Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo

1995 ◽  
Vol 80 (3) ◽  
pp. 952-957 ◽  
Author(s):  
C. F. Deacon
Keyword(s):  
Human Plasma ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals A synthetic glucagon-like peptide-1 analog with improved plasma stability

1998 ◽  
Vol 159 (1) ◽  
pp. 93-102 ◽  
Author(s):  
U Ritzel ◽  
U Leonhardt ◽  
M Ottleben ◽  
A Ruhmann ◽  
K Eckart ◽  
...  
Keyword(s):  
Amino Acid ◽  
Plasma Insulin ◽  
Rat Plasma ◽  
Plasma Stability ◽  
Terminal Amino Acid ◽  
Terminal Amino ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is the most potent endogenous insulin-stimulating hormone. In the present study the plasma stability and biological activity of a GLP-1 analog, [Ser]GLP-1(7-36)amide, in which the second N-terminal amino acid alanine was replaced by serine, was evaluated in vitro and in vivo. Incubation of GLP-1 with human or rat plasma resulted in degradation of native GLP-1(7-36)amide to GLP-1(9-36)amide, while [Ser]GLP-1(7-36)amide was not significantly degraded by plasma enzymes. Using glucose-responsive HIT-T15 cells, [Ser]GLP-1(7-36)amide showed strong insulinotropic activity, which was inhibited by the specific GLP-1 receptor antagonist exendin-4(9-39)amide. Simultaneous i.v. injection of [Ser]GLP-1(7-36)amide and glucose in rats induced a twofold higher increase in plasma insulin levels than unmodified GLP-1(7-36)amide with glucose and a fivefold higher increase than glucose alone. [Ser]GLP-1(7-36)amide induced a 1.5-fold higher increase in plasma insulin than GLP-1(7-36)amide when given 1 h before i.v. application of glucose. The insulinotropic effect of [Ser]GLP-1(7-36)amide was suppressed by i.v. application of exendin-4(9-39)amide. The present data demonstrate that replacement of the second N-terminal amino acid alanine by serine improves the plasma stability of GLP-1(7-36)amide. The insulinotropic action in vitro and in vivo was not impaired significantly by this modification.

Glucagon-like Peptide 1 Receptor Agonists, Diabetic Retinopathy and Angiogenesis: The AngioSafe Type 2 Diabetes Study

2019 ◽  
Vol 105 (4) ◽  
pp. e1549-e1560 ◽  
Author(s):  
Bénédicte Gaborit ◽  
Jean-Baptiste Julla ◽  
Samaher Besbes ◽  
Matthieu Proust ◽  
Clara Vincentelli ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Fundus Photography ◽  
Endothelial Cell Proliferation ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Aims Recent trials provide conflicting results on the association between glucagon-like peptide 1 receptor agonists (GLP-1RA) and diabetic retinopathy (DR). The aim of the AngioSafe type 2 diabetes (T2D) study was to determine the role of GLP-1RA in angiogenesis using clinical and preclinical models. Methods We performed two studies in humans. In study 1, we investigated the effect of GLP-1RA exposure from T2D diagnosis on the severity of DR, as diagnosed with retinal imaging (fundus photography). In study 2, a randomized 4-week trial, we assessed the effect of liraglutide on circulating hematopoietic progenitor cells (HPCs), and angio-miRNAs. We then studied the experimental effect of Exendin-4, on key steps of angiogenesis: in vitro on human endothelial cell proliferation, survival and three-dimensional vascular morphogenesis; and in vivo on ischemia-induced neovascularization of the retina in mice. Results In the cohort of 3154 T2D patients, 10% displayed severe DR. In multivariate analysis, sex, disease duration, glycated hemoglobin (HbA1c), micro- and macroangiopathy, insulin therapy and hypertension remained strongly associated with severe DR, while no association was found with GLP-1RA exposure (o 1.139 [0.800–1.622], P = .47). We further showed no effect of liraglutide on HPCs, and angio-miRNAs. In vitro, we demonstrated that exendin-4 had no effect on proliferation and survival of human endothelial cells, no effect on total length and number of capillaries. Finally, in vivo, we showed that exendin-4 did not exert any negative effect on retinal neovascularization. Conclusions The AngioSafe T2D studies provide experimental and clinical data confirming no effect of GLP-1RA on angiogenesis and no association between GLP-1 exposure and severe DR.

Oral intake of slowly digestible α-glucan, isomaltodextrin, stimulates glucagon-like peptide-1 secretion in the small intestine of rats

2019 ◽  
Vol 123 (6) ◽  
pp. 619-626
Author(s):  
Yoshihiko Komuro ◽  
Takashi Kondo ◽  
Shingo Hino ◽  
Tatsuya Morita ◽  
Naomichi Nishimura
Keyword(s):  
Small Intestine ◽  
Oral Delivery ◽  
Oral Intake ◽  
Membrane Vesicles ◽  
Rat Small Intestine ◽  
Maize Starch ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

AbstractTo investigate whether oral intake of highly branched α-glucan isomaltodextrin (IMD) could stimulate ileal glucagon-like peptide-1 (GLP-1) secretion, we examined (1) the digestibility of IMD, (2) the digestion and absorption rates of IMD, in rat small intestine and (3) portal GLP-1 concentration in rats given IMD. In Expt 1, ileorectostomised rats were given a 3 % IMD diet for 10 d. Separately, a 16-h in vitro digestion of IMD, using porcine pancreatic α-amylase and brush-border membrane vesicles from rat small intestine, was conducted. In Expt 2, upon 24-h fasting, rats were given any of glucose, IMD and high-amylose maize starch (HAMS) (1 g/kg of body weight). In Expt 3, caecectomised rats were given 0·2 % neomycin sulphate and a 5 % IMD diet for 10 d. The in vivo and in vitro digestibility of IMD was 70–80 %. The fraction of IMD digested in vitro for the first 120 min was 67 % of that in maize starch. The AUC for 0–120 min of plasma glucose concentration was significantly lower in HAMS group and tended to be lower in IMD group than in the glucose group. Finally, we also observed that, when compared with control rats, glucose of IMD significantly stimulated and improved the concentration of portal active GLP-1 in antibiotic-administered, caecectomised rats. We concluded that IMD was slowly digested and the resulting glucose stimulated GLP-1 secretion in rat small intestine. Oral delivery of slowly released IMD glucose to the small intestine probably exerts important, yet unknown, physiological effects on the recipient.

Activation of glucagon-like peptide-1 receptor inhibits growth and promotes apoptosis of human pancreatic cancer cells in a cAMP-dependent manner

2014 ◽  
Vol 306 (12) ◽  
pp. E1431-E1441 ◽  
Author(s):  
Hejun Zhao ◽  
Rui Wei ◽  
Liang Wang ◽  
Qing Tian ◽  
Ming Tao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Dependent Manner ◽  
Pancreatic Cancer Cells ◽  
Tumor Tissues ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) promotes pancreatic β-cell regeneration through GLP-1 receptor (GLP-1R) activation. However, whether it promotes exocrine pancreas growth and thereby increases the risk of pancreatic cancer has been a topic of debate in recent years. Clinical data and animal studies published so far have been controversial. In the present study, we report that GLP-1R activation with liraglutide inhibited growth and promoted apoptosis in human pancreatic cancer cell lines in vitro and attenuated pancreatic tumor growth in a mouse xenograft model in vivo. These effects of liraglutide were mediated through activation of cAMP production and consequent inhibition of Akt and ERK1/2 signaling pathways in a GLP-1R-dependent manner. Moreover, we examined GLP-1R expression in human pancreatic cancer tissues and found that 43.3% of tumor tissues were GLP-1R-null. In the GLP-1R-positive tumor tissues (56.7%), the level of GLP-1R was lower compared with that in tumor-adjacent normal pancreatic tissues. Furthermore, the GLP-1R-positive tumors were significantly smaller than the GLP-1R-null tumors. Our study shows for the first time that GLP-1R activation has a cytoreductive effect on human pancreatic cancer cells in vitro and in vivo, which may help address safety concerns of GLP-1-based therapies in the context of human pancreatic cancer.

Comparison of the glucose dependency of glucagon-like peptide-1(7–37) and glyburide in vitro and in vivo

Metabolism ◽  
1996 ◽  
Vol 45 (3) ◽  
pp. 404-409 ◽  
Author(s):  
Diane M. Hargrove ◽  
Nancy A. Nardone ◽  
Lorna M. Persson ◽  
Kim M. Andrews ◽  
Kandace L. Shepherd ◽  
...  
Keyword(s):  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 response to whey protein is less diminished by dipeptidyl peptidase-4 in comparison with responses to dextrin, a lipid and casein in rats

2020 ◽  
pp. 1-10 ◽  
Author(s):  
Yuki Shimizu ◽  
Hiroshi Hara ◽  
Tohru Hira
Keyword(s):  
Whey Protein ◽  
Dipeptidyl Peptidase ◽  
Dietary Proteins ◽  
Sprague Dawley ◽  
Dipeptidyl Peptidase 4 ◽  
Sprague Dawley Rats ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Although glucose is the best-known nutrient to stimulate glucagon-like peptide-1 (GLP-1) secretion, dietary peptides also potently stimulate GLP-1 secretion. Certain peptide fragments derived from dietary proteins possess dipeptidyl peptidase-4 (DPP-4) inhibitory activity in vitro. Hence, we hypothesised that dietary peptides protect GLP-1 from degradation through attenuating DPP-4 activity in vivo. Here, we compared GLP-1 responses with dietary proteins, a carbohydrate and a lipid (Intralipos) in rats having or not having plasma DPP-4 activity. Plasma GLP-1 concentrations clearly increased by oral administration of whey protein (2–4 g/kg), but not by that of dextrin (2–4 g/kg), in control rats (untreated Sprague–Dawley rats and F344/Jcl rats), having DPP-4 activity. In contrast, dextrin administration increased the plasma GLP-1 concentrations as the whey protein administration did, in rats having reduced or no DPP-4 activity (a DPP-4 inhibitor, sitagliptin-treated Sprague–Dawley rats or DPP-4-deficient F344/DuCrl/Crlj rats). DPP-4 inhibition by sitagliptin treatment also enhanced GLP-1 response to Intralipos, and casein, but the treatment did not further enhance GLP-1 response to whey protein. Intestinal GLP-1 content and gastric emptying rate were not associated with differences in GLP-1 responses to test nutrients. The luminal contents from rats administered whey protein decreased DPP-4 activity in vitro. These results suggest that GLP-1 released by dextrin, Intralipos and casein was immediately degraded by DPP-4, while GLP-1 released by whey protein was less degraded. Our study provides novel in vivo evidence supporting the hypothesis that dietary peptides not only stimulate GLP-1 secretion but also inhibit DPP-4 activity to potentiate GLP-1 response.

scholarly journals Evaluation of efficacy- versus affinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1

2021 ◽  
Author(s):  
Amaara Marzook ◽  
Shiqian Chen ◽  
Phil Pickford ◽  
Maria Lucey ◽  
Yifan Wang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
G Protein ◽  
Early Endosomes ◽  
Important Regulator ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
G Protein Coupled

AbstractThe glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment of type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestin versus G protein coupling show improved metabolic actions in vivo. However, two prototypical G protein-favouring GLP-1R agonists, P5 and exendin-F1, are reported to show divergent effects on insulin secretion. In this study we aimed to resolve this discrepancy by performing a side-by-side characterisation of these two ligands across a variety of in vitro and in vivo assays. Exendin-F1 showed reduced acute efficacy versus P5 for several readouts, including recruitment of mini-G proteins, G protein-coupled receptor kinases (GRKs) and β-arrestin-2. Maximal responses were also lower for both GLP-1R internalisation and the presence of active GLP-1R-mini-Gs complexes in early endosomes with exendin-F1 treatment. In contrast, prolonged insulin secretion in vitro and sustained anti-hyperglycaemic efficacy in mice were both greater with exendin-F1 than with P5. We conclude that the particularly low acute efficacy of exendin-F1 and associated reductions in GLP-1R downregulation appear to be more important than preservation of endosomal signalling to allow sustained insulin secretion responses. This has implications for the ongoing development of affinity- versus efficacy-driven biased GLP-1R agonists as treatments for metabolic disease.

scholarly journals Insulin Regulates Glucagon-Like Peptide-1 Secretion from the Enteroendocrine L Cell

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 580-591 ◽  
Author(s):  
Gareth E. Lim ◽  
Guan J. Huang ◽  
Nina Flora ◽  
Derek LeRoith ◽  
Christopher J. Rhodes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Oral Glucose ◽  
Phosphatidylinositol 3 Kinase ◽  
Insulin Resistant ◽  
L Cell ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Phosphatidylinositol 3

Insulin resistance and type 2 diabetes mellitus are associated with impaired postprandial secretion of glucagon-like peptide-1 (GLP-1), a potent insulinotropic hormone. The direct effects of insulin and insulin resistance on the L cell are unknown. We therefore hypothesized that the L cell is responsive to insulin and that insulin resistance impairs GLP-1 secretion. The effects of insulin and insulin resistance were examined in well-characterized L cell models: murine GLUTag, human NCI-H716, and fetal rat intestinal cells. MKR mice, a model of chronic hyperinsulinemia, were used to assess the function of the L cell in vivo. In all cells, insulin activated the phosphatidylinositol 3 kinase-Akt and MAPK kinase (MEK)-ERK1/2 pathways and stimulated GLP-1 secretion by up to 275 ± 58%. Insulin resistance was induced by 24 h pretreatment with 10−7m insulin, causing a marked reduction in activation of Akt and ERK1/2. Furthermore, both insulin-induced GLP-1 release and secretion in response to glucose-dependent insulinotropic peptide and phorbol-12-myristate-13-acetate were significantly attenuated. Whereas inhibition of phosphatidylinositol 3 kinase with LY294002 potentiated insulin-induced GLP-1 release, secretion was abrogated by inhibiting the MEK-ERK1/2 pathway with PD98059 or by overexpression of a kinase-dead MEK1-ERK2 fusion protein. Compared with controls, MKR mice were insulin resistant and displayed significantly higher fasting plasma insulin levels. Furthermore, they had significantly higher basal GLP-1 levels but displayed impaired GLP-1 secretion after an oral glucose challenge. These findings indicate that the intestinal L cell is responsive to insulin and that insulin resistance in vitro and in vivo is associated with impaired GLP-1 secretion. Insulin is a novel secretagogue of the incretin hormone, glucagon-like peptide-1 (GLP-1), and L cell insulin resistance impairs heterologous secretagogue-induced GLP-1 secretion in vitro and in vivo.

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