Coregulator Sin3a promotes postnatal murine β-cell fitness by regulating genes in Ca2+ homeostasis, cell survival, vesicle biosynthesis, glucose metabolism, and stress response

Swi-independent 3a and 3b (Sin3a and Sin3b) are paralogous transcriptional coregulators that direct cellular differentiation, survival, and function. Here, we report that mouse Sin3a and Sin3b are co-produced in most pancreatic cells during embryogenesis but become much more enriched in endocrine cells in adults, implying continued essential roles in mature endocrine-cell function. Mice with loss of Sin3a in endocrine progenitors were normal during early postnatal stages but gradually developed diabetes before weaning. These physiological defects were preceded by the compromised survival, insulin-vesicle packaging, insulin secretion, and nutrient-induced Ca2+ influx of Sin3a-deficient β-cells. RNA-seq coupled with candidate chromatin-immunoprecipitation assays revealed several genes that could be directly regulated by Sin3a in β-cells, which modulate Ca2+/ion transport, cell survival, vesicle/membrane trafficking, glucose metabolism, and stress responses. Lastly, mice with loss of both Sin3a and Sin3b in multipotent embryonic pancreatic progenitors had significantly reduced islet-cell mass at birth, caused by decreased endocrine-progenitor production and increased β-cell death. These findings highlight the stage-specific requirements for the presumed “general” coregulators Sin3a and Sin3b in islet β-cells, with Sin3a being dispensable for differentiation but required for postnatal function and survival.

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Imeglimin Ameliorates β-cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway

10.2337/figshare.16654780.v1 ◽

2021 ◽

Author(s):

Jinghe Li ◽

Ryota Inoue ◽

Yu Togashi ◽

Tomoko Okuyama ◽

Aoi Satoh ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Cell Survival ◽

Cell Apoptosis ◽

Cell Function ◽

Cell Mass ◽

Β Cells ◽

Β Cell ◽

Akita Mice ◽

The Impact

The effects of imeglimin, a novel anti-diabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules including Chop (Ddit3), Gadd34 (Ppp1r15a), Atf3, and Sdf2l1, and decreased eIF2α phosphorylation, after treatment with thapsigargin, and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect ER stress-induced β-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell (<a>hPSC)-derived β-like cells</a>. <a>Taken together, imeglimin modulates ER homeostasis pathway, which results in the prevention of β-cell apoptosis both in vitro and in vivo.</a>

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Imeglimin Ameliorates β-cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway

10.2337/figshare.16654780 ◽

2021 ◽

Author(s):

Jinghe Li ◽

Ryota Inoue ◽

Yu Togashi ◽

Tomoko Okuyama ◽

Aoi Satoh ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Cell Survival ◽

Cell Apoptosis ◽

Cell Function ◽

Cell Mass ◽

Β Cells ◽

Β Cell ◽

Akita Mice ◽

The Impact

The effects of imeglimin, a novel anti-diabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules including Chop (Ddit3), Gadd34 (Ppp1r15a), Atf3, and Sdf2l1, and decreased eIF2α phosphorylation, after treatment with thapsigargin, and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect ER stress-induced β-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell (<a>hPSC)-derived β-like cells</a>. <a>Taken together, imeglimin modulates ER homeostasis pathway, which results in the prevention of β-cell apoptosis both in vitro and in vivo.</a>

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NKX6.1 transcription factor: a crucial regulator of pancreatic β cell development, identity, and proliferation

Stem Cell Research & Therapy ◽

10.1186/s13287-020-01977-0 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Idil I. Aigha ◽

Essam M. Abdelalim

Keyword(s):

Transcription Factor ◽

Cell Function ◽

Disease Modeling ◽

Critical Role ◽

Cell Mass ◽

Cell Development ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Β Cell Function

Abstract Understanding the biology underlying the mechanisms and pathways regulating pancreatic β cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin-producing β cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive to β cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1+/NKX6.1+), warrants their future commitment to monohormonal β cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1+/NKX6.1−) results in an undesirable generation of non-functional polyhormonal β cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a means to increase β cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

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A Sustained Activation of Pancreatic NMDARs Is a Novel Factor of β-Cell Apoptosis and Dysfunction

Endocrinology ◽

10.1210/en.2017-00366 ◽

2017 ◽

Vol 158 (11) ◽

pp. 3900-3913 ◽

Cited By ~ 13

Author(s):

Xiao-Ting Huang ◽

Shao-Jie Yue ◽

Chen Li ◽

Yan-Hong Huang ◽

Qing-Mei Cheng ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Apoptosis ◽

Cell Function ◽

Cell Mass ◽

Nuclear Factor Κb ◽

Β Cells ◽

Β Cell ◽

Stimulation Of ◽

Sustained Activation

Abstract Type 2 diabetes, which features β-cell failure, is caused by the decrease of β-cell mass and insulin secretory function. Current treatments fail to halt the decrease of functional β-cell mass. Strategies to prevent β-cell apoptosis and dysfunction are highly desirable. Recently, our group and others have reported that blockade of N-methyl-d-aspartate receptors (NMDARs) in the islets has been proposed to prevent the progress of type 2 diabetes through improving β-cell function. It suggests that a sustained activation of the NMDARs may exhibit deleterious effect on β-cells. However, the exact functional impact and mechanism of the sustained NMDAR stimulation on islet β-cells remains unclear. Here, we identify a sustained activation of pancreatic NMDARs as a novel factor of apoptotic β-cell death and function. The sustained treatment with NMDA results in an increase of intracellular [Ca2+] and reactive oxygen species, subsequently induces mitochondrial membrane potential depolarization and a decrease of oxidative phosphorylation expression, and then impairs the mitochondrial function of β-cells. NMDA specifically induces the mitochondrial-dependent pathway of apoptosis in β-cells through upregulation of the proapoptotic Bim and Bax, and downregulation of antiapoptotic Bcl-2. Furthermore, a sustained stimulation of NMDARs impairs β-cell insulin secretion through decrease of pancreatic duodenal homeobox-1 (Pdx-1) and adenosine triphosphate synthesis. The activation of nuclear factor–κB partly contributes to the reduction of Pdx-1 expression induced by overstimulation of NMDARs. In conclusion, we show that the sustained stimulation of NMDARs is a novel mediator of apoptotic signaling and β-cell dysfunction, providing a mechanistic insight into the pathological role of NMDARs activation in diabetes.

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Biphasic Response of Pancreatic β-Cell Mass to Ablation of Tuberous Sclerosis Complex 2 in Mice

Molecular and Cellular Biology ◽

10.1128/mcb.01695-07 ◽

2008 ◽

Vol 28 (9) ◽

pp. 2971-2979 ◽

Cited By ~ 119

Author(s):

Yutaka Shigeyama ◽

Toshiyuki Kobayashi ◽

Yoshiaki Kido ◽

Naoko Hashimoto ◽

Shun-ichiro Asahara ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Cell Function ◽

Cell Mass ◽

Mammalian Target Of Rapamycin ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Islet Mass ◽

Β Cell Function

ABSTRACT Recent studies have demonstrated the importance of insulin or insulin-like growth factor 1 (IGF-1) for regulation of pancreatic β-cell mass. Given the role of tuberous sclerosis complex 2 (TSC2) as an upstream molecule of mTOR (mammalian target of rapamycin), we examined the effect of TSC2 deficiency on β-cell function. Here, we show that mice deficient in TSC2, specifically in pancreatic β cells (βTSC2−/− mice), manifest increased IGF-1-dependent phosphorylation of p70 S6 kinase and 4E-BP1 in islets as well as an initial increased islet mass attributable in large part to increases in the sizes of individual β cells. These mice also exhibit hypoglycemia and hyperinsulinemia at young ages (4 to 28 weeks). After 40 weeks of age, however, the βTSC2−/− mice develop progressive hyperglycemia and hypoinsulinemia accompanied by a reduction in islet mass due predominantly to a decrease in the number of β cells. These results thus indicate that TSC2 regulates pancreatic β-cell mass in a biphasic manner.

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VMP1-related autophagy induced by a fructose-rich diet in β-cells: its prevention by incretins

Clinical Science ◽

10.1042/cs20170010 ◽

2017 ◽

Vol 131 (8) ◽

pp. 673-687 ◽

Cited By ~ 5

Author(s):

Bárbara Maiztegui ◽

Verónica Boggio ◽

Carolina L. Román ◽

Luis E. Flores ◽

Héctor Del Zotto ◽

...

Keyword(s):

Caspase 3 ◽

Cell Function ◽

Cell Damage ◽

Cell Mass ◽

Ultrastructural Changes ◽

Mrna Levels ◽

Model Assessment ◽

Β Cells ◽

Β Cell ◽

Insulin Mrna

The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3 weeks) with a commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, β-cell mass, morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1) expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3 days) without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes, suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type 2 diabetes mellitus.

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Gut Metabolite Trimethylamine N-Oxide Protects INS-1 β-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions

Biomolecules ◽

10.3390/biom11121892 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1892

Author(s):

Emily S. Krueger ◽

Joseph L. Beales ◽

Kacie B. Russon ◽

Weston S. Elison ◽

Jordan R. Davis ◽

...

Keyword(s):

Cell Function ◽

Cell Mass ◽

Caloric Intake ◽

Islet Function ◽

Β Cells ◽

Β Cell ◽

Granule Formation ◽

Β Cell Function ◽

Molecular Effects ◽

And Function

Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic β-cell function is a hallmark of diet-induced T2D, which is linked to hyperglycemia and hyperlipidemia. While TMAO production via the gut microbiome-liver axis is well defined, its molecular effects on metabolic tissues are unclear, since studies in various tissues show deleterious and beneficial TMAO effects. We investigated the molecular effects of TMAO on functional β-cell mass. We hypothesized that TMAO may damage functional β-cell mass by inhibiting β-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 β-cells and primary rat islets with physiological TMAO concentrations and compared functional β-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded β-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in β-cells and primary islet function. Acute 40µM TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1α unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects β-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.

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Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

10.1101/2021.05.24.445193 ◽

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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Metformin Preserves β-Cell Compensation in Insulin Secretion and Mass Expansion in Prediabetic Nile Rats

International Journal of Molecular Sciences ◽

10.3390/ijms22010421 ◽

2021 ◽

Vol 22 (1) ◽

pp. 421

Author(s):

Hui Huang ◽

Bradi R. Lorenz ◽

Paula Horn Zelmanovitz ◽

Catherine B. Chan

Keyword(s):

Insulin Secretion ◽

Cell Function ◽

Cell Mass ◽

Metformin Treatment ◽

Β Cells ◽

Β Cell ◽

Β Cell Function ◽

Glucose Output ◽

Mass Expansion

Prediabetes is a high-risk condition for type 2 diabetes (T2D). Pancreatic β-cells adapt to impaired glucose regulation in prediabetes by increasing insulin secretion and β-cell mass expansion. In people with prediabetes, metformin has been shown to prevent prediabetes conversion to diabetes. However, emerging evidence indicates that metformin has negative effects on β-cell function and survival. Our previous study established the Nile rat (NR) as a model for prediabetes, recapitulating characteristics of human β-cell compensation in function and mass expansion. In this study, we investigated the action of metformin on β-cells in vivo and in vitro. A 7-week metformin treatment improved glucose tolerance by reducing hepatic glucose output and enhancing insulin secretion. Although high-dose metformin inhibited β-cell glucose-stimulated insulin secretion in vitro, stimulation of β-cell insulin secretion was preserved in metformin-treated NRs via an indirect mechanism. Moreover, β-cells in NRs receiving metformin exhibited increased endoplasmic reticulum (ER) chaperones and alleviated apoptotic unfold protein response (UPR) without changes in the expression of cell identity genes. Additionally, metformin did not suppress β-cell mass compensation or proliferation. Taken together, despite the conflicting role indicated by in vitro studies, administration of metformin does not exert a negative effect on β-cell function or cell mass and, instead, early metformin treatment may help protect β-cells from exhaustion and decompensation.

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