Selective and sequential loss of transcriptional factors: A hallmark of β‐cell failure in type 2 diabetes?

Shirakawa, Jun; Terauchi, Yasuo

doi:10.1111/jdi.12212

Cited by 4 publications

(4 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…P values by one-way ANOVA followed by Dunnett's multiple comparisons test were *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. signaling, including PDX1 as well the insulin gene itself 50,67,68 . Loss of the MAF factors appears at the top of a cascade of β-cell transcription factor loss in the process of β-cell de-differentiation 69 , with results in rodents demonstrating that these factors are highly sensitive targets with respect to hyperglycemia or oxidative stress. The reported loss of MAFB expression in diabetic islets warrants further investigation results presented here indicate this has detrimental consequences as residual MAFB−/− β-like cells produced in our differentiations fail to generate functional glucose-responsive cells after transplantation and results in EndoC-βH2 cells support a critical role of MAFB in β-cell identity.…”

Section: Discussionmentioning

confidence: 99%

Loss of the transcription factor MAFB limits β-cell derivation from human PSCs

et al. 2020

View full text Add to dashboard Cite

Next generation sequencing studies have highlighted discrepancies in β-cells which exist between mice and men. Numerous reports have identified MAF BZIP Transcription Factor B (MAFB) to be present in human β-cells postnatally, while its expression is restricted to embryonic and neo-natal β-cells in mice. Using CRISPR/Cas9-mediated gene editing, coupled with endocrine cell differentiation strategies, we dissect the contribution of MAFB to β-cell development and function specifically in humans. Here we report that MAFB knockout hPSCs have normal pancreatic differentiation capacity up to the progenitor stage, but favor somatostatin-and pancreatic polypeptide-positive cells at the expense of insulin-and glucagonproducing cells during endocrine cell development. Our results describe a requirement for MAFB late in the human pancreatic developmental program and identify it as a distinguishing transcription factor within islet cell subtype specification. We propose that hPSCs represent a powerful tool to model human pancreatic endocrine development and associated disease pathophysiology.

show abstract

Section: Discussionmentioning

confidence: 99%

Loss of the transcription factor MAFB limits β-cell derivation from human PSCs

et al. 2020

View full text Add to dashboard Cite

show abstract

“…PRKCA is a kinase involved in glucose transporter activation (Lee et al 2015) and SLC2A2, also known as glucose transporter 2 (GLUT2), is a bidirectional glucose transporter that is responsible for the bulk of glucose transportation in the cell (Mueckler and Thorens 2013). SLC2A2 and its regulator gene, NR4A1, are transcriptionally and translationally sensitive to oxidative stress (Lee et al 2014;Shimizu et al 2015;Shirakawa and Terauchi 2014). We presume that these disturbances in metabolic profiles and the transcriptome converge to explain increased ROS generation and glucose metabolic dysfunction after MNPs@ SiO 2 (RITC) exposure in vitro.…”

Section: Discussionmentioning

confidence: 99%

Silica-coated magnetic nanoparticles induce glucose metabolic dysfunction in vitro via the generation of reactive oxygen species

et al. 2019

View full text Add to dashboard Cite

Nanoparticles are a useful material in biomedicine given their unique properties and biocompatibility; however, there is increasing concern regarding the potential toxicity of nanoparticles with respect to cell metabolism. Some evidence suggests that nanoparticles can disrupt glucose and energy homeostasis. In this study, we investigated the metabolomic, transcriptomic, and integrated effects of silica-coated magnetic nanoparticles containing rhodamine B isothiocyanate dye [MNPs@ SiO 2 (RITC)] on glucose metabolism in human embryonic kidney 293 (HEK293) cells. Using gas chromatography-tandem mass spectrometry, we analysed the metabolite profiles of 14 organic acids (OAs), 20 amino acids (AAs), and 13 fatty acids (FAs) after treatment with 0.1 or 1.0 µg/µl MNPs@SiO 2 (RITC) for 12 h. The metabolic changes were highly related to reactive oxygen species (ROS) generation and glucose metabolism. Additionally, effects on the combined metabolome and transcriptome or "metabotranscriptomic network" indicated a relationship between ROS generation and glucose metabolic dysfunction. In the experimental validation, MNPs@SiO 2 (RITC) treatment significantly decreased the amount of glucose in cells and was associated with a reduction in glucose uptake efficiency. Decreased glucose uptake efficiency was also related to ROS generation and impaired glucose metabolism in the metabotranscriptomic network. Our results suggest that exposure to high concentrations of MNPs@SiO 2 (RITC) produces maladaptive alterations in glucose metabolism and specifically glucose uptake as well as related metabolomic and transcriptomic disturbances via increased ROS generation. These findings further indicate that an integrated metabotranscriptomics approach provides useful and sensitive toxicological assessment for nanoparticles.

show abstract

“…A decrease of MafA transcriptional activity regulated by miR-149 may contribute to the iAs-induced impairment of β-cell function (72). Such decreases in MafA, Pdx1 , or Nkx6.1 are generally considered indications of β-cell failure or de-differentiation (91). Other model systems of iAs exposure, in which gene expression levels of these transcription factors were measured, did not report such a de-differentiation phenotype (23).…”

Section: Model System Evidence For Pancreatic β-Cell Involvementmentioning

confidence: 99%

Braving the Element: Pancreatic β-Cell Dysfunction and Adaptation in Response to Arsenic Exposure

Carmean

Seino

2019

Front. Endocrinol.

View full text Add to dashboard Cite

Type 2 diabetes mellitus (T2DM) is a serious global health problem, currently affecting an estimated 451 million people worldwide. T2DM is characterized by hyperglycemia and low insulin relative to the metabolic demand. The precise contributing factors for a given individual vary, but generally include a combination of insulin resistance and insufficient insulin secretion. Ultimately, the progression to diabetes occurs only after β-cells fail to meet the needs of the individual. The stresses placed upon β-cells in this context manifest as increased oxidative damage, local inflammation, and ER stress, often inciting a destructive spiral of β-cell death, increased metabolic stress due to further insufficiency, and additional β-cell death. Several pathways controlling insulin resistance and β-cell adaptation/survival are affected by a class of exogenous bioactive compounds deemed endocrine disrupting chemicals (EDCs). Epidemiological studies have shown that, in several regions throughout the world, exposure to the EDC inorganic arsenic (iAs) correlates significantly with T2DM. It has been proposed that a lifetime of exposure to iAs may exacerbate problems with both insulin sensitivity as well as β-cell function/survival, promoting the development of T2DM. This review focuses on the mechanisms of iAs action as they relate to known adaptive and maladaptive pathways in pancreatic β-cells.

show abstract

Selective and sequential loss of transcriptional factors: A hallmark of β‐cell failure in type 2 diabetes?

Cited by 4 publications

References 6 publications

Loss of the transcription factor MAFB limits β-cell derivation from human PSCs

Loss of the transcription factor MAFB limits β-cell derivation from human PSCs

Silica-coated magnetic nanoparticles induce glucose metabolic dysfunction in vitro via the generation of reactive oxygen species

Braving the Element: Pancreatic β-Cell Dysfunction and Adaptation in Response to Arsenic Exposure

Contact Info

Product

Resources

About