scholarly journals Alanyl-glutamine improves pancreatic β-cell function following ex vivo inflammatory challenge

2014 ◽  
Vol 224 (3) ◽  
pp. 261-271 ◽  
Author(s):  
Vinicius Fernandes Cruzat ◽  
Kevin Noel Keane ◽  
Anita Lavarda Scheinpflug ◽  
Robson Cordeiro ◽  
Mario J Soares ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Ex Vivo ◽  
Sirtuin 1 ◽  
Protective Effects ◽  
Pancreatic Β Cell ◽  
Cell Integrity ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell

Obesity-associated diabetes and concomitant inflammation may compromise pancreatic β-cell integrity and function. l-glutamine and l-alanine are potent insulin secretagogues, with antioxidant and cytoprotective properties. Herein, we studied whether the dipeptide l-alanyl-l-glutamine (Ala-Gln) could exert protective effects via sirtuin 1/HUR (SIRT1/HUR) signalling in β-cells, against detrimental responses following ex vivo stimulation with inflammatory mediators derived from macrophages (IMMs). The macrophages were derived from blood obtained from obese subjects. Macrophages were exposed (or not) to lipopolysaccharide (LPS) to generate a pro-inflammatory cytokine cocktail. The cytokine profile was determined following analysis by flow cytometry. Insulin-secreting BRIN–BD11 β-cells were exposed to IMMs and then cultured with or without Ala-Gln for 24 h. Chronic insulin secretion, the l-glutamine–glutathione (GSH) axis, and the level of insulin receptor β (IR-β), heat shock protein 70 (HSP70), SIRT1/HUR, CCAAT-enhancer-binding protein homologous protein (CHOP) and cytochrome c oxidase IV (COX IV) were evaluated. Concentrations of cytokines, including interleukin 1β (IL1β), IL6, IL10 and tumour necrosis factor alpha (TNFα) in the IMMs, were higher following exposure to LPS. Subsequently, when β-cells were exposed to IMMs, chronic insulin secretion, and IR-β and COX IV levels were decreased, but these effects were partially or fully attenuated by the addition of Ala-Gln. The glutamine–GSH axis and HSP70 levels, which were compromised by IMMs, were also restored by Ala-Gln, possibly due to protection of SIRT1/HUR levels, and a reduction of CHOP expression. Using an ex vivo inflammatory approach, we have demonstrated Ala-Gln-dependent β-cell protection mediated by coordinated effects on the glutamine–GSH axis, and the HSP pathway, maintenance of mitochondrial metabolism and stimulus–secretion coupling essential for insulin release.

scholarly journals Favorable Effects of GLP-1 Receptor Agonist against Pancreatic β-Cell Glucose Toxicity and the Development of Arteriosclerosis: “The Earlier, the Better” in Therapy with Incretin-Based Medicine

2021 ◽  
Vol 22 (15) ◽  
pp. 7917
Author(s):  
Hideaki Kaneto ◽  
Tomohiko Kimura ◽  
Masashi Shimoda ◽  
Atsushi Obata ◽  
Junpei Sanada ◽  
...  
Keyword(s):  
Large Scale ◽  
Cell Function ◽  
Apoptotic Cell ◽  
Early Stage ◽  
Insulin Biosynthesis ◽  
Protective Effects ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Toxicity

Fundamental pancreatic β-cell function is to produce and secrete insulin in response to blood glucose levels. However, when β-cells are chronically exposed to hyperglycemia in type 2 diabetes mellitus (T2DM), insulin biosynthesis and secretion are decreased together with reduced expression of insulin transcription factors. Glucagon-like peptide-1 (GLP-1) plays a crucial role in pancreatic β-cells; GLP-1 binds to the GLP-1 receptor (GLP-1R) in the β-cell membrane and thereby enhances insulin secretion, suppresses apoptotic cell death and increase proliferation of β-cells. However, GLP-1R expression in β-cells is reduced under diabetic conditions and thus the GLP-1R activator (GLP-1RA) shows more favorable effects on β-cells at an early stage of T2DM compared to an advanced stage. On the other hand, it has been drawing much attention to the idea that GLP-1 signaling is important in arterial cells; GLP-1 increases nitric oxide, which leads to facilitation of vascular relaxation and suppression of arteriosclerosis. However, GLP-1R expression in arterial cells is also reduced under diabetic conditions and thus GLP-1RA shows more protective effects on arteriosclerosis at an early stage of T2DM. Furthermore, it has been reported recently that administration of GLP-1RA leads to the reduction of cardiovascular events in various large-scale clinical trials. Therefore, we think that it would be better to start GLP-1RA at an early stage of T2DM for the prevention of arteriosclerosis and protection of β-cells against glucose toxicity in routine medical care.

scholarly journals Resveratrol and curcumin enhance pancreatic β-cell function by inhibiting phosphodiesterase activity

2014 ◽  
Vol 223 (2) ◽  
pp. 107-117 ◽  
Author(s):  
Michael Rouse ◽  
Antoine Younès ◽  
Josephine M Egan
Keyword(s):  
Insulin Secretion ◽  
Cell Lines ◽  
Cell Function ◽  
Human Islets ◽  
Dependent Manner ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pde Inhibitors ◽  
Β Cell Function

Resveratrol (RES) and curcumin (CUR) are polyphenols that are found in fruits and turmeric, and possess medicinal properties that are beneficial in various diseases, such as heart disease, cancer, and type 2 diabetes mellitus (T2DM). Results from recent studies have indicated that their therapeutic properties can be attributed to their anti-inflammatory effects. Owing to reports stating that they protect against β-cell dysfunction, we studied their mechanism(s) of action in β-cells. In T2DM, cAMP plays a critical role in glucose- and incretin-stimulated insulin secretion as well as overall pancreatic β-cell health. A potential therapeutic target in the management of T2DM lies in regulating the activity of phosphodiesterases (PDEs), which degrade cAMP. Both RES and CUR have been reported to act as PDE inhibitors in various cell types, but it remains unknown if they do so in pancreatic β-cells. In our current study, we found that both RES (0.1–10 μmol/l) and CUR (1–100 pmol/l)-regulated insulin secretion under glucose-stimulated conditions. Additionally, treating β-cell lines and human islets with these polyphenols led to increased intracellular cAMP levels in a manner similar to 3-isobutyl-1-methylxanthine, a classic PDE inhibitor. When we investigated the effects of RES and CUR on PDEs, we found that treatment significantly downregulated the mRNA expression of most of the 11 PDE isozymes, including PDE3B, PDE8A, and PDE10A, which have been linked previously to regulation of insulin secretion in islets. Furthermore, RES and CUR inhibited PDE activity in a dose-dependent manner in β-cell lines and human islets. Collectively, we demonstrate a novel role for natural-occurring polyphenols as PDE inhibitors that enhance pancreatic β-cell function.

scholarly journals Oxytocin signal contributes to the adaptative growth of islets during gestation

2021 ◽  
Author(s):  
Ping Gu ◽  
Yuege Lin ◽  
Qi Wan ◽  
Dongming Su ◽  
Qun Shu
Keyword(s):  
Insulin Secretion ◽  
Pregnant Women ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Adaptation ◽  
Β Cell Function ◽  
Insulinoma Cells

Background: Increased insulin production and secretion by pancreatic β-cells are important for ensuring the high insulin demand during gestation. However, the underlying mechanism of β-cell adaptation during gestation or in gestational diabetes mellitus (GDM) remains unclear. Oxytocin is an important physiological hormone in gestation and delivery, and it also contributes to the maintenance of β-cell function. The aim of this study was to investigate the role of oxytocin in β-cell adaptation during pregnancy. Methods: The relationship between the blood oxytocin level and pancreatic β-cell function in patients with GDM and healthy pregnant women was investigated. Gestating and non-gestating mice were used to evaluate the in vivo effect of oxytocin signal on β-cells during pregnancy. In vitro experiments were performed on INS-1 insulinoma cells. Results: The blood oxytocin levels were lower in patients with GDM than in healthy pregnant women and were associated with impaired pancreatic β-cell function. Acute administration of oxytocin increased insulin secretion in both gestating and non-gestating mice. A three-week oxytocin treatment promoted the proliferation of pancreatic β-cells and increased the β-cell mass in gestating but not non-gestating mice. Antagonism of oxytocin receptors by atosiban impaired insulin secretion and induced GDM in gestating but not non-gestating mice. Oxytocin enhanced glucose-stimulated insulin secretion, activated the mitogen-activated protein kinase pathway, and promoted cell proliferation in INS-1 cells. Conclusions: These findings provide strong evidence that oxytocin is needed for β-cell adaptation during pregnancy to maintain β-cell function, and lack of oxytocin could be associated with the risk of GDM.

scholarly journals A fluorescent timer reporter enables sorting of insulin secretory granules by age

2020 ◽  
Vol 295 (27) ◽  
pp. 8901-8911 ◽  
Author(s):  
Belinda Yau ◽  
Lori Hays ◽  
Cassandra Liang ◽  
D. Ross Laybutt ◽  
Helen E. Thomas ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Islet Cells ◽  
Ex Vivo ◽  
Secretory Granules ◽  
Β Cells ◽  
Β Cell ◽  
Short Period ◽  
Insulin Granule

Within the pancreatic β-cells, insulin secretory granules (SGs) exist in functionally distinct pools, displaying variations in motility as well as docking and fusion capability. Current therapies that increase insulin secretion do not consider the existence of these distinct SG pools. Accordingly, these approaches are effective only for a short period, with a worsening of glycemia associated with continued decline in β-cell function. Insulin granule age is underappreciated as a determinant for why an insulin granule is selected for secretion and may explain why newly synthesized insulin is preferentially secreted from β-cells. Here, using a novel fluorescent timer protein, we aimed to investigate the preferential secretion model of insulin secretion and identify how granule aging is affected by variation in the β-cell environment, such as hyperglycemia. We demonstrate the use of a fluorescent timer construct, syncollin-dsRedE5TIMER, which changes its fluorescence from green to red over 18 h, in both microscopy and fluorescence-assisted organelle-sorting techniques. We confirm that the SG-targeting construct localizes to insulin granules in β-cells and does not interfere with normal insulin SG behavior. We visualize insulin SG aging behavior in MIN6 and INS1 β-cell lines and in primary C57BL/6J mouse and nondiabetic human islet cells. Finally, we separated young and old insulin SGs, revealing that preferential secretion of younger granules occurs in glucose-stimulated insulin secretion. We also show that SG population age is modulated by the β-cell environment in vivo in the db/db mouse islets and ex vivo in C57BL/6J islets exposed to different glucose environments.

The importance of redox shuttles to pancreatic β-cell energy metabolism and function

2006 ◽  
Vol 34 (5) ◽  
pp. 811-814 ◽  
Author(s):  
K. Bender ◽  
P. Newsholme ◽  
L. Brennan ◽  
P. Maechler
Keyword(s):  
Insulin Secretion ◽  
Energy Metabolism ◽  
Electron Transport ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Nutrient Metabolism ◽  
Β Cell Function ◽  
Malate Aspartate Shuttle

The coupling of cytosolic glycolytic NADH production with the mitochondrial electron transport chain is crucial for pancreatic β-cell function and energy metabolism. The activity of lactate dehydrogenase in the β-cell is low, thus glycolysis-derived electrons are transported towards the mitochondrial matrix by a NADH shuttle system, which in turn regenerates cytosolic NAD+. Mitochondrial electron transport then produces ATP, the main coupling factor for insulin secretion. Aralar1, a Ca2+-sensitive member of the malate–aspartate shuttle expressed in β-cells, has been found to play a significant role in nutrient-stimulated insulin secretion and β-cell function. Increased capacity of Aralar1 enhances the responsiveness of the cell to glucose. Conversely, inhibition of the malate–aspartate shuttle results in impaired glucose metabolism and insulin secretion. Current research investigates potentiating or attenuating activities of various amino acids on insulin secretion, mitochondrial membrane potential and NADH production in Aralar1-overexpressing β-cells. This work may provide evidence for a central role of Aralar1 in the regulation of nutrient metabolism in the β-cells.

scholarly journals An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jinyoung Kim ◽  
Kihyoun Park ◽  
Min Jung Kim ◽  
Hyejin Lim ◽  
Kook Hwan Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Therapeutic Modality ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Islet Amyloid ◽  
Amyloid Accumulation ◽  
Human Diabetes

AbstractWe have reported that autophagy is crucial for clearance of amyloidogenic human IAPP (hIAPP) oligomer, suggesting that an autophagy enhancer could be a therapeutic modality against human diabetes with amyloid accumulation. Here, we show that a recently identified autophagy enhancer (MSL-7) reduces hIAPP oligomer accumulation in human induced pluripotent stem cell-derived β-cells (hiPSC-β-cells) and diminishes oligomer-mediated apoptosis of β-cells. Protective effects of MSL-7 against hIAPP oligomer accumulation and hIAPP oligomer-mediated β-cell death are significantly reduced in cells with knockout of MiTF/TFE family members such as Tfeb or Tfe3. MSL-7 improves glucose tolerance and β-cell function of hIAPP+ mice on high-fat diet, accompanied by reduced hIAPP oligomer/amyloid accumulation and β-cell apoptosis. Protective effects of MSL-7 against hIAPP oligomer-mediated β-cell death and the development of diabetes are also significantly reduced by β-cell-specific knockout of Tfeb. These results suggest that an autophagy enhancer could have therapeutic potential against human diabetes characterized by islet amyloid accumulation.

scholarly journals Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Brenda Strutt ◽  
Sandra Szlapinski ◽  
Thineesha Gnaneswaran ◽  
Sarah Donegan ◽  
Jessica Hill ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glucose Transporter ◽  
Cell Mass ◽  
Elevated Serum ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Transporter 2 ◽  
Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

Effects of pharmacological inhibition of NADPH oxidase or iNOS on pro-inflammatory cytokine, palmitic acid or H2O2-induced mouse islet or clonal pancreatic β-cell dysfunction

2010 ◽  
Vol 30 (6) ◽  
pp. 445-453 ◽  
Author(s):  
Marta Michalska ◽  
Gabriele Wolf ◽  
Reinhard Walther ◽  
Philip Newsholme
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Nadph Oxidase ◽  
Inflammatory Cytokine ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Mouse Islets ◽  
Pro Inflammatory Cytokines

Various pancreatic β-cell stressors including cytokines and saturated fatty acids are known to induce oxidative stress, which results in metabolic disturbances and a reduction in insulin secretion. However, the key mechanisms underlying dysfunction are unknown. We investigated the effects of prolonged exposure (24 h) to pro-inflammatory cytokines, H2O2 or PA (palmitic acid) on β-cell insulin secretion, ATP, the NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) component p47phox and iNOS (inducible nitric oxide synthase) levels using primary mouse islets or clonal rat BRIN-BD11 β-cells. Addition of a pro-inflammatory cytokine mixture [IL-1β (interleukin-1β), TNF-α (tumour necrosis factor-α) and IFN-γ (interferon-γ)] or H2O2 (at sub-lethal concentrations) inhibited chronic (24 h) levels of insulin release by at least 50% (from islets and BRIN-BD11 cells), while addition of the saturated fatty acid palmitate inhibited acute (20 min) stimulated levels of insulin release from mouse islets. H2O2 decreased ATP levels in the cell line, but elevated p47phox and iNOS levels as did cytokine addition. Similar effects were observed in mouse islets with respect to elevation of p47phox and iNOS levels. Addition of antioxidants SOD (superoxide dismutase), Cat (catalase) and NAC (N-acetylcysteine) attenuated H2O2 or the saturated fatty acid palmitate-dependent effects, but not cytokine-induced dysfunction. However, specific chemical inhibitors of NADPH oxidase and/or iNOS appear to significantly attenuate the effects of cytokines, H2O2 or fatty acids in islets. While pro-inflammatory cytokines are known to increase p47phox and iNOS levels in β-cells, we now report that H2O2 can increase levels of the latter two proteins, suggesting a key role for positive-feedback redox sensitive regulation of β-cell dysfunction.

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.

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