scholarly journals Differences in signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide

2019 ◽  
Author(s):  
Philip Pickford ◽  
Maria Lucey ◽  
Zijian Fang ◽  
Stavroula Bitsi ◽  
Johannes Broichhagen ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Cell Types ◽  
Cellular Level ◽  
Control Blood Glucose ◽  
C Terminus ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Impact

AbstractBackground and purposeAmino acid substitutions at the N-termini of glucagon-like peptide-1 receptor agonist (GLP-1RA) peptides result in distinct patterns of intracellular signalling, sub-cellular trafficking and efficacy in vivo. Here we aimed to determine whether sequence differences at the ligand C-termini of clinically approved GLP-1RAs exendin-4 and lixisenatide lead to similar phenomena. We also sought to establish the impact of the C-terminus on signal bias resulting from modifications elsewhere in the molecule.Experimental approachExendin-4, lixisenatide, and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types. Fluorescent ligands and new time-resolved FRET approaches were developed to study agonist behaviours at the cellular and sub-cellular level. Anti-hyperglycaemic and anorectic effects of each parent ligand, and their biased derivatives, were assessed in mice.Key resultsLixisenatide and exendin-4 showed equal binding affinity, but lixisenatide was 5-fold less potent for cAMP signalling. Both peptides were rapidly endocytosed, but the GLP-1R recycled more slowly to the plasma membrane after lixisenatide treatment. These combined deficits resulted in reduced maximal sustained insulin secretion and reduced anti-hyperglycaemic and anorectic effects in mice. N-terminal substitutions to both ligands had favourable effects on their pharmacology, resulting in improved insulin release and lowering of blood glucose.Conclusion and implicationsChanges to the C-terminus of exendin-4 affect signalling potency and GLP-1R trafficking via mechanisms unrelated to GLP-1R occupancy. These differences were associated with changes in their ability to control blood glucose and therefore may be therapeutically relevant.

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.

scholarly journals Tropism Modification of Adenovirus Vectors by Peptide Ligand Insertion into Various Positions of the Adenovirus Serotype 41 Short-Fiber Knob Domain

2006 ◽  
Vol 81 (6) ◽  
pp. 2688-2699 ◽  
Author(s):  
Andrea Hesse ◽  
Daniela Kosmides ◽  
Roland E. Kontermann ◽  
Dirk M. Nettelbeck
Keyword(s):  
Gene Transfer ◽  
Cell Types ◽  
Short Fiber ◽  
Peptide Ligand ◽  
Cell Binding ◽  
Adenovirus Serotype ◽  
C Terminus ◽  
Genetic Targeting

ABSTRACT Recombinant adenoviruses have emerged as promising agents in therapeutic gene transfer, genetic vaccination, and viral oncolysis. Therapeutic applications of adenoviruses, however, would benefit substantially from targeted virus cell entry, for example, into cancer or immune cells, as opposed to the broad tropism that adenoviruses naturally possess. Such tropism modification of adenoviruses requires the deletion of their natural cell binding properties and the incorporation of cell binding ligands. The short fibers of subgroup F adenoviruses have recently been suggested as a tool for genetic adenovirus detargeting based on the reduced infectivity of corresponding adenovectors with chimeric fibers in vitro and in vivo. The goal of our study was to determine functional insertion sites for peptide ligands in the adenovirus serotype 41 (Ad41) short fiber knob. With a model peptide, CDCRGDCFC, we could demonstrate that ligand incorporation into three of five analyzed loops of the knob, namely, EG, HI, and IJ, is feasible without a loss of fiber trimerization. The resulting adenovectors showed enhanced infectivity for various cell types, which was superior to that of viruses with the same peptide fused to the fiber C terminus. Strategies to further augment gene transfer efficacy by extension of the fiber shaft, insertion of tandem copies of the ligand peptide, or extension of the ligand-flanking linkers failed, indicating that precise ligand positioning is pivotal. Our study establishes that internal ligand incorporation into a short-shafted adenovirus fiber is feasible and suggests the Ad41 short fiber with ligand insertion into the top (IJ loop) or side (EG and HI loops) of the knob domain as a novel platform for genetic targeting of therapeutic adenoviruses.

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

Incretin release from gut is acutely enhanced by sugar but not by sweeteners in vivo

2009 ◽  
Vol 296 (3) ◽  
pp. E473-E479 ◽  
Author(s):  
Yukihiro Fujita ◽  
Rhonda D. Wideman ◽  
Madeleine Speck ◽  
Ali Asadi ◽  
David S. King ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Sweet Taste ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Dependent Manner ◽  
Glucose Levels ◽  
Zucker Diabetic Fatty Rats ◽  
Glucagon Like Peptide 1

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are released during meals from endocrine cells located in the gut mucosa and stimulate insulin secretion from pancreatic β-cells in a glucose-dependent manner. Although the gut epithelium senses luminal sugars, the mechanism of sugar sensing and its downstream events coupled to the release of the incretin hormones are not clearly elucidated. Recently, it was reported that sucralose, a sweetener that activates the sweet receptors of taste buds, triggers incretin release from a murine enteroendocrine cell line in vitro. We confirmed that immunoreactivity of α-gustducin, a key G-coupled protein involved in taste sensing, is sometimes colocalized with GIP in rat duodenum. We investigated whether secretion of incretins in response to carbohydrates is mediated via taste receptors by feeding rats the sweet-tasting compounds saccharin, acesulfame potassium, d-tryptophan, sucralose, or stevia. Oral gavage of these sweeteners did not reduce the blood glucose excursion to a subsequent intraperitoneal glucose tolerance test. Neither oral sucralose nor oral stevia reduced blood glucose levels in Zucker diabetic fatty rats. Finally, whereas oral glucose increased plasma GIP levels ∼4-fold and GLP-1 levels ∼2.5-fold postadministration, none of the sweeteners tested significantly increased levels of these incretins. Collectively, our findings do not support the concept that release of incretins from enteroendocrine cells is triggered by carbohydrates via a pathway identical to the sensation of “sweet taste” in the tongue.

scholarly journals The Acute Impact of Ingestion of Sourdough and Whole-Grain Breads on Blood Glucose, Insulin, and Incretins in Overweight and Obese Men

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Anita Mofidi ◽  
Zachary M. Ferraro ◽  
Katherine A. Stewart ◽  
Hilary M. F. Tulk ◽  
Lindsay E. Robinson ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Glucose Homeostasis ◽  
Area Under The Curve ◽  
Glycemic Response ◽  
Whole Grain ◽  
Glucose Response ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Impact ◽  
Randomized Crossover Study

Consumption of whole-grain and sourdough breads is associated with improved glucose homeostasis. We examined the impact of commercial breads on biomarkers of glucose homeostasis in subjects at risk for glucose intolerance. In a randomized, crossover study, overweight or obese males ingested 11-grain, sprouted-grain, 12-grain, sourdough, or white bread on different occasions, matched for available carbohydrate (50 g) in part 1 (n=12) and bread mass (107 g) in part 2 (n=11), and blood glucose, insulin and glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were determined for 3 h. In part 1, glucose response for sprouted-grain was lower than 11-grain, sourdough, and white breads. Insulin area under the curve (AUC) for sourdough and white was lower than 11-grain and sprouted-grain breads. GLP-1 response to sourdough was lower than all breads. In part 2, glucose and insulin AUC for sourdough was greater than 11-grain, sprouted-grain, and 12-grain breads. Sprouted-grain bread improved glycemia by lowering glucose response and increasing GLP-1 response. In overweight and obese men, the glycemic response to sprouted grain bread was reduced in both parts 1 and 2 while the other whole-grain test breads did not improve metabolic responses in the acute postprandial state.

scholarly journals A 2020 view of tension-based cortical morphogenesis

2020 ◽  
Vol 117 (52) ◽  
pp. 32868-32879
Author(s):  
David C. Van Essen
Keyword(s):  
Cell Types ◽  
Tissue Level ◽  
Cellular Level ◽  
General Hypothesis ◽  
Cortical Gray Matter ◽  
Level I ◽  
Key Aspects ◽  
Des Model

Mechanical tension along the length of axons, dendrites, and glial processes has been proposed as a major contributor to morphogenesis throughout the nervous system [D. C. Van Essen, Nature 385, 313–318 (1997)]. Tension-based morphogenesis (TBM) is a conceptually simple and general hypothesis based on physical forces that help shape all living things. Moreover, if each axon and dendrite strive to shorten while preserving connectivity, aggregate wiring length would remain low. TBM can explain key aspects of how the cerebral and cerebellar cortices remain thin, expand in surface area, and acquire their distinctive folds. This article reviews progress since 1997 relevant to TBM and other candidate morphogenetic mechanisms. At a cellular level, studies of diverse cell types in vitro and in vivo demonstrate that tension plays a major role in many developmental events. At a tissue level, I propose a differential expansion sandwich plus (DES+) revision to the original TBM model for cerebral cortical expansion and folding. It invokes tangential tension and “sulcal zipping” forces along the outer cortical margin as well as tension in the white matter core, together competing against radially biased tension in the cortical gray matter. Evidence for and against the DES+ model is discussed, and experiments are proposed to address key tenets of the DES+ model. For cerebellar cortex, a cerebellar multilayer sandwich (CMS) model is proposed that can account for many distinctive features, including its unique, accordion-like folding in the adult, and experiments are proposed to address its specific tenets.

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