scholarly journals β-cells operate collectively to help maintain glucose homeostasis

2019 ◽  
Author(s):  
Boris Podobnik ◽  
Dean Korošak ◽  
Maša Skelin Klemen ◽  
Andraž Stožer ◽  
Jurij Dolenšek ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Glucose Homeostasis ◽  
Cell Activity ◽  
Cell Communication ◽  
Calcium Oscillations ◽  
Homeostatic Function ◽  
Entire Cell ◽  
Collective Phenomenon ◽  
Gap Junctional

Residing in the islets of Langerhans in the pancreas, beta cells contribute to glucose homeostasis by managing the body’s insulin supply. A circulating hypothesis has been that healthy beta cells heavily engage in cell-to-cell communication to perform their homeostatic function. We provide strong evidence in favor of this hypothesis in the form of (i) a dynamical network model that faithfully mimics fast calcium oscillations in response to above-threshold glucose stimulation and (ii) empirical data analysis that reveals a qualitative shift in the cross-correlation structure of measured signals below and above the threshold glucose concentration. Combined together, these results point to a glucose-induced transition in beta-cell activity thanks to increasing coordination through gap-junctional signaling and paracrine interactions. The model further suggests how the conservation of entire cell-cell conductance, observed in coupled but not uncoupled beta cells, emerges as a collective phenomenon. An overall implication is that improving the ability to monitor beta-cell signaling should offer means to better understand the pathogenesis of diabetes mellitus.

Tetraethylammonium modifies gap junctions between pancreatic beta-cells

1981 ◽  
Vol 240 (3) ◽  
pp. C116-C120 ◽  
Author(s):  
M. S. Sheppard ◽  
P. Meda
Keyword(s):  
Beta Cell ◽  
Gap Junctions ◽  
Beta Cells ◽  
Insulin Release ◽  
Pancreatic Beta Cells ◽  
Freeze Fracture ◽  
Potassium Conductance ◽  
Median Number ◽  
Rat Islets Of Langerhans ◽  
Gap Junctional

Gap junctions between pancreatic beta-cells were quantitatively assessed in freeze-fracture replicas of isolated rat islets of Langerhans incubated for 90 min with or without the potassium conductance blocker tetraethylammonium (TEA). The results show that TEA increases the median number of particles per beta-cell gap junction but not the frequency of gap junctions at both nonstimulating and threshold-stimulating concentrations of glucose. TEA increased the relative gap junctional area at both concentrations of glucose. TEA had no effect on insulin release at a basal concentration of glucose but potentiated that release at the threshold glucose level. Thus TEA modifies beta-cell gap junctions independently of its effect on insulin release. However, the junctional changes observed were greater when insulin release was also elevated.

scholarly journals TCF7L2 in mouse pancreatic beta cells plays a crucial role in glucose homeostasis by regulating beta cell mass

Diabetologia ◽  
2013 ◽  
Vol 57 (3) ◽  
pp. 542-553 ◽  
Author(s):  
Iseki Takamoto ◽  
Naoto Kubota ◽  
Keizo Nakaya ◽  
Katsuyoshi Kumagai ◽  
Shinji Hashimoto ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Glucose Homeostasis ◽  
Crucial Role ◽  
Pancreatic Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass

scholarly journals Glucose-dependent activation, activity, and deactivation of beta cell networks in acute mouse pancreas tissue slices

2020 ◽  
Author(s):  
Jurij Dolenšek ◽  
Maša Skelin Klemen ◽  
Marko Gosak ◽  
Lidija Križančić-Bombek ◽  
Viljem Pohorec ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Insulin Release ◽  
Glucose Concentration ◽  
Calcium Oscillations ◽  
Tissue Slices ◽  
Mouse Pancreas ◽  
Network Parameters ◽  
Cell Networks ◽  
Glucose Dependence

AbstractGlucose progressively stimulates insulin release over a wide range of concentrations. However, the nutrient coding underlying activation, activity, and deactivation of beta cells affecting insulin release remains only partially described. Experimental data indicate that nutrient sensing in coupled beta cells in islets is predominantly a collective trait, overriding to a large extent functional differences between cells. However, some degree of heterogeneity between coupled beta cells may play important roles. To further elucidate glucose-dependent modalities in coupled beta cells, the degree of functional heterogeneity, and uncover the emergent collective operations, we combined acute mouse pancreas tissue slices with functional multicellular calcium imaging. We recorded beta cell calcium responses from threshold (7 mM) to supraphysiological (16 mM) glucose concentrations with high spatial and temporal resolution. This enabled the analysis of both classical physiological parameters and complex network parameters, as well as their comparison at the level of individual cells. The activation profile displayed two major glucose concentration-dependent features, shortening of delays to initial activation, and shortening of delays until half activation with increasing glucose concentration. Inversely, during deactivation both delays to initial deactivation and until half deactivation were progressively longer with increasing glucose concentration. The plateau activity with fast calcium oscillations expressed two types of glucose-dependence. Physiological concentrations mostly affected the frequency of oscillations, whereas supraphysiological concentrations progressively prolonged the duration of oscillations. Most of the measured functional network parameters also showed clear glucose-dependence. In conclusion, we propose novel understanding for glucose-dependent coding properties in beta cell networks, and its deciphering may have repercussions for our understanding of the normal physiology of glucose homeostasis as well as of disturbances of metabolic homeostasis, such as diabetes mellitus.

scholarly journals SAT-166 Techniques For Direct Imaging Of Beta-cell Activity And Glucose Homeostasis In Zebrafish

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jennifer Ikle ◽  
Rob Tryon ◽  
Christopher Emfinger ◽  
Kryzysztof Hyrc ◽  
Maria Remedi ◽  
...  
Keyword(s):  
Beta Cell ◽  
Glucose Homeostasis ◽  
Cell Activity ◽  
Direct Imaging

scholarly journals Protein-Mediated Interactions of Pancreatic Islet Cells

Scientifica ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-22 ◽  
Author(s):  
Paolo Meda
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Islet Cell ◽  
Islet Cells ◽  
Cell Communication ◽  
Cell Types ◽  
Integral Membrane Protein ◽  
Normal Function ◽  
Cell Functions ◽  
Islet Cell Types

The islets of Langerhans collectively form the endocrine pancreas, the organ that is soley responsible for insulin secretion in mammals, and which plays a prominent role in the control of circulating glucose and metabolism. Normal function of these islets implies the coordination of different types of endocrine cells, noticeably of the beta cells which produce insulin. Given that an appropriate secretion of this hormone is vital to the organism, a number of mechanisms have been selected during evolution, which now converge to coordinate beta cell functions. Among these, several mechanisms depend on different families of integral membrane proteins, which ensure direct (cadherins, N-CAM, occludin, and claudins) and paracrine communications (pannexins) between beta cells, and between these cells and the other islet cell types. Also, other proteins (integrins) provide communication of the different islet cell types with the materials that form the islet basal laminae and extracellular matrix. Here, we review what is known about these proteins and their signaling in pancreaticβ-cells, with particular emphasis on the signaling provided by Cx36, given that this is the integral membrane protein involved in cell-to-cell communication, which has so far been mostly investigated for effects on beta cell functions.

scholarly journals NMDA receptor inhibition increases, synchronizes, and stabilizes the collective pancreatic beta cell activity: Insights through multilayer network analysis

2021 ◽  
Vol 17 (5) ◽  
pp. e1009002
Author(s):  
Marko Šterk ◽  
Lidija Križančić Bombek ◽  
Maša Skelin Klemen ◽  
Marjan Slak Rupnik ◽  
Marko Marhl ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Nmda Receptor ◽  
Beta Cell ◽  
Nmda Receptors ◽  
Beta Cells ◽  
Cell Activity ◽  
Calcium Waves ◽  
Multilayer Network ◽  
Receptor Inhibition

NMDA receptors promote repolarization in pancreatic beta cells and thereby reduce glucose-stimulated insulin secretion. Therefore, NMDA receptors are a potential therapeutic target for diabetes. While the mechanism of NMDA receptor inhibition in beta cells is rather well understood at the molecular level, its possible effects on the collective cellular activity have not been addressed to date, even though proper insulin secretion patterns result from well-synchronized beta cell behavior. The latter is enabled by strong intercellular connectivity, which governs propagating calcium waves across the islets and makes the heterogeneous beta cell population work in synchrony. Since a disrupted collective activity is an important and possibly early contributor to impaired insulin secretion and glucose intolerance, it is of utmost importance to understand possible effects of NMDA receptor inhibition on beta cell functional connectivity. To address this issue, we combined confocal functional multicellular calcium imaging in mouse tissue slices with network science approaches. Our results revealed that NMDA receptor inhibition increases, synchronizes, and stabilizes beta cell activity without affecting the velocity or size of calcium waves. To explore intercellular interactions more precisely, we made use of the multilayer network formalism by regarding each calcium wave as an individual network layer, with weighted directed connections portraying the intercellular propagation. NMDA receptor inhibition stabilized both the role of wave initiators and the course of waves. The findings obtained with the experimental antagonist of NMDA receptors, MK-801, were additionally validated with dextrorphan, the active metabolite of the approved drug dextromethorphan, as well as with experiments on NMDA receptor KO mice. In sum, our results provide additional and new evidence for a possible role of NMDA receptor inhibition in treatment of type 2 diabetes and introduce the multilayer network paradigm as a general strategy to examine effects of drugs on connectivity in multicellular systems.

scholarly journals Expression of a tetracycline-controlled transactivator (Tet-On/Off system) in beta cells reduces insulin expression and secretion in mice

2021 ◽  
Author(s):  
Nathalie Jouvet ◽  
Khalil Bouyakdan ◽  
Cindy Baldwin ◽  
Jadwiga Marcinkiewicz ◽  
Thierry Alquier ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Beta Cells ◽  
Glucose Homeostasis ◽  
Cell Biology ◽  
Cell Function ◽  
Genetic Manipulation ◽  
Ectopic Expression ◽  
Whole Body ◽  
Specific Gene

ABSTRACTControllable genetic manipulation is an indispensable tool in research, greatly advancing our understanding of cell biology and physiology. However, in beta cells, transgene silencing, low inducibility, ectopic expression and off-targets effects on cell function and glucose homeostasis are a persistent challenge. In this study, we investigated whether an inducible, Tet-Off system with beta-cell specific MIP-itTA driven expression of TetO-CreJaw/J could circumvent previous issues of specificity, efficacy and toxicity. Following assessment of tissue-specific gene recombination; beta cell architecture; in vitro and in vivo glucose-stimulated insulin secretion (GSIS); and whole-body glucose homeostasis, we discovered that expression of any tetracycline-controlled transactivator (e.g. itTA, rtTA or tTA) in beta cells significantly reduced Insulin gene expression and decreased insulin content. This translated into lower pancreatic insulin levels and reduced insulin secretion in mice carrying a MIP-itTA transgene, independent of Cre-recombinase expression or doxycycline treatment. These results raise significant concern regarding the use of Tet-On or Tet-Off systems for genome editing in beta cells and emphasize the need to control for effects of transactivator expression. Our study echoes ongoing challenges faced by fundamental researchers focused on beta cells and highlights the need for consistent and careful control of experiments using these research tools.

scholarly journals Repositioning the Alpha Cell in Postprandial Metabolism

Endocrinology ◽  
2020 ◽  
Vol 161 (11) ◽  
Author(s):  
Kimberley El ◽  
Megan E Capozzi ◽  
Jonathan E Campbell
Keyword(s):  
Glucose Homeostasis ◽  
Cell Function ◽  
Cell Activity ◽  
Cell Communication ◽  
Glucagon Secretion ◽  
Historical Narrative ◽  
Β Cell ◽  
Postprandial Metabolism ◽  
Open Questions ◽  
Β Cell Function

Abstract Glucose homeostasis is maintained in large part due to the actions of the pancreatic islet hormones insulin and glucagon, secreted from β- and α-cells, respectively. The historical narrative positions these hormones in opposition, with insulin primarily responsible for glucose-lowering and glucagon-driving elevations in glucose. Recent progress in this area has revealed a more complex relationship between insulin and glucagon, highlighted by data demonstrating that α-cell input is essential for β-cell function and glucose homeostasis. Moreover, the common perception that glucagon levels decrease following a nutrient challenge is largely shaped by the inhibitory effects of glucose administration alone on the α-cell. Largely overlooked is that a mixed nutrient challenge, which is more representative of typical human feeding, actually stimulates glucagon secretion. Thus, postprandial metabolism is associated with elevations, not decreases, in α-cell activity. This review discusses the recent advances in our understanding of how α-cells regulate metabolism, with a particular focus on the postprandial state. We highlight α- to β-cell communication, a term that describes how α-cell input into β-cells is a critical axis that regulates insulin secretion and glucose homeostasis. Finally, we discuss the open questions that have the potential to advance this field and continue to evolve our understanding of the role that α-cells play in postprandial metabolism.

scholarly journals The SSBP3 Co-Regulator Is a Novel Driver of Islet Cell Structure and Function

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A327-A327
Author(s):  
Eliana Toren ◽  
Yanping Liu ◽  
Chad Hunter
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Glucose Homeostasis ◽  
Islet Cell ◽  
Target Genes ◽  
Cell Structure ◽  
Cell Architecture ◽  
Islet 1 ◽  
And Function

Abstract The activities of transcriptional complexes drive the proper development and function of insulin producing beta-cells, ultimately required for the regulation of glucose homeostasis. Our prior work helped to establish that the LIM-homeodomain transcription factor (TF), Islet-1 (Isl1), directly interacts with the Ldb1 co-regulator in developing and adult beta-cells. We further found that a member of the Single Stranded DNA-Binding Protein (SSBP) co-regulator family, SSBP3, interacts with the Isl1:Ldb1 complex in beta-cells and primary islets to impact critical target genes MafA and Glp1R. Members of the SSBP family of co-regulators stabilize TF complexes in various tissues, ranging from brain to skin, by binding directly to Ldb1 and protecting the factors from ubiquitin-mediated turnover. Because of this, we hypothesized that SSBP3 would have similarly critical roles as Isl1 and Ldb1 for beta-cell development and function in vivo. To assess this, we first developed a novel SSBP3 floxed mouse line, where Cre-mediated recombination is predicted to impart loss of the Ldb1-interacting domain, plus an early termination. We bred this mouse into a Pax6-Cre transgenic line to recombine SSBP3 in the developing pancreatic islet, a model termed SSBP3islet. We found that SSBP3islet neonates become progressively hyperglycemic and both male and female mice are glucose intolerant as early as postnatal day (P) 21. These results are similar to previous Ldb1 and Isl1 knockouts in the embryonic islet, both of which were hyperglycemic by P10. We observed a reduction of the beta-cell maturity marker, MafA, and disruptions in islet cell architecture with an apparent increase in both glucagon+ alpha-cells and ghrelin+epsilon-cells at P10 and P28. In ongoing studies we are generating embryonic day (E)18.5 embryos to determine islet development defects and will conduct chromatin immunoprecipitation (ChIP) experiments to determine the beta-cell and islet genes directly bound by SSBP3 in vivo. These experiments will further elucidate the regulation of islet function by LIM complexes, knowledge that is central not only for our understanding of glucose homeostasis but for the development of novel diabetes therapeutics.

scholarly journals Inhibition of Notch activity promotes pancreatic cytokeratin 5-positive cell differentiation to beta cells and improves glucose homeostasis following acute pancreatitis

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Xiaoyi Zhang ◽  
Jing Tao ◽  
Jia Yu ◽  
Ning Hu ◽  
Xuanzhe Zhang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Beta Cell ◽  
Beta Cells ◽  
Glucose Homeostasis ◽  
Cell Injury ◽  
Cell Loss ◽  
Notch Activity ◽  
Endocrine Insufficiency ◽  
Cytokeratin 5 ◽  
Notch Inhibition

AbstractSome individuals develop prediabetes and/or diabetes following acute pancreatitis (AP). AP-induced beta-cell injury and the limited regenerative capacity of beta cells might account for pancreatic endocrine insufficiency. Previously, we found that only a few pancreatic cytokeratin 5 positive (Krt5+) cells differentiated into beta cells in the murine AP model, which was insufficient to maintain glucose homeostasis. Notch signaling determines pancreatic progenitor differentiation in pancreas development. This study aimed to examine whether Notch signaling inhibition could promote pancreatic Krt5+ cell differentiation into beta cells and improve glucose homeostasis following AP. Pancreatic tissues from patients with acute necrotizing pancreatitis (ANP) were used to evaluate beta-cell injury, Krt5+ cell activation and differentiation, and Notch activity. The murine AP model was induced by cerulein, and the effect of Notch inhibition on Krt5+ cell differentiation was evaluated both in vivo and in vitro. The results demonstrated beta-cell loss in ANP patients and AP mice. Krt5+ cells were activated in ANP pancreases along with persistently elevated Notch activity, which resulted in the formation of massive duct-like structures. AP mice that received Notch inhibitor showed that impaired glucose tolerance was reversed 7 and 15 days following AP, and increased numbers of newborn small islets due to increased differentiation of Krt5+ cells to beta cells to some extent. In addition, Krt5+ cells isolated from AP mice showed increased differentiation to beta cells by Notch inhibition. Collectively, these findings suggest that beta-cell loss contributes to pancreatic endocrine insufficiency following AP, and inhibition of Notch activity promotes pancreatic Krt5+ cell differentiation to beta cells and improves glucose homeostasis. The findings from this study may shed light on the potential treatment of prediabetes/diabetes following AP.

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