scholarly journals Growth-Promoting Effect of Rh(D) Antibody on Human Pancreatic Islet Cells

2008 ◽  
Vol 93 (9) ◽  
pp. 3560-3567
Author(s):  
John M. Feller ◽  
Ann M. Simpson ◽  
Margaret Nelson ◽  
M. Anne Swan ◽  
Philip J. O'Connell ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Islet Cell ◽  
Islet Cells ◽  
Flow Cytometric Analysis ◽  
Antigen Expression ◽  
Immunofluorescent Staining ◽  
Promoting Effect ◽  
Cell Hyperplasia ◽  
Proliferative Effect

Context/Objective: Hyperinsulinism with islet cell hyperplasia is a frequent complication, of unknown cause, in hemolytic disease of the newborn, occurring in Rh(D)-positive infants of Rh-isoimmunized Rh(D)-negative mothers, but not in infants with other hemolytic disorders. We investigated the possibility that trans-placentally acquired anti-D Ig is the cause of both conditions. Design: Monolayer cultures of human islet cells were exposed to sera from Rh-isoimmunized mothers and newborns, where jaundice, hyperinsulinism, and hypoglycemia in the infant had ensued. Parallel cultures with anti-D, specific anti-D monoclonal antibodies, normal human Ig (15 μg/ml), and serum controls were also undertaken. Islet cell proliferation was determined by [3H]thymidine incorporation. Insulin storage and chronic and acute insulin secretion to glucose were analyzed by RIA. Rh(D) surface antigen expression was determined on islet cells by flow cytometric analysis. Results: Islet cell proliferation and insulin secretion were significantly greater in coculture with test sera (P < 0.01; n = 8) and with anti-D (P < 0.001; n = 8), compared with either controls or Ig. After 8 d of growth, the static incubation experiment showed a 3.5-fold response to glucose stimulus in all sera. Rh(D) antigen expression was detected on the islet cell surface by flow cytometry, and islet cell morphology was normal. Colocalization of the proliferation marker Ki67 with insulin by immunofluorescent staining further indicated that Rh(D) antibody promoted islet growth. Conclusions: The anti-Rh(D) islet cell proliferative effect generates neonatal hyperinsulinism in Rh isoimmunization. Anti-Rh(D) may have application for islet cell proliferation in diabetes mellitus treatment for Rh(D)-positive subjects. Further analysis is required.

scholarly journals Identification of a small molecule that stimulates human β-cell proliferation and insulin secretion, and protects against cytotoxic stress in rat insulinoma cells

2019 ◽  
Author(s):  
Hans E. Hohmeier ◽  
Lu Zhang ◽  
Brandon Taylor ◽  
Samuel Stephens ◽  
Peter McNamara ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Small Molecule ◽  
Islet Cell ◽  
Human Islet ◽  
Luciferase Reporter ◽  
Β Cell ◽  
Cytotoxic Stress ◽  
Insulinoma Cells ◽  
Rat Insulinoma

AbstractA key event in the development of both major forms of diabetes is the loss of functional pancreatic islet β-cell mass. Strategies aimed at enhancing β-cell regeneration have long been pursued, but methods for reliably inducing human β-cell proliferation with full retention of key functions such as glucose-stimulated insulin secretion (GSIS) are still very limited. We have previously reported that overexpression of the homeobox transcription factor Nkx6.1 stimulates β-cell proliferation, while also enhancing GSIS and providing protection against β-cell cytotoxicity through induction of the VGF prohormone. We developed an Nkx6.1 pathway screen by stably transfecting 832/13 rat insulinoma cells with a VGF promoter-luciferase reporter construct, using the resultant cell line to screen a 630,000 compound chemical library. We isolated three compounds with consistent effects to stimulate human islet cell proliferation. Further studies of the most potent of these compounds, GNF-9228, revealed that it selectively activates human β-cell relative to α-cell proliferation and has no effect on δ-cell replication. In addition, pre-treatment, but not short term exposure of human islets to GNF-9228 enhances GSIS. GNF-9228 also protects 832/13 insulinoma cells against ER stress- and inflammatory cytokine-induced cytotoxicity. In contrast to recently emergent Dyrk1a inhibitors that stimulate human islet cell proliferation, GNF-9228 does not activate NFAT translocation. These studies have led to identification of a small molecule with pleiotropic positive effects on islet biology, including stimulation of human β-cell proliferation and insulin secretion, and protection against multiple agents of cytotoxic stress.

scholarly journals Maternal Low Protein Isocaloric Diet Suppresses Pancreatic β-Cell Proliferation in Mouse Offspring via miR-15b

Endocrinology ◽  
2016 ◽  
Vol 157 (12) ◽  
pp. 4782-4793 ◽  
Author(s):  
Yutong Su ◽  
Xiuli Jiang ◽  
Yanli Li ◽  
Feng Li ◽  
Yulong Cheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Islet Cells ◽  
Control Diet ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Isocaloric Diet ◽  
Low Protein ◽  
And Control

The mechanism underlying the increased susceptibility of type 2 diabetes in offspring of maternal malnutrition is poorly determined. Here we tested the hypothesis that functional microRNAs (miRNAs) mediated the maternal low-protein (LP) isocaloric diet induced pancreatic β-cell impairment. We performed miRNA profiling in the islets from offspring of LP and control diet mothers to explore the potential functional miRNAs responsible for β-cell dysfunction. We found that LP offspring exhibited impaired glucose tolerance due to decreased β-cell mass and insulin secretion. Reduction in the β-cell proliferation rate and cell size contributed to the decreased β-cell mass. MiR-15b was up-regulated in the islets of LP offspring. The up-regulated miR-15b inhibited pancreatic β-cell proliferation via targeting cyclin D1 and cyclin D2. Inhibition of miR-15b in LP islet cells restored β-cell proliferation and insulin secretion. Our findings demonstrate that miR-15b is critical for the regulation of pancreatic β-cells in offspring of maternal protein restriction, which may provide a further insight for β-cell exhaustion originated from intrauterine growth restriction.

scholarly journals Betacellulin-Induced α-Cell Proliferation Is Mediated by ErbB3 and ErbB4, and May Contribute to β-Cell Regeneration

2021 ◽  
Vol 8 ◽  
Author(s):  
Young-Sun Lee ◽  
Gyun Jee Song ◽  
Hee-Sook Jun
Keyword(s):  
Cell Proliferation ◽  
Recombinant Adenovirus ◽  
Islet Cells ◽  
Erbb Receptors ◽  
Cell Regeneration ◽  
Β Cells ◽  
Β Cell ◽  
Direct Role ◽  
Proliferative Effect ◽  
Epidermal Growth

Betacellulin (BTC), an epidermal growth factor family, is known to promote β-cell regeneration. Recently, pancreatic α-cells have been highlighted as a source of new β-cells. We investigated the effect of BTC on α-cells. Insulin+glucagon+ double stained bihormonal cell levels and pancreatic and duodenal homeobox-1 expression were increased in mice treated with recombinant adenovirus-expressing BTC (rAd-BTC) and β-cell-ablated islet cells treated with BTC. In the islets of rAd-BTC-treated mice, both BrdU+glucagon+ and BrdU+insulin+ cell levels were significantly increased, with BrdU+glucagon+ cells showing the greater increase. Treatment of αTC1-9 cells with BTC significantly increased proliferation and cyclin D2 expression. BTC induced phosphorylation of ErbB receptors in αTC1-9 cells. The proliferative effect of BTC was mediated by ErbB-3 or ErbB-4 receptor kinase. BTC increased phosphorylation of ERK1/2, AKT, and mTOR and PC1/3 expression and GLP-1 production in α-cells, but BTC-induced proliferation was not changed by the GLP-1 receptor antagonist, exendin-9. We suggest that BTC has a direct role in α-cell proliferation via interaction with ErbB-3 and ErbB-4 receptors, and these increased α-cells might be a source of new β-cells.

scholarly journals Exploration of NPTX2 in Islets of Langerhans

2020 ◽  
Vol 21 (2) ◽  
Author(s):  
Lindsay Elisha Wald
Keyword(s):  
Type 1 Diabetes ◽  
Insulin Secretion ◽  
Islet Cells ◽  
The Body ◽  
Immunofluorescent Staining ◽  
Β Cells ◽  
Healthy Human ◽  
Neuronal Pentraxin ◽  
The Brain

NPTX2 (neuronal pentraxin-2) is a synaptic protein found abundantly in only two locations in a healthy human body: the brain and the pancreas, specifically islet of Langerhans cells. NPTX2’s role in the brain has been a focus of study in the pathology of Parkinson’s disease, as it is upregulated in PD patients. Its primary functions in the brain are to establish excitatory synapses and to recruit alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors to said synapses. These AMPA receptors signal for the neurotransmitter, glutamate, that regulates insulin secretion. This is of pathological significance to the onset of type 1 diabetes. Type 1 diabetes is characterized by the depletion of islet β-cells in the pancreas, which are responsible for insulin secretion. Without a supply of insulin, fatal consequences will ensue. NPTX2’s function in the pancreas is unstudied and extremely relevant to unraveling the complex processes that the body undergoes with the onset of this autoimmune disease. In recent mRNA studies, NPTX2 mRNA was significantly downregulated in type 1 diabetes. To understand the underlying cause of this downregulation and its potential role in the destruction of islet β-cells, it is first necessary to localize NPTX2 in the islet cells of type 1 diabetic, auto-antibody positive, and control donors. Immunofluorescent staining indicates that NPTX2’s co-expression in 

scholarly journals Pancreatic islet cell autophagy during aging in rats

2013 ◽  
Vol 36 (2) ◽  
pp. 72 ◽  
Author(s):  
Shuang Wang ◽  
Qian-qian Sun ◽  
Bing Xiang ◽  
Xiu-Jun Li
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Pancreatic Islet ◽  
Islet Cell ◽  
Islet Cells ◽  
Cell Structure ◽  
Fasting Blood Glucose ◽  
Pancreatic Islet Cell ◽  
Pancreatic Cell ◽  
Old Rats

Purpose: Autophagy induces pancreatic β cell death. The purpose of the present study was to examine the hypothesis that the extent of pancreatic autophagy is associated with aging and age-related diabetes. Methods: Pancreatic tissue and blood samples were collected from Sprague Dawley rats receiving a normal diet at 2 (the young group), 6 (the adult group), 12 (the middle-age group) and 20-24 (the aged group) months of age. Body weight and fasting blood glucose, serum lipid levels and serum insulin levels were determined. Pancreatic cell structure and autophagy were determined using transmission electron microscopy of rats at 6, 12 and 24 months of age. Lamp2 and LC3b protein expression levels were determined by both immunohistochemistry and Western blot analyses, and islet cell apoptosis was assessed using the TUNEL assay. Results: Fasting blood glucose, triglyceride and FFA levels increased significantly with age (p < 0.05). Compared with levels seen in two-month-old rats, insulin secretion of islet cells in vitro was significantly reduced at 6, 12, and 20 months of age (p < 0.05). Autophagosomes were only observed in islet cells of 24 month-old rats. Increased expression of the autophagic markers, Lamp2 and LC3b, was observed with age. A significant increase in apoptotic index was observed between young rats (two-months-old) and older rats (six-, 12- and 24-months-old), but no differences were observed between rats six, 12 and 24 months of age. Conclusion: Appearance of autophagosomes and increased Lamp2 and LC3b expression in pancreatic islet cells coincided with a significant decrease in insulin secretion and elevation of fasting blood glucose in aged rats.

scholarly journals Effects of lactate on pancreatic islets. Lactate efflux as a possible determinant of islet-cell depolarization by glucose

1989 ◽  
Vol 259 (2) ◽  
pp. 507-511 ◽  
Author(s):  
L Best ◽  
A P Yates ◽  
J E Meats ◽  
S Tomlinson
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Islet Cell ◽  
Islet Cells ◽  
Sodium Lactate ◽  
High Concentration ◽  
Subsequent Removal ◽  
Transient Rise ◽  
Cell Depolarization ◽  
Subsequent Withdrawal

The secretion of insulin from perifused rat pancreatic islets was stimulated by raising the glucose concentration from 5.6 to 20 mM or by exposure to tolbutamide. The addition of sodium lactate (40 mM) to islets perifused in the presence of glucose (5.6 mM) resulted in a small, transient, rise in the rate of secretion. The subsequent removal of lactate, but not glucose or tolbutamide, from the perifusate produced a dramatic potentiation of insulin release. The rate of efflux of 45Ca2+ was also increased when islets were exposed to a high concentration of glucose or lactate or to tolbutamide, and again subsequently upon withdrawal of lactate. Efflux of 86Rb+ was modestly inhibited upon addition of lactate and markedly enhanced by the subsequent withdrawal of lactate from islets. The output of [14C]lactate from islets incubated in the presence of [U-14C]glucose increased linearly with increasing concentrations of glucose (1-25 mM). It is proposed that the activation of islets by the addition or withdrawal of lactate is not due to increased oxidative flux, but occurs as a result of the electrogenic passage of lactate ions across the plasma membrane, resulting in islet-cell depolarization, Ca2+ entry and insulin secretion. The production of lactate via the glycolytic pathway, and the subsequent efflux of lactate from the islet cells with concomitant exchange of H+ for Na+, could be a major determinant of depolarization and hence insulin secretion, in response to glucose.

Effect of Silencing Information Regulator on Islet β Cells in High Glucose Environment Through Regulation of Phosphatidylinositol 3 Kinase (PI3K)/Protein Kinase B (AKT)/Nuclear Factor-κ-Gene Binding Pathway

2021 ◽  
Vol 11 (8) ◽  
pp. 1624-1629
Author(s):  
Nali Liu ◽  
Beijing Zhu ◽  
Xin Wei
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
High Glucose ◽  
Islet Cell ◽  
Control Group ◽  
Diabetic Patients ◽  
Phosphatidylinositol 3 Kinase ◽  
Sod Activity ◽  
Sirt1 Expression ◽  
Cell Supernatant

Islet β-cell regeneration is beneficial for treating diabetic patients. Silencing information regulator (SIRT1) has a regulatory role in endocrine diseases. However, SIRT1’s role in islet β cells remains unclear. MIN6 cells were cultured and assigned into control group, high glucose group, and SIRT1 group (treated with SIRT1 agonist, Resveratrol) followed by analysis of SIRT1 expression by Real time PCR and ELISA, cell proliferation by MTT assay, apoptosis activity by Caspase3 activity kit, secretion of TNF-α and IL-2 by ELISA, insulin secretion, ROS and SOD generation and expression of PI3K/Akt/NF-κB signaling by Western blot. SIRT1 mRNA was decreased in high glucose environment and its secretion in cell supernatant was reduced, with inhibited cell proliferation, increased Caspase3 activity and secretion of TNF-α and IL-2, decreased insulin secretion and SOD activity, increased ROS content, pAKT phosphorylation and NF-κB expression. Resveratrol significantly promoted SIRT1 expression and cell proliferation, decreased Caspase3 activity and secretion of TNF-α and IL-2, increased insulin secretion and SOD activity, as well as decreased ROS content, pAKT phosphorylation and NF-κB expression (P <0.05). SIRT1 is decreased in high glucose environment, and SIRT1 expression can inhibit islet cell apoptosis, inhibit oxidative stress and inflammation, and promote islet cell proliferation and insulin secretion by regulating PI3K/Akt/NF-κB signaling.

Effect of Glucose Metabolism-Associated Protein-1 on Exendin-4-Treated Pancreatic Islet Cell Function

2020 ◽  
Vol 10 (7) ◽  
pp. 1015-1021
Author(s):  
Jing Feng ◽  
Cuiwen Kong ◽  
Min Wang ◽  
Yingchuan Xu ◽  
Yingwei Chang
Keyword(s):  
Cell Proliferation ◽  
Glucose Metabolism ◽  
Islet Cell ◽  
Caspase 3 ◽  
Cell Function ◽  
Islet Cells ◽  
Control Group ◽  
Sod Activity ◽  
Fas L ◽  
Islet Cell Function

Exendin-4 regulates blood sugar. Glucose metabolism-associated protein-1 (GMRP-1) regulates islet cell function. Therefore, this paper intends to analyze the effect of GMRP-1 on Exendin-4treated islet cells. The islet cell MIN6 cells were separated into control group, Exendin-4 group, GMRP-1 overexpressing+ Exendin-4 group, and GMRP-1 siRNA+ Exendin-4 group followed by analysis of the expression of GMRP-1 by quantitative real-time PCR and Western blot, cell proliferation by MTT, cell apoptosis by flow cytometry, Bcl-2, Bax, Fas and Fas-L expression by real-time PCR, as well as caspase-3 activity, reactive oxygen species (ROS) and superoxide dismutase (SOD) activity. Exendin-4 and GMRP-1 overexpression+ Exendin-4 significantly increased GMRP-1 expression and promoted cell proliferation, decreased apoptotic rate and Caspase-3 activity, increased Bcl-2 and Fas-L expression, reduced Fas and Bax expression, as well as decreased ROS generation and increased SOD activity (P < 0 05), and the changes in GMRP-1 overexpression+ Exendin-4 group was more significant (P < 0 01). However, GMRP-1 siRNA+ Exendin-4 group significantly down-regulated GMRP-1 expression, decreased MIN6 cell prolifer- ation, increased cell apoptosis and Caspase-3 activity, decreased Bcl-2 and Fas-L expression, elevated Fas and Bax expression, increased ROS content and decreased SOD activity compared to control group and Exendin-4 group (P < 0 05). Up-regulation of GMRP-1 expression promoted Exendin-4-induced proliferation and inhibited apoptosis of islet cells. Down-regulation of GMRP-1 expression reversed Exendin-4's effect on islet cells.

Measurement of pancreatic islet cell proliferation by heavy water labeling

2007 ◽  
Vol 293 (5) ◽  
pp. E1459-E1464 ◽  
Author(s):  
Songyuan Chen ◽  
Scott Turner ◽  
Ellen Tsang ◽  
Julie Stark ◽  
Holly Turner ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Heavy Water ◽  
Islet Cell ◽  
Bone Marrow Cells ◽  
Islet Cells ◽  
Therapeutic Agents ◽  
Pancreatic Islet Cell ◽  
Highly Correlated

We describe a sensitive technique for measuring long-term islet cell proliferation rates in vivo in rats. Pancreatic islets were isolated and the incorporation of deuterium (2H) from heavy water (2H2O) into the deoxyribose moiety of DNA was measured by GC-MS. The results of heavy water labeling and BrdU staining were compared. The two methods were highly correlated ( r = 0.9581, P < 0.001). Based on long-term heavy water labeling, ∼50% of islet cells divided in rats between 8 and 15 wk of age. Of interest, long-term BrdU administration suppressed proliferation of islet cells significantly, but not of bone marrow cells. Physiological evidence further supported the validity of the method: older animals (24 wk old) had 60% lower islet cell proliferation rates than younger rats (5 wk old), and partial (50%) pancreatectomy increased proliferation by 20%. In addition, cholecystokinin-8 treatment significantly stimulated proliferation in pancreatectomized rats only. In summary, heavy water labeling is a quantitative approach for measuring islet cell proliferation and testing therapeutic agents.

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