scholarly journals The Myokine Irisin Is Released in Response to Saturated Fatty Acids and Promotes Pancreatic β-Cell Survival and Insulin Secretion

Diabetes ◽  
2017 ◽  
Vol 66 (11) ◽  
pp. 2849-2856 ◽  
Author(s):  
Annalisa Natalicchio ◽  
Nicola Marrano ◽  
Giuseppina Biondi ◽  
Rosaria Spagnuolo ◽  
Rossella Labarbuta ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Cell Survival ◽  
Saturated Fatty Acids ◽  
Pancreatic Β Cell ◽  
Β Cell

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 Saturated Fatty Acids Synergize with Elevated Glucose to Cause Pancreatic β-Cell Death

Endocrinology ◽  
2003 ◽  
Vol 144 (9) ◽  
pp. 4154-4163 ◽  
Author(s):  
Wissal El-Assaad ◽  
Jean Buteau ◽  
Marie-Line Peyot ◽  
Christopher Nolan ◽  
Raphael Roduit ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cell Death ◽  
Saturated Fatty Acids ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Elevated Glucose

scholarly journals Arachidonic acid actions on functional integrity and attenuation of the negative effects of palmitic acid in a clonal pancreatic β-cell line

2010 ◽  
Vol 120 (5) ◽  
pp. 195-206 ◽  
Author(s):  
Deirdre C. Keane ◽  
Hilton K. Takahashi ◽  
Shalinee Dhayal ◽  
Noel G. Morgan ◽  
Rui Curi ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Arachidonic Acid ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Palmitic Acid ◽  
Cell Line ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Lipoxygenase Inhibitors ◽  
Cox 1

Chronic exposure of pancreatic β-cells to saturated non-esterified fatty acids can lead to inhibition of insulin secretion and apoptosis. Several previous studies have demonstrated that saturated fatty acids such as PA (palmitic acid) are detrimental to β-cell function compared with unsaturated fatty acids. In the present study, we describe the effect of the polyunsaturated AA (arachidonic acid) on the function of the clonal pancreatic β-cell line BRIN-BD11 and demonstrate AA-dependent attenuation of PA effects. When added to β-cell incubations at 100 μM, AA can stimulate cell proliferation and chronic (24 h) basal insulin secretion. Microarray analysis and/or real-time PCR indicated significant AA-dependent up-regulation of genes involved in proliferation and fatty acid metabolism [e.g. Angptl (angiopoietin-like protein 4), Ech1 (peroxisomal Δ3,5,Δ2,4-dienoyl-CoA isomerase), Cox-1 (cyclo-oxygenase-1) and Cox-2, P<0.05]. Experiments using specific COX and LOX (lipoxygenase) inhibitors demonstrated the importance of COX-1 activity for acute (20 min) stimulation of insulin secretion, suggesting that AA metabolites may be responsible for the insulinotropic effects. Moreover, concomitant incubation of AA with PA dose-dependently attenuated the detrimental effects of the saturated fatty acid, so reducing apoptosis and decreasing parameters of oxidative stress [ROS (reactive oxygen species) and NO levels] while improving the GSH/GSSG ratio. AA decreased the protein expression of iNOS (inducible NO synthase), the p65 subunit of NF-κB (nuclear factor κB) and the p47 subunit of NADPH oxidase in PA-treated cells. These findings indicate that AA has an important regulatory and protective β-cell action, which may be beneficial to function and survival in the ‘lipotoxic’ environment commonly associated with Type 2 diabetes mellitus.

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 Glucolipotoxicity of the pancreatic β-cell: myth or reality?

2008 ◽  
Vol 36 (5) ◽  
pp. 901-904 ◽  
Author(s):  
Vincent Poitout
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Insulin Secretion ◽  
Insulin Gene ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
In Vitro Systems ◽  
Insulin Gene Expression

The glucolipotoxicity hypothesis postulates that chronically elevated levels of glucose and fatty acids adversely affect pancreatic β-cell function and thereby contribute to the deterioration of insulin secretion in Type 2 diabetes. Whereas ample experimental evidence in in vitro systems supports the glucolipotoxicity hypothesis, the contribution of this phenomenon to β-cell dysfunction in human Type 2 diabetes has been questioned. The reasons for this controversy include: differences between in vitro systems and in vivo situations; time-dependent effects of fatty acids on insulin secretion (acutely stimulatory and chronically inhibitory); and the ill-defined use of the suffix ‘-toxicity’. In vitro, prolonged exposure of insulin-secreting cells or isolated islets to concomitantly elevated levels of fatty acids and glucose impairs insulin secretion, inhibits insulin gene expression and, under certain circumstances, induces β-cell death by apoptosis. Recent studies in our laboratory have shown that cyclical and alternate infusions of glucose and Intralipid in rats impair insulin gene expression, providing evidence that inhibition of the insulin gene under glucolipotoxic conditions is an early defect that might indeed contribute to β-cell failure in Type 2 diabetes, although this hypothesis remains to be tested in humans.

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.

scholarly journals Insulin secretion in health and disease: nutrients dictate the pace

2015 ◽  
Vol 75 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Romano Regazzi ◽  
Adriana Rodriguez-Trejo ◽  
Cécile Jacovetti
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Cell Mass ◽  
Insulin Biosynthesis ◽  
Β Cells ◽  
Β Cell ◽  
Altered Expression ◽  
Cell Dysfunction ◽  
Dietary Nutrients ◽  
Underlying Mechanisms

Insulin is a key hormone controlling metabolic homeostasis. Loss or dysfunction of pancreatic β-cells lead to the release of insufficient insulin to cover the organism needs, promoting diabetes development. Since dietary nutrients influence the activity of β-cells, their inadequate intake, absorption and/or utilisation can be detrimental. This review will highlight the physiological and pathological effects of nutrients on insulin secretion and discuss the underlying mechanisms. Glucose uptake and metabolism in β-cells trigger insulin secretion. This effect of glucose is potentiated by amino acids and fatty acids, as well as by entero-endocrine hormones and neuropeptides released by the digestive tract in response to nutrients. Glucose controls also basal and compensatory β-cell proliferation and, along with fatty acids, regulates insulin biosynthesis. If in the short-term nutrients promote β-cell activities, chronic exposure to nutrients can be detrimental to β-cells and causes reduced insulin transcription, increased basal secretion and impaired insulin release in response to stimulatory glucose concentrations, with a consequent increase in diabetes risk. Likewise, suboptimal early-life nutrition (e.g. parental high-fat or low-protein diet) causes altered β-cell mass and function in adulthood. The mechanisms mediating nutrient-induced β-cell dysfunction include transcriptional, post-transcriptional and translational modifications of genes involved in insulin biosynthesis and secretion, carbohydrate and lipid metabolism, cell differentiation, proliferation and survival. Altered expression of these genes is partly caused by changes in non-coding RNA transcripts induced by unbalanced nutrient uptake. A better understanding of the mechanisms leading to β-cell dysfunction will be critical to improve treatment and find a cure for diabetes.

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