scholarly journals Extracellular Matrix–Associated Factors Play Critical Roles in Regulating Pancreatic β-Cell Proliferation and Survival

Endocrinology ◽  
2019 ◽  
Vol 160 (8) ◽  
pp. 1885-1894 ◽  
Author(s):  
Shannon E Townsend ◽  
Maureen Gannon
Keyword(s):  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Cell Mass ◽  
Vascular Endothelial ◽  
Β Cells ◽  
Β Cell ◽  
Cellular Communication Network ◽  
Treatment Of Diabetes ◽  
Specific Receptors ◽  
Endothelial Growth Factor

Abstract This review describes formation of the islet basement membrane and the function of extracellular matrix (ECM) components in β-cell proliferation and survival. Implications for islet transplantation are discussed. The insulin-producing β-cell is key for maintaining glucose homeostasis. The islet microenvironment greatly influences β-cell survival and proliferation. Within the islet, β-cells contact the ECM, which is deposited primarily by intraislet endothelial cells, and this interaction has been shown to modulate proliferation and survival. ECM-localized growth factors, such as vascular endothelial growth factor and cellular communication network 2, signal through specific receptors and integrins on the β-cell surface. Further understanding of how the ECM functions to influence β-cell proliferation and survival will provide targets for enhancing functional β-cell mass for the treatment of diabetes.

scholarly journals Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Brenda Strutt ◽  
Sandra Szlapinski ◽  
Thineesha Gnaneswaran ◽  
Sarah Donegan ◽  
Jessica Hill ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glucose Transporter ◽  
Cell Mass ◽  
Elevated Serum ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Transporter 2 ◽  
Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

scholarly journals NF-κB activity during pancreas development regulates adult β-cell mass by modulating neonatal β-cell proliferation and apoptosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Dror Sever ◽  
Anat Hershko-Moshe ◽  
Rohit Srivastava ◽  
Roy Eldor ◽  
Daniel Hibsher ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Developmental Stages ◽  
Cell Mass ◽  
Diabetes Incidence ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Regulatory Circuit ◽  
Proliferation And Apoptosis

AbstractNF-κB is a well-characterized transcription factor, widely known for its roles in inflammation and immune responses, as well as in control of cell division and apoptosis. However, its function in β-cells is still being debated, as it appears to depend on the timing and kinetics of its activation. To elucidate the temporal role of NF-κB in vivo, we have generated two transgenic mouse models, the ToIβ and NOD/ToIβ mice, in which NF-κB activation is specifically and conditionally inhibited in β-cells. In this study, we present a novel function of the canonical NF-κB pathway during murine islet β-cell development. Interestingly, inhibiting the NF-κB pathway in β-cells during embryogenesis, but not after birth, in both ToIβ and NOD/ToIβ mice, increased β-cell turnover, ultimately resulting in a reduced β-cell mass. On the NOD background, this was associated with a marked increase in insulitis and diabetes incidence. While a robust nuclear immunoreactivity of the NF-κB p65-subunit was found in neonatal β-cells, significant activation was not detected in β-cells of either adult NOD/ToIβ mice or in the pancreata of recently diagnosed adult T1D patients. Moreover, in NOD/ToIβ mice, inhibiting NF-κB post-weaning had no effect on the development of diabetes or β-cell dysfunction. In conclusion, our data point to NF-κB as an important component of the physiological regulatory circuit that controls the balance of β-cell proliferation and apoptosis in the early developmental stages of insulin-producing cells, thus modulating β-cell mass and the development of diabetes in the mouse model of T1D.

scholarly journals Adaptive β-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression

2013 ◽  
Vol 305 (1) ◽  
pp. E149-E159 ◽  
Author(s):  
Rachel E. Stamateris ◽  
Rohit B. Sharma ◽  
Douglas A. Hollern ◽  
Laura C. Alonso
Keyword(s):  
Cell Proliferation ◽  
Cell Mass ◽  
Extended Period ◽  
Time Frame ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Cyclin D2 ◽  
Mass Expansion

Type 2 diabetes (T2D) is caused by relative insulin deficiency, due in part to reduced β-cell mass ( 11 , 62 ). Therapies aimed at expanding β-cell mass may be useful to treat T2D ( 14 ). Although feeding rodents a high-fat diet (HFD) for an extended period (3–6 mo) increases β-cell mass by inducing β-cell proliferation ( 16 , 20 , 53 , 54 ), evidence suggests that adult human β-cells may not meaningfully proliferate in response to obesity. The timing and identity of the earliest initiators of the rodent compensatory growth response, possible therapeutic targets to drive proliferation in refractory human β-cells, are not known. To develop a model to identify early drivers of β-cell proliferation, we studied mice during the first week of HFD exposure, determining the onset of proliferation in the context of diet-related physiological changes. Within the first week of HFD, mice consumed more kilocalories, gained weight and fat mass, and developed hyperglycemia, hyperinsulinemia, and glucose intolerance due to impaired insulin secretion. The β-cell proliferative response also began within the first week of HFD feeding. Intriguingly, β-cell proliferation increased before insulin resistance was detected. Cyclin D2 protein expression was increased in islets by day 7, suggesting it may be an early effector driving compensatory β-cell proliferation in mice. This study defines the time frame and physiology to identify novel upstream regulatory signals driving mouse β-cell mass expansion, in order to explore their efficacy, or reasons for inefficacy, in initiating human β-cell proliferation.

SerpinB1 improves insulin sensitivity

2016 ◽  
Vol 9 (411) ◽  
pp. ec10-ec10
Author(s):  
Annalisa M. VanHook
Keyword(s):  
Cell Proliferation ◽  
Insulin Sensitivity ◽  
Cell Mass ◽  
Dependent Manner ◽  
Wild Type ◽  
Β Cells ◽  
Β Cell ◽  
Cell Hyperplasia ◽  
Link Type ◽  
Proteomic Approach

Pancreatic β cells adjust the secretion of insulin in response to acute changes in plasma glucose concentration. These cells also compensate for long-term changes in insulin sensitivity by adjusting their activity or numbers, or both (see Tarasov and Rorsman). In addition to being insulin resistant, mice lacking the liver insulin receptor (LIRKO mice) also exhibit β cell hyperplasia that depends on factors released from the liver. Using a proteomic approach, El Ouaamari etal. found that the abundance of the protease inhibitor serpinB1 was greater in liver extracts, liver explant–conditioned medium, and serum from LIRKO mice than in those from wild-type mice. SerpinB1 abundance correlated inversely with insulin sensitivity in human patients with risk factors for type 2 diabetes. Recombinant human serpinB1 stimulated the proliferation of β cells in cultured mouse and human islets in a dose-dependent manner. Elastase is a protease inhibited by serpinB1, and forms of serpinB1 that do not inhibit elastase activity did not stimulate proliferation of cultured mouse β cells. Compounds that inhibit elastase also promoted the proliferation of cultured mouse β cells. In mice, elastase inhibitors stimulated the proliferation of both endogenous β cells and the β cells of human islet grafts. Furthermore, overexpression of serpinb1 increased the regeneration of β cells following β cell ablation in zebrafish embryos. In several models of acute and chronic insulin resistance, serpinb1 knockout mice exhibited reduced β cell proliferation compared with wild-type controls. However, β cell proliferation was not abolished in serpinb1 knockouts, indicating that additional factors can induce compensatory proliferation of β cells. Phosphoproteomic analyses demonstrated that treatment of cultured mouse β cells with human serpinB1 stimulated signaling through several pathways that promote cell proliferation and survival. Commentary by Tarasov and Rorsman considers how these findings might be put to clinical use.A. El Ouaamari, E. Dirice, N. Gedeon, J. Hu, J.-Y. Zhou, J. Shirakawa, L. Hou, J. Goodman, C. Karampelias, G. Qiang, J. Boucher, R. Martinez, M. A. Gritsenko, D. F. De Jesus, S. Kahraman, S. Bhatt, R. D. Smith, H.-D. Beer, P. Jungtrakoon, Y. Gong, A. B. Goldfine, C. W. Liew, A. Doria, O. Andersson, W.-J. Qian, E. Remold-O’Donnell, R. N. Kulkarni, SerpinB1 promotes pancreatic β cell proliferation. CellMetab. 23, 194–205 (2016). [PubMed] A. I. Tarasov, P. Rorsman, Dramatis personae in β-cell mass regulation: Enter SerpinB1. CellMetab. 23, 8–10 (2016). [Online Journal]

scholarly journals Trefoil Factor 2 Promotes Cell Proliferation in Pancreatic β-Cells through CXCR-4-Mediated ERK1/2 Phosphorylation

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 54-64 ◽  
Author(s):  
Kazuki Orime ◽  
Jun Shirakawa ◽  
Yu Togashi ◽  
Kazuki Tajima ◽  
Hideaki Inoue ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Mass ◽  
Brdu Incorporation ◽  
Trefoil Factor ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Min6 Cells ◽  
Trefoil Factor 2 ◽  
Chemokine Receptor 4

Decreased β-cell mass is a hallmark of type 2 diabetes, and therapeutic approaches to increase the pancreatic β-cell mass have been expected. In recent years, gastrointestinal incretin peptides have been shown to exert a cell-proliferative effect in pancreatic β-cells. Trefoil factor 2 (TFF2), which is predominantly expressed in the surface epithelium of the stomach, plays a role in antiapoptosis, migration, and proliferation. The TFF family is expressed in pancreatic β-cells, whereas the role of TFF2 in pancreatic β-cells has been obscure. In this study, we investigated the mechanism by which TFF2 enhances pancreatic β-cell proliferation. The effects of TFF2 on cell proliferation were evaluated in INS-1 cells, MIN6 cells, and mouse islets using an adenovirus vector containing TFF2 or a recombinant TFF2 peptide. The forced expression of TFF2 led to an increase in bromodeoxyuridine (BrdU) incorporation in both INS-1 cells and islets, without any alteration in insulin secretion. TFF2 significantly increased the mRNA expression of cyclin A2, D1, D2, D3, and E1 in islets. TFF2 peptide increased ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. A MAPK kinase inhibitor (U0126) abrogated the TFF2 peptide-mediated proliferation of MIN6 cells. A CX-chemokine receptor-4 antagonist also prevented the TFF2 peptide-mediated increase in ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. These results indicated that TFF2 is involved in β-cell proliferation at least partially via CX-chemokine receptor-4-mediated ERK1/2 phosphorylation, suggesting TFF2 may be a novel target for inducing β-cell proliferation.

scholarly journals Selective Deletion of Pten in Pancreatic β Cells Leads to Increased Islet Mass and Resistance to STZ-Induced Diabetes

2006 ◽  
Vol 26 (7) ◽  
pp. 2772-2781 ◽  
Author(s):  
Bangyan L. Stiles ◽  
Christine Kuralwalla-Martinez ◽  
Wei Guo ◽  
Caroline Gregorian ◽  
Ying Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Mass ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell ◽  
Islet Mass ◽  
Pten Loss ◽  
Lipid Phosphatase ◽  
Streptozotocin Induced Diabetes ◽  
Phosphatase And Tensin Homologue

ABSTRACT Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid phosphatase. PTEN inhibits the action of phosphatidylinositol-3-kinase and reduces the levels of phosphatidylinositol triphosphate, a crucial second messenger for cell proliferation and survival, as well as insulin signaling. In this study, we deleted Pten specifically in the insulin producing β cells during murine pancreatic development. Pten deletion leads to increased cell proliferation and decreased cell death, without significant alteration of β-cell differentiation. Consequently, the mutant pancreas generates more and larger islets, with a significant increase in total β-cell mass. PTEN loss also protects animals from developing streptozotocin-induced diabetes. Our data demonstrate that PTEN loss in β cells is not tumorigenic but beneficial. This suggests that modulating the PTEN-controlled signaling pathway is a potential approach for β-cell protection and regeneration therapies.

scholarly journals Generation and characterization of a novel mouse model that allows spatiotemporal quantification of pancreatic β-cell proliferation

2020 ◽  
Author(s):  
Ada Admin ◽  
Shinsuke Tokumoto ◽  
Daisuke Yabe ◽  
Hisato Tatsuoka ◽  
Ryota Usui ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Three Dimensional ◽  
Spatiotemporal Analysis ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Partial Pancreatectomy ◽  
Diet Induced Obesity ◽  
Treatment Of Diabetes

Pancreatic β-cell proliferation has been gaining much attention as a therapeutic target for prevention and treatment of diabetes. In order to evaluate potential β-cell mitogens, accurate and reliable methods for detection and quantification of the β-cell proliferation rate are indispensable. In this study, we developed a novel tool that specifically labels replicating β cells as mVenus<sup>+</sup> cells by using RIP-Cre;R26Fucci2aR mice expressing the fluorescent ubiquitination-based cell cycle indicator Fucci2a in β cells. In response to β-cell proliferation stimuli such as insulin receptor antagonist S961 and diet-induced obesity (DIO), the number of EdU<sup>+</sup> insulin<sup>+ </sup>cells per insulin<sup>+ </sup>cells and the number of mVenus<sup>+ </sup>cells per <a>mCherry<sup>+ </sup>mVenus<sup>-</sup> cells + mCherry<sup>- </sup>mVenus<sup>+</sup> cells</a> were similarly increased in these mice. Three-dimensional imaging of optically cleared pancreas tissue from these mice enabled quantification of replicating β cells in the islets and morphometric analysis of the islets following known mitogenic interventions such as S961, DIO, pregnancy and partial pancreatectomy. Thus, this novel mouse line is a powerful tool for spatiotemporal analysis and quantification of β-cell proliferation in response to mitogenic stimulation.

scholarly journals Lrrc55 is a novel prosurvival factor in pancreatic islets

2019 ◽  
Vol 317 (5) ◽  
pp. E794-E804 ◽  
Author(s):  
Guneet Makkar ◽  
Vipul Shrivastava ◽  
Brittyne Hlavay ◽  
Marle Pretorius ◽  
Barry D. Kyle ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Er Stress ◽  
Pancreatic Islets ◽  
Prolactin Receptor ◽  
Cell Mass ◽  
Cell Number ◽  
Dependent Manner ◽  
Β Cells ◽  
Β Cell ◽  
Insulin Synthesis

Pancreatic islets adapt to the increase in insulin demand during pregnancy by upregulating β-cell number, insulin synthesis, and secretion. These changes require prolactin receptor (PrlR) signaling, as mice with PrlR deletion are glucose intolerant with a lower β-cell mass. Prolactin also prevents β-cell apoptosis. Many genes participate in these adaptive changes in the islet, and Lrrc55 is one of the most upregulated genes with unknown function in islets. Because Lrrc55 expression increases in parallel to the increase in β-cell number and insulin production during pregnancy, we hypothesize that Lrrc55 might regulate β-cell proliferation/apoptosis (thus β-cell number) and insulin synthesis. Here, we found that Lrrc55 expression was upregulated by >60-fold during pregnancy in a PrlR-dependent manner, and this increase was restricted only to the islets. Overexpression of Lrrc55 in β-cells had minimal effect on β-cell proliferation and glucose-stimulated insulin secretion but protected β-cells from glucolipotoxicity-induced reduction in insulin gene expression. Moreover, Lrrc55 protects β-cells from glucolipotoxicity-induced apoptosis, with upregulation of prosurvival signals and downregulation of proapoptotic signals of the endoplasmic reticulum (ER) stress pathway. Furthermore, Lrrc55 attenuated calcium depletion induced by glucolipotoxicity, which may contribute to its antiapoptotic effect. Hence our findings suggest that Lrrc55 is a novel prosurvival factor that is upregulated specifically in islets during pregnancy, and it prevents conversion of adaptive unfolded protein response to unresolved ER stress and apoptosis in β-cells. Lrrc55 could be a potential therapeutic target in diabetes by reducing ER stress and promoting β-cell survival.

scholarly journals Increase in β-Cell Mass in Transplanted Porcine Neonatal Pancreatic Cell Clusters Is Due to Proliferation of β-Cells and Differentiation of Duct Cells*

Endocrinology ◽  
2001 ◽  
Vol 142 (5) ◽  
pp. 2115-2122 ◽  
Author(s):  
N. Trivedi ◽  
J. Hollister-Lock ◽  
M. D. Lopez-Avalos ◽  
J. J. O’Neil ◽  
M. Keegan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Mass ◽  
Insulin Content ◽  
Double Immunostaining ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Cell ◽  
Cell Clusters ◽  
Duct Cells ◽  
Neonatal Pig

Abstract A 20-fold increase in β-cell mass has been found after transplantation of porcine neonatal pancreatic cell clusters (NPCCs). Here the mechanisms leading to this increased β-cell mass were studied. NPCCs (4000 islet equivalents) generated after 8 days culture of digested neonatal pig pancreas were transplanted beneath the renal capsule of streptozotocin (STZ) diabetic and normoglycemic nude mice. Grafts were removed at 10 days, 6 weeks, and 20 weeks after transplantation for immunostaining and insulin content. Proliferation of β-cells and duct cells was assessed morphometrically using double immunostaining for Ki-67 with insulin or cytokeratin 7 (CK7). Graft maturation was assessed with double immunostaining of CK7 and insulin. Apoptosis was determined using propidium iodide staining. β-cell proliferation in NPCCs was higher after 8 days of culture compared with that found in neonatal pig pancreas. After transplantation, β-cell proliferation remained high at 10 days, decreased somewhat at 6 weeks, and was much lower 20 weeks after transplantation. Diabetic recipients not cured at 6 weeks after transplantation had significantly higherβ -cell proliferation compared with those cured and to normoglycemic recipients. The size of individual β-cells, as determined by cross-sectional area, increased as the grafts matured. Graft insulin content was 20-fold increased at 20 weeks after transplantation compared with 8 days cultured NPCCs. The proliferation index of duct cells was significantly higher in neonatal pig pancreas than in 8 days cultured NPCCs and in 10-day-old grafts. The incidence of apoptosis in duct cells appeared to be low. About 20% of duct cells 10 days post transplantation showed costaining for CK7 and insulin, a marker of protodifferentiation. In conclusion, the increase in β-cell mass after transplantation of NPCCs is due to both proliferation of differentiated β-cells and differentiation of duct cells intoβ -cells.

scholarly journals Lactation improves pancreatic β cell mass and function through serotonin production

2020 ◽  
Vol 12 (541) ◽  
pp. eaay0455
Author(s):  
Joon Ho Moon ◽  
Hyeongseok Kim ◽  
Hyunki Kim ◽  
Jungsun Park ◽  
Wonsuk Choi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Proliferation ◽  
Glucose Tolerance ◽  
Serotonin Receptor ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Beneficial Effects

Pregnancy imposes a substantial metabolic burden on women through weight gain and insulin resistance. Lactation reduces the risk of maternal postpartum diabetes, but the mechanisms underlying this benefit are unknown. Here, we identified long-term beneficial effects of lactation on β cell function, which last for years after the cessation of lactation. We analyzed metabolic phenotypes including β cell characteristics in lactating and non-lactating humans and mice. Lactating and non-lactating women showed comparable glucose tolerance at 2 months after delivery, but after a mean of 3.6 years, glucose tolerance in lactated women had improved compared to non-lactated women. In humans, the disposition index, a measure of insulin secretory function of β cells considering the degree of insulin sensitivity, was higher in lactated women at 3.6 years after delivery. In mice, lactation improved glucose tolerance and increased β cell mass at 3 weeks after delivery. Amelioration of glucose tolerance and insulin secretion were maintained up to 4 months after delivery in lactated mice. During lactation, prolactin induced serotonin production in β cells. Secreted serotonin stimulated β cell proliferation through serotonin receptor 2B in an autocrine and paracrine manner. In addition, intracellular serotonin acted as an antioxidant to mitigate oxidative stress and improved β cell survival. Together, our results suggest that serotonin mediates the long-term beneficial effects of lactation on female metabolic health by increasing β cell proliferation and reducing oxidative stress in β cells.

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