scholarly journals REST is a major negative regulator of endocrine differentiation during pancreas organogenesis

2021 ◽  
Author(s):  
Meritxell Rovira ◽  
Goutham Atla ◽  
Miguel Angel Maestro ◽  
Vane Grau ◽  
Javier García-Hurtado ◽  
...  
Keyword(s):  
Endocrine Cells ◽  
Cell Formation ◽  
Negative Regulator ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Endocrine Differentiation ◽  
Pancreatic Progenitors ◽  
Conditional Allele ◽  
Embryonic Pancreas ◽  
Dependent Inhibition

Multiple transcription factors have been shown to promote pancreatic β-cell differentiation, yet much less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrinogenesis in the embryonic pancreas. However, pancreatic Rest knockout mice failed to show abnormal numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we observed a marked increase in pancreatic endocrine cell formation. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts and induced β-cell-specific genes in human adult duct-derived organoids. We also defined genomic sites that are bound and repressed by REST in the embryonic pancreas. Our findings show that REST-dependent inhibition ensures a balanced production of endocrine cells from embryonic pancreatic progenitors.

scholarly journals REST is a major negative regulator of endocrine differentiation during pancreas organogenesis

2021 ◽  
Author(s):  
Meritxell Rovira ◽  
Goutham Atla ◽  
Miguel Angel Maestro ◽  
Vane Grau ◽  
Javier García-Hurtado ◽  
...  
Keyword(s):  
Endocrine Cells ◽  
Negative Regulator ◽  
Β Cell ◽  
Knock Out ◽  
Endocrine Differentiation ◽  
Conditional Allele ◽  
Embryonic Pancreas ◽  
Pancreatic Endocrine Cells ◽  
Knock Out Mice

SUMMARYUnderstanding genomic regulatory mechanisms of pancreas differentiation is relevant to the pathophysiology of diabetes mellitus, and to the development of replacement therapies. Numerous transcription factors promote β cell differentiation, although less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrine gene programs in the embryonic pancreas. However, pancreaticRestknock-out mice failed to show increased numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we now observe a marked increase in the formation of pancreatic endocrine cells. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts, and induced β-cell specific genes in human adult duct-derived organoids. Finally, we define REST genomic programs that suppress pancreatic endocrine differentiation. These results establish a crucial role of REST as a negative regulator of pancreatic endocrine differentiation.

scholarly journals Nuclear factor κB–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity

2015 ◽  
Vol 212 (8) ◽  
pp. 1239-1254 ◽  
Author(s):  
Elisabeth K. Malle ◽  
Nathan W. Zammit ◽  
Stacey N. Walters ◽  
Yen Chin Koay ◽  
Jianmin Wu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Association Studies ◽  
Nuclear Factor Κb ◽  
Negative Regulator ◽  
Genome Wide Association Studies ◽  
Nuclear Factor ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
The Metabolic Syndrome

The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB–inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell–intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity.

scholarly journals Pancreatic β-cell replacement: advances in protocols used for differentiation of pancreatic progenitors to β-like cells

2015 ◽  
Author(s):  
Muhammad Waseem Ghani ◽  
Li Ye ◽  
Zhao Yi ◽  
Hammad Ghani ◽  
Muhammad Waseem Birmani ◽  
...  
Keyword(s):  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Replacement ◽  
Pancreatic Progenitors

scholarly journals Threshold-Dependent Cooperativity of Pdx1 and Oc1 in Pancreatic Progenitors Establishes Competency for Endocrine Differentiation and β-Cell Function

Cell Reports ◽  
2016 ◽  
Vol 15 (12) ◽  
pp. 2637-2650 ◽  
Author(s):  
Kathryn D. Henley ◽  
Diana E. Stanescu ◽  
Peter A. Kropp ◽  
Christopher V.E. Wright ◽  
Kyoung-Jae Won ◽  
...  
Keyword(s):  
Cell Function ◽  
Β Cell ◽  
Endocrine Differentiation ◽  
Pancreatic Progenitors ◽  
Β Cell Function

scholarly journals Munc-18 Associates with Syntaxin and Serves as a Negative Regulator of Exocytosis in the Pancreatic β-Cell

2000 ◽  
Vol 275 (52) ◽  
pp. 41521-41527 ◽  
Author(s):  
Wei Zhang ◽  
Alexander Efanov ◽  
Shao-Nian Yang ◽  
Gabriel Fried ◽  
Susanne Kölare ◽  
...  
Keyword(s):  
Negative Regulator ◽  
Pancreatic Β Cell ◽  
Β Cell

scholarly journals MafA is a dedicated activator of the insulin gene in vivo

2008 ◽  
Vol 198 (2) ◽  
pp. 271-279 ◽  
Author(s):  
Isabella Artner ◽  
Yan Hang ◽  
Min Guo ◽  
Guoqiang Gu ◽  
Roland Stein
Keyword(s):  
Transcriptional Control ◽  
Ectopic Expression ◽  
Cell Formation ◽  
Β Cells ◽  
Β Cell ◽  
In Ovo ◽  
Over Expression ◽  
Embryonic Pancreas ◽  
And Function

As successful generation of insulin-producing cells could be used for diabetes treatment, a concerted effort is being made to understand the molecular programs underlying islet β-cell formation and function. The closely related MafA and MafB transcription factors are both key mammalian β-cell regulators. MafA and MafB are co-expressed in insulin+β-cells during embryogenesis, while in the adult pancreas only MafA is produced in β-cells and MafB in glucagon+α-cells. MafB−/− animals are also deficient in insulin+ and glucagon+ cell production during embryogenesis. However, only MafA over-expression selectively induced endogenous Insulin mRNA production in cell line-based assays, while MafB specifically promoted Glucagon expression. Here, we analyzed whether these factors were sufficient to induce insulin+ and/or glucagon+ cell formation within embryonic endoderm using the chick in ovo electroporation assay. Ectopic expression of MafA, but not MafB, promoted Insulin production; however, neither MafA nor MafB were capable of inducing Glucagon. Co-electroporation of MafA with the Ngn3 transcription factor resulted in the development of more organized cell clusters containing both insulin- and glucagon-producing cells. Analysis of chimeric proteins of MafA and MafB demonstrated that chick Insulin activation depended on sequences within the MafA C-terminal DNA-binding domain. MafA was also bound to Insulin and Glucagon transcriptional control sequences in mouse embryonic pancreas and β-cell lines. Collectively, these results demonstrate a unique ability for MafA to independently activate Insulin transcription.

scholarly journals Expression of Mixed Lineage Kinase-1 in Pancreatic β-Cell Lines at Different Stages of Maturation and during Embryonic Pancreas Development

1997 ◽  
Vol 272 (26) ◽  
pp. 16364-16373 ◽  
Author(s):  
Henry J. DeAizpurua ◽  
David S. Cram ◽  
Gaetano Naselli ◽  
Lisa Devereux ◽  
Donna S. Dorow
Keyword(s):  
Cell Lines ◽  
Pancreas Development ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Mixed Lineage Kinase ◽  
Embryonic Pancreas

Adipokines as key players in β cell function and failure

2019 ◽  
Vol 133 (22) ◽  
pp. 2317-2327 ◽  
Author(s):  
Nicolás Gómez-Banoy ◽  
James C. Lo
Keyword(s):  
Metabolic Diseases ◽  
Cell Function ◽  
Whole Body ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Axis ◽  
Β Cell Function ◽  
Prevalence Of Obesity ◽  
Specific Factors ◽  
Whole Body Metabolism

Abstract The growing prevalence of obesity and its related metabolic diseases, mainly Type 2 diabetes (T2D), has increased the interest in adipose tissue (AT) and its role as a principal metabolic orchestrator. Two decades of research have now shown that ATs act as an endocrine organ, secreting soluble factors termed adipocytokines or adipokines. These adipokines play crucial roles in whole-body metabolism with different mechanisms of action largely dependent on the tissue or cell type they are acting on. The pancreatic β cell, a key regulator of glucose metabolism due to its ability to produce and secrete insulin, has been identified as a target for several adipokines. This review will focus on how adipokines affect pancreatic β cell function and their impact on pancreatic β cell survival in disease contexts such as diabetes. Initially, the “classic” adipokines will be discussed, followed by novel secreted adipocyte-specific factors that show therapeutic promise in regulating the adipose–pancreatic β cell axis.

INCRETIN AND DIABETES

2011 ◽  
pp. 5-10
Author(s):  
Huu Dang Tran
Keyword(s):  
Type 2 Diabetes ◽  
Cell Proliferation ◽  
Glycaemic Control ◽  
Animal Studies ◽  
Dipeptidyl Peptidase ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Glucose Sensitivity ◽  
Cell Glucose

The incretins are peptide hormones secreted from the gut in response to food. They increase the secretion of insulin. The incretin response is reduced in patients with type 2 diabetes so drugs acting on incretins may improve glycaemic control. Incretins are metabolised by dipeptidyl peptidase, so selectively inhibiting this enzyme increases the concentration of circulating incretins. A similar effect results from giving an incretin analogue that cannot be cleaved by dipeptidyl peptidase. Studies have identified other actions including improvement in pancreatic β cell glucose sensitivity and, in animal studies, promotion of pancreatic β cell proliferation and reduction in β cell apoptosis.

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