scholarly journals A Combined Drug Treatment That Reduces Mitochondrial Iron and Reactive Oxygen Levels Recovers Insulin Secretion in NAF-1-Deficient Pancreatic Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1160
Author(s):  
Ola Karmi ◽  
Yang-Sung Sohn ◽  
Henri-Baptiste Marjault ◽  
Tal Israeli ◽  
Gil Leibowitz ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Critical Role ◽  
Combined Treatment ◽  
Reactive Oxygen ◽  
Wolfram Syndrome ◽  
Iron Chelator ◽  
Cellular Growth ◽  
Β Cell ◽  
Pancreatic Cells ◽  
Mitochondrial Iron

Decreased insulin secretion, associated with pancreatic β-cell failure, plays a critical role in many human diseases including diabetes, obesity, and cancer. While numerous studies linked β-cell failure with enhanced levels of reactive oxygen species (ROS), the development of diabetes associated with hereditary conditions that result in iron overload, e.g., hemochromatosis, Friedreich's ataxia, and Wolfram syndrome type 2 (WFS-T2; a mutation in CISD2, encoding the [2Fe-2S] protein NAF-1), underscores an additional link between iron metabolism and β-cell failure. Here, using NAF-1-repressed INS-1E pancreatic cells, we observed that NAF-1 repression inhibited insulin secretion, as well as impaired mitochondrial and ER structure and function. Importantly, we found that a combined treatment with the cell permeant iron chelator deferiprone and the glutathione precursor N-acetyl cysteine promoted the structural repair of mitochondria and ER, decreased mitochondrial labile iron and ROS levels, and restored glucose-stimulated insulin secretion. Additionally, treatment with the ferroptosis inhibitor ferrostatin-1 decreased cellular ROS formation and improved cellular growth of NAF-1 repressed pancreatic cells. Our findings reveal that suppressed expression of NAF-1 is associated with the development of ferroptosis-like features in pancreatic cells, and that reducing the levels of mitochondrial iron and ROS levels could be used as a therapeutic avenue for WFS-T2 patients.

scholarly journals RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes

2021 ◽  
Author(s):  
John T Walker ◽  
Diane C Saunders ◽  
Vivek Rai ◽  
Chunhua Dai ◽  
Peter Orchard ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Association Studies ◽  
Critical Role ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Β Cells ◽  
Β Cell ◽  
Gene Regulatory

A hallmark of type 2 diabetes (T2D), a major cause of world-wide morbidity and mortality, is dysfunction of insulin-producing pancreatic islet β cells. T2D genome-wide association studies (GWAS) have identified hundreds of signals, mostly in the non-coding genome and overlapping β cell regulatory elements, but translating these into biological mechanisms has been challenging. To identify early disease-driving events, we performed single cell spatial proteomics, sorted cell transcriptomics, and assessed islet physiology on pancreatic tissue from short-duration T2D and control donors. Here, through integrative analyses of these diverse modalities, we show that multiple gene regulatory modules are associated with early-stage T2D β cell-intrinsic defects. One notable example is the transcription factor RFX6, which we show is a highly connected β cell hub gene that is reduced in T2D and governs a gene regulatory network associated with insulin secretion defects and T2D GWAS variants. We validated the critical role of RFX6 in β cells through direct perturbation in primary human islets followed by physiological and single nucleus multiome profiling, which showed reduced dynamic insulin secretion and large-scale changes in the β cell transcriptome and chromatin accessibility landscape. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs, and individuals and thus we anticipate this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits with GWAS data.

scholarly journals Nitric oxide interacts with cholinoceptors to modulate insulin secretion by pancreatic β cells

2020 ◽  
Vol 472 (10) ◽  
pp. 1469-1480
Author(s):  
Bashair M. Mussa ◽  
Ankita Srivastava ◽  
Abdul Khader Mohammed ◽  
Anthony J. M. Verberne
Keyword(s):  
Nitric Oxide ◽  
Insulin Secretion ◽  
Cell Viability ◽  
Combined Treatment ◽  
No Production ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Tnf Α ◽  
Ifn Γ

Abstract Dysfunction of the pancreatic β cells leads to several chronic disorders including diabetes mellitus. Several mediators and mechanisms are known to be involved in the regulation of β cell secretory function. In this study, we propose that cytokine-induced nitric oxide (NO) production interacts with cholinergic mechanisms to modulate insulin secretion from pancreatic β cells. Using a rat insulinoma cell line INS-1, we demonstrated that β cell viability decreases significantly in the presence of SNAP (NO donor) in a concentration- and time-dependent manner. Cell viability was also found to be decreased in the presence of a combined treatment of SNAP with SMN (muscarinic receptor antagonist). We then investigated the impact of these findings on insulin secretion and found a significant reduction in glucose uptake by INS-1 cells in the presence of SNAP and SMN as compared with control. Nitric oxide synthase 3 gene expression was found to be significantly reduced in response to combined treatment with SNAP and SMN suggesting an interaction between the cholinergic and nitrergic systems. The analysis of gene and protein expression further pin-pointed the involvement of M3 muscarinic receptors in the cholinergic pathway. Upon treatment with cytokines, reduced cell viability was observed in the presence of TNF-α and IFN-γ. A significant reduction in insulin secretion was also noted after treatment with TNF-α and IFN-γ and IL1-β. The findings of the present study have shown for the first time that the inhibition of the excitatory effects of cholinergic pathways on glucose-induced insulin secretion may cause β cell injury and dysfunction of insulin secretion in response to cytokine-induced NO production.

scholarly journals Adipose tissue macrophages orchestrate β cell adaptation in obesity through secreting miRNA-containing extracellular vesicles

2020 ◽  
Author(s):  
Hong Gao ◽  
Zhenlong Luo ◽  
Zhongmou Jin ◽  
Yudong Ji ◽  
Wei Ying
Keyword(s):  
Adipose Tissue ◽  
Insulin Secretion ◽  
Extracellular Vesicles ◽  
Critical Role ◽  
Β Cells ◽  
Β Cell ◽  
Cell Adaptation ◽  
Cell Functions ◽  
Cell Responses ◽  
Adipose Tissue Macrophages

AbstractObesity induces an adaptive expansion of β cell mass and insulin secretion abnormality. Here, we explore a novel role of adipose tissue macrophages (ATMs) in mediating obesity-induced β cell function and proliferation through releasing miRNA-containing extracellular vesicles (EVs). ATM EVs derived from obese mice notably suppress insulin secretion in both in vivo and in vitro experiments, whereas there are more proliferating β cells in the islets treated with obese ATM EVs. Depletion of miRNAs blunts the ability of obese ATM EVs to regulate β cell responses. miR-155, a highly enriched miRNA within obese ATM EVs, exerts profound regulation on β cell functions, as evidenced by impaired insulin secretion and increased β cell proliferation after miR-155 overexpression in β cells. By contrast, knockout of miR-155 can attenuate the regulation of obese ATM EVs on β cell responses. We further demonstrate that the miR-155-Mafb axis plays a critical role in controlling β cell responses. Taken together, these studies show a novel mechanism by which ATM-derived EVs act as endocrine cargoes delivering miRNAs and subsequently mediating β cell adaptation and functional dysfunction in obesity.

scholarly journals Chronic pulsatile hyperglycemia reduces insulin secretion and increases accumulation of reactive oxygen species in fetal sheep islets

2011 ◽  
Vol 212 (3) ◽  
pp. 327-342 ◽  
Author(s):  
Alice S Green ◽  
Xiaochuan Chen ◽  
Antoni R Macko ◽  
Miranda J Anderson ◽  
Amy C Kelly ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Insulin Secretion ◽  
Oxidative Damage ◽  
Cell Function ◽  
Reactive Oxygen ◽  
Insulin Content ◽  
Oxygen Species ◽  
Β Cell ◽  
Fetal Sheep ◽  
Β Cell Function

Children from diabetic pregnancies have a greater incidence of type 2 diabetes. Our objective was to determine if exposure to mild–moderate hyperglycemia, by modeling managed diabetic pregnancies, affects fetal β-cell function. In sheep fetuses, β-cell responsiveness was examined after 2 weeks of sustained hyperglycemia with 3 pulses/day, mimicking postprandial excursions, and compared to saline-infused controls (n=10). Two pulsatile hyperglycemia (PHG) treatments were studied: mild (mPHG,n=5) with +15% sustained and +55% pulse; and moderate (PHG,n=10) with +20% sustained and +100% pulse. Fetal glucose-stimulated insulin secretion and glucose-potentiated arginine insulin secretion were lower (P<0.05) in PHG (0.86±0.13 and 2.91±0.39 ng/ml plasma insulin) but not in mPHG fetuses (1.21±0.08 and 4.25±0.56 ng/ml) compared to controls (1.58±0.25 and 4.51±0.56 ng/ml). Islet insulin content was 35% lower in PHG and 35% higher in mPHG vs controls (P<0.01). Insulin secretion and maximally stimulated insulin release were also reduced (P<0.05) in PHG islets due to lower islet insulin content. Isolated PHG islets also had 63% greater (P<0.01) reactive oxygen species (ROS) accumulation at 11.1 mmol/l glucose than controls (P<0.01), but oxidative damage was not detected in islet proteins. PHG fetuses showed evidence of oxidative damage to skeletal muscle proteins (P<0.05) but not insulin resistance. Our findings show that PHG induced dysregulation of islet ROS handling and decreased islet insulin content, but these outcomes are independent. The β-cell outcomes were dependent on the severity of hyperglycemia because mPHG fetuses had no distinguishable impairments in ROS handling or insulin secretion but greater insulin content.

scholarly journals System-L amino acid transporters play a key role in pancreatic β-cell signalling and function

2016 ◽  
Vol 56 (3) ◽  
pp. 175-187 ◽  
Author(s):  
Qi Cheng ◽  
Violeta D Beltran ◽  
Stanley M H Chan ◽  
Jeremy R Brown ◽  
Alan Bevington ◽  
...  
Keyword(s):  
Amino Acids ◽  
Insulin Secretion ◽  
Amino Acid ◽  
Mammalian Cells ◽  
Critical Role ◽  
Cell Signalling ◽  
Amino Acid Transporters ◽  
Β Cell ◽  
System L ◽  
And Function

Abstract The branched-chain amino acids (BCAA) leucine, isoleucine and valine, are essential amino acids that play a critical role in cellular signalling and metabolism. They acutely stimulate insulin secretion and activate the regulatory serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1), a kinase that promotes increased β-cell mass and function. The effects of BCAA on cellular function are dependent on their active transport into the mammalian cells via amino acid transporters and thus the expression and activity of these transporters likely influence β-cell signalling and function. In this report, we show that the System-L transporters are required for BCAA uptake into clonal β-cell lines and pancreatic islets, and that these are essential for signalling to mTORC1. Further investigation revealed that the System-L amino acid transporter 1 (LAT1) is abundantly expressed in the islets, and that knockdown of LAT1 using siRNA inhibits mTORC1 signalling, leucine-stimulated insulin secretion and islet cell proliferation. In summary, we show that the LAT1 is required for regulating β-cell signalling and function in islets and thus may be a novel pharmacological/nutritional target for the treatment and prevention of type 2 diabetes.

scholarly journals Upregulation of β-cell genes and improved function in rodent islets following chronic glucokinase activation

2011 ◽  
Vol 47 (1) ◽  
pp. 59-67 ◽  
Author(s):  
D Gill ◽  
K J Brocklehurst ◽  
H W G Brown ◽  
D M Smith
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Chronic Treatment ◽  
Critical Role ◽  
Insulin Content ◽  
Dependent Manner ◽  
Β Cell ◽  
Rat Islets ◽  
Mouse Islets

Glucokinase (GK) plays a critical role in controlling blood glucose; GK activators have been shown to stimulate insulin secretion acutely bothin vitroandin vivo. Sustained stimulation of insulin secretion could potentially lead to β-cell exhaustion; this study examines the effect of chronic GK activation on β-cells. Gene expression and insulin secretion were measured in rodent islets treatedin vitrowith GKA71 for 72 h. Key β-cell gene expression was measured in rat, mouse and global GK heterozygous knockout mouse islets (gkdel/wt). Insulin secretion, after chronic exposure to GKA71, was measured in perifused rat islets. GKA71 acutely increased insulin secretion in rat islets in a glucose-dependent manner. Chronic culture of mouse islets with GKA71 in 5 mmol/l glucose significantly increased the expression of insulin, IAPP, GLUT2, PDX1 and PC1 and decreased the expression of C/EBPβ compared with 5 mmol/l glucose alone. Similar increases were shown for insulin, GLUT2, IAPP and PC1 in chronically treated rat islets. Insulin mRNA was also increased in GKA71-treatedgkdel/wtislets. No changes inGKmRNA were observed. Glucose-stimulated insulin secretion was improved in perifused rat islets following chronic treatment with GKA71. This was associated with a greater insulin content and GK protein level. Chronic treatment of rodent islets with GKA71 showed an upregulation of key β-cell genes including insulin and an increase in insulin content and GK protein compared with glucose alone.

scholarly journals Glucagon Potentiates Insulin Secretion Via β-Cell GCGR at Physiological Concentrations of Glucose

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2495
Author(s):  
Yulin Zhang ◽  
Chengsheng Han ◽  
Wenzhen Zhu ◽  
Guoyi Yang ◽  
Xiaohong Peng ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
High Glucose ◽  
Critical Role ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulation ◽  
Primary Mouse ◽  
High Concentrations ◽  
Glucose Stimulated Insulin Secretion ◽  
Glucagon Receptors

Incretin-potentiated glucose-stimulated insulin secretion (GSIS) is critical to maintaining euglycemia, of which GLP-1 receptor (GLP-1R) on β-cells plays an indispensable role. Recently, α-cell-derived glucagon but not intestine-derived GLP-1 has been proposed as the critical hormone that potentiates GSIS via GLP-1R. However, the function of glucagon receptors (GCGR) on β-cells remains elusive. Here, using GCGR or GLP-1R antagonists, in combination with glucagon, to treat single β-cells, α-β cell clusters and isolated islets, we found that glucagon potentiates insulin secretion via β-cell GCGR at physiological but not high concentrations of glucose. Furthermore, we transfected primary mouse β-cells with RAB-ICUE (a genetically encoded cAMP fluorescence indicator) to monitor cAMP level after glucose stimulation and GCGR activation. Using specific inhibitors of different adenylyl cyclase (AC) family members, we revealed that high glucose concentration or GCGR activation independently evoked cAMP elevation via AC5 in β-cells, thus high glucose stimulation bypassed GCGR in promoting insulin secretion. Additionally, we generated β-cell-specific GCGR knockout mice which glucose intolerance was more severe when fed a high-fat diet (HFD). We further found that β-cell GCGR activation promoted GSIS more than GLP-1R in HFD, indicating the critical role of GCGR in maintaining glucose homeostasis during nutrient overload.

scholarly journals Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2801
Author(s):  
Ramkumar Mohan ◽  
Seokwon Jo ◽  
Elina Da Sol Chung ◽  
Eunice Oribamise ◽  
Amber Lockridge ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Survival ◽  
Glucose Intolerance ◽  
Gene Dosage ◽  
Critical Role ◽  
Chow Diet ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Female Mice ◽  
Glcnac Transferase

The nutrient-sensor O-GlcNAc transferase (Ogt), the sole enzyme that adds an O-GlcNAc-modification onto proteins, plays a critical role for pancreatic β-cell survival and insulin secretion. We hypothesized that β-cell Ogt overexpression would confer protection from β-cell failure in response to metabolic stressors, such as high-fat diet (HFD) and streptozocin (STZ). Here, we generated a β-cell-specific Ogt in overexpressing (βOgtOE) mice, where a significant increase in Ogt protein level and O-GlcNAc-modification of proteins were observed in islets under a normal chow diet. We uncovered that βOgtOE mice show normal peripheral insulin sensitivity and glucose tolerance with a regular chow diet. However, when challenged with an HFD, only female βOgtOE (homozygous) Hz mice developed a mild glucose intolerance, despite increased insulin secretion and normal β-cell mass. While female mice are normally resistant to low-dose STZ treatments, the βOgtOE Hz mice developed hyperglycemia and glucose intolerance post-STZ treatment. Transcriptome analysis between islets with loss or gain of Ogt by RNA sequencing shows common altered pathways involving pro-survival Erk and Akt and inflammatory regulators IL1β and NFkβ. Together, these data show a possible gene dosage effect of Ogt and the importance O-GlcNAc cycling in β-cell survival and function to regulate glucose homeostasis.

scholarly journals A putative long noncoding RNA-encoded micropeptide maintains cellular homeostasis in pancreatic β-cells

2020 ◽  
Author(s):  
Mark Li ◽  
Fan Shao ◽  
Qingwen Qian ◽  
Wenjie Yu ◽  
Zeyuan Zhang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Cell Function ◽  
Transmembrane Domain ◽  
Critical Role ◽  
Human Pancreas ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

ABSTRACTMicropeptides (microproteins) encoded by transcripts previously annotated as long noncoding RNA (IncRNAs) are emerging as important mediators of fundamental biological processes in health and disease. Here we applied two computational tools to identify putative micropeptides encoded by lncRNAs that are expressed in the human pancreas. We experimentally verified one such micropeptide encoded by a β-cell- and neural cell-enriched lncRNA TUNAR (also known as TUNA, HI-LNC78 or LINC00617). We named this highly conserved 48-amino-acid micropeptide Beta cell- and Neural cell-regulin (BNLN). BNLN contains a single-pass transmembrane domain and localized at the endoplasmic reticulum in pancreatic β-cells. Overexpression of BNLN lowered ER calcium levels, increased cytosolic calcium levels, and maintained ER homeostasis in response to high glucose challenge. To determine the physiological and pathological roles of BNLN, we assessed the BNLN expression in islets from mice fed with a high-fat diet and a regular diet, and found that BNLN is suppressed by diet-induced obesity (DIO). Conversely, overexpression of BNLN elevated glucose-stimulated insulin secretion in INS-1 cells. Lastly, BNLN overexpression enhanced insulin secretion in islets from lean and obese mice as well as from humans. Taken together, our study provides the first evidence that lncRNA-encoded micropeptides play a critical role in pancreatic β-cell function and provides a foundation for future comprehensive analyses of micropeptide function and pathophysiological impact on diabetes.

scholarly journals Adipose Tissue Macrophages Modulate Obesity-Associated β Cell Adaptations through Secreted miRNA-Containing Extracellular Vesicles

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2451
Author(s):  
Hong Gao ◽  
Zhenlong Luo ◽  
Zhongmou Jin ◽  
Yudong Ji ◽  
Wei Ying
Keyword(s):  
Cell Proliferation ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
Extracellular Vesicles ◽  
Critical Role ◽  
Cell Mass ◽  
Β Cell ◽  
Cell Adaptation ◽  
Cell Responses ◽  
Adipose Tissue Macrophages

Obesity induces an adaptive expansion of β cell mass and insulin secretion abnormality. Expansion of adipose tissue macrophages (ATMs) is a hallmark of obesity. Here, we assessed a novel role of ATMs in mediating obesity-induced β cell adaptation through the release of miRNA-containing extracellular vesicles (EVs). In both in vivo and in vitro experiments, we show that ATM EVs derived from obese mice notably suppress insulin secretion and enhance β cell proliferation. We also observed similar phenotypes from human islets after obese ATM EV treatment. Importantly, depletion of miRNAs blunts the effects of obese ATM EVs, as evidenced by minimal effects of obese DicerKO ATM EVs on β cell responses. miR-155 is a highly enriched miRNA within obese ATM EVs and miR-155 overexpressed in β cells impairs insulin secretion and enhances β cell proliferation. In contrast, knockout of miR-155 attenuates the regulation of obese ATM EVs on β cell responses. We further demonstrate that the miR-155-Mafb axis plays a critical role in controlling β cell responses. These studies show a novel mechanism by which ATM-derived EVs act as endocrine vehicles delivering miRNAs and subsequently mediating obesity-associated β cell adaptation and dysfunction.

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