Endothelin-converting enzyme-1 regulates glucagon-like peptide-1 receptor signalling and resensitisation

2019 ◽  
Vol 476 (3) ◽  
pp. 513-533 ◽  
Author(s):  
Jing Lu ◽  
Gary B. Willars
Keyword(s):  
Cell Mass ◽  
Hek293 Cells ◽  
Converting Enzyme ◽  
Receptor Ligands ◽  
Β Cell ◽  
Extracellular Signal ◽  
Endosomal Acidification ◽  
Endothelin Converting Enzyme ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Following nutrient ingestion, glucagon-like peptide 1 (GLP-1) is secreted from intestinal L-cells and mediates anti-diabetic effects, most notably stimulating glucose-dependent insulin release from pancreatic β-cells but also inhibiting glucagon release, promoting satiety and weight reduction and potentially enhancing or preserving β-cell mass. These effects are mediated by the GLP-1 receptor (GLP-1R), which is a therapeutic target in type 2 diabetes. Although agonism at the GLP-1R has been well studied, desensitisation and resensitisation are perhaps less well explored. An understanding of these events is important, particularly in the design and use of novel receptor ligands. Here, using either HEK293 cells expressing the recombinant human GLP-1R or the pancreatic β-cell line, INS-1E with endogenous expressesion of the GLP-1R, we demonstrate GLP-1R desensitisation and subsequent resensitisation following removal of extracellular GLP-1 7-36 amide. Resensitisation is dependent on receptor internalisation, endosomal acidification and receptor recycling. Resensitisation is also regulated by endothelin-converting enzyme-1 (ECE-1) activity, most likely through proteolysis of GLP-1 in endosomes and the facilitation of GLP-1R dephosphorylation and recycling. Inhibition of ECE-1 activity also increases GLP-1-induced activation of extracellular signal-regulated kinase and generation of cAMP, suggesting processes dependent upon the lifetime of the internalised ligand–receptor complex.

scholarly journals Pharmacological Effects of EGLP-1, a Novel Analog of Glucagon-Like Peptide-1, on Carbohydrate and Lipid Metabolism

2018 ◽  
Vol 48 (3) ◽  
pp. 1112-1122 ◽  
Author(s):  
Huashan Gao ◽  
Ziwei Song ◽  
Qian Zhao ◽  
You Wu ◽  
Shanshan Tang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Lipid Metabolism ◽  
Cell Function ◽  
Hormone Sensitive Lipase ◽  
Hek293 Cells ◽  
Cell Area ◽  
Β Cell ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Background/Aims: Abnormal glucose metabolism and lipid metabolism are two key issues in Type 1 diabetes mellitus (T1DM). Insulin can control carbohydrate metabolism adequately, but cannot regulate lipid metabolism well in patients with T1DM. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have cured type 2 diabetes mellitus in clinical trials and have improved T1DM glycemic control in preclinical studies. However, previous studies have not reported whether GLP-1 can lower the serum concentration of non-esterified fatty acids (NEFAs). In this study, we examine whether GLP-1 can affect serum NEFA levels. Methods: The bioactivity of EGLP-1 (a novel GLP-1 analog) in vitro was analyzed in CG-HEK293 cells and with high-performance liquid chromatography. An intraperitoneal glucose tolerance test (IPGTT) was used to analyze the acute and sustained hypoglycemic effects of EGLP-1 in normal C57BL/6J mice. Streptozotocin-induced hyperglycemic mice were used to study the effects of EGLP-1 on blood glucose and NEFAs as well as its mechanism. Results: EGLP-1 activated GLP-1R and resisted dipeptidyl peptidase-IV digestion in vitro. Additionally, EGLP-1 had an insulinotropic action in vivo that lasted for approximately 6 h. In Streptozotocin-induced hyperglycemic mice, EGLP-1 improved hyperglycemia, inhibited food intake, and increased β-cell area. Serum physiological indexes showed that insulin and C-peptide levels were increased, while NEFA and triacylglycerol concentrations were decreased. Western blot analysis revealed that EGLP-1 significantly reduced phosphorylated-hormone sensitive lipase (pHSL) levels in white adipose tissue. Conclusions: EGLP-1 can improve hyperglycemia by increasing islet β-cell area and improving β-cell function, possibly due to reduced NEFA content in serum by lowering pHSL levels.

scholarly journals Elevated basal and post-feed glucagon-like peptide 1 (GLP-1) concentrations in the neonatal period

2009 ◽  
Vol 160 (1) ◽  
pp. 53-58 ◽  
Author(s):  
Raja Padidela ◽  
Michael Patterson ◽  
Nawfal Sharief ◽  
Mohammed Ghatei ◽  
Khalid Hussain
Keyword(s):  
Neonatal Period ◽  
Plasma Concentrations ◽  
Cell Mass ◽  
Newborn Infants ◽  
Β Cell ◽  
Reverse Phase ◽  
Chromatography Analysis ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Design And Methods

BackgroundGlucagon-like peptide 1 (GLP-1) is an incretin hormone that stimulates glucose-induced insulin secretion, increases β-cell proliferation, neogenesis and β-cell mass. In adults, plasma concentrations of amidated GLP-1 are typically within the 5–10 pmol/l range in the fasting state and increases to ∼50 pmol/l after ingestion of a mixed meal.Research design and methodsWe measured plasma glucose, insulin and amidated forms of GLP-1 prefeed and then at 20 and 60 min post-feed following ingestion of a 60–70 ml of standard milk feed in preterm (n=10, 34–37 weeks) and term newborn infants (n=12, 37–42 weeks). Reverse-phase fast protein liquid chromatography was used to characterise the molecular nature of the circulating GLP-1.ResultsMean birth weight was 3.18 kg and mean age at sampling for GLP-1 was 7.7 days. The mean basal GLP-1 concentration was 79.1 pmol/l, which increased to 156.6 pmol/l (±70.9, P<0.001) and 121.5 pmol/l (±59.2) at 20 and 60 min respectively. Reverse-phase chromatography analysis suggested that the majority of GLP-1 immunoreactivity (>75%) represented GLP-1 (7–36) amide and (9–36) amide.ConclusionsBasal and post-feed amidated GLP-1 concentrations in neonates are grossly raised with the major fractions of circulating GLP-1 being (7–36) amide and (9–36) amide. Elevated GLP-1 concentrations in the newborn period may have a role in regulating maturation of enteroendocrine system and also of increasing pancreatic β-cell mass and regeneration. The high levels of GLP-1 may be due to immaturity of the dipeptidyl peptidase IV and or lower glomerular filtration rate in the neonatal period. Further studies are required to understand the role of GLP-1 in the neonatal period.

Identification of transcriptional targets during pancreatic growth after partial pancreatectomy and exendin-4 treatment

2006 ◽  
Vol 24 (2) ◽  
pp. 133-143 ◽  
Author(s):  
Diva D. De León ◽  
Cyrus Farzad ◽  
Michael F. Crutchlow ◽  
John Brestelli ◽  
John Tobias ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Mass ◽  
Β Cell ◽  
Cell Specification ◽  
Partial Pancreatectomy ◽  
Pancreatic Growth ◽  
Germ Cell Specification ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
And Function

After partial pancreatectomy (Ppx), substantial regeneration of the endocrine and exocrine pancreatic compartments has been shown in adult rodents. Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor agonist that augments endocrine β-cell mass by stimulating neogenesis, proliferation, and cell survival. After Ppx, treatment with Ex-4 ameliorates hyperglycemia by stimulating β-cell mass recovery. We utilized a cDNA microarray approach to identify genes differentially regulated during pancreatic regeneration after Ppx and/or Ex-4 administration. The pancreatic remnant after Ppx showed a large number of differentially regulated genes. In contrast, Ex-4 treatment resulted in a smaller number of differentially regulated genes. Of note, a common subset of genes regulated by Ex-4 and after Ppx was identified, including three members of the mitogenic Reg gene family, Reg2, -3γ, and -3β, as well as fragilis, a gene that maintains pluripotency during germ cell specification, and Serpin b1a, a member of an intracellular protease inhibitor family involved in cell survival. These observations were confirmed by real-time PCR. We determined that Reg3β protein is also induced in the acinar pancreas after Ppx, suggesting a novel role for this factor in pancreatic growth or response to injury. Finally, comparison of transcription factor-binding sites present in the proximal promoters of these genes identified potential common transcription factors that may regulate these genes. Chromatin immunoprecipitation analyses confirmed Reg3γ as a novel transcriptional target of Foxa2 (HNF3β). Our data suggest molecular pathways that may regulate pancreatic growth and offer a unique set of candidate genes to target in the development of therapies aimed at improving pancreatic growth and function.

scholarly journals Glucagon-Like Peptide-1 Induces Cell Proliferation and Pancreatic-Duodenum Homeobox-1 Expression and Increases Endocrine Cell Mass in the Pancreas of Old, Glucose-Intolerant Rats

Endocrinology ◽  
2000 ◽  
Vol 141 (12) ◽  
pp. 4600-4605 ◽  
Author(s):  
Riccardo Perfetti ◽  
Jie Zhou ◽  
Máire E. Doyle ◽  
Josephine M. Egan
Keyword(s):  
Cell Proliferation ◽  
Messenger Rna ◽  
Cell Mass ◽  
Wistar Rat ◽  
Normal Glucose Tolerance ◽  
Insulin Content ◽  
Β Cell ◽  
Pancreatic Cell ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Glucose homeostasis in mammals is maintained by insulin secretion from the β-cells of the islets of Langerhans. Type 2 diabetes results either from primary β-cell failure alone and/or a failure to secrete enough insulin to overcome insulin resistance. Here, we show that continuous infusion of glucagon-like peptide-1 (7–36) (GLP-1; an insulinotropic agent), to young and old animals, had effects on the β-cell of the pancreas other than simply on the insulin secretory apparatus. Our previous studies on a rodent model of glucose intolerance, the aging Wistar rat, show that a plateau in islet size, insulin content, and β-cell mass is reached at 13 months, despite a continuing increase in body weight. Continuous sc infusion of GLP-1 (1.5 pm/kg·min), over 5 days, resulted in normal glucose tolerance. Our current results in both young and old rats demonstrate that treatment caused an up-regulation of pancreatic-duodenum homeobox-1 (PDX-1) expression in islets and total pancreas, induced pancreatic cell proliferation, and β-cell neogenesis. The effects on levels of PDX-1 messenger RNA were abrogated by simultaneous infusion of Exendin (9–39), a specific antagonist of GLP-1. PDX-1 protein levels increased 4-fold in whole pancreata and 6-fold in islets in response to treatment.β -cell mass increased to 7.2 ± 0.58 from 4.88 ± 0.38 mg, treated vs. control, respectively, P&lt; 0.02. Total pancreatic insulin content also increased from 0.55± 0.02 to 1.32 ± 0.11 μg/mg total pancreatic protein. Therefore, GLP-1 would seem to be a unique therapy that can stimulate pancreatic cell proliferation and β-cell differentiation in the pancreas of rodents.

scholarly journals Effect of Glucagon-Like Peptide-1 on β- and α-Cell Function in Isolated Islet and Whole Pancreas Transplant Recipients

2009 ◽  
Vol 94 (1) ◽  
pp. 181-189 ◽  
Author(s):  
Michael R. Rickels ◽  
Rebecca Mueller ◽  
James F. Markmann ◽  
Ali Naji
Keyword(s):  
Insulin Secretion ◽  
Cell Mass ◽  
Pancreas Transplant ◽  
Second Phase ◽  
Transplant Recipients ◽  
Β Cell ◽  
Hyperglycemic Clamp ◽  
Glucagon Suppression ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Context: Glucose-dependent insulin secretion is often impaired after islet transplantation where reduced β-cell secretory capacity indicates a low functional β-cell mass. Objective: We sought to determine whether glucagon-like peptide-1 (GLP-1) enhanced glucose-dependent insulin secretion and glucagon suppression in islet recipients, and whether GLP-1 effects were dependent on functional β-cell mass by simultaneously studying recipients of whole pancreas transplants. Setting: The study was performed in a clinical and translational research center. Participants: Five intraportal islet and six portally drained pancreas transplant recipients participated in the study. Intervention: Subjects underwent glucose-potentiated arginine testing with GLP-1 (1.5 pmol · kg−1 · min−1) or placebo infused on alternate randomized occasions, with 5 g arginine injected under basal and hyperglycemic clamp conditions. Results: Basal glucose was lower with increases in insulin and decreases in glucagon during GLP-1 vs. placebo in both groups. During the hyperglycemic clamp, a significantly greater glucose infusion rate was required with GLP-1 vs. placebo in both groups (P &lt; 0.05), an effect more pronounced in the pancreas vs. islet group (P &lt; 0.01). The increased glucose infusion rate was associated with significant increases in second-phase insulin secretion in both groups (P &lt; 0.05) that also tended to be greater in the pancreas vs. islet group (P = 0.08), whereas glucagon was equivalently suppressed by the hyperglycemic clamp during GLP-1 and placebo infusions in both groups. The GLP-1-induced increase in second-phase insulin correlated with the β-cell secretory capacity (P &lt; 0.001). The proinsulin secretory ratio (PISR) during glucose-potentiated arginine was significantly greater with GLP-1 vs. placebo infusion in both groups (P &lt; 0.05). Conclusions: GLP-1 induced enhancement of glucose-dependent insulin secretion, but not glucagon suppression, in islet and pancreas transplant recipients, an effect dependent on the functional β-cell mass that may be associated with depletion of mature β-cell secretory granules.

scholarly journals Role of Phosphatidylinositol 3-Kinaseγ in the β-Cell: Interactions with Glucagon-Like Peptide-1

Endocrinology ◽  
2006 ◽  
Vol 147 (7) ◽  
pp. 3318-3325 ◽  
Author(s):  
Li-Xin Li ◽  
Patrick E. MacDonald ◽  
Diane S. Ahn ◽  
Gavin Y. Oudit ◽  
Peter H. Backx ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion

Glucagon-like peptide-1 (GLP-1) increases β-cell function and growth through protein kinase A- and phosphatidylinositol-3-kinase (PI3-K)/protein kinase B, respectively. GLP-1 acts via a G protein-coupled receptor, and PI3-Kγ is known to be activated by Gβγ. Therefore, the role of PI3-Kγ in the chronic effects of GLP-1 on the β-cell was investigated using PI3-Kγ knockout (KO) mice treated with the GLP-1 receptor agonist, exendin-4 (Ex4; 1 nmol/kg sc every 24 h for 14 d). In vivo, glucose and insulin responses were similar in PBS- and Ex4-treated KO and wild-type (WT) mice. However, glucose-stimulated insulin secretion was markedly impaired in islets from PBS-KO mice (P &lt; 0.05), and this was partially normalized by chronic Ex4 treatment (P &lt; 0.05). In contrast, insulin content was increased in PBS-KO islets, and this was paradoxically decreased by Ex4 treatment, compared with the stimulatory effect of Ex4 on WT islets (P &lt; 0.05–0.01). Transfection of INS-1E β-cells with small interfering RNA for PI3-Kγ similarly decreased glucose-stimulated insulin secretion (P &lt; 0.01) and increased insulin content. Basal values for β-cell mass, islet number and proliferation, glucose transporter 2, glucokinase, and insulin receptor substrate-2 were increased in PBS-KO mice (P &lt; 0.05–0.001) and, although they were increased by Ex4 treatment of WT animals (P &lt; 0.05), they were decreased in Ex4-KO mice (P &lt; 0.05–0.01). These findings indicate that PI3-Kγ deficiency impairs insulin secretion, resulting in compensatory islet growth to maintain normoglycemia. Chronic Ex4 treatment normalizes the secretory defect, thereby relieving the pressure for expansion of β-cell mass. These studies reveal a new role for PI3-Kγ as a positive regulator of insulin secretion, and reinforce the importance of GLP-1 for the maintenance of normal β-cell function.

scholarly journals The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror

2021 ◽  
Vol 22 (17) ◽  
pp. 9504
Author(s):  
María Sofía Martínez ◽  
Alexander Manzano ◽  
Luis Carlos Olivar ◽  
Manuel Nava ◽  
Juan Salazar ◽  
...  
Keyword(s):  
Cell Function ◽  
Cell Mass ◽  
Glucagon Secretion ◽  
Endocrine Regulation ◽  
Β Cell ◽  
Cell Hyperplasia ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Glucagon Like Peptide 1 ◽  
Chronic Hyperglycaemia

Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon’s secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans’ islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (β) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to β cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.

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