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 Human EndoC-βH1 β-cells form pseudoislets with improved glucose sensitivity and enhanced GLP-1 signaling in the presence of islet-derived endothelial cells

2018 ◽  
Vol 314 (5) ◽  
pp. E512-E521 ◽  
Author(s):  
Michael G. Spelios ◽  
Lauren A. Afinowicz ◽  
Regine C. Tipon ◽  
Eitan M. Akirav
Keyword(s):  
Endothelial Cells ◽  
Insulin Secretion ◽  
Cell Biology ◽  
Three Dimensional ◽  
Cell Types ◽  
Human Islets ◽  
Glucose Sensing ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Levels

Three-dimensional (3D) pseudoislets (PIs) can be used for the study of insulin-producing β-cells in free-floating islet-like structures similar to that of primary islets. Previously, we demonstrated the ability of islet-derived endothelial cells (iECs) to induce PIs using murine insulinomas, where PI formation enhanced insulin production and glucose responsiveness. In this report, we examined the ability of iECs to spontaneously induce the formation of free-floating 3D PIs using the EndoC-βH1 human β-cell line murine MS1 iEC. Within 14 days, the coculturing of both cell types produced fully humanized EndoC-βH1 PIs with little to no contaminating murine iECs. The size and shape of these PIs were similar to primary human islets. iEC-induced PIs demonstrated reduced dysregulated insulin release under low glucose levels and higher insulin secretion in response to high glucose and exendin-4 [a glucagon-like peptide-1 (GLP-1) analog] compared with monolayer cells cultured alone. Interestingly, iEC-PIs were also better at glucose sensing in the presence of extendin-4 compared with PIs generated on a low-adhesion surface plate in the absence of iECs and showed an overall improvement in cell viability. iEC-induced PIs exhibited increased expression of key genes involved in glucose transport, glucose sensing, β-cell differentiation, and insulin processing, with a concomitant decrease in glucagon mRNA expression. The enhanced responsiveness to exendin-4 was associated with increased protein expression of GLP-1 receptor and phosphokinase A. This rapid coculture system provides an unlimited number of human PIs with improved insulin secretion and GLP-1 responsiveness for the study of β-cell biology.

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.

scholarly journals Glucose homeostasis is regulated by pancreatic β-cell cilia via endosomal EphA-processing

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Francesco Volta ◽  
M. Julia Scerbo ◽  
Anett Seelig ◽  
Robert Wagner ◽  
Nils O’Brien ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Basal Body ◽  
Primary Cilia ◽  
Epithelial To Mesenchymal Transition ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Mesenchymal Transition ◽  
Glucose Levels

Abstract Diabetes mellitus affects one in eleven adults worldwide. Most suffer from Type 2 Diabetes which features elevated blood glucose levels and an inability to adequately secrete or respond to insulin. Insulin producing β-cells have primary cilia which are implicated in the regulation of glucose metabolism, insulin signaling and secretion. To better understand how β-cell cilia affect glucose handling, we ablate cilia from mature β-cells by deleting key cilia component Ift88. Here we report that glucose homeostasis and insulin secretion deteriorate over 12 weeks post-induction. Cilia/basal body components are required to suppress spontaneous auto-activation of EphA3 and hyper-phosphorylation of EphA receptors inhibits insulin secretion. In β-cells, loss of cilia/basal body function leads to polarity defects and epithelial-to-mesenchymal transition. Defective insulin secretion from IFT88-depleted human islets and elevated pEPHA3 in islets from diabetic donors both point to a role for cilia/basal body proteins in human glucose homeostasis.

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 Effect of Ishophloroglucin A, A Component of Ishige okamurae, on Glucose Homeostasis in the Pancreas and Muscle of High Fat Diet-Fed Mice

Marine Drugs ◽  
2019 ◽  
Vol 17 (11) ◽  
pp. 608 ◽  
Author(s):  
Hye-Won Yang ◽  
Myeongjoo Son ◽  
Junwon Choi ◽  
Seyeon Oh ◽  
You-Jin Jeon ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Functional Food ◽  
Glucose Transporter ◽  
Fasting Glucose ◽  
High Fat ◽  
Β Cells ◽  
Glucose Levels ◽  
Ishige Okamurae ◽  
Prevention Of Diabetes

Ishophloroglucin A (IPA), a component of Ishige okamurae (IO), was previously evaluated to standardize the antidiabetic potency of IO. However, the potential of IPA as a functional food for diabetes prevention has not yet been evaluated. Here, we investigated if 1.35 mg/kg IPA, which is the equivalent content of IPA in 75 mg/kg IO, improved glucose homeostasis in high-fat diet (HFD)-induced diabetes after 12 weeks of treatment. IPA significantly ameliorated glucose intolerance, reducing fasting glucose levels as well as 2 h glucose levels in HFD mice. In addition, IPA exerted a protective effect on the pancreatic function in HFD mice via pancreatic β-cells and C-peptide. The level of glucose transporter 4 (GLUT4) in the muscles of HFD mice was stimulated by IPA intake. Our results suggested that IPA, which is a component of IO, can improve glucose homeostasis via GLUT4 in the muscles of HFD mice. IO may be used as a functional food for the prevention of diabetes.

scholarly journals Combined use of GABA and sitagliptin promotes human β-cell proliferation and reduces apoptosis

2020 ◽  
Author(s):  
Wenjuan Liu ◽  
Harry Kevin Lau ◽  
Dong Ok Son ◽  
Tianru Jin ◽  
Yehong Yang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4 ◽  
Glucose Levels ◽  
Cell Counts ◽  
Therapeutic Benefits ◽  
Combined Use ◽  
Glucagon Like Peptide 1

γ-aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent β-cell survival and function. In human β-cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1RA drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin (Sita), a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic β-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human β-cell. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, Sita, or both. The oral administration of either GABA or Sita ameliorated blood glucose levels, increased transplanted human β-cell counts and plasma human insulin levels. Importantly, combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. Proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, PDX-1+, or Nkx6.1+ β-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of α-Klotho, a protein with protective and stimulatory effects on β cells, was also augmented. Our study indicates that combined use of GABA and Sita produced greater therapeutic benefits, which are likely due to an enhancement of β-cell proliferation and a decrease in apoptosis.

scholarly journals The Glucose Transporter 2 Undergoes Plasma Membrane Endocytosis and Lysosomal Degradation in a Secretagogue-Dependent Manner

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4056-4064 ◽  
Author(s):  
June Chunqiu Hou ◽  
Dumaine Williams ◽  
Jérôme Vicogne ◽  
Jeffrey E. Pessin
Keyword(s):  
Plasma Membrane ◽  
Insulin Secretion ◽  
Cell Surface ◽  
Glucose Transporter ◽  
Cell Function ◽  
Glucose Sensing ◽  
Dependent Manner ◽  
Β Cells ◽  
Rapid Degradation ◽  
Glucose Transporter 2

Abstract In β-cells of the pancreas, the glucose transporter (GLUT)-2 facilitative glucose transporter protein is localized to the plasma membrane and functions as part of the glucose sensing mechanism for the stimulation of insulin secretion. We observed that expressed GLUT2 protein in the cultured Min6B1 cell line undergoes enhanced endocytosis at high extracellular glucose concentrations that stimulate insulin secretion. Moreover, the internalized GLUT2 protein undergoes rapid degradation induced by chronic high-glucose or arginine stimulation but does not undergo plasma membrane recycling or accumulation in any microscopically apparent intracellular membrane compartment. The rapid degradation of GLUT2 was prevented by lysosomal inhibition (chloroquine) concomitant with the accumulation of GLUT2 in endomembrane structures. In contrast, neither endocytosis nor the lack of internal membrane localized GLUT2 remained completely unaffected by proteosomal inhibition (lactacystin) or an heat shock protein-90 inhibitor (geldanamycin). Moreover, the endocytosis and degradation of GLUT2 was specific for β-cells because expression of GLUT2 in 3T3L1 adipocytes remained cell surface localized and did not display a rapid rate of degradation. Together, these data demonstrate that hyperglycemia directly affects β-cell function and activates a trafficking pathway that results in the rapid endocytosis and degradation of the cell surface GLUT2 glucose transporter.

Channel regulation of glucose sensing in the pancreatic β-cell

2008 ◽  
Vol 295 (6) ◽  
pp. E1298-E1306 ◽  
Author(s):  
Marcia Hiriart ◽  
Lydia Aguilar-Bryan
Keyword(s):  
Experimental Research ◽  
Glucose Sensing ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Adverse Conditions ◽  
Glucose Levels ◽  
Channel Regulation

Mammalian β-cells are acutely and chronically regulated by sensing surrounding glucose levels that determine the rate at which insulin is secreted, to maintain euglycemia. Experimental research in vitro and in vivo has shown that, when these cells are exposed to adverse conditions like long periods of hypoglycemia or hyperglycemia, their capability to sense glucose is decreased. Understanding the normal physiology and identifying the main players along this route becomes paramount. In this review, we have taken on the task of looking at the role that ion channels play in the regulation of this process, delineating the different families, and describing the signaling that parallels the glucose sensing process that results in insulin release.

scholarly journals PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniela Nasteska ◽  
Nicholas H. F. Fine ◽  
Fiona B. Ashford ◽  
Federica Cuozzo ◽  
Katrina Viloria ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Metabolic Stress ◽  
Human Islets ◽  
Islet Function ◽  
Β Cells ◽  
Β Cell ◽  
Ionic Fluxes ◽  
Transcriptomic Level ◽  
Adult Islet

AbstractTranscriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

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