scholarly journals The Many Lives of Myc in the Pancreatic β-Cell

2020 ◽  
pp. jbc.REV120.011149
Author(s):  
Carolina Rosselot ◽  
Sharon Baumel-Alterzon ◽  
Yansui Li ◽  
Gabriel Brill ◽  
Luca Lambertini ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Diabetic Patients ◽  
Cell Regeneration ◽  
Diabetes Research ◽  
Β Cells ◽  
Β Cell

Diabetes results from insufficient numbers of functional pancreatic β-cells. Thus, increasing the number of available functional β-cells ex vivo for transplantation, or regenerating them in situ in diabetic patients, is a major focus of diabetes research. The transcription factor, Myc, discovered decades ago, lies at the nexus of most, if not all, known proliferative pathways. Based on this, many studies in the 1990’s and early 2000’s explored the potential of harnessing Myc expression to expand β-cells for diabetes treatment. Nearly all these studies in β-cells used pathophysiological or supraphysiological levels of Myc and reported enhanced β-cell death, de-differentiation or the formation of insulinomas if co-overexpressed with Bcl-xL, an inhibitor of apoptosis. This obviously reduced the enthusiasm for Myc as a therapeutic target for β-cell regeneration. However, recent studies indicate that “gentle” induction of Myc expression enhances β-cell replication without induction of cell death or loss of insulin secretion, suggesting that appropriate levels of Myc could have therapeutic potential for β-cell regeneration. Furthermore, although it has been known for decades that Myc is induced by glucose in β-cells very little is known about how this essential anabolic transcription factor perceives and responds to nutrients and increased insulin demand in vivo. Here we summarize the previous and recent knowledge of Myc in the β-cell, its potential for β-cell regeneration and its physiological importance for neonatal and adaptive β-cell expansion.

scholarly journals An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jinyoung Kim ◽  
Kihyoun Park ◽  
Min Jung Kim ◽  
Hyejin Lim ◽  
Kook Hwan Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Therapeutic Modality ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Islet Amyloid ◽  
Amyloid Accumulation ◽  
Human Diabetes

AbstractWe have reported that autophagy is crucial for clearance of amyloidogenic human IAPP (hIAPP) oligomer, suggesting that an autophagy enhancer could be a therapeutic modality against human diabetes with amyloid accumulation. Here, we show that a recently identified autophagy enhancer (MSL-7) reduces hIAPP oligomer accumulation in human induced pluripotent stem cell-derived β-cells (hiPSC-β-cells) and diminishes oligomer-mediated apoptosis of β-cells. Protective effects of MSL-7 against hIAPP oligomer accumulation and hIAPP oligomer-mediated β-cell death are significantly reduced in cells with knockout of MiTF/TFE family members such as Tfeb or Tfe3. MSL-7 improves glucose tolerance and β-cell function of hIAPP+ mice on high-fat diet, accompanied by reduced hIAPP oligomer/amyloid accumulation and β-cell apoptosis. Protective effects of MSL-7 against hIAPP oligomer-mediated β-cell death and the development of diabetes are also significantly reduced by β-cell-specific knockout of Tfeb. These results suggest that an autophagy enhancer could have therapeutic potential against human diabetes characterized by islet amyloid accumulation.

scholarly journals NEUROD1 Is Required for the Early α and β Endocrine Differentiation in the Pancreas

2021 ◽  
Vol 22 (13) ◽  
pp. 6713
Author(s):  
Romana Bohuslavova ◽  
Ondrej Smolik ◽  
Jessica Malfatti ◽  
Zuzana Berkova ◽  
Zaneta Novakova ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Cell Mass ◽  
Neonatal Diabetes ◽  
Diabetes Research ◽  
Pancreas Development ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Islet Cell ◽  
Endocrine Differentiation

Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex interactions of signaling pathways and transcription factor networks regulate the specification, growth, and differentiation of cell types in the developing pancreas. Many of the same regulators continue to modulate gene expression and cell fate of the adult pancreas. The transcription factor NEUROD1 is essential for the maturation of β cells and the expansion of the pancreatic islet cell mass. Mutations of the Neurod1 gene cause diabetes in humans and mice. However, the different aspects of the requirement of NEUROD1 for pancreas development are not fully understood. In this study, we investigated the role of NEUROD1 during the primary and secondary transitions of mouse pancreas development. We determined that the elimination of Neurod1 impairs the expression of key transcription factors for α- and β-cell differentiation, β-cell proliferation, insulin production, and islets of Langerhans formation. These findings demonstrate that the Neurod1 deletion altered the properties of α and β endocrine cells, resulting in severe neonatal diabetes, and thus, NEUROD1 is required for proper activation of the transcriptional network and differentiation of functional α and β cells.

GENETICALLY ENGINEERED PIG MODELS FOR TRANSLATIONAL DIABETES RESEARCH

2013 ◽  
Vol 25 (1) ◽  
pp. 320 ◽  
Author(s):  
Eckhard Wolf
Keyword(s):  
Mouse Models ◽  
Cell Mass ◽  
Physiological Age ◽  
Diabetic Patients ◽  
Diabetes Research ◽  
Rodent Models ◽  
Β Cells ◽  
Β Cell ◽  
Transgenic Pigs ◽  
Genetic Modifications

Animal models play crucial roles for understanding disease mechanisms and for the development and evaluation of therapeutic strategies. In biomedicine, classical rodent models are most widely used for several reasons, including standardization of genetics and environment, cost efficiency, and the possibility to introduce targeted genetic modifications for the generation of tailored disease models. However, due to differences in anatomical and physiological characteristics, rodent models do not always reflect the situation of human patients sufficiently well to be predictive in terms of efficacy and safety of new therapies. In this respect, the pig has been discussed as a missing link between mouse models and human patients. As a monogastric omnivore, the pig shares many anatomical and physiological similarities with humans. Importantly, the techniques for genetic modification of pigs have been refined to a level allowing almost the same spectrum of alterations as in mouse models (Aigner et al. 2010 J. Mol. Med. (Berl.) 88, 653–664). These include inducible transgene expression systems (Klymiuk et al. 2012 FASEB J. 26, 1086–1099) as well as the introduction of targeted genetic modifications (Klymiuk et al. 2012 J. Mol. Med. (Berl.) 90, 597–608). A major focus of our laboratory is the generation, characterisation, and implementation of pig models for translational diabetes research. Transgenic pigs expressing a dominant negative receptor for the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) demonstrated a crucial role of the GIP system for the physiological age-related expansion of pancreatic β-cell mass. Moreover, this animal model shares important characteristics of type 2 diabetes mellitus: impaired incretin effect, reduced glucose tolerance and insulin secretion, and a progressive reduction of β-cell mass (Renner et al. 2010 Diabetes 59, 1228–1238). More recently, we used this model to search for metabolic biomarkers which are associated with progression in the pre-diabetic period and identified specific amino acid and lipid signatures as candidate biomarkers (Renner et al. 2012 Diabetes 61, 2166–2175). Further, we created the first pig model for permanent neonatal diabetes by expression C94Y mutant insulin in the β-cells of transgenic pigs. In addition to their use as biomedical models, pigs may also serve as organ and tissue donors for xenotransplantation. Transplantation of encapsulated porcine pancreatic islets to type 1 diabetic patients with severe unaware hypoglycemia has already entered clinical studies, but encapsulation may shorten the lifespan of the islets. Therefore, in order to overcome the rejection of pig islets by human T-cells, we generated transgenic pigs expressing the optimized CTLA-4Ig variant LEA29Y in the pancreatic β-cells. Islets from LEA29Y transgenic pigs rescued diabetes and were protected against rejection in a humanized mouse model (Klymiuk et al. 2012 Diabetes 61, 1527–1532).

Role of NF-κB in β-cell death

2008 ◽  
Vol 36 (3) ◽  
pp. 334-339 ◽  
Author(s):  
Danielle Melloul
Keyword(s):  
Cell Death ◽  
Lymphocytic Infiltration ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell ◽  
Ifn Γ ◽  
Induced Apoptosis

Apoptotic β-cell death appears to be central to the pathogenesis of Type 1 diabetes mellitus and in islet graft rejection. The β-cell destruction is partially mediated by cytokines, such as IL-1β (interleukin 1β), TNFα (tumour necrosis factor α) and IFN-γ (interferon γ). IL-1β and TNFα mediate activation of the transcription factor NF-κB (nuclear factor κB) pathway. Use of a degradation-resistant NF-κB protein inhibitor (ΔNIκBα), specifically expressed in β-cells, significantly reduced IL-1β+IFN-γ-induced apoptosis. Moreover, in vivo, it protected against multiple low-dose streptozocin-induced diabetes, with reduced intra-islet lymphocytic infiltration. Thus β-cell-specific activation of NF-κB is a key event in the progressive loss of β-cells in diabetes. Inhibition of this process could be a potential effective strategy for β-cell protection.

scholarly journals In vivo generation and regeneration of β cells in zebrafish

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Bingyuan Yang ◽  
Brittney A. Covington ◽  
Wenbiao Chen
Keyword(s):  
Animal Models ◽  
Cell Regeneration ◽  
Pathological Feature ◽  
Β Cells ◽  
Β Cell ◽  
Regenerative Capacity ◽  
Chemical Genetic ◽  
Current State ◽  
Signaling Mechanisms

AbstractThe pathological feature of diabetes, hyperglycemia, is a result of an inadequate number and/or function of insulin producing β cells. Replenishing functional β cells is a strategy to cure the disease. Although β-cell regeneration occurs in animal models under certain conditions, human β cells are refractory to proliferation. A better understanding of both the positive and the negative regulatory mechanisms of β-cell regeneration in animal models is essential to develop novel strategies capable of inducing functional β cells in patients. Zebrafish are an attractive model system for studying β-cell regeneration due to the ease to which genetic and chemical-genetic approaches can be used as well as their high regenerative capacity. Here, we highlight the current state of β-cell regeneration studies in zebrafish with an emphasis on cell signaling mechanisms.

β-cell Regenerative Potential of Selected Herbal Extracts in Alloxan Induced Diabetic Rats

2019 ◽  
Vol 16 (3) ◽  
pp. 278-284 ◽  
Author(s):  
Anoja Priyadarshani Attanayake ◽  
Kamani Ayoma Perera Wijewardana Jayatilaka ◽  
Lakmini Kumari Boralugoda Mudduwa ◽  
Chitra Pathirana
Keyword(s):  
Plant Extracts ◽  
Biochemical Parameters ◽  
Serum Insulin ◽  
Diabetic Rats ◽  
Albino Rats ◽  
Cell Regeneration ◽  
Β Cells ◽  
Β Cell ◽  
Medicinal Plant Extracts

Background:Effective β-cell regeneration is a recognized therapeutic strategy in the treatment of type 1 diabetes mellitus. Regeneration of β-cells could be achieved via exogenous natural sources as medicinal plant extracts. Medicinal plants selected for the investigation were Spondias pinnata (Linn. f.) Kurz, Coccinia grandis (L.) Voigt and Gmelina arborea Roxb. The objective was to determine the β-cell regenerative potential of these plant extracts in alloxan-induced diabetic rats. Alloxan monohydrate was used to induce diabetes (150 mg/kg, ip).Methods:Wistar albino rats were divided into six groups (n=6); healthy untreated rats (healthy control), alloxan-induced diabetic untreated rats (diabetic control), diabetic rats received the extracts (treatment groups) of S. pinnata (1.0 g/kg), C. grandis (0.75 g/kg), G. arobrea (1.00 g/kg) and diabetic rats received glibenclamide (0.5 mg/kg; positive control). The above treatment was continued for 30 days. On the 30th day, the rats were sacrificed and biochemical parameters were determined. In addition, histopathology and immunohistochemistry on the pancreatic tissue were done on the 30th day.Results:According to the results obtained for biochemical parameters, there was a significant increase in the concentrations of serum insulin and C-peptide in plant extracts treated diabetic rats (p < 0.05). The extract of C. grandis produced the highest degree of β-cell regeneration demonstrated through an increase in the number of islets and percentage of the insulin-secreting β-cells (75%) in the pancreas of diabetic rats (p < 0.05) based on the histopathology and immunohistochemistry findings.Conclusion:The results revealed that the selected extracts of C. grandis (0.75 g/kg), G. arborea (1.00 g/kg) and S. pinnata (1.00 g/kg) exerted β-cell regenerative potential in diabetic rats. The three plant extracts would be valued as natural agents of prompting the β-cell regeneration in vivo.

scholarly journals Protection of pancreatic β-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies

2007 ◽  
Vol 193 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Shin Tsunekawa ◽  
Naoki Yamamoto ◽  
Katsura Tsukamoto ◽  
Yuji Itoh ◽  
Yukiko Kaneko ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Islet Cells ◽  
Binding Protein ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

The aim of this study was to investigate the in vivo and in vitro effects of exendin-4, a potent glucagon-like peptide 1 agonist, on the protection of the pancreatic β-cells against their cell death. In in vivo experiments, we used β-cell-specific calmodulin-overexpressing mice where massive apoptosis takes place in their β-cells, and we examined the effects of chronic treatment with exendin-4. Chronic and s.c. administration of exendin-4 reduced hyperglycemia. The treatment caused significant increases of the insulin contents of the pancreas and islets, and retained the insulin-positive area. Dispersed transgenic islet cells lived only shortly, and several endoplasmic reticulum (ER) stress-related molecules such as immunoglobulin-binding protein (Bip), inositol-requiring enzyme-1α, X-box-binding protein-1 (XBP-1), RNA-activated protein kinase-like endoplasmic reticulum kinase, activating transcription factor-4, and C/EBP-homologous protein (CHOP) were more expressed in the transgenic islets. We also found that the spliced form of XBP-1, a marker of ER stress, was also increased in β-cell-specific calmodulin-overexpressing transgenic islets. In the quantitative real-time PCR analyses, the expression levels of Bip and CHOP were reduced in the islets from the transgenic mice treated with exendin-4. These findings suggest that excess of ER stress occurs in the transgenic β-cells, and the suppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.

scholarly journals MafB Is Critical for Glucagon Production and Secretion in Mouse Pancreatic α Cells In Vivo

2018 ◽  
Vol 38 (8) ◽  
Author(s):  
Megumi C. Katoh ◽  
Yunshin Jung ◽  
Chioma M. Ugboma ◽  
Miki Shimbo ◽  
Akihiro Kuno ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Population ◽  
Pancreatic Polypeptide ◽  
Transporter Gene ◽  
Β Cells ◽  
Β Cell ◽  
Cell Numbers ◽  
Gene Expression Analyses

ABSTRACT The MafB transcription factor is expressed in pancreatic α and β cells during development but becomes exclusive to α cells in adult rodents. Mafb -null ( Mafb −/− ) mice were reported to have reduced α- and β-cell numbers throughout embryonic development. To further analyze the postnatal function of MafB in the pancreas, we generated endocrine cell-specific ( Mafb Δ Endo ) and tamoxifen-dependent ( Mafb Δ TAM ) Mafb knockout mice. Mafb Δ Endo mice exhibited reduced populations of insulin-positive (insulin + ) and glucagon + cells at postnatal day 0, but the insulin + cell population recovered by 8 weeks of age. In contrast, the Arx + glucagon + cell fraction and glucagon expression remained decreased even in adulthood. Mafb Δ TAM mice, with Mafb deleted after pancreas maturation, also demonstrated diminished glucagon + cells and glucagon content without affecting β cells. A decreased Arx + glucagon + cell population in Mafb Δ Endo mice was compensated for by an increased Arx + pancreatic polypeptide + cell population. Furthermore, gene expression analyses from both Mafb Δ Endo and Mafb Δ TAM islets revealed that MafB is a key regulator of glucagon expression in α cells. Finally, both mutants failed to respond to arginine, likely due to impaired arginine transporter gene expression and glucagon production ability. Taken together, our findings reveal that MafB is critical for the functional maintenance of mouse α cells in vivo , including glucagon production and secretion, as well as in development.

scholarly journals Dual-Reporter β-Cell-Specific Male Transgenic Rats for the Analysis of β-Cell Functional Mass and Enrichment by Flow Cytometry

Endocrinology ◽  
2015 ◽  
Vol 157 (3) ◽  
pp. 1299-1306 ◽  
Author(s):  
Julien Ghislain ◽  
Ghislaine Fontés ◽  
Caroline Tremblay ◽  
Melkam A. Kebede ◽  
Vincent Poitout
Keyword(s):  
Insulin Secretion ◽  
Fluorescent Protein ◽  
Ex Vivo ◽  
Yellow Fluorescent Protein ◽  
Cell Mass ◽  
Renilla Luciferase ◽  
Diabetes Research ◽  
Β Cells ◽  
Transgenic Rats ◽  
Β Cell

Abstract Mouse β-cell-specific reporter lines have played a key role in diabetes research. Although the rat provides several advantages, its use has lagged behind the mouse due to the relative paucity of genetic models. In this report we describe the generation and characterization of transgenic rats expressing a Renilla luciferase (RLuc)-enhanced yellow fluorescent protein (YFP) fusion under control of a 9-kb genomic fragment from the rat ins2 gene (RIP7-RLuc-YFP). Analysis of RLuc luminescence and YFP fluorescence revealed that reporter expression is restricted to β-cells in the adult rat. Physiological characteristics including body weight, fat and lean mass, fasting and fed glucose levels, glucose and insulin tolerance, and β-cell mass were similar between two RIP7-RLuc-YFP lines and wild-type littermates. Glucose-induced insulin secretion in isolated islets was indistinguishable from controls in one of the lines, whereas surprisingly, insulin secretion was defective in the second line. Consequently, subsequent studies were limited to the former line. We asked whether transgene activity was responsive to glucose as shown previously for the ins2 gene. Exposing islets ex vivo to high glucose (16.7 mM) or in vivo infusion of glucose for 24 hours increased luciferase activity in islets, whereas the fraction of YFP-positive β-cells after glucose infusion was unchanged. Finally, we showed that fluorescence-activated cell sorting of YFP-positive islet cells can be used to enrich for β-cells. Overall, this transgenic line will enable for the first time the application of both fluorescence and bioluminescence/luminescence-based approaches for the study of rat β-cells.

scholarly journals Loss of Foxd3 Results in Decreased β-Cell Proliferation and Glucose Intolerance During Pregnancy

Endocrinology ◽  
2011 ◽  
Vol 152 (12) ◽  
pp. 4589-4600 ◽  
Author(s):  
Jennifer L. Plank ◽  
Audrey Y. Frist ◽  
Alison W. LeGrone ◽  
Mark A. Magnuson ◽  
Patricia A. Labosky
Keyword(s):  
Cell Proliferation ◽  
Cell Mass ◽  
Diabetic Patients ◽  
Β Cells ◽  
Β Cell ◽  
Forkhead Box ◽  
Physiological Demands ◽  
Mass Expansion ◽  
Specific Deletion

A complete molecular understanding of β-cell mass expansion will be useful for the improvement of therapies to treat diabetic patients. During normal periods of metabolic challenges, such as pregnancy, β-cells proliferate, or self-renew, to meet the new physiological demands. The transcription factor Forkhead box D3 (Foxd3) is required for maintenance and self-renewal of several diverse progenitor cell lineages, and Foxd3 is expressed in the pancreatic primordium beginning at 10.5 d postcoitum, becoming localized predominantly to β-cells after birth. Here, we show that mice carrying a pancreas-specific deletion of Foxd3 have impaired glucose tolerance, decreased β-cell mass, decreased β-cell proliferation, and decreased β-cell size during pregnancy. In addition, several genes known to regulate proliferation, Foxm1, Skp2, Ezh2, Akt2, and Cdkn1a, are misregulated in islets isolated from these Foxd3 mutant mice. Together, these data place Foxd3 upstream of several pathways critical for β-cell mass expansion in vivo.

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