scholarly journals CBP/p300 HAT maintains the gene network critical for β cell identity and functional maturity

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Linlin Zhang ◽  
Chunxiang Sheng ◽  
Feiye Zhou ◽  
Kecheng Zhu ◽  
Shushu Wang ◽  
...  
Keyword(s):  
Cell Function ◽  
Tricarboxylic Acid Cycle ◽  
Dominant Role ◽  
Glucose Sensing ◽  
Sequencing Analysis ◽  
Creb Binding Protein ◽  
Β Cell ◽  
Cell Identity ◽  
Β Cell Function

AbstractLoss of β cell identity and functional immaturity are thought to be involved in β cell failure in type 2 diabetes. CREB-binding protein (CBP) and its paralogue p300 act as multifunctional transcriptional co-activators and histone acetyltransferases (HAT) with extensive biological functions. However, whether the regulatory role of CBP/p300 in islet β cell function depends on the HAT activity remains uncertain. In this current study, A-485, a selective inhibitor of CBP/p300 HAT activity, greatly impaired glucose-stimulated insulin secretion from rat islets in vitro and in vivo. RNA-sequencing analysis showed a comprehensive downregulation of β cell and α cell identity genes in A-485-treated islets, without upregulation of dedifferentiation markers and derepression of disallowed genes. A-485 treatment decreased the expressions of genes involved in glucose sensing, not in glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. In the islets of prediabetic db/db mice, CBP/p300 displayed a significant decrease with key genes for β cell function. The deacetylation of histone H3K27 as well as the transcription factors Hnf1α and Foxo1 was involved in CBP/p300 HAT inactivation-repressed expressions of β cell identity and functional genes. These findings highlight the dominant role of CBP/p300 HAT in the maintenance of β cell identity by governing transcription network.

scholarly journals Copine 3 “CPNE3” is a novel regulator for insulin secretion and glucose uptake in pancreatic β-cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Waseem El-Huneidi ◽  
Shabana Anjum ◽  
Abdul Khader Mohammed ◽  
Hema Unnikannan ◽  
Rania Saeed ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Uptake ◽  
Cancer Progression ◽  
Cell Function ◽  
Human Islets ◽  
Glucose Sensing ◽  
Β Cell ◽  
Β Cell Function ◽  
Novel Target

AbstractCopine 3 (CPNE3) is a calcium-dependent phospholipid-binding protein that has been found to play an essential role in cancer progression and stages. However, its role in pancreatic β-cell function has not been investigated. Therefore, we performed a serial of bioinformatics and functional experiments to explore the potential role of Cpne3 on insulin secretion and β-cell function in human islets and INS-1 (832/13) cells. RNA sequencing and microarray data revealed that CPNE3 is highly expressed in human islets compared to other CPNE genes. In addition, expression of CPNE3 was inversely correlated with HbA1c and reduced in human islets from hyperglycemic donors. Silencing of Cpne3 in INS-1 cells impaired glucose-stimulated insulin secretion (GSIS), insulin content and glucose uptake efficiency without affecting cell viability or inducing apoptosis. Moreover, mRNA and protein expression of the key regulators in glucose sensing and insulin secretion (Insulin, GLUT2, NeuroD1, and INSR) were downregulated in Cpne3-silenced cells. Taken together, data from the present study provides a new understanding of the role of CPNE3 in maintaining normal β-cell function, which might contribute to developing a novel target for future management of type 2 diabetes therapy.

scholarly journals The role of gut microbiota and amino metabolism in the effects of improvement of islet β-cell function after modified jejunoileal bypass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cai Tan ◽  
Zhihua Zheng ◽  
Xiaogang Wan ◽  
Jiaqing Cao ◽  
Ran Wei ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Cell Function ◽  
Body Weight Gain ◽  
Fasting Blood Glucose ◽  
Jejunoileal Bypass ◽  
Β Cell ◽  
Β Cell Function ◽  
Branched Chain

AbstractThe change in gut microbiota is an important mechanism of the amelioration of type 2 diabetes mellitus (T2DM) after bariatric surgery. Here, we observe that the modified jejunoileal bypass effectively decreases body weight gain, fasting blood glucose, and lipids level in serum; additionally, islet β-cell function, glucose tolerance, and insulin resistance were markedly ameliorated. The hypoglycemic effect and the improvement in islet β-cell function depend on the changes in gut microbiota structure. modified jejunoileal bypass increases the abundance of gut Escherichia coli and Ruminococcus gnavus and the levels of serum glycine, histidine, and glutamine in T2DM rats; and decreases the abundance of Prevotella copri and the levels of serum branched chain amino acids, which are significantly related to the improvement of islet β-cell function in T2DM rats. Our results suggest that amino acid metabolism may contribute to the islet β-cell function in T2DM rats after modified jejunoileal bypass and that improving gut microbiota composition is a potential therapeutic strategy for T2DM.

scholarly journals Functional Role of Serotonin in Insulin Secretion in a Diet-Induced Insulin-Resistant State

Endocrinology ◽  
2014 ◽  
Vol 156 (2) ◽  
pp. 444-452 ◽  
Author(s):  
Kyuho Kim ◽  
Chang-Myung Oh ◽  
Mica Ohara-Imaizumi ◽  
Sangkyu Park ◽  
Jun Namkung ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Cell Function ◽  
Β Cell ◽  
Pancreas Perfusion ◽  
Insulin Resistant ◽  
Β Cell Function ◽  
Resistant State ◽  
Insulin Resistant State

The physiological role of serotonin, or 5-hydroxytryptamine (5-HT), in pancreatic β-cell function was previously elucidated using a pregnant mouse model. During pregnancy, 5-HT increases β-cell proliferation and glucose-stimulated insulin secretion (GSIS) through the Gαq-coupled 5-HT2b receptor (Htr2b) and the 5-HT3 receptor (Htr3), a ligand-gated cation channel, respectively. However, the role of 5-HT in β-cell function in an insulin-resistant state has yet to be elucidated. Here, we characterized the metabolic phenotypes of β-cell-specific Htr2b−/− (Htr2b βKO), Htr3a−/− (Htr3a knock-out [KO]), and β-cell-specific tryptophan hydroxylase 1 (Tph1)−/− (Tph1 βKO) mice on a high-fat diet (HFD). Htr2b βKO, Htr3a KO, and Tph1 βKO mice exhibited normal glucose tolerance on a standard chow diet. After 6 weeks on an HFD, beginning at 4 weeks of age, both Htr3a KO and Tph1 βKO mice developed glucose intolerance, but Htr2b βKO mice remained normoglycemic. Pancreas perfusion assays revealed defective first-phase insulin secretion in Htr3a KO mice. GSIS was impaired in islets isolated from HFD-fed Htr3a KO and Tph1 βKO mice, and 5-HT treatment improved insulin secretion from Tph1 βKO islets but not from Htr3a KO islets. Tph1 and Htr3a gene expression in pancreatic islets was not affected by an HFD, and immunostaining could not detect 5-HT in pancreatic islets from mice fed an HFD. Taken together, these results demonstrate that basal 5-HT levels in β-cells play a role in GSIS through Htr3, which becomes more evident in a diet-induced insulin-resistant state.

Role of Mitochondria in β-Cell Function and Dysfunction

2014 ◽  
pp. 633-657
Author(s):  
Pierre Maechler ◽  
Ning Li ◽  
Marina Casimir ◽  
Laurène Vetterli ◽  
Francesca Frigerio ◽  
...  
Keyword(s):  
Cell Function ◽  
Β Cell ◽  
Β Cell Function

Role of Mitochondria in β-Cell Function and Dysfunction

2014 ◽  
pp. 1-24
Author(s):  
Pierre Maechler ◽  
Ning Li ◽  
Marina Casimir ◽  
Laurène Vetterli ◽  
Francesca Frigerio ◽  
...  
Keyword(s):  
Cell Function ◽  
Β Cell ◽  
Β Cell Function

The role of aging and senescence on pancreatic β-cell function and proliferation

2017 ◽  
Vol 108 ◽  
pp. S71
Author(s):  
Richard Kehm ◽  
Oliver Kluth ◽  
Annette Schürmann ◽  
Tilman Grune ◽  
Annika Höhn
Keyword(s):  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function

scholarly journals Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

2021 ◽  
Author(s):  
Chien-Wen Chen ◽  
Bo-Jhih Guan ◽  
Mohammed R Alzahrani ◽  
Zhaofeng Gao ◽  
Long Gao ◽  
...  
Keyword(s):  
Er Stress ◽  
Stress Responses ◽  
Cell Function ◽  
Cell Plasticity ◽  
Β Cells ◽  
Β Cell ◽  
Cell Identity ◽  
Β Cell Function ◽  
Novel Biomarkers ◽  
High Degree

Pancreatic β-cells undergo high levels of endoplasmic reticulum (ER) stress due to their role in insulin secretion. Hence, they require sustainable and efficient adaptive stress responses to cope with the stress. Whether duration and episodes of chronic ER stress directly compromises β-cell identity is largely unknown. We show that under reversible, chronic ER stress, β-cells undergo a distinct transcriptional and translational reprogramming. During reprogramming, expression of master regulators of β-cell function and identity and proinsulin processing is impaired. Upon recovery from stress, β-cells regain their identity, highlighting a high-degree of adaptive β-cell plasticity. Remarkably, when stress episodes exceed a certain threshold, β-cell identity is gradually lost. Single cell RNA-seq analysis of islets from type 1 diabetes (T1D) patients, identifies the severe deregulation of the chronic stress-adaptation program, and reveals novel biomarkers for progression of T1D. Our results suggest β-cell adaptive exhaustion (βEAR) is a significant component of the pathogenesis of T1D.

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