scholarly journals Reduced miR-184-3p expression occurring in Type 2 diabetic pancreatic islets protects β-cells from lipotoxic and proinflammatory apoptosis via a CRTC1-dependent mechanism

2021 ◽  
Author(s):  
Giuseppina E. Grieco ◽  
Noemi Brusco ◽  
Laura Nigi ◽  
Caterina Formichi ◽  
Daniela Fignani ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Pancreatic Islets ◽  
Molecular Mechanisms ◽  
Cell Mass ◽  
Protective Mechanism ◽  
Β Cells ◽  
Β Cell ◽  
Specific Transcription Factor ◽  
Cell Functions

AbstractLoss of functional β-cell mass in Type 2 diabetes (T2D) involves molecular mechanisms including β-cell apoptosis, dysfunction, and/or dedifferentiation. MicroRNA miR-184-3p has been demonstrated to be involved in multiple β-cell functions including insulin secretion, proliferation and survival. However, downstream targets and upstream regulators of miR-184-3p have not yet been fully elucidated. Here, we showed that levels of miR-184-3p are reduced in human T2D pancreatic islets and that its reduction protected β-cells from lipotoxic- and inflammatory-induced apoptosis. Interestingly, CREB-Transcriptional Coactivator-1 (CRTC1) is a direct target of miR-184-3p and indeed its expression is upregulated in human T2D pancreatic islets. The downregulation of miR-184-3p in β-cells induced the upregulation of CRTC1 both at mRNA and protein level. Of note, miR-184-3p protection effect was dependent on CRTC1, since its silencing in human β-cells abrogates the protective mechanism exerted by miR-184-3p inhibition. Additionally, we found that the β-cell specific transcription factor NKX6.1, whose DNA binding sites were predicted to be present in human and mouse MIR184 gene promoter sequence, was reduced in T2D human pancreatic islets, in line with miR-184-3p downregulation, and was positively correlated with microRNA expression. Using chromatin immunoprecipitation analysis and mRNA silencing experiments, we demonstrated that NKX6.1 directly controls both human and murine miR-184 expression.In conclusion, we found that miR-184-3p expression is controlled by the β-cell specific transcription factor NKX6.1 and that miR-184-3p reduction protects β-cells from apoptosis through the upregulation of its target gene CRTC1.

scholarly journals NEUROD1 Is Required for the Early α and β Endocrine Differentiation in the Pancreas

2021 ◽  
Vol 22 (13) ◽  
pp. 6713
Author(s):  
Romana Bohuslavova ◽  
Ondrej Smolik ◽  
Jessica Malfatti ◽  
Zuzana Berkova ◽  
Zaneta Novakova ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Cell Mass ◽  
Neonatal Diabetes ◽  
Diabetes Research ◽  
Pancreas Development ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Islet Cell ◽  
Endocrine Differentiation

Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex interactions of signaling pathways and transcription factor networks regulate the specification, growth, and differentiation of cell types in the developing pancreas. Many of the same regulators continue to modulate gene expression and cell fate of the adult pancreas. The transcription factor NEUROD1 is essential for the maturation of β cells and the expansion of the pancreatic islet cell mass. Mutations of the Neurod1 gene cause diabetes in humans and mice. However, the different aspects of the requirement of NEUROD1 for pancreas development are not fully understood. In this study, we investigated the role of NEUROD1 during the primary and secondary transitions of mouse pancreas development. We determined that the elimination of Neurod1 impairs the expression of key transcription factors for α- and β-cell differentiation, β-cell proliferation, insulin production, and islets of Langerhans formation. These findings demonstrate that the Neurod1 deletion altered the properties of α and β endocrine cells, resulting in severe neonatal diabetes, and thus, NEUROD1 is required for proper activation of the transcriptional network and differentiation of functional α and β cells.

scholarly journals Adaptive β-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression

2013 ◽  
Vol 305 (1) ◽  
pp. E149-E159 ◽  
Author(s):  
Rachel E. Stamateris ◽  
Rohit B. Sharma ◽  
Douglas A. Hollern ◽  
Laura C. Alonso
Keyword(s):  
Cell Proliferation ◽  
Cell Mass ◽  
Extended Period ◽  
Time Frame ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Cyclin D2 ◽  
Mass Expansion

Type 2 diabetes (T2D) is caused by relative insulin deficiency, due in part to reduced β-cell mass ( 11 , 62 ). Therapies aimed at expanding β-cell mass may be useful to treat T2D ( 14 ). Although feeding rodents a high-fat diet (HFD) for an extended period (3–6 mo) increases β-cell mass by inducing β-cell proliferation ( 16 , 20 , 53 , 54 ), evidence suggests that adult human β-cells may not meaningfully proliferate in response to obesity. The timing and identity of the earliest initiators of the rodent compensatory growth response, possible therapeutic targets to drive proliferation in refractory human β-cells, are not known. To develop a model to identify early drivers of β-cell proliferation, we studied mice during the first week of HFD exposure, determining the onset of proliferation in the context of diet-related physiological changes. Within the first week of HFD, mice consumed more kilocalories, gained weight and fat mass, and developed hyperglycemia, hyperinsulinemia, and glucose intolerance due to impaired insulin secretion. The β-cell proliferative response also began within the first week of HFD feeding. Intriguingly, β-cell proliferation increased before insulin resistance was detected. Cyclin D2 protein expression was increased in islets by day 7, suggesting it may be an early effector driving compensatory β-cell proliferation in mice. This study defines the time frame and physiology to identify novel upstream regulatory signals driving mouse β-cell mass expansion, in order to explore their efficacy, or reasons for inefficacy, in initiating human β-cell proliferation.

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

2020 ◽  
Vol 11 (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.

scholarly journals BBT improves glucose homeostasis by ameliorating β-cell dysfunction in type 2 diabetic mice

2015 ◽  
Vol 224 (3) ◽  
pp. 327-341 ◽  
Author(s):  
Xin-gang Yao ◽  
Xin Xu ◽  
Gai-hong Wang ◽  
Min Lei ◽  
Ling-ling Quan ◽  
...  
Keyword(s):  
Cell Death ◽  
Protective Action ◽  
Fasting Blood Glucose ◽  
Oral Glucose ◽  
Diabetic Mice ◽  
Β Cells ◽  
Β Cell ◽  
Cell Functions ◽  
Type 2 Diabetic

Impaired glucose-stimulated insulin secretion (GSIS) and increasing β-cell death are two typical dysfunctions of pancreatic β-cells in individuals that are destined to develop type 2 diabetes, and improvement of β-cell function through GSIS enhancement and/or inhibition of β-cell death is a promising strategy for anti-diabetic therapy. In this study, we discovered that the small molecule, N-(2-benzoylphenyl)-5-bromo-2-thiophenecarboxamide (BBT), was effective in both potentiating GSIS and protecting β-cells from cytokine- or streptozotocin (STZ)-induced cell death. Results of further studies revealed that cAMP/PKA and long-lasting (L-type) voltage-dependent Ca2+ channel/CaMK2 pathways were involved in the action of BBT against GSIS, and that the cAMP/PKA pathway was essential for the protective action of BBT on β-cells. An assay using the model of type 2 diabetic mice induced by high-fat diet combined with STZ (STZ/HFD) demonstrated that BBT administration efficiently restored β-cell functions as indicated by the increased plasma insulin level and decrease in the β-cell loss induced by STZ/HFD. Moreover, the results indicated that BBT treatment decreased fasting blood glucose and HbA1c and improved oral glucose tolerance further highlighting the potential of BBT in anti-hyperglycemia research.

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

Endocrinology ◽  
2017 ◽  
Vol 158 (11) ◽  
pp. 3900-3913 ◽  
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.

scholarly journals G6PD Up-Regulation Promotes Pancreatic β-Cell Dysfunction

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 793-803 ◽  
Author(s):  
Joo-Won Lee ◽  
A Hyun Choi ◽  
Mira Ham ◽  
Ji-Won Kim ◽  
Sung Sik Choe ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Cell Apoptosis ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Ros Accumulation ◽  
Glucose Stimulated Insulin Secretion ◽  
Reduced Nicotinamide Adenine Dinucleotide

Increased reactive oxygen species (ROS) induce pancreatic β-cell dysfunction during progressive type 2 diabetes. Glucose-6-phosphate dehydrogenase (G6PD) is a reduced nicotinamide adenine dinucleotide phosphate-producing enzyme that plays a key role in cellular reduction/oxidation regulation. We have investigated whether variations in G6PD contribute to β-cell dysfunction through regulation of ROS accumulation and β-cell gene expression. When the level of G6PD expression in pancreatic islets was examined in several diabetic animal models, such as db/db mice and OLEFT rats, G6PD expression was evidently up-regulated in pancreatic islets in diabetic animals. To investigate the effect of G6PD on β-cell dysfunction, we assessed the levels of cellular ROS, glucose-stimulated insulin secretion and β-cell apoptosis in G6PD-overexpressing pancreatic β-cells. In INS-1 cells, G6PD overexpression augmented ROS accumulation associated with increased expression of prooxidative enzymes, such as inducible nitric oxide synthase and reduced nicotinamide adenine dinucleotide phosphate oxidase. G6PD up-regulation also caused decrease in glucose-stimulated insulin secretion in INS-1 cells and primary pancreatic islets. Moreover, elevated G6PD expression led to β-cell apoptosis, concomitant with the increase in proapoptotic gene expression. On the contrary, suppression of G6PD with small interference RNA attenuated palmitate-induced β-cell apoptosis. Together, these data suggest that up-regulation of G6PD in pancreatic β-cells would induce β-cell dysregulation through ROS accumulation in the development of type 2 diabetes.

Arachidonic acid fights palmitate: new insights into fatty acid toxicity in β-cells

2010 ◽  
Vol 120 (5) ◽  
pp. 179-181 ◽  
Author(s):  
Henrik Ortsäter
Keyword(s):  
Type 2 Diabetes ◽  
Arachidonic Acid ◽  
Fatty Acid ◽  
Saturated Fatty Acids ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Self Protection

Saturated fatty acids are toxic to pancreatic β-cells. By inducing apoptosis, they contribute to a decrease in β-cell mass, a hallmark of Type 2 diabetes. In the present issue of Clinical Science, Keane and co-workers show that the polyunsaturated fatty acid arachidonic acid protects the β-cell against the toxic effects of palmitate. As Type 2 diabetes is characterized by subclinical inflammation, and arachidonic acid and metabolites thereof are produced during states of inflammation, it is possible that pancreatic β-cells use arachidonic acid as a compound for self-protection.

scholarly journals Dynamics of β-cell turnover: evidence for β-cell turnover and regeneration from sources of β-cells other than β-cell replication in the HIP rat

2009 ◽  
Vol 297 (2) ◽  
pp. E323-E330 ◽  
Author(s):  
Erica Manesso ◽  
Gianna M. Toffolo ◽  
Yoshifumi Saisho ◽  
Alexandra E. Butler ◽  
Aleksey V. Matveyenko ◽  
...  
Keyword(s):  
Cell Mass ◽  
Cell Formation ◽  
Cell Regeneration ◽  
Cell Turnover ◽  
Cell Replication ◽  
Wild Type ◽  
Β Cells ◽  
Β Cell ◽  
Islet Amyloid

Type 2 diabetes is characterized by hyperglycemia, a deficit in β-cells, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). These characteristics are recapitulated in the human IAPP transgenic (HIP) rat. We developed a mathematical model to quantify β-cell turnover and applied it to nondiabetic wild type (WT) vs. HIP rats from age 2 days to 10 mo to establish 1) whether β-cell formation is derived exclusively from β-cell replication, or whether other sources of β-cells (OSB) are present, and 2) to what extent, if any, there is attempted β-cell regeneration in the HIP rat and if this is through β-cell replication or OSB. We conclude that formation and maintenance of adult β-cells depends largely (∼80%) on formation of β-cells independent from β-cell duplication. Moreover, this source adaptively increases in the HIP rat, implying attempted β-cell regeneration that substantially slows loss of β-cell mass.

scholarly journals Identification of a novel lncRNA (G3R1) regulated by GLIS3 in pancreatic β-cells

2020 ◽  
Vol 65 (3) ◽  
pp. 59-67
Author(s):  
David W Scoville ◽  
Artiom Gruzdev ◽  
Anton M Jetten
Keyword(s):  
Pancreatic Islets ◽  
Knockout Mouse ◽  
Cell Function ◽  
Significant Loss ◽  
Messenger Rnas ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Phenotypic Analysis ◽  
Cell Functions

Recent advances in high throughput RNA sequencing have revealed that, in addition to messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs) play an important role in the regulation of many cell functions and of organ development. While a number of lncRNAs have been identified in pancreatic islets, their function remains largely undetermined. Here, we identify a novel long ncRNA regulated by the transcription factor GLIS3, which we refer to as GLIS3 regulated 1 (G3R1). This lncRNA was identified for its significant loss of expression in GLIS3 knockout mouse pancreatic islets. G3R1 appears to be specifically expressed in mouse pancreatic β-cells and in a β-cell line (βTC-6). ChIP-seq analysis indicated that GLIS3 and other islet-enriched transcription factors bind near the G3R1 gene, suggesting they directly regulate G3R1 transcription. Similarly, an apparent human homolog of G3R1 displays a similar expression pattern, with additional expression seen in human brain. In order to determine the function of G3R1 in mouse pancreatic β-cells, we utilized CRISPR to develop a knockout mouse where ~80% of G3R1 sequence is deleted. Phenotypic analysis of these mice did not reveal any impairment in β-cell function or glucose regulation, indicating the complexity underlying the study of lncRNA function.

scholarly journals Lrrc55 is a novel prosurvival factor in pancreatic islets

2019 ◽  
Vol 317 (5) ◽  
pp. E794-E804 ◽  
Author(s):  
Guneet Makkar ◽  
Vipul Shrivastava ◽  
Brittyne Hlavay ◽  
Marle Pretorius ◽  
Barry D. Kyle ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Er Stress ◽  
Pancreatic Islets ◽  
Prolactin Receptor ◽  
Cell Mass ◽  
Cell Number ◽  
Dependent Manner ◽  
Β Cells ◽  
Β Cell ◽  
Insulin Synthesis

Pancreatic islets adapt to the increase in insulin demand during pregnancy by upregulating β-cell number, insulin synthesis, and secretion. These changes require prolactin receptor (PrlR) signaling, as mice with PrlR deletion are glucose intolerant with a lower β-cell mass. Prolactin also prevents β-cell apoptosis. Many genes participate in these adaptive changes in the islet, and Lrrc55 is one of the most upregulated genes with unknown function in islets. Because Lrrc55 expression increases in parallel to the increase in β-cell number and insulin production during pregnancy, we hypothesize that Lrrc55 might regulate β-cell proliferation/apoptosis (thus β-cell number) and insulin synthesis. Here, we found that Lrrc55 expression was upregulated by >60-fold during pregnancy in a PrlR-dependent manner, and this increase was restricted only to the islets. Overexpression of Lrrc55 in β-cells had minimal effect on β-cell proliferation and glucose-stimulated insulin secretion but protected β-cells from glucolipotoxicity-induced reduction in insulin gene expression. Moreover, Lrrc55 protects β-cells from glucolipotoxicity-induced apoptosis, with upregulation of prosurvival signals and downregulation of proapoptotic signals of the endoplasmic reticulum (ER) stress pathway. Furthermore, Lrrc55 attenuated calcium depletion induced by glucolipotoxicity, which may contribute to its antiapoptotic effect. Hence our findings suggest that Lrrc55 is a novel prosurvival factor that is upregulated specifically in islets during pregnancy, and it prevents conversion of adaptive unfolded protein response to unresolved ER stress and apoptosis in β-cells. Lrrc55 could be a potential therapeutic target in diabetes by reducing ER stress and promoting β-cell survival.

Sign in / Sign up

Export Citation Format

Share Document