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 Puerarin Protects Pancreatic β-Cells in Obese Diabetic Mice via Activation of GLP-1R Signaling

2016 ◽  
Vol 30 (3) ◽  
pp. 361-371 ◽  
Author(s):  
Lei Yang ◽  
Dongdong Yao ◽  
Haiyuan Yang ◽  
Yingjie Wei ◽  
Yunru Peng ◽  
...  
Keyword(s):  
Protective Effect ◽  
Cell Survival ◽  
Body Weight Gain ◽  
Cell Mass ◽  
The Body ◽  
Diabetic Mice ◽  
Β Cell ◽  
Beneficial Effects ◽  
Glucagon Like Peptide 1 ◽  
And Function

Abstract Diabetes is characterized by a loss and dysfunction of the β-cell. Glucagon-like peptide 1 receptor (GLP-1R) signaling plays an important role in β-cell survival and function. It is meaningful to identify promising agents from natural products which might activate GLP-1R signaling. In this study, puerarin, a diet isoflavone, was evaluated its beneficial effects on β-cell survival and GLP-1R pathway. We showed that puerarin reduced the body weight gain, normalized blood glucose, and improved glucose tolerance in high-fat diet-induced and db/db diabetic mice. Most importantly, increased β-cell mass and β-cell proliferation but decreased β-cell apoptosis were observed in puerarin-treated diabetic mice as examined by immunostaining of mice pancreatic sections. The protective effect of puerarin on β-cell survival was confirmed in isolated mouse islets treated with high glucose. Further mechanism studies showed that the circulating level of GLP-1 in mice was unaffected by puerarin. However, puerarin enhanced GLP-1R signaling by up-regulating expressions of GLP-1R and pancreatic and duodenal homeobox 1, which subsequently led to protein kinase B (Akt) activation but forkhead box O1 inactivation, and promoted β-cell survival. The protective effect of puerarin was remarkably suppressed by Exendin(9–39), an antagonist of GLP-1R. Our study demonstrated puerarin improved glucose homeostasis in obese diabetic mice and identified a novel role of puerarin in protecting β-cell survival by mechanisms involving activation of GLP-1R signaling and downstream targets.

scholarly journals Assessment of β-Cell Mass and α- and β-Cell Survival and Function by Arginine Stimulation in Human Autologous Islet Recipients

Diabetes ◽  
2014 ◽  
Vol 64 (2) ◽  
pp. 565-572 ◽  
Author(s):  
R. Paul Robertson ◽  
Lindsey D. Bogachus ◽  
Elizabeth Oseid ◽  
Susan Parazzoli ◽  
Mary Elizabeth Patti ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Mass ◽  
Β Cell ◽  
And Function

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.

scholarly journals Puerarin protects pancreatic β-cell survival via PI3K/Akt signaling pathway

2014 ◽  
Vol 53 (1) ◽  
pp. 71-79 ◽  
Author(s):  
Zhipeng Li ◽  
Zhaoshui Shangguan ◽  
Yijie Liu ◽  
Jihua Wang ◽  
Xuejun Li ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Mass ◽  
Akt Signaling ◽  
Pancreatic Β Cell ◽  
Diabetic Mice ◽  
Akt Signaling Pathway ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion ◽  
And Function

Pancreatic β-cell loss because of apoptosis is the major cause of type 1 diabetes (T1D) and late stage T2D. Puerarin possesses anti-diabetic properties; whether it acts directly on pancreatic β-cell is not clear. This study was designed to investigate the effects of puerarin on pancreatic β-cell survival and function. Diabetes was induced in male C57BL/6 mice by a single peritoneal injection of streptozotocin (STZ). Pancreatic β-cell survival and function were assessed in diabetic mice by measuring β-cell apoptosis, β-cell mass, pancreatic insulin content, and glucose tolerance, and in cultured islets and clonial MIN6 β-cells by measuring β-cell viability and apoptosis and glucose-stimulated insulin secretion. We found that pre-treatment with puerarin decreased the incidence of STZ-induced diabetes. Puerarin increased pancreatic β-cell mass via β-cell apoptosis inhibition in diabetic mice, and increased serum insulin, whereas it decreased blood glucose levels and improved glucose tolerance. In cultured islets and MIN6 cells, puerarin protected β-cell from cobalt chloride (CoCl2)-induced apoptosis and restored the impaired capacity of glucose-stimulated insulin secretion. Puerarin protection of β-cell survival involved the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. In conclusion, puerarin protects pancreatic β-cell function and survival via direct effects on β-cells, and its protection of β-cell survival is mediated by the PI3K/Akt pathway. As a safe natural plant extraction, puerarin might serve as a preventive and/or therapeutic approach for diabetes.

Downregulation of Fas activity rescues early onset of diabetes in c-KitWv/+ mice

2013 ◽  
Vol 304 (6) ◽  
pp. E557-E565 ◽  
Author(s):  
Zhi-Chao Feng ◽  
Matthew Riopel ◽  
Jinming Li ◽  
Lisa Donnelly ◽  
Rennian Wang
Keyword(s):  
Cell Survival ◽  
Cell Apoptosis ◽  
Fas Ligand ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Apoptotic Pathway ◽  
Β Cell Function ◽  
And Function

c-Kit and its ligand stem cell factor (SCF) are important for β-cell survival and maturation; meanwhile, interactions between the Fas receptor (Fas) and Fas ligand are capable of triggering β-cell apoptosis. Disruption of c-Kit signaling leads to severe loss of β-cell mass and function with upregulation of Fas expression in c-Kit Wv/+ mouse islets, suggesting that there is a critical balance between c-Kit and Fas activation in β-cells. In the present study, we investigated the interrelationship between c-Kit and Fas activation that mediates β-cell survival and function. We generated double mutant, c-Kit Wv/+ ;Fas lpr/lpr ( Wv −/−), mice to study the physiological and functional role of Fas with respect to β-cell function in c-Kit Wv/+ mice. Isolated islets from these mice and the INS-1 cell line were used. We observed that islets in c-Kit Wv/+ mice showed a significant increase in β-cell apoptosis along with upregulated p53 and Fas expression. These results were verified in vitro in INS-1 cells treated with SCF or c-Kit siRNA combined with a p53 inhibitor and Fas siRNA. In vivo, Wv −/− mice displayed improved β-cell function, with significantly enhanced insulin secretion and increased β-cell mass and proliferation compared with Wv +/+ mice. This improvement was associated with downregulation of the Fas-mediated caspase-dependent apoptotic pathway and upregulation of the cFlip/NF-κB pathway. These findings demonstrate that a balance between the c-Kit and Fas signaling pathways is critical in the regulation of β-cell survival 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.

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 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.

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