scholarly journals Decrease in Ins+Glut2LO β-cells with advancing age in mouse and human pancreas

2017 ◽  
Vol 233 (3) ◽  
pp. 229-241 ◽  
Author(s):  
Christine A Beamish ◽  
Sofia Mehta ◽  
Brenda J Strutt ◽  
Subrata Chakrabarti ◽  
Manami Hara ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Cell Mass ◽  
Positive Association ◽  
Human Islets ◽  
Human Pancreas ◽  
Fetal Life ◽  
Β Cells ◽  
Β Cell ◽  
Cell Clusters ◽  
Glucose Transporter 2

The presence and location of resident pancreatic β-cell progenitors is controversial. A subpopulation of insulin-expressing but glucose transporter-2-low (Ins+Glut2LO) cells may represent multipotent pancreatic progenitors in adult mouse and in human islets, and they are enriched in small, extra-islet β-cell clusters (<5 β cells) in mice. Here, we sought to identify and compare the ontogeny of these cells in mouse and human pancreata throughout life. Mouse pancreata were collected at postnatal days 7, 14, 21, 28, and at 3, 6, 12, and 18 months of age, and in the first 28 days after β-cell mass depletion following streptozotocin (STZ) administration. Samples of human pancreas were examined during fetal life (22–30 weeks gestation), infancy (0–1 year), childhood (2–9), adolescence (10–17), and adulthood (18–80). Tissues were analyzed by immunohistochemistry for the expression and location of insulin, GLUT2 and Ki67. The proportion of β cells within clusters relative to that in islets was higher in pancreas of human than of mouse at all ages examined, and decreased significantly at adolescence. In mice, the total number of Ins+Glut2LO cells decreased after 7 days concurrent with the proportion of clusters. These cells were more abundant in clusters than in islets in both species. A positive association existed between the appearance of new β cells after the STZ treatment of young mice, particularly in clusters and smaller islets, and an increased proportional presence of Ins+Glut2LO cells during early β-cell regeneration. These data suggest that Ins+Glut2LO cells are preferentially located within β-cell clusters throughout life in pancreas of mouse and human, and may represent a source of β-cell plasticity.

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.

Proper mTORC1 Activity Is Required for Glucose Sensing and Early Adaptation in Human Pancreatic β Cells

2020 ◽  
Author(s):  
Qicheng Ni ◽  
Jiaxi Song ◽  
Yichen Wang ◽  
Jiajun Sun ◽  
Jing Xie ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Fasting Glucose ◽  
Dynamic Change ◽  
Human Islets ◽  
Glucose Sensing ◽  
Β Cells ◽  
Β Cell ◽  
Strong Negative Correlation ◽  
Glucose Levels ◽  
Glucose Transporter 2

Abstract Context The mechanistic target of rapamycin complex I (mTORC1) is crucial for β-cell identity and function in rodents. However, its possible relevance to the physiopathology of diabetes in humans remains unclear. Objective This work aimed to understand the participation of mTORC1 in human β cells in prediabetes and diabetes. Design We evaluated the PS6 immunofluorescence intensity in islets of pancreatic sections from 12 nondiabetic (ND), 11 impaired fasting glucose (IFG), and 11 glycemic-controlled type 2 diabetic (T2D) individuals. We also assessed the dynamic change of mTORC1 activity in β cells of db/db mice with new-onset diabetes. Results There exists intercellular heterogeneity of mTORC1 activities in human islets. Islet mTORC1 activity was independently and positively correlated with FBG in ND, but not in IFG and T2D. Moreover, we did not detect significant change in mTORC1 activities between T2D and ND. Of note, the islet mTORC1 activities were significantly higher in IFG than in ND. We further stratified IFG individuals according to their islet PS6 levels and found that IFG-PS6high exhibited remarkably higher urocortin3 and glucose transporter 2 expression in their β cells compared to IFG-PS6low. Consistently, we also detected a significant increase in mTORC1 activities in prediabetic db/db mice compared to nondiabetic littermates. Interestingly, mTORC1 activities determined β-cell adaptation or failure in db/db mice: A strong negative correlation was found between islet mTORC1 activities and fasting glucose levels in db/db mice during their diabetes progression. Conclusions Our finding highlights a dynamic islet mTORC1 response in β-cell adaption/failure in human T2D.

scholarly journals Promotion of β-Cell Differentiation in Pancreatic Precursor Cells by Adult Islet Cells

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 570-579 ◽  
Author(s):  
Wei Chen ◽  
Salma Begum ◽  
Lynn Opare-Addo ◽  
Justin Garyu ◽  
Thomas F. Gibson ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Glucose Transporter ◽  
Islet Cells ◽  
Precursor Cells ◽  
Cell Contact ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Transporter 2 ◽  
Adult Islet

It is thought that differentiation of β-cell precursors into mature cells is largely autonomous, but under certain conditions differentiation can be modified by external factors. The factors that modify β-cell differentiation have not been identified. In this study, we tested whether adult islet cells can affect the differentiation process in mouse and human pancreatic anlage cells. We assessed β-cell proliferation and differentiation in mouse and human pancreatic anlage cells cocultured with adult islet cells or βTC3 cells using cellular, molecular, and immunohistochemical methods. Differentiation of murine anlage cells into β-cells was induced by mature islet cells. It was specific for β-cells and not a general feature of endodermal derived cells. β-Cell differentiation required cell-cell contact. The induced cells acquired features of mature β-cells including increased expression of β-cell transcription factors and surface expression of receptor for stromal cell-derived factor 1 and glucose transporter-2 (GLUT-2). They secreted insulin in response to glucose and could correct hyperglycemia in vivo when cotransplanted with vascular cells. Human pancreatic anlage cells responded in a similar manner and showed increased expression of pancreatic duodenal homeobox 1 and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A and increased production of proinsulin when cocultured with adult islets. We conclude that mature β-cells can modify the differentiation of precursor cells and suggest a mechanism whereby changes in differentiation of β-cells can be affected by other β-cells. Mature β cells affect differentiation of pancreatic anlage cells into functional β cells. The differentiated cells respond to glucose and ameliorate diabetes.

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 The Cells of the Islets of Langerhans

2018 ◽  
Vol 7 (3) ◽  
pp. 54 ◽  
Author(s):  
Gabriela Da Silva Xavier
Keyword(s):  
Islets Of Langerhans ◽  
Islet Cell ◽  
Islet Cells ◽  
Cell Mass ◽  
Current Data ◽  
Treatment Modalities ◽  
Human Pancreas ◽  
Β Cells ◽  
Β Cell ◽  
Islet Mass

Islets of Langerhans are islands of endocrine cells scattered throughout the pancreas. A number of new studies have pointed to the potential for conversion of non-β islet cells in to insulin-producing β-cells to replenish β-cell mass as a means to treat diabetes. Understanding normal islet cell mass and function is important to help advance such treatment modalities: what should be the target islet/β-cell mass, does islet architecture matter to energy homeostasis, and what may happen if we lose a particular population of islet cells in favour of β-cells? These are all questions to which we will need answers for islet replacement therapy by transdifferentiation of non-β islet cells to be a reality in humans. We know a fair amount about the biology of β-cells but not quite as much about the other islet cell types. Until recently, we have not had a good grasp of islet mass and distribution in the human pancreas. In this review, we will look at current data on islet cells, focussing more on non-β cells, and on human pancreatic islet mass and distribution.

scholarly journals The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ting Yuan ◽  
Karthika Annamalai ◽  
Shruti Naik ◽  
Blaz Lupse ◽  
Shirin Geravandi ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cell Mass ◽  
Human Islets ◽  
Hippo Signaling ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Large Tumor

AbstractDiabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces β-cell apoptosis and impaired function. LATS2 deficiency in β-cells and primary isolated human islets as well as β-cell specific LATS2 ablation in mice improves β-cell viability, insulin secretion and β-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in β-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates β-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating β-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic β-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic β-cell survival and function in diabetes.

Insulin signalling in islets

2008 ◽  
Vol 36 (3) ◽  
pp. 290-293 ◽  
Author(s):  
Shanta J. Persaud ◽  
Dany Muller ◽  
Peter M. Jones
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Insulin Signalling ◽  
Cell Mass ◽  
Human Islets ◽  
Human Islet ◽  
Mrna Levels ◽  
Small Interfering Rnas ◽  
Β Cells ◽  
Β Cell

Studies in transgenic animals, rodent insulin-secreting cell lines and rodent islets suggest that insulin acts in an autocrine manner to regulate β-cell mass and gene expression. Very little is known about the in vitro roles played by insulin in human islets, and the regulatory role of insulin in protecting against β-cell apoptosis. We have identified mRNAs encoding IRs (insulin receptors) and downstream signalling elements in dissociated human islet β-cells by single-cell RT (reverse transcription)–PCR, and perifusion studies have indicated that insulin does not have an autocrine role to regulate insulin secretion from human islets, but activation of the closely related IGF-1 (insulin-like growth factor 1) receptors is linked to inhibition of insulin secretion. Knockdown of IR mRNA by siRNAs (small interfering RNAs) decreased IR protein expression without affecting IGF-1 receptor levels, and blocked glucose stimulation of preproinsulin gene expression. Similar results were obtained when human islet IRS (IR substrate)-2 was knocked down, whereas depletion of IRS-1 caused an increase in preproinsulin mRNA levels. Studies using the mouse MIN6 β-cell line indicated that glucose protected β-cells from undergoing apoptosis and that this was a consequence, at least in part, of insulin release in response to elevated glucose. IGF-1 also exerted anti-apoptotic effects. These data indicate that insulin can exert autocrine effects in human islets through receptors on β-cells. It protects β-cells against apoptosis and increases preproinsulin mRNA synthesis, but does not affect insulin secretion.

scholarly journals SGLT2 inhibitors therapy protects glucotoxicity-induced β-cell failure in a mouse model of human KATP-induced diabetes trough mitigation of oxidative and ER stress

2021 ◽  
Author(s):  
Zeenat A. Shyr ◽  
Zihan Yan ◽  
Alessandro Ustione ◽  
Erin M. Egan ◽  
Maria S. Remedi
Keyword(s):  
Er Stress ◽  
Glucose Transporter ◽  
Cell Function ◽  
Cell Mass ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Insulin Content ◽  
Β Cell ◽  
Glucose Transporter 2 ◽  
Β Cell Function

AbstractProgressive loss of pancreatic β-cell functional mass and anti-diabetic drug responsivity are classic findings in diabetes, frequently attributed to compensatory insulin hypersecretion and β-cell exhaustion. However, loss of β-cell mass and identity still occurs in mouse models of human KATP-gain-of-function induced Neonatal Diabetes Mellitus (NDM), in the absence of insulin secretion. Here we studied the mechanisms underlying and temporal progression of glucotoxicity-induced loss of functional β-cell mass in NDM mice, and the effects of sodium-glucose transporter 2 inhibitors (SGLT2i) therapy. Upon tamoxifen induction of transgene expression, NDM mice developed severe diabetes followed by an unexpected loss of insulin content, decreased proinsulin processing and proinsulin accumulation at 2-weeks of diabetes. This was accompanied by a marked increase in β-cell oxidative and ER stress, without changes in islet cell identity. Strikingly, early treatment with the SGLT2 inhibitor dapagliflozin restored insulin content, decreased proinsulin:insulin ratio and reduced oxidative and ER stress. However, despite reduction of blood glucose, dapagliflozin therapy was ineffective in restoring β-cell function in NDM mice when tit was initiated at >40 days of diabetes, when loss of β-cell mass and identity had already occurred. These results have important clinical implications as they demonstrate that: i) hyperglycemia per se, and not insulin hypersecretion, drives β-cell failure in diabetes, ii) recovery of β-cell function by SGLT2 inhibitors is through reduction of oxidative and ER stress, iii) SGLT2 inhibitors revert/prevent β-cell failure when used in early stages of diabetes, but not when loss of β-cell mass/identity already occurred, iv) common execution pathways underlie loss and recovery of β-cell function in different forms of diabetes.

scholarly journals Neratinib protects pancreatic beta cells in diabetes

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Amin Ardestani ◽  
Sijia Li ◽  
Karthika Annamalai ◽  
Blaz Lupse ◽  
Shirin Geravandi ◽  
...  
Keyword(s):  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Cell Mass ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell

Abstract The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.

scholarly journals Bromodomain protein inhibition protects β-cells from cytokine-induced death and dysfunction via antagonism of NF-κB pathway

2020 ◽  
Author(s):  
Vinny Negi ◽  
Jeongkyung Lee ◽  
Ruya Liu ◽  
Eliana M. Perez-Garcia ◽  
Feng Li ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Bet Inhibitors ◽  
Β Cell Function ◽  
Underlying Mechanisms

ABSTRACTCytokine induced β-cell apoptosis is the major pathogenic mechanism in type 1 diabetes (T1D). Despite significant advances in understanding underlying mechanisms, few drugs have been translated to protect β-cells in T1D. Epigenetic modulators such as bromodomain-containing BET (Bromo- and Extra-Terminal) proteins are important regulators of immune responses. Pre-clinical studies have demonstrated a protective effect of BET inhibitors in NOD (non-obese diabetes) mouse model of T1D. However, the role of BET proteins in β-cell function in response to cytokines is unknown. Here we demonstrate that I-BET, a BET protein inhibitor, protected β-cells from cytokine induced dysfunction and death. In vivo administration of I-BET to mice exposed to low-dose STZ (streptozotocin), a model of T1D, significantly reduced β-cell apoptosis and preserved β-cell mass, suggesting a cytoprotective function of I-BET. Furthermore, human islets treated with I-BET displayed better glucose stimulated insulin secretion compared to controls, when exposed to cytokines. Mechanistically, RNA-Seq analysis revealed I-BET treatment suppressed pathways involved in apoptosis, including NF-kB signaling, while maintaining the expression of genes critical for β-cell function, such as Pdx1 and Ins1. Taken together, this study demonstrates that I-BET is effective in protecting β-cells from cytokine-induced dysfunction and apoptosis, and may have potential therapeutic values in T1D.

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