Role of cyclic AMP signaling in the production and function of the incretin hormone glucagon-like peptide-1

Introduction: Ample evidence demonstrates cardiovascular protection by incretin hormone glucagon-like peptide-1 (GLP-1) through the cyclic AMP axis. GLP-1 is known for its inotropic effect on heart, however, the role of GLP-1 in heart failure remains uncertain. Hypothesis: To explore the pathophysiological role of GLP-1 in heart failure Methods: Pressure overload-induced heart failure model was generated by transverse aortic constriction in mice (TAC). Results: At 4 week after the operation, TAC exhibited systolic left-ventricular dysfunction, myocardial hypertrophy and augmented apoptosis. Unexpectedly, circulating GLP-1 concentration was markedly decreased in TAC (in pM; 0.86±0.10 for TAC versus 2.13±0.54 for sham) with concomitant reduction of myocardial cyclic AMP concentration (in pmole/mg protein; 33.0±1.4 for TAC versus 42.2±1.5). TAC exhibited pathological changes in signaling molecules of myocardial contractility [SERCA, phospho-phospholamban(Serine16; pPL), β-myosin heavy chain (MYH7)], remodeling (Akt/mTOR/S6K), and cell death markers (procaspase-3/Bcl2 for apoptosis and PINK/PARKIN complex for mitophagy detecting damaged mitochondria). All of these changes observed in TAC heart were reversed selectively by treatment with GLP-1 analog exendin-4 (Ex4; 24nmole/kg/day for 4 weeks) and indirect supplement of GLP-1 by a DPP4 inhibitor alogliptin (ALO; 10mg/kg/day for 4 weeks). In vitro TUNEL assay using cultured cardiomyocytes revealed that Ex-4 reduced myocardial apoptosis in a cAMP/EPAC1-dependent but PKA-independent manner (Figure). Conclusions: Pressure-overloaded heart failure exhibits decline in GLP-1, leading to cAMP/EPAC1-dependent impairment in myocardial apoptosis, and cAMP/PKA/pPL/SERCA-dependent myocardial contractile dysfunction. Our data suggest the distinct role of PKA and EPAC in pathophysiology underlying heart failure.

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New insights into the role of cAMP in the production and function of the incretin hormone glucagon-like peptide-1 (GLP-1)

Cellular Signalling ◽

10.1016/j.cellsig.2009.09.032 ◽

2010 ◽

Vol 22 (1) ◽

pp. 1-8 ◽

Cited By ~ 31

Author(s):

Zhiwen Yu ◽

Tianru Jin

Keyword(s):

Incretin Hormone ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

And Function

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Uncoupling protein 2 negatively regulates glucose-induced glucagon-like peptide 1 secretion

Journal of Molecular Endocrinology ◽

10.1530/jme-11-0114 ◽

2012 ◽

Vol 48 (2) ◽

pp. 151-158 ◽

Cited By ~ 9

Author(s):

Hongjie Zhang ◽

Jing Li ◽

Xiangying Liang ◽

Yun Luo ◽

Ke Zen ◽

...

Keyword(s):

Cell Model ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Mrna Levels ◽

Incretin Hormone ◽

Mucosal Layer ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Deficient Mice

It is known that endogenous levels of the incretin hormone glucagon-like peptide 1 (GLP1) can be enhanced by various secretagogues, but the mechanism underlying GLP1 secretion is still not fully understood. We assessed the possible effect of uncoupling protein 2 (UCP2) on GLP1 secretion in mouse intestinal tract and NCI-H716 cells, a well-characterized human enteroendocrine L cell model. Localization of UCP2 and GLP1 in the gastrointestinal tract was assessed by immunofluorescence staining. Ucp2 mRNA levels in gut were analyzed by quantitative RT-PCR. Human NCI-H716 cells were transiently transfected with siRNAs targeting UCP2. The plasma and ileum tissue levels of GLP1 (7–36) amide were measured using an ELISA kit. UCP2 was primarily expressed in the mucosal layer and colocalized with GLP1 in gastrointestinal mucosa. L cells secreting GLP1 also expressed UCP2. After glucose administration, UCP2-deficient mice showed increased glucose-induced GLP1 secretion compared with wild-type littermates. GLP1 secretion increased after NCI-H716 cells were transfected with siRNAs targeting UCP2. UCP2 was markedly upregulated in ileum tissue from ob/ob mice, and GLP1 secretion decreased compared with normal mice. Furthermore, GLP1 secretion increased after administration of genipin by oral gavage. Taken together, these results reveal an inhibitory role of UCP2 in glucose-induced GLP1 secretion.

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Signal bias at glucagon family receptors: rationale and downstream impacts

10.1101/2020.04.26.062372 ◽

2020 ◽

Author(s):

Ben Jones ◽

Emma Rose McGlone ◽

Zijian Fang ◽

Phil Pickford ◽

Ivan R Corrêa ◽

...

Keyword(s):

Insulin Secretion ◽

Energy Metabolism ◽

Cyclic Amp ◽

Selective Reduction ◽

Preclinical Studies ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Glucose Output ◽

Downstream Impacts

AbstractReceptors for the peptide hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) are important regulators of insulin secretion and energy metabolism. Recently described GLP-1 receptor agonists showing signal bias in favour of cyclic AMP over β-arrestin-2 recruitment have delivered promising results in preclinical studies. Here we first sought to establish the role of β-arrestins in the control of intracellular signalling and trafficking responses at the closely related GLP-1, GIP and GCG receptors, through studies performed in cells depleted of both β-arrestin isoforms. We also generated analogues of GLP-1, GCG and GIP which in some cases showed selective reduction in β-arrestin-2 recruitment versus cAMP signalling compared to the parent peptide. Despite reduced acute signalling potency and/or efficacy, some biased GLP-1 and GIP analogues increased maximal sustained insulin secretion from INS-1 832/3 clonal beta cells, although only at high agonist concentrations. Biased GCG analogues did not affect maximal insulin release, or glucose output in hepatocytes.

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A sandwich ELISA for measurement of the primary glucagon-like peptide-1 metabolite

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00005.2017 ◽

2017 ◽

Vol 313 (3) ◽

pp. E284-E291 ◽

Cited By ~ 4

Author(s):

Nicolai J. Wewer Albrechtsen ◽

Ali Asmar ◽

Frederik Jensen ◽

Signe Törang ◽

Lene Simonsen ◽

...

Keyword(s):

Type 2 Diabetes ◽

Sandwich Elisa ◽

Active Form ◽

Primary Metabolite ◽

Incretin Hormone ◽

Dipeptidyl Peptidase 4 ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the gastrointestinal tract. It is best known for its glucose-dependent insulinotropic effects. GLP-1 is secreted in its intact (active) form (7–36NH2) but is rapidly degraded by the dipeptidyl peptidase 4 (DPP-4) enzyme, converting >90% to the primary metabolite (9–36NH2) before reaching the targets via the circulation. Although originally thought to be inactive or antagonistic, GLP-1 9–36NH2 may have independent actions, and it is therefore relevant to be able to measure it. Because reliable assays were not available, we developed a sandwich ELISA recognizing both GLP-1 9–36NH2 and nonamidated GLP-1 9–37. The ELISA was validated using analytical assay validation guidelines and by comparing it to a subtraction-based method, hitherto employed for estimation of GLP-1 9–36NH2. Its accuracy was evaluated from measurements of plasma obtained during intravenous infusions (1.5 pmol × kg−1 × min−1) of GLP-1 7–36NH2 in healthy subjects and patients with type 2 diabetes. Plasma levels of the endogenous GLP-1 metabolite increased during a meal challenge in patients with type 2 diabetes, and treatment with a DPP-4 inhibitor fully blocked its formation. Accurate measurements of the GLP-1 metabolite may contribute to understanding its physiology and role of GLP-1 in diabetes.

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Regulation of Na+/H+ exchanger NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal tubule cells

AJP Renal Physiology ◽

10.1152/ajprenal.00082.2009 ◽

2009 ◽

Vol 297 (6) ◽

pp. F1647-F1655 ◽

Cited By ~ 81

Author(s):

Luciene R. Carraro-Lacroix ◽

Gerhard Malnic ◽

Adriana C. C. Girardi

Keyword(s):

Receptor Agonist ◽

Surface Expression ◽

Inhibitory Effect ◽

Proximal Tubule Cells ◽

Incretin Hormone ◽

Downstream Effectors ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Renal Proximal Tubule Cells

The gut incretin hormone glucagon-like peptide 1 (GLP-1) is released in response to ingested nutrients and enhances insulin secretion. In addition to its insulinotropic properties, GLP-1 has been shown to have natriuretic actions paralleled by a diminished proton secretion. We therefore studied the role of the GLP-1 receptor agonist exendin-4 in modulating the activity of Na+/H+ exchanger NHE3 in LLC-PK1 cells. We found that NHE3-mediated Na+-dependent intracellular pH (pHi) recovery decreased ∼50% after 30-min treatment with 1 nM exendin-4. Pharmacological inhibitors and cAMP analogs that selectively activate protein kinase A (PKA) or the exchange protein directly activated by cAMP (EPAC) demonstrated that regulation of NHE3 activity by exendin-4 requires activation of both cAMP downstream effectors. This conclusion was based on the following observations: 1) the PKA antagonist H-89 completely prevented the effect of the PKA activator but only partially blocked the exendin-4-induced NHE3 inhibition; 2) the MEK1/2 inhibitor U-0126 abolished the effect of the EPAC activator but only diminished the exendin-4-induced NHE3 inhibition; 3) combination of H-89 and U-0126 fully prevented the effect of exendin-4 on NHE3; 4) no additive effect in the inhibition of NHE3 activity was observed when exendin-4, PKA, and EPAC activators were used together. Mechanistically, the inhibitory effect of exendin-4 on pHi recovery was associated with an increase of NHE3 phosphorylation. Conversely, this inhibition took place without changes in the surface expression of the transporter. We conclude that GLP-1 receptor agonists modulate sodium homeostasis in the kidney, most likely by affecting NHE3 activity.

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