of a 68Ga-labeled GLP-1r agonist. The effect of hyperinsulinemia on GLP-1r was assessed using sequential positron emission tomography (PET), both in the fasted state and during a clamp. The impact of tissue perfusion, which could account for changes in GLP-1r agonist uptake, was also investigated using 68Ga-DOTA imaging.ResultsGLP-1r binding potential in the obese pancreas was reduced by 75% compared with lean animals. Similar reductions were evident for fat tissue, but not for the duodenum. In the lean group, induced hyperinsulinemia reduced pancreatic GLP-1r density to a level comparable with that of the obese group. The reduction in blood to tissue transfer of the GLP-1r ligand paralleled that of tissue perfusion estimated using 68Ga-DOTA.ConclusionsThese observations establish that a reduction in abdominal tissue perfusion and a lower GLP-1r density account for the diminished insulinotropic effect of GLP-1 agonists in type 2 diabetes.

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New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling

Cited by 45 publications

References 245 publications

Oligo-Fucoidan Improves Diabetes-Induced Renal Fibrosis via Activation of Sirt-1, GLP-1R, and Nrf2/HO-1: An In Vitro and In Vivo Study

Oligo-Fucoidan Improves Diabetes-Induced Renal Fibrosis via Activation of Sirt-1, GLP-1R, and Nrf2/HO-1: An In Vitro and In Vivo Study

Interplay Between Systemic Metabolic Cues and Autonomic Output: Connecting Cardiometabolic Function and Parasympathetic Circuits

Pancreatic GLP-1r binding potential is reduced in insulin-resistant pigs

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