scholarly journals GLP1-derived nonapeptide GLP1(28–36)amide protects pancreatic β-cells from glucolipotoxicity

2012 ◽  
Vol 213 (2) ◽  
pp. 143-154 ◽  
Author(s):  
Zhengu Liu ◽  
Violeta Stanojevic ◽  
Luke J Brindamour ◽  
Joel F Habener
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Insulin Secretion ◽  
Islet Cells ◽  
Blood Levels ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Functions

Type 2 diabetes, often associated with obesity, results from a deficiency of insulin production and action manifested in increased blood levels of glucose and lipids that further promote insulin resistance and impair insulin secretion. Glucolipotoxicity caused by elevated plasma glucose and lipid levels is a major cause of impaired glucose-stimulated insulin secretion from pancreatic β-cells, due to increased oxidative stress, and insulin resistance. Glucagon-like peptide-1 (GLP1), an insulinotropic glucoincretin hormone, is known to promote β-cell survival via its actions on its G-protein-coupled receptor on β-cells. Here, we report that a nonapeptide, GLP1(28–36)amide, derived from the C-terminal domain of the insulinotropic GLP1, exerts cytoprotective actions on INS-1 β-cells and on dispersed human islet cells in vitro in conditions of glucolipotoxicity and increased oxidative stress independently of the GLP1 receptor. The nonapeptide appears to enter preferably stressed, glucolipotoxic cells compared with normal unstressed cells. It targets mitochondria and improves impaired mitochondrial membrane potential, increases cellular ATP levels, inhibits cytochrome c release, caspase activation, and apoptosis, and enhances the viability and survival of INS-1 β-cells. We propose that GLP1(28–36)amide might be useful in alleviating β-cell stress and might improve β-cell functions and survival.

scholarly journals Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions

MedChemComm ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 280-293
Author(s):  
Anna Munder ◽  
Yoni Moskovitz ◽  
Aviv Meir ◽  
Shirin Kahremany ◽  
Laura Levy ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cellular Stress ◽  
Pamam Dendrimers ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Functions ◽  
Functional Maturation ◽  
Glucose Stimulated Insulin Secretion

The nanoscale composite improved β-cell functions in terms of rate of proliferation, glucose-stimulated insulin secretion, resistance to cellular stress and functional maturation.

scholarly journals Perilipin2 down-regulation in β cells impairs insulin secretion under nutritional stress and damages mitochondria

2020 ◽  
Author(s):  
Akansha Mishra ◽  
Siming Liu ◽  
Joseph Promes ◽  
Mikako Harata ◽  
William Sivitz ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Islet Cells ◽  
Cell Metabolism ◽  
Nutritional Stress ◽  
Β Cells ◽  
Β Cell ◽  
Down Regulation

Perilipin 2 (PLIN2) is the lipid droplet (LD) protein in β cells that increases under nutritional stress. Down-regulation of PLIN2 is often sufficient to reduce LD accumulation. To determine whether PLIN2 positively or negatively affects β cell function under nutritional stress, PLIN2 was down-regulated in mouse β cells, INS1 cells, and human islet cells. β cell specific deletion of PLIN2 in mice on a high fat diet reduced glucose-stimulated insulin secretion (GSIS) in vivo and in vitro. Down-regulation of PLIN2 in INS1 cells blunted GSIS after 24 h incubation with 0.2 mM palmitic acids. Down-regulation of PLIN2 in human pseudoislets cultured at 5.6 mM glucose impaired both phases of GSIS, indicating that PLIN2 is critical for GSIS. Down-regulation of PLIN2 decreased specific OXPHOS proteins in all three models and reduced oxygen consumption rates in INS1 cells and mouse islets. Moreover, we found that PLIN2 deficient INS1 cells increased the distribution of a fluorescent oleic acid analog to mitochondria and showed signs of mitochondrial stress as indicated by susceptibility to fragmentation and alterations of acyl-carnitines and glucose metabolites. Collectively, PLIN2 in β cells have an important role in preserving insulin secretion, β cell metabolism and mitochondrial function under nutritional stress.

scholarly journals Downregulation of lncRNA TUG1 Affects Apoptosis and Insulin Secretion in Mouse Pancreatic β Cells

2015 ◽  
Vol 35 (5) ◽  
pp. 1892-1904 ◽  
Author(s):  
Dan-dan Yin ◽  
Er-bao Zhang ◽  
Liang-hui You ◽  
Ning Wang ◽  
Lin-tao Wang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Annexin V ◽  
Pancreatic Tissue ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Lncrna Tug1

Background: Increasing evidence indicates that long noncoding RNAs (IncRNAs) perform specific biological functions in diverse processes. Recent studies have reported that IncRNAs may be involved in β cell function. The aim of this study was to characterize the role of IncRNA TUG1 in mouse pancreatic β cell functioning both in vitro and in vivo. Methods: qRT-PCR analyses were performed to detect the expression of lncRNA TUG1 in different tissues. RNAi, MTT, TUNEL and Annexin V-FITC assays and western blot, GSIS, ELISA and immunochemistry analyses were performed to detect the effect of lncRNA TUG1 on cell apoptosis and insulin secretion in vitro and in vivo. Results: lncRNA TUG1 was highly expressed in pancreatic tissue compared with other organ tissues, and expression was dynamically regulated by glucose in Nit-1 cells. Knockdown of lncRNA TUG1 expression resulted in an increased apoptosis ratio and decreased insulin secretion in β cells both in vitro and in vivo . Immunochemistry analyses suggested decreased relative islet area after treatment with lncRNA TUG1 siRNA. Conclusion: Downregulation of lncRNA TUG1 expression affected apoptosis and insulin secretion in pancreatic β cells in vitro and in vivo. lncRNA TUG1 may represent a factor that regulates the function of pancreatic β cells.

scholarly journals Protection of pancreatic β-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies

2007 ◽  
Vol 193 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Shin Tsunekawa ◽  
Naoki Yamamoto ◽  
Katsura Tsukamoto ◽  
Yuji Itoh ◽  
Yukiko Kaneko ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Islet Cells ◽  
Binding Protein ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

The aim of this study was to investigate the in vivo and in vitro effects of exendin-4, a potent glucagon-like peptide 1 agonist, on the protection of the pancreatic β-cells against their cell death. In in vivo experiments, we used β-cell-specific calmodulin-overexpressing mice where massive apoptosis takes place in their β-cells, and we examined the effects of chronic treatment with exendin-4. Chronic and s.c. administration of exendin-4 reduced hyperglycemia. The treatment caused significant increases of the insulin contents of the pancreas and islets, and retained the insulin-positive area. Dispersed transgenic islet cells lived only shortly, and several endoplasmic reticulum (ER) stress-related molecules such as immunoglobulin-binding protein (Bip), inositol-requiring enzyme-1α, X-box-binding protein-1 (XBP-1), RNA-activated protein kinase-like endoplasmic reticulum kinase, activating transcription factor-4, and C/EBP-homologous protein (CHOP) were more expressed in the transgenic islets. We also found that the spliced form of XBP-1, a marker of ER stress, was also increased in β-cell-specific calmodulin-overexpressing transgenic islets. In the quantitative real-time PCR analyses, the expression levels of Bip and CHOP were reduced in the islets from the transgenic mice treated with exendin-4. These findings suggest that excess of ER stress occurs in the transgenic β-cells, and the suppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.

scholarly journals The Plasticity of Pancreatic β-Cells

Metabolites ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 218
Author(s):  
Norikiyo Honzawa ◽  
Kei Fujimoto
Keyword(s):  
Insulin Secretion ◽  
Progenitor Cells ◽  
Islet Cells ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Cell Plasticity ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Impaired Insulin

Type 2 diabetes is caused by impaired insulin secretion and/or insulin resistance. Loss of pancreatic β-cell mass detected in human diabetic patients has been considered to be a major cause of impaired insulin secretion. Additionally, apoptosis is found in pancreatic β-cells; β-cell mass loss is induced when cell death exceeds proliferation. Recently, however, β-cell dedifferentiation to pancreatic endocrine progenitor cells and β-cell transdifferentiation to α-cell was reported in human islets, which led to a new underlying molecular mechanism. Hyperglycemia inhibits nuclear translocation and expression of forkhead box-O1 (FoxO1) and induces the expression of neurogenin-3(Ngn3), which is required for the development and maintenance of pancreatic endocrine progenitor cells. This new hypothesis (Foxology) is attracting attention because it explains molecular mechanism(s) underlying β-cell plasticity. The lineage tracing technique revealed that the contribution of dedifferentiation is higher than that of β-cell apoptosis retaining to β-cell mass loss. In addition, islet cells transdifferentiate each other, such as transdifferentiation of pancreatic β-cell to α-cell and vice versa. Islet cells can exhibit plasticity, and they may have the ability to redifferentiate into any cell type. This review describes recent findings in the dedifferentiation and transdifferentiation of β-cells. We outline novel treatment(s) for diabetes targeting islet cell plasticity.

scholarly journals MAFA and T3 Drive Maturation of Both Fetal Human Islets and Insulin-Producing Cells Differentiated From hESC

2015 ◽  
Vol 100 (10) ◽  
pp. 3651-3659 ◽  
Author(s):  
Cristina Aguayo-Mazzucato ◽  
Amanda DiIenno ◽  
Jennifer Hollister-Lock ◽  
Christopher Cahill ◽  
Arun Sharma ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Islet Cells ◽  
Embryonic Stem ◽  
Human Islets ◽  
Insulin Content ◽  
Β Cells ◽  
Β Cell ◽  
Functional Maturation ◽  
Glucose Responsiveness

Context: Human embryonic stem cells (hESCs) differentiated toward β-cells and fetal human pancreatic islet cells resemble each other transcriptionally and are characterized by immaturity with a lack of glucose responsiveness, low levels of insulin content, and impaired proinsulin-to-insulin processing. However, their response to stimuli that promote functionality have not been compared. Objective: The objective of the study was to evaluate the effects of our previous strategies for functional maturation developed in rodents in these two human models of β-cell immaturity and compare their responses. Design, Settings, Participants, and Interventions: In proof-of-principle experiments using either adenoviral-mediated overexpression of V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA) or the physiologically driven path via thyroid hormone (T3) and human fetal islet-like cluster (ICC) functional maturity was evaluated. Then the effects of T3 were evaluated upon the functional maturation of hESCs differentiated toward β-cells. Main Outcome Measures: Functional maturation was evaluated by the following parameters: glucose responsiveness, insulin content, expression of the mature β-cell transcription factor MAFA, and proinsulin-to-insulin processing. Results: ICCs responded positively to MAFA overexpression and T3 treatment as assessed by two different maturation parameters: increased insulin secretion at 16.8 mM glucose and increased proinsulin-to-insulin processing. In hESCs differentiated toward β-cells, T3 enhanced MAFA expression, increased insulin content (probably mediated by the increased MAFA), and increased insulin secretion at 16.8 mM glucose. Conclusion: T3 is a useful in vitro stimulus to promote human β-cell maturation as shown in both human fetal ICCs and differentiated hESCs. The degree of maturation induced varied in the two models, possibly due to the different developmental status at the beginning of the study.

scholarly journals Expression of Neurexin, Neuroligin, and Their Cytoplasmic Binding Partners in the Pancreatic β-Cells and the Involvement of Neuroligin in Insulin Secretion

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6006-6017 ◽  
Author(s):  
Arthur T. Suckow ◽  
Davide Comoletti ◽  
Megan A. Waldrop ◽  
Merrie Mosedale ◽  
Sonya Egodage ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Surface ◽  
Synapse Formation ◽  
Islet Cells ◽  
Inhibitory Synapses ◽  
Β Cells ◽  
Β Cell ◽  
Neuronal Synapses ◽  
The Central Nervous System

The composition of the β-cell exocytic machinery is very similar to that of neuronal synapses, and the developmental pathway of β-cells and neurons substantially overlap. β-Cells secrete γ-aminobutyric acid and express proteins that, in the brain, are specific markers of inhibitory synapses. Recently, neuronal coculture experiments have identified three families of synaptic cell-surface molecules (neurexins, neuroligins, and SynCAM) that drive synapse formation in vitro and that control the differentiation of nascent synapses into either excitatory or inhibitory fully mature nerve terminals. The inhibitory synapse-like character of the β-cells led us to hypothesize that members of these families of synapse-inducing adhesion molecules would be expressed in β-cells and that the pattern of expression would resemble that associated with neuronal inhibitory synaptogenesis. Here, we describe β-cell expression of the neuroligins, neurexins, and SynCAM, and show that neuroligin expression affects insulin secretion in INS-1 β-cells and rat islet cells. Our findings demonstrate that neuroligins and neurexins are expressed outside the central nervous system and help confer an inhibitory synaptic-like phenotype onto the β-cell surface. Analogous to their role in synaptic neurotransmission, neurexin-neuroligin interactions may play a role in the formation of the submembrane insulin secretory apparatus.

Glucose-dependent expansion of pancreatic β-cells by the protein p8 in vitro and in vivo

2006 ◽  
Vol 291 (6) ◽  
pp. E1168-E1176 ◽  
Author(s):  
Günter Päth ◽  
Anne Opel ◽  
Martin Gehlen ◽  
Veit Rothhammer ◽  
Xinjie Niu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Protein Expression ◽  
Cell Expansion ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
C Peptide

p8 protein expression is known to be upregulated in the exocrine pancreas during acute pancreatitis. Own previous work revealed glucose-dependent p8 expression also in endocrine pancreatic β-cells. Here we demonstrate that glucose-induced INS-1 β-cell expansion is preceded by p8 protein expression. Moreover, isopropylthiogalactoside (IPTG)-induced p8 overexpression in INS-1 β-cells (p8-INS-1) enhances cell proliferation and expansion in the presence of glucose only. Although β-cell-related gene expression (PDX-1, proinsulin I, GLUT2, glucokinase, amylin) and function (insulin content and secretion) are slightly reduced during p8 overexpression, removal of IPTG reverses β-cell function within 24 h to normal levels. In addition, insulin secretion of p8-INS-1 β-cells in response to 0–25 mM glucose is not altered by preceding p8-induced β-cell expansion. Adenovirally transduced p8 overexpression in primary human pancreatic islets increases proliferation, expansion, and cumulative insulin secretion in vitro. Transplantation of mock-transduced control islets under the kidney capsule of immunosuppressed streptozotocin-diabetic mice reduces blood glucose and increases human C-peptide serum concentrations to stable levels after 3 days. In contrast, transplantation of equal numbers of p8-transduced islets results in a continuous decrease of blood glucose and increase of human C-peptide beyond 3 days, indicating p8-induced expansion of transplanted human β-cells in vivo. This is underlined by a doubling of insulin content in kidneys containing p8-transduced islet grafts explanted on day 9. These results establish p8 as a novel molecular mediator of glucose-induced pancreatic β-cell expansion in vitro and in vivo and support the notion of existing β-cell replication in the adult organism.

Glucolipotoxicity-induced oxidative stress is related to mitochondrial dysfunction and apoptosis of pancreatic β-cell

2020 ◽  
Vol 16 ◽  
Author(s):  
Jorge E. Vela-Guajardo ◽  
Salvador Garza-González ◽  
Noemí García
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Insulin Secretion ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Dynamics ◽  
Atp Synthesis ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Diabetes Development

: Glucolipotoxicity-induced oxidative stress and mitochondrial dysfunction of pancreatic β-cells are one of the mechanisms that have been related to the low insulin secretion and cell death during diabetes development. In early or non-chronic stages, the pancreatic β-cells respond to hyperglycemia or hyperlipidemia, stimulating insulin secretion. However, the chronic effect of both leads to the establishment of glucolipotoxicity which induces constant overstimulation of pancreatic β-cells, a condition that leads to cell death by apoptosis. The mechanism described, at this moment, is the accelerated mitochondrial dysfunction triggered by the high production of reactive oxygen species (ROS) due to excess nutrients. At first, mitochondria respond to over-nutrition accelerating oxygen consumption and consequently increasing the ATP synthesis. A permanent increase of ATP/ADP ratio leads to a constant inhibition of K+ ATP-channel and therefore a continuous insulin secretion accompanied by an increase in ROS. Finally, ROS accumulation compromises mitochondrial function due to the uncontrolled oxidation of proteins, lipids, and DNA generating functional alterations such as a drop of membrane potential, deregulation of mitochondrial dynamics, low rate of ATP synthesis and consequently the cell death. This review aims to describe the effect of glucolipotoxicity-induced oxidative stress and its relationship with mitochondrial dysfunction in β-cell during type 2 diabetes development.

The Effect of Oxidative Stress and Antioxidant Therapies on Pancreatic B-cell Dysfunction: Results from in Vitro and in Vivo Studies

2020 ◽  
Vol 27 ◽  
Author(s):  
Ioanna A. Anastasiou ◽  
Ioanna Eleftheriadou ◽  
Anastasios Tentolouris ◽  
Chrysi Koliaki ◽  
Ourania A. Kosta ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
In Vivo Studies ◽  
Limited Evidence ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Natural Extracts ◽  
Endogenous Antioxidant

Background: Oxidative stress is a hallmark of many diseases. A growing body of evidence suggests that hyperglycemiainduced oxidative stress plays an important role in pancreatic β-cells dysfunction and apoptosis as well as in the development and progression of diabetic complications. Considering the vulnerability of pancreatic β-cells to oxidative damage, induction of endogenous antioxidant enzymes or exogenous antioxidant administration has been proposed to protect pancreatic β-cells from damage. Objectives: The present review aims to provide evidence of the effect of oxidative stress and antioxidant therapies on pancreatic β-cell function, based on in vitro and in vivo studies. Methods: The medline and embase databases were searched to retrieve available data. Results: Due to poor endogenous antioxidant mechanisms pancreatic β-cells are extremely sensitive to reactive oxygen species (ROS). Many natural extracts have been tested in vitro in pancreatic β-cell lines in terms of their antioxidant and diabetes mellitus ameliorating effects, and the majority of them have shown a dose-dependent protective role. On the other hand, there is relatively limited evidence regarding the in vitro antioxidant effects of antidiabetic drugs on pancreatic β-cells. About in vivo studies several natural extracts have shown beneficial effects in the setting of diabetes by decreasing blood glucose and lipid levels, increasing insulin sensitivity, and by up-regulating intrinsic antioxidant enzyme activity. However, there is limited evidence obtained from in vivo studies regarding antidiabetic drugs. Conclusion: Antioxidants hold promise for developing strategies aimed at the prevention or treatment of diabetes mellitus associated with pancreatic β-cells dysfunction, as supported by in vitro and in vivo studies. However, more in vitro studies are required about drugs.

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