Pathological β-Cell Endoplasmic Reticulum Stress in Type 2 Diabetes: Current Evidence

Shrestha, Neha; Franco, Elisa De; Arvan, Peter; Cnop, Miriam

doi:10.3389/fendo.2021.650158

Cited by 77 publications

(73 citation statements)

References 71 publications

(67 reference statements)

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“…ATF4 and HSPA5 , independently validated as negative regulators, have not been previously implicated in GSIS, but are important players in endoplasmic reticulum (ER) stress response [ 23 , 24 ]. Clinical and genetic evidence suggests that ER stress is one of the molecular mechanisms underlying β-cell dysfunction [ 25 , 26 ]. ATF4 has been implicated in protection against dedifferentiation and β-cell loss under conditions of ER stress [ 23 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion

et al. 2022

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Type 2 diabetes (T2D) is a chronic metabolic disorder affecting almost half a billion people worldwide. Impaired function of pancreatic β-cells is both a hallmark of T2D and an underlying factor in the pathophysiology of the disease. Understanding the cellular mechanisms regulating appropriate insulin secretion has been of long-standing interest in the scientific and clinical communities. To identify novel genes regulating insulin secretion we developed a robust arrayed siRNA screen measuring basal, glucose-stimulated, and augmented insulin secretion by EndoC-βH1 cells, a human β-cell line, in a 384-well plate format. We screened 521 candidate genes selected by text mining for relevance to T2D biology and identified 23 positive and 68 negative regulators of insulin secretion. Among these, we validated ghrelin receptor (GHSR), and two genes implicated in endoplasmic reticulum stress, ATF4 and HSPA5. Thus, we have demonstrated the feasibility of using EndoC-βH1 cells for large-scale siRNA screening to identify candidate genes regulating β-cell insulin secretion as potential novel drug targets. Furthermore, this screening format can be adapted to other disease-relevant functional endpoints to enable large-scale screening for targets regulating cellular mechanisms contributing to the progressive loss of functional β-cell mass occurring in T2D.

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Section: Discussionmentioning

confidence: 99%

Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion

et al. 2022

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“…Collectively, these data suggest that in rodents, β cells from females are more resilient to ER stress. Considering the well-established links between ER stress and T2D (81,(84)(85)(86), our data suggests a model in which female β cells maintain better function in T2D because they are more resilient to ER stress and UPR activation. While this model will be important to test in further detail in future studies, our findings highlight the importance of including both sexes in islet and β cell studies to make accurate conclusions about β cell gene expression and function in both normal contexts and in disease.…”

Section: Discussionmentioning

confidence: 68%

“…While it is possible that female islets are resistant to Tg-induced cell death, we found a significant increase in apoptosis in female and male islet cells treated with 10 μM Tg (Figure 3E, F), suggesting that female islets were simply more resilient to mild ER stress than male islets. To determine whether this increased ER stress resilience was caused by differential UPR signaling, we monitored levels of several protein markers of UPR activation including binding immunoglobulin protein (BiP), phosphorylated inositol-requiring enzyme 1 (pIRE1), phosphorylated eukaryotic initiation factor a (peIF2a), and C/EBP homologous protein (CHOP) ( 81, 82 ) after treating male and female islets with 1 μM Tg for 24-hours. We found no sex difference in UPR protein markers between male and female islets without Tg treatment (Figure 3G-J; Figure 3-figure supplement 3A) and observed a significant increase in levels of pIRE1α and CHOP in islets from both sexes and BiP in female islets after a 24-hour Tg treatment (Figure 3G-J; Figure 3-figure supplement 3A).…”

Section: Resultsmentioning

confidence: 99%

Sex differences in islet stress responses support female beta cell resilience

Brownrigg

Xia

Chu

et al. 2022

Preprint

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Type 2 diabetes risk is ∼40% higher in men than in pre-menopausal women. Despite evidence that sex differences in pancreatic β cells play a role in this differential diabetes risk, few studies have examined diabetes-associated changes to β cell function in each sex. Our single-cell analysis of human β cells revealed profound sex-specific changes to gene expression and function in type 2 diabetes. To gain deeper insight into sex differences in β cells, we generated a well-powered islet RNAseq dataset from 20-week-old male and female mice with equivalent insulin sensitivity. This unbiased analysis revealed differential enrichment of unfolded protein response pathway-associated genes, where female islets showed higher expression of genes linked with protein synthesis, folding, and processing. This differential expression was biologically significant, as female islets were more resilient to endoplasmic reticulum (ER) stress induction with thapsigargin. Specifically, female islets maintained better insulin secretion and showed a distinct transcriptional response under ER stress compared with males. Given the known links between ER stress and T2D pathogenesis, our findings suggest sex differences in β cells contribute to the differential T2D risk between men and women.

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“…2G), confirming the scRNA-seq findings. Defective protein processing is a hallmark of the less differentiated β -cells (Lenghel et al 2020; Shrestha et al 2021), suggesting that TH+ β -cells may represent such a phenotype. To clarify this, we queried the “Beta-cell Hub” which features transcriptomic comparison of the immature and mature human β -cell states modeled by stem-cell derived β -like (sc- β− like) cells and human islet origin β -cells (Fang et al 2019; Weng et al 2020).…”

Section: Resultsmentioning

confidence: 99%

DNA methylation Dependent Restriction of Tyrosine Hydroxylase Contributes to Pancreatic β-cell Heterogeneity

Parveen

Wang

Bhattacharya

et al. 2022

Preprint

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The molecular and functional heterogeneity of pancreatic β-cells is well recognized. Pancreatic islets harbor a small subset of β-cells that co-express Tyrosine Hydroxylase (TH), an enzyme involved in synthesis of catecholamines that repress insulin secretion. Restriction of this sub-population within islets is essential for appropriate insulin secretion. However, the distinguishing characteristics of this subpopulation and the mechanisms that restrict TH expression in β-cells are not known. Here, we define the specific molecular and metabolic characteristics of the TH+ β-cells and show that TH expression in β-cells is restricted by DNA methylation patterning during β-cell lineage specification. Ablation of de novo DNA methyltransferase Dnmt3a in the pancreatic- and endocrine-progenitor lineages results in a dramatic increase in the proportion of TH+ β-cells, while β-cell specific ablation of Dnmt3a has no effect on this sub-population. We demonstrate that maintenance of Th promoter DNA methylation patterns is essential for its continued restriction in postnatal β-cells, and that loss of DNA methylation dysregulates TH expression in β-cells in response to chronic overnutrition, contributing to impairment of β-cell identity. These data highlight the essential requirement of DNA methylation patterning in regulating endocrine cell fates, and reveal a novel role of DNA methylation in β-cell heterogeneity.

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Pathological β-Cell Endoplasmic Reticulum Stress in Type 2 Diabetes: Current Evidence

Cited by 77 publications

References 71 publications

Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion

Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion

Sex differences in islet stress responses support female beta cell resilience

DNA methylation Dependent Restriction of Tyrosine Hydroxylase Contributes to Pancreatic β-cell Heterogeneity

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