scholarly journals Lipid droplets protect human β cells from lipotoxic-induced stress and cell identity changes

2021 ◽  
Author(s):  
Xin Tong ◽  
Roland Stein
Keyword(s):  
Er Stress ◽  
Cell Function ◽  
Cell Activity ◽  
Cell Types ◽  
Human Cell Line ◽  
Human Islet ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
Identity Changes

Free fatty acids (FFAs) are often stored in lipid droplet (LD) depots for eventual metabolic and/or synthetic use in many cell types, such a muscle, liver, and fat. In pancreatic islets, overt LD accumulation was detected in humans but not mice. LD buildup in islets was principally observed after roughly 11 years of age, increasing throughout adulthood under physiologic conditions, and also enriched in type 2 diabetes. To obtain insight into the role of LDs in human islet β cell function, the levels of a key LD scaffold protein, perilipin2 (PLIN2), were manipulated by lentiviral-mediated knock-down (KD) or over-expression (OE) in EndoCβH2-Cre cells, a human cell line with adult islet β-like properties. Glucose stimulated insulin secretion was blunted in PLIN2KD cells and improved in PLIN2OE cells. An unbiased transcriptomic analysis revealed that limiting LD formation induced effectors of endoplasmic reticulum (ER) stress that compromised the expression of critical β cell function and identity genes. These changes were essentially reversed by PLIN2OE or using the ER stress inhibitor, tauroursodeoxycholic acid. These results strongly suggest that LDs are essential for adult human islet β cell activity by preserving FFA homeostasis.<br>

scholarly journals Lipid droplets protect human β cells from lipotoxic-induced stress and cell identity changes

2021 ◽  
Author(s):  
Xin Tong ◽  
Roland Stein
Keyword(s):  
Er Stress ◽  
Cell Function ◽  
Cell Activity ◽  
Cell Types ◽  
Human Cell Line ◽  
Human Islet ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
Identity Changes

Free fatty acids (FFAs) are often stored in lipid droplet (LD) depots for eventual metabolic and/or synthetic use in many cell types, such a muscle, liver, and fat. In pancreatic islets, overt LD accumulation was detected in humans but not mice. LD buildup in islets was principally observed after roughly 11 years of age, increasing throughout adulthood under physiologic conditions, and also enriched in type 2 diabetes. To obtain insight into the role of LDs in human islet β cell function, the levels of a key LD scaffold protein, perilipin2 (PLIN2), were manipulated by lentiviral-mediated knock-down (KD) or over-expression (OE) in EndoCβH2-Cre cells, a human cell line with adult islet β-like properties. Glucose stimulated insulin secretion was blunted in PLIN2KD cells and improved in PLIN2OE cells. An unbiased transcriptomic analysis revealed that limiting LD formation induced effectors of endoplasmic reticulum (ER) stress that compromised the expression of critical β cell function and identity genes. These changes were essentially reversed by PLIN2OE or using the ER stress inhibitor, tauroursodeoxycholic acid. These results strongly suggest that LDs are essential for adult human islet β cell activity by preserving FFA homeostasis.<br>

scholarly journals Lipid droplets protect human β cells from lipotoxic-induced stress and cell identity changes

2021 ◽  
Author(s):  
Xin Tong ◽  
Roland W Stein
Keyword(s):  
Er Stress ◽  
Cell Function ◽  
Cell Activity ◽  
Cell Types ◽  
Human Cell Line ◽  
Human Islet ◽  
Structural Protein ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

Free fatty acids (FFAs) are often stored in lipid droplet (LD) depots for eventual metabolic and/or synthetic use in many cell types, such a muscle, liver, and fat. In pancreatic islets, overt LD accumulation was detected in humans but not mice. LD buildup in islets was principally observed after roughly 11 years of age, increasing throughout adulthood under physiologic conditions, and also enriched in type 2 diabetes. To obtain insight into the role of LDs in human islet β cell function, the levels of a key LD structural protein, perilipin2 (PLIN2), were manipulated by lentiviral-mediated knock-down (KD) or over-expression (OE) in EndoCβH2-Cre cells, a human cell line with adult islet β-like properties. Glucose stimulated insulin secretion was blunted in PLIN2KD cells and improved in PLIN2OE cells. An unbiased transcriptomic analysis revealed that limiting LD formation induced effectors of endoplasmic reticulum (ER) stress that compromised the expression of critical β cell function and identity genes. These changes were aggravated by exogenous treatment with FFAs toxic to islet β cells, and essentially reversed by PLIN2OE or using the ER stress inhibitor, tauroursodeoxycholic acid. These results strongly suggest that LDs are essential for adult human islet β cell activity by preserving FFA homeostasis.

scholarly journals Pericytes contribute to the islet basement membranes to promote beta-cell gene expression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lina Sakhneny ◽  
Alona Epshtein ◽  
Limor Landsman
Keyword(s):  
Gene Expression ◽  
Cell Function ◽  
Basement Membranes ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell ◽  
Cell Clustering ◽  
Β Cell Function ◽  
Cell Gene Expression ◽  
Glucose Stimulated Insulin Secretion

Abstractβ-Cells depend on the islet basement membrane (BM). While some islet BM components are produced by endothelial cells (ECs), the source of others remains unknown. Pancreatic pericytes directly support β-cells through mostly unidentified secreted factors. Thus, we hypothesized that pericytes regulate β-cells through the production of BM components. Here, we show that pericytes produce multiple components of the mouse pancreatic and islet interstitial and BM matrices. Several of the pericyte-produced ECM components were previously implicated in β-cell physiology, including collagen IV, laminins, proteoglycans, fibronectin, nidogen, and hyaluronan. Compared to ECs, pancreatic pericytes produce significantly higher levels of α2 and α4 laminin chains, which constitute the peri-islet and vascular BM. We further found that the pericytic laminin isoforms differentially regulate mouse β-cells. Whereas α2 laminins promoted islet cell clustering, they did not affect gene expression. In contrast, culturing on Laminin-421 induced the expression of β-cell genes, including Ins1, MafA, and Glut2, and significantly improved glucose-stimulated insulin secretion. Thus, alongside ECs, pericytes are a significant source of the islet BM, which is essential for proper β-cell function.

scholarly journals Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3328
Author(s):  
Eloisa Aparecida Vilas-Boas ◽  
Davidson Correa Almeida ◽  
Leticia Prates Roma ◽  
Fernanda Ortis ◽  
Angelo Rafael Carpinelli
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Nadph Oxidase ◽  
Er Stress ◽  
Cell Function ◽  
Caloric Intake ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

A high caloric intake, rich in saturated fats, greatly contributes to the development of obesity, which is the leading risk factor for type 2 diabetes (T2D). A persistent caloric surplus increases plasma levels of fatty acids (FAs), especially saturated ones, which were shown to negatively impact pancreatic β-cell function and survival in a process called lipotoxicity. Lipotoxicity in β-cells activates different stress pathways, culminating in β-cells dysfunction and death. Among all stresses, endoplasmic reticulum (ER) stress and oxidative stress have been shown to be strongly correlated. One main source of oxidative stress in pancreatic β-cells appears to be the reactive oxygen species producer NADPH oxidase (NOX) enzyme, which has a role in the glucose-stimulated insulin secretion and in the β-cell demise during both T1 and T2D. In this review, we focus on the acute and chronic effects of FAs and the lipotoxicity-induced β-cell failure during T2D development, with special emphasis on the oxidative stress induced by NOX, the ER stress, and the crosstalk between NOX and ER stress.

scholarly journals Bioactive Phytochemicals Isolated from Akebia quinata Enhances Glucose-Stimulated Insulin Secretion by Inducing PDX-1

Plants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1087
Author(s):  
Dahae Lee ◽  
Jin Su Lee ◽  
Jurdas Sezirahiga ◽  
Hak Cheol Kwon ◽  
Dae Sik Jang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Experimental Studies ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Etoh Extract ◽  
Chemical Structures ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
Phosphoinositide 3 Kinase

Chocolate vine (Akebia quinata) is consumed as a fruit and is also used in traditional medicine. In order to identify the bioactive components of A. quinata, a phytosterol glucoside stigmasterol-3-O-β-d-glucoside (1), three triterpenoids maslinic acid (2), scutellaric acid (3), and hederagenin (4), and three triterpenoidal saponins akebia saponin PA (5), hederacoside C (6), and hederacolchiside F (7) were isolated from a 70% EtOH extract of the fruits of A. quinata (AKQU). The chemical structures of isolates 1–7 were determined by analyzing the 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data. Here, we evaluated the effects of AKQU and compounds 1–7 on insulin secretion using the INS-1 rat pancreatic β-cell line. Glucose-stimulated insulin secretion (GSIS) was evaluated in INS-1 cells using the GSIS assay. The expression levels of the proteins related to pancreatic β-cell function were detected by Western blotting. Among the isolates, stigmasterol-3-O-β-d-glucoside (1) exhibited strong GSIS activity and triggered the overexpression of pancreas/duodenum homeobox protein-1 (PDX-1), which is implicated in the regulation of pancreatic β-cell survival and function. Moreover, isolate 1 markedly induced the expression of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), insulin receptor substrate-2 (IRS-2), phosphoinositide 3-kinase (PI3K), and Akt, which regulate the transcription of PDX-1. The results of our experimental studies indicated that stigmasterol-3-O-β-d-glucoside (1) isolated from the fruits of A. quinata can potentially enhance insulin secretion, and might alleviate the reduction in GSIS during the development of T2DM.

scholarly journals Rice Bran Phenolic Extracts Modulate Insulin Secretion and Gene Expression Associated with β-Cell Function

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1889 ◽  
Author(s):  
Nancy Saji ◽  
Nidhish Francis ◽  
Lachlan J. Schwarz ◽  
Christopher L. Blanchard ◽  
Abishek B. Santhakumar
Keyword(s):  
Insulin Secretion ◽  
Rice Bran ◽  
Cell Function ◽  
Β Cell ◽  
Free Radical Damage ◽  
Glucose Transporter 2 ◽  
Expression Of Genes ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
Phenolic Extracts

Oxidative stress is known to modulate insulin secretion and initiate gene alterations resulting in impairment of β-cell function and type 2 diabetes mellitus (T2DM). Rice bran (RB) phenolic extracts contain bioactive properties that may target metabolic pathways associated with the pathogenesis of T2DM. This study aimed to examine the effect of stabilized RB phenolic extracts on the expression of genes associated with β-cell function such as glucose transporter 2 (Glut2), pancreatic and duodenal homeobox 1 (Pdx1), sirtuin 1 (Sirt1), mitochondrial transcription factor A (Tfam), and insulin 1 (Ins1) in addition to evaluating its impact on glucose-stimulated insulin secretion. It was observed that treatment with different concentrations of RB phenolic extracts (25-250 µg/mL) significantly increased the expression of Glut2, Pdx1, Sirt1, Tfam, and Ins1 genes and glucose-stimulated insulin secretion under both normal and high glucose conditions. RB phenolic extracts favourably modulated the expression of genes involved in β-cell dysfunction and insulin secretion via several mechanisms such as synergistic action of polyphenols targeting signalling molecules, decreasing free radical damage by its antioxidant activity, and stimulation of effectors or survival factors of insulin secretion.

scholarly journals Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

2008 ◽  
Vol 199 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Ernest Sargsyan ◽  
Henrik Ortsäter ◽  
Kristofer Thorn ◽  
Peter Bergsten
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Er Stress ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Eukaryotic Translation ◽  
Β Cell Function ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response

Elevated levels of glucose and lipids are characteristics of individuals with type 2 diabetes mellitus (T2DM). The enhanced nutrient levels have been connected with deterioration of β-cell function and impaired insulin secretion observed in these individuals. A strategy to improve β-cell function in individuals with T2DM has been intermittent administration of KATP channel openers. After such treatment, both the magnitude and kinetics of insulin secretion are markedly improved. In an attempt to further delineate mechanisms of how openers of KATP channels improve β-cell function, the effects of diazoxide on markers of endoplasmic reticulum (ER) stress was determined in β-cells exposed to the fatty acid palmitate. The eukaryotic translation factor 2-alpha kinase 3 (EIF2AK3; also known as PERK) and endoplasmic reticulum to nucleus signaling 1 (ERN1; also known as IRE1) pathways, but not the activating transcription factor (ATF6) pathway of the unfolded protein response, are activated in such lipotoxic β-cells. Inclusion of diazoxide during culture attenuated activation of the EIF2AK3 pathway but not the ERN1 pathway. This attenuation was associated with reduced levels of DNA-damage inducible transcript 3 (DDIT3; also known as CHOP) and β-cell apoptosis was decreased. It is concluded that reduction of ER stress may be a mechanism by which diazoxide improves β-cell function.

scholarly journals Protein restriction in early life is associated with changes in insulin sensitivity and pancreatic β-cell function during pregnancy

2012 ◽  
Vol 109 (2) ◽  
pp. 236-247 ◽  
Author(s):  
Letícia Martins Ignácio-Souza ◽  
Sílvia Regina Reis ◽  
Vanessa Cristina Arantes ◽  
Bárbara Laet Botosso ◽  
Roberto Vilela Veloso ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Early Life ◽  
Cell Function ◽  
Secretory Process ◽  
Insulin Biosynthesis ◽  
Β Cell ◽  
Pregnant Rats ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

Malnutrition in early life impairs glucose-stimulated insulin secretion in adulthood. Conversely, pregnancy is associated with a significant increase in glucose-stimulated insulin secretion under conditions of normoglycaemia. A failure in β-cell adaptive changes may contribute to the onset of diabetes. Thus, glucose homeostasis and β-cell function were evaluated in control-fed pregnant (CP) and non-pregnant (CNP) or protein-restricted pregnant (LPP) and non-pregnant (LPNP) rats, from fetal to adult life, and in protein-restricted rats that were recovered after weaning (RP and RNP). The typical insulin resistance of pregnancy was not observed in the RP rats, nor did pregnancy increase the insulin content/islet in the LPP group. The glucose dose–response curves from pregnant rats were shifted to the left in relation to the non-pregnant rats, except in the recovered group. Glucose utilisation but not oxidation in islets from the RP and LPP groups was reduced at a concentration of 8·3 mm-glucose compared with islets from the CP group. Cyclic AMP content and the potentiation of glucose-stimulated insulin secretion by isobutylmethylxanthine at a concentration of 2·8 mm-glucose indicated increased adenylyl cyclase 3 activity but reduced protein kinase A-α activity in islets from the RP and LPP rats. Protein kinase C (PKC)-α but not phospholipase C (PLC)-β1 expression was reduced in islets from the RP group. Phorbol-12-myristate 13-acetate produced a less potent stimulation of glucose-stimulated insulin secretion in the RP group. Thus, the alterations exhibited by islets from the LPP group appeared to be due to reduced islet mass and/or insulin biosynthesis. In the RP group the loss of the adaptive capacity apparently resulted from uncoupling between glucose metabolism and the amplifying signals of the secretory process, as well as a severe attenuation of the PLC/PKC pathway.

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.

scholarly journals Spontaneous restoration of functional β-cell mass in obese SM/J mice

2020 ◽  
Author(s):  
Mario A Miranda ◽  
Caryn Carson ◽  
Celine L St Pierre ◽  
Juan F Macias-Velasco ◽  
Jing W Hughes ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Mitotic Index ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Physiological Mechanisms ◽  
Β Cell Function ◽  
Basal Insulin Secretion ◽  
Glucose Stimulated Insulin Secretion ◽  
Mass Expansion

AbstractMaintenance of functional β-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause β-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and β-cell function during SM/J’s diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase β-cell mass but not α-cell mass. Obese SM/J mice do not show elevated β-cell mitotic index, but rather elevated α-cell mitotic index. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. These results establish that β-cell mass expansion and improved β-cell function underlie the resolution of hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional β-cell mass can be recovered in the context of obesity.

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