Pancreatic β Cell Dedifferentiation in Diabetes and Redifferentiation following Insulin Therapy

Wang, Zhiyu; York, Nathaniel W.; Nichols, Colin G.; Remedi, Marı́a S.

doi:10.1016/j.cmet.2014.03.010

Cited by 369 publications

(392 citation statements)

References 57 publications

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“…Dedifferentiation of beta cells is a topic of current islet research, and important contributions have been published by several groups in recent years during the course of this study [8,13,14]. In addition, Hang et al showed that MafA is required in adult beta cells for the maintenance of their phenotype but not for their initial differentiation [31], which is consistent with our results.…”

Section: Discussionsupporting

confidence: 81%

“…Reversing the dedifferentiation of insulin-negative beta cells restores beta cell function after the normalisation of hyperglycaemia [13,33], suggesting that beta cells are plastic until a certain stage. Our study suggests that inducing the redifferentiation of beta cells using extrinsic factors may be an effective treatment for diabetes and MafA may be a potential therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, recent studies have identified factors critical for the maintenance of a mature beta cell phenotype. The loss of a mature beta cell phenotype results in the dedifferentiation of beta cells [8,[12][13][14][15][16], which may be implicated in compromised beta cell function in diabetes, although the molecular mechanisms remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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MafA is critical for maintenance of the mature beta cell phenotype in mice

2014

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Aims/hypothesis The plasticity of adult somatic cells allows for their dedifferentiation or conversion to different cell types, although the relevance of this to disease remains elusive. Perturbation of beta cell identity leading to dedifferentiation may be implicated in the compromised functions of beta cells in diabetes, which is a current topic of islet research. This study aims to investigate whether or not v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), a mature beta cell marker, is involved in maintaining mature beta cell phenotypes. Methods The fate and gene expression of beta cells were analysed in Mafa knockout (KO) mice and mouse models of diabetes in which the expression of MafA was reduced in the majority of beta cells. Results Loss of MafA reduced the beta to alpha cell ratio in pancreatic islets without elevating blood glucose to diabetic levels. Lineage tracing analyses showed reduced/lost expression of insulin in most beta cells, with a minority of the former beta cells converted to glucagon-expressing cells in Mafa KO mice. The upregulation of genes that are normally repressed in mature beta cells or transcription factors that are transiently expressed in endocrine progenitors was identified in Mafa KO islets as a hallmark of dedifferentiation. The compromised beta cells in db/db and multiple low-dose streptozotocin mice underwent similar dedifferentiation with expression of Mafb, which is expressed in immature beta cells. Conclusions/interpretation The maturation factor MafA is critical for the homeostasis of mature beta cells and regulates cell plasticity. The loss of MafA in beta cells leads to a deeper loss of cell identity, which is implicated in diabetes pathology.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MafA is critical for maintenance of the mature beta cell phenotype in mice

2014

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“…However, findings in transgenic mice suggest that new b-cells arise from existing b-cells (Dor et al 2004). Recent studies indicate that b-cells may dedifferentiate under metabolic stresses (Talchai et al 2012), and that insulin therapy can cause redifferentiation of dedifferentiated b-cells (Wang et al 2014). RYGB surgery resulting in b-cell redifferentiation may also lead to increased b-cell ratio and mass, as observed in our animal model.…”

Section: Discussionsupporting

confidence: 48%

Pancreatic hyperplasia after gastric bypass surgery in a GK rat model of non-obese type 2 diabetes

Zhou

Qian

et al. 2015

Journal of Endocrinology

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Gastric bypass surgery produces clear antidiabetic effects in a substantial proportion of morbidly obese patients. In view of the recent trend away from 'bariatric' surgery and toward 'metabolic' surgery, it is important to elucidate the enhancing effect of bypass surgery on pancreatic b-cell mass, which is related to diabetes remission in non-obese patients. We investigated the effects of gastric bypass surgery on glycemic control and other pancreatic changes in a spontaneous non-obese type 2 diabetes Goto-Kakizaki rat model. Significant improvements in postprandial hyperglycemia and plasma c-peptide level were observed when glucose was administered orally post-surgery. Other important events observed after surgery were enhanced first phase insulin secretion in a in site pancreatic perfusion experiment, pancreatic hyperplasia, improved islet structure (revealed by immunohistochemical analysis), striking increase in b-cell mass, slight increase in ratio of b-cell area to total pancreas area, and increased number of small islets closely related to exocrine ducts. No notable changes were observed in ratio of b-cell to non-b endocrine cell area, b-cell apoptosis, or b-cell proliferation. These findings demonstrate that gastric bypass surgery in this rat model increases endocrine cells and pancreatic hyperplasia, and reflect the important role of the gastrointestinal system in regulation of metabolism. Key Words" type 2 diabetes mellitus " gastric bypass surgery

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“…their ability to transdifferentiate to other cell types (JONAS et al 1999;PAPIZAN et al 2011;TALCHAI et al 2012;WANG et al 2014). …”

Section: Discussionmentioning

confidence: 99%

Genetic Drivers of Pancreatic Islet Function

et al. 2018

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The majority of gene loci that have been associated with type 2 diabetes play a role in pancreatic islet function. To evaluate the role of islet gene expression in the etiology of diabetes, we sensitized a genetically diverse mouse population with a Western diet high in fat (45%-kcal) and sucrose (34%) and carried out genome-wide association mapping of diabetes-related phenotypes. We quantified mRNA abundance in the islets and identified 18,820 expression quantitative trait loci. We applied mediation analysis to identify candidate causal driver genes at loci that affect the abundance of numerous transcripts. These include two genes previously associated with monogenic diabetes (PDX1 and HNF4A), as well as three genes with nominal association with diabetes-related traits in humans (FAM83E, IL6ST, and SAT2). We grouped transcripts into gene modules and mapped regulatory loci for modules enriched with transcripts specific for α-cells, and another specific for δ-cells. However, no single module enriched for β-cell-specific transcripts, suggesting heterogeneity of gene expression patterns within the β-cell population. A module enriched in transcripts associated with branched chain amino acid metabolism was the most strongly correlated with physiological traits that reflect insulin resistance. Although the mice in this study were not overtly diabetic, the analysis of pancreatic islet gene expression under dietary-induced stress enabled us to identify correlated variation in groups of genes that are functionally linked to diabetes-associated physiological traits. Our analysis suggests an expected degree of concordance between diabetes-associated loci in the mouse with those found in human populations and demonstrates how the mouse can provide evidence to support nominal associations found in human genome-wide association mapping.4

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Pancreatic β Cell Dedifferentiation in Diabetes and Redifferentiation following Insulin Therapy

Cited by 369 publications

References 57 publications

MafA is critical for maintenance of the mature beta cell phenotype in mice

MafA is critical for maintenance of the mature beta cell phenotype in mice

Pancreatic hyperplasia after gastric bypass surgery in a GK rat model of non-obese type 2 diabetes

Genetic Drivers of Pancreatic Islet Function

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