scholarly journals A Simple Matter of Life and Death—The Trials of Postnatal Beta-Cell Mass Regulation

2012 ◽  
Vol 2012 ◽  
pp. 1-20 ◽  
Author(s):  
Elena Tarabra ◽  
Stella Pelengaris ◽  
Michael Khan
Keyword(s):  
Cell Differentiation ◽  
Beta Cell ◽  
Glucose Homeostasis ◽  
Pancreatic Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Signalling Pathways ◽  
Life And Death ◽  
Cell Numbers ◽  
Differentiation And Proliferation

Pancreatic beta-cells, which secrete the hormone insulin, are the key arbiters of glucose homeostasis. Defective beta-cell numbers and/or function underlie essentially all major forms of diabetes and must be restored if diabetes is to be cured. Thus, the identification of the molecular regulators of beta-cell mass and a better understanding of the processes of beta-cell differentiation and proliferation may provide further insight for the development of new therapeutic targets for diabetes. This review will focus on the principal hormones and nutrients, as well as downstream signalling pathways regulating beta-cell mass in the adult. Furthermore, we will also address more recently appreciated regulators of beta-cell mass, such as microRNAs.

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 Multi-Organ Crosstalk with Endocrine Pancreas: A Focus on How Gut Microbiota Shapes Pancreatic Beta-Cells

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 104
Author(s):  
Elisa Fernández-Millán ◽  
Carlos Guillén
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Cell Biology ◽  
Pancreatic Beta Cells ◽  
Metabolic Diseases ◽  
Cell Function ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Short Chain Fatty Acids

Type 2 diabetes (T2D) results from impaired beta-cell function and insufficient beta-cell mass compensation in the setting of insulin resistance. Current therapeutic strategies focus their efforts on promoting the maintenance of functional beta-cell mass to ensure appropriate glycemic control. Thus, understanding how beta-cells communicate with metabolic and non-metabolic tissues provides a novel area for investigation and implicates the importance of inter-organ communication in the pathology of metabolic diseases such as T2D. In this review, we provide an overview of secreted factors from diverse organs and tissues that have been shown to impact beta-cell biology. Specifically, we discuss experimental and clinical evidence in support for a role of gut to beta-cell crosstalk, paying particular attention to bacteria-derived factors including short-chain fatty acids, lipopolysaccharide, and factors contained within extracellular vesicles that influence the function and/or the survival of beta cells under normal or diabetogenic conditions.

scholarly journals Update on the Protective Molecular Pathways Improving Pancreatic Beta-Cell Dysfunction

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Alessandra Puddu ◽  
Roberta Sanguineti ◽  
François Mach ◽  
Franco Dallegri ◽  
Giorgio Luciano Viviani ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Dysfunction ◽  
Molecular Pathways ◽  
Cell Dysfunction

The primary function of pancreatic beta-cells is to produce and release insulin in response to increment in extracellular glucose concentrations, thus maintaining glucose homeostasis. Deficient beta-cell function can have profound metabolic consequences, leading to the development of hyperglycemia and, ultimately, diabetes mellitus. Therefore, strategies targeting the maintenance of the normal function and protecting pancreatic beta-cells from injury or death might be crucial in the treatment of diabetes. This narrative review will update evidence from the recently identified molecular regulators preserving beta-cell mass and function recovery in order to suggest potential therapeutic targets against diabetes. This review will also highlight the relevance for novel molecular pathways potentially improving beta-cell dysfunction.

scholarly journals Dynamic Regulation of JAK-STAT Signaling Through the Prolactin Receptor Predicted by Computational Modeling

2020 ◽  
Author(s):  
Ryland D. Mortlock ◽  
Senta K. Georgia ◽  
Stacey D. Finley
Keyword(s):  
Experimental Data ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Prolactin Receptor ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Receptor Internalization ◽  
Proliferative Potential ◽  
Stat Signaling

Abstract Introduction The expansion of insulin-producing beta cells during pregnancy is critical to maintain glucose homeostasis in the face of increasing insulin resistance. Prolactin receptor (PRLR) signaling is one of the primary mediators of beta cell expansion during pregnancy, and loss of PRLR signaling results in reduced beta cell mass and gestational diabetes. Harnessing the proliferative potential of prolactin signaling to expand beta cell mass outside of the context of pregnancy requires quantitative understanding of the signaling at the molecular level. Methods A mechanistic computational model was constructed to describe prolactin-mediated JAK-STAT signaling in pancreatic beta cells. The effect of different regulatory modules was explored through ensemble modeling. A Bayesian approach for likelihood estimation was used to fit the model to experimental data from the literature. Results Including receptor upregulation, with either inhibition by SOCS proteins, receptor internalization, or both, allowed the model to match experimental results for INS-1 cells treated with prolactin. The model predicts that faster dimerization and nuclear import rates of STAT5B compared to STAT5A can explain the higher STAT5B nuclear translocation. The model was used to predict the dose response of STAT5B translocation in rat primary beta cells treated with prolactin and reveal possible strategies to modulate STAT5 signaling. Conclusions JAK-STAT signaling must be tightly controlled to obtain the biphasic response in STAT5 activation seen experimentally. Receptor up-regulation, combined with SOCS inhibition, receptor internalization, or both is required to match experimental data. Modulating reactions upstream in the signaling can enhance STAT5 activation to increase beta cell survival.

scholarly journals Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Rebeca Fernandez-Ruiz ◽  
Ainhoa García-Alamán ◽  
Yaiza Esteban ◽  
Joan Mir-Coll ◽  
Berta Serra-Navarro ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Proliferation ◽  
Cell Replication ◽  
Trophic Effect ◽  
Beta Cell Replication

AbstractExpanding the mass of pancreatic insulin-producing beta cells through re-activation of beta cell replication has been proposed as a therapy to prevent or delay the appearance of diabetes. Pancreatic beta cells exhibit an age-dependent decrease in their proliferative activity, partly related to changes in the systemic environment. Here we report the identification of CCN4/Wisp1 as a circulating factor more abundant in pre-weaning than in adult mice. We show that Wisp1 promotes endogenous and transplanted adult beta cell proliferation in vivo. We validate these findings using isolated mouse and human islets and find that the beta cell trophic effect of Wisp1 is dependent on Akt signaling. In summary, our study reveals the role of Wisp1 as an inducer of beta cell replication, supporting the idea that the use of young blood factors may be a useful strategy to expand adult beta cell mass.

scholarly journals BACE1, but not BACE2, function is critical for metabolic disorders induced by high-fat diets in C57BL/6N mice

2021 ◽  
Author(s):  
Thomas W Rosahl ◽  
Lynn A Hyde ◽  
Patrick T Reilly ◽  
Marie-France Champy ◽  
Kristin J Belongie ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Glucose Tolerance ◽  
Beta Cell ◽  
Pancreatic Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
High Fat ◽  
Modest Improvement ◽  
Peripheral Tissues

Beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is required for the production of toxic amyloid peptides and is highly expressed in the brain, but also to a lesser extent in major peripheral organs such as muscle and liver. In contrast, BACE2 is mainly expressed in peripheral tissues and is enriched in pancreatic beta cells, where it regulates beta-cell function and mass. Previous reports demonstrated that loss of BACE1 function decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice, whereas mice lacking Bace2 exhibit reduced blood glucose levels, improved intraperitoneal glucose tolerance and increased beta-cell mass. Impaired glucose homeostasis and insulin resistance are hallmarks of type 2 diabetes and have been implicated in Alzheimers disease. Therefore, we tested the contribution of the individual BACE isoforms to those metabolic phenotypes by placing Bace1 knockout (KO), Bace2 KO, Bace1/2 double knockout (dKO) and wild-type (WT) mice on a high-fat high-cholesterol diet (HFD) for 16 weeks. Bace1 KO and Bace1/2 dKO mice showed decreased body weight and improved glucose tolerance and insulin resistance vs. WT mice. Conversely, Bace2 KO mice did not show any significant differences in body weight, glucose tolerance or insulin resistance under our experimental conditions. Finally, subchronic MBi-3 mediated BACE1/2 inhibition in mice in conjunction with a HFD resulted in a modest improvement of glucose tolerance. Our data indicate that lack of BACE1, but not BACE2, function contributes mainly to the metabolic phenotypic changes observed in Bace1/2 dKO mice, suggesting that inhibition of BACE1 has the greater role (vs. BACE2) in any potential improvements in metabolic homeostasis.

scholarly journals MicroRNA-24 promotes pancreatic beta cells toward dedifferentiation to avoid endoplasmic reticulum stress-induced apoptosis

2019 ◽  
Vol 11 (9) ◽  
pp. 747-760 ◽  
Author(s):  
Yunxia Zhu ◽  
Yi Sun ◽  
Yuncai Zhou ◽  
Yan Zhang ◽  
Tao Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Beta Cell ◽  
Er Stress ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Stress Conditions ◽  
Beta Cell Apoptosis ◽  
Induced Apoptosis

AbstractCurrent research indicates that beta cell loss in type 2 diabetes may be attributed to beta cell dedifferentiation rather than apoptosis; however, the mechanisms by which this occurs remain poorly understood. Our previous study demonstrated that elevation of microRNA-24 (miR-24) in a diabetic setting caused beta cell dysfunction and replicative deficiency. In this study, we focused on the role of miR-24 in beta cell apoptosis and dedifferentiation under endoplasmic reticulum (ER) stress conditions. We found that miR-24 overabundance protected beta cells from thapsigargin-induced apoptosis at the cost of accelerating the impairment of glucose-stimulated insulin secretion (GSIS) and enhancing the presence of dedifferentiation markers. Ingenuity® Pathway Analysis (IPA) revealed that elevation of miR-24 had an inhibitory effect on XBP1 and ATF4, which are downstream effectors of two key branches of ER stress, by inhibiting its direct target, Ire1α. Notably, elevated miR-24 initiated another pathway that targeted Mafa and decreased GSIS function in surviving beta cells, thus guiding their dedifferentiation under ER stress conditions. Our results demonstrated that the elevated miR-24, to the utmost extent, preserves beta cell mass by inhibiting apoptosis and inducing dedifferentiation. This study not only provides a novel mechanism by which miR-24 dominates beta cell turnover under persistent metabolic stress but also offers a therapeutic consideration for treating diabetes by inducing dedifferentiated beta cells to re-differentiation.

scholarly journals The Harmine and Exendin-4 Combination Markedly Expands Human Beta Cell Mass In Vivo: Quantification and Visualization By iDISCO+ 3D Imaging

2020 ◽  
Author(s):  
Carolina Rosselot ◽  
Alexandra Alvarsson ◽  
Peng Wang ◽  
Yansui Li ◽  
Kunal Kumar ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Proliferation ◽  
Light Sheet Microscopy ◽  
Human Beta Cell

AbstractSince all diabetes results from reductions in numbers of functional pancreatic beta cells, beta cell regenerative drugs are required for optimal and scalable future diabetes treatment. While many diabetes drugs are in clinical use, none increases human beta cell numbers. We have shown that a combination of the DYRK1A inhibitor, harmine, with the GLP1 receptor agonist, exendin-4, markedly increases human beta cell proliferation in vitro. However, technological limitations have prevented assessment of human beta cell mass in vivo. Here, we describe a novel method that combines iDISCO+ tissue clearing, insulin immunolabeling, light sheet microscopy, and volumetric quantification of human beta cells transplanted into immunodeficient mice. We demonstrate a striking seven-fold in vivo increase in human beta cell mass in response to three months of combined harmine-exendin-4 combination infusion, accompanied by lower blood glucose levels, increased plasma human insulin concentrations and enhanced beta cell proliferation. These studies unequivocally demonstrate for the first time that pharmacologic human beta cell expansion is a realistic and achievable path to diabetes therapy, and provide a rigorous, entirely novel and reproducible tool for quantifying human beta cell mass in vivo.

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