The fate of intracellular S1P regulates lipid droplet turnover and lipotoxicity in pancreatic beta-cells.

Lipotoxicity has been considered the main cause of pancreatic beta-cell failure during type 2 diabetes development. Lipid droplets (LD) are believed to regulate the beta-cell sensitivity to free fatty acids (FFA), but the underlying molecular mechanisms are largely unclear. Accumulating evidence points, however, to an important role of intracellular sphingosine-1-phosphate (S1P) metabolism in lipotoxicity-mediated disturbances of beta-cell function.

To Be or Not to Be: The Divergent Action and Metabolism of Sphingosine-1 Phosphate in Pancreatic Beta-Cells in Response to Cytokines and Fatty Acids.

Sphingosine-1 phosphate (S1P) is a bioactive sphingolipid with multiple functions conveyed by the activation of cell surface receptors and/or intracellular mediators. A growing body of evidence indicates its important role in pancreatic insulin-secreting beta-cells that are necessary for maintenance of glucose homeostasis. The dysfunction and/or death of beta-cells lead to diabetes development.

Proinflammatory cytokines induce rapid, NO-independent apoptosis, expression of chemotactic mediators and interleukin-32 secretion in human pluripotent stem cell-derived beta cells.

Aims/hypothesis: The aim of this study was to examine the effects of proinflammatory cytokines on cells of different developmental stages during the generation of stem cell-derived beta cells (SC-beta cells) from human pluripotent stem cells (hPSCs). We wanted to find out to what extent human SC-beta cells are suitable as an experimental cellular model and, with regard to a possible therapeutic use, whether SC-beta cells have a comparable vulnerability to cytokines as bona fide beta cells.

Methods: hPSCs were differentiated towards pancreatic organoids (SC-organoids) using a 3D production protocol.

Sphingosine-1 Phosphate Lyase Regulates Sensitivity of Pancreatic Beta-Cells to Lipotoxicity.

Elevated levels of free fatty acids (FFAs) have been related to pancreatic beta-cell failure in type 2 diabetes (T2DM), though the underlying mechanisms are not yet fully understood. FFAs have been shown to dysregulate formation of bioactive sphingolipids, such as ceramides and sphingosine-1 phosphate (S1P) in beta-cells. The aim of this study was to analyze the role of sphingosine-1 phosphate lyase (SPL), a key enzyme of the sphingolipid pathway that catalyzes an irreversible degradation of S1P, in the sensitivity of beta-cells to lipotoxicity.

Sphingolipids in Type 1 Diabetes: Focus on Beta-Cells.

Type 1 diabetes (T1DM) is a chronic autoimmune disease, with a strong genetic background, leading to a gradual loss of pancreatic beta-cells, which secrete insulin and control glucose homeostasis. Patients with T1DM require life-long substitution with insulin and are at high risk for development of severe secondary complications. The incidence of T1DM has been continuously growing in the last decades, indicating an important contribution of environmental factors.

Immunometabolism in type 2 diabetes mellitus: tissue-specific interactions.

The immune system is frequently described in the context of its protective function against infections and its role in the development of autoimmunity. For more than a decade, the interactions between the immune system and metabolic processes have been reported, in effect creating a new research field, termed immunometabolism. Accumulating evidence supports the hypothesis that the development of metabolic diseases may be linked to inflammation, and reflects, in some cases, the activation of immune responses.

MCPIP1 regulates the sensitivity of pancreatic beta-cells to cytokine toxicity.

The autoimmune-mediated beta-cell death in type 1 diabetes (T1DM) is associated with local inflammation (insulitis). We examined the role of MCPIP1 (monocyte chemotactic protein-induced protein 1), a novel cytokine-induced antiinflammatory protein, in this process. Basal MCPIP1 expression was lower in rat vs.

Overexpression of sphingosine-1-phosphate lyase protects insulin-secreting cells against cytokine toxicity.

Increasing evidence suggests a crucial role of inflammation in cytokine-mediated β-cell dysfunction and death in type 1 diabetes mellitus, although the mechanisms are incompletely understood. Sphingosine 1-phosphate (S1P) is a multifunctional bioactive sphingolipid involved in the development of many autoimmune and inflammatory diseases. Here, we investigated the role of intracellular S1P in insulin-secreting INS1E cells by genetically manipulating the S1P-metabolizing enzyme S1P lyase (SPL).

Sensitivity profile of the human EndoC-βH1 beta cell line to proinflammatory cytokines.

Aims/hypothesis: The aim of this study was to perform a detailed analysis of cytokine toxicity in the new human EndoC-βH1 beta cell line.

Methods: The expression profile of the antioxidative enzymes in the new human EndoC-βH1 beta cells was characterised and compared with that of primary beta cells in the human pancreas. The effects of proinflammatory cytokines on reactive oxygen species formation, insulin secretory responsiveness and apoptosis of EndoC-βH1 beta cells were determined.

Improved antioxidative defence protects insulin-producing cells against homocysteine toxicity.

Homocysteine (HC) is considered to play an important role in the development of metabolic syndrome complications. Insulin-producing cells are prone to HC toxicity and this has been linked to oxidative stress. However, the exact mechanisms remain unknown.

Physiological characterization of the human EndoC-βH1 β-cell line.

In the new human EndoC-βH1 β-cell line, a detailed analysis of the physiological characteristics was performed. This new human β-cell line expressed all target structures on the gene and protein level, which are crucial for physiological function and insulin secretion induced by glucose and other secretagogues. Glucose influx measurements revealed an excellent uptake capacity of EndoC-βH1 β-cells by the Glut1 and Glut2 glucose transporters.

Unveiling a common mechanism of apoptosis in β-cells and neurons in Friedreich's ataxia.

Friedreich's ataxia (FRDA) is a neurodegenerative disorder associated with cardiomyopathy and diabetes. Effective therapies for FRDA are an urgent unmet need; there are currently no options to prevent or treat this orphan disease. FRDA is caused by reduced expression of the mitochondrial protein frataxin.

Limited GADD45α expression and function in IL-1β toxicity towards insulin-producing cells.

Growth arrest and DNA damage-inducible (GADD) 45 proteins are regulators of cell death and survival. The proinflammatory cytokine IL-1β strongly increases the level of the transcript encoding GADD45α in rat insulin-producing INS-1E cells. The activation of Gadd45α gene is clearly dependent on JNK and NF-κB activation and the synthesis of the secondary mediator nitric oxide (NO).

IL-1β hampers glucose-stimulated insulin secretion in Cohen diabetic rat islets through mitochondrial cytochrome c oxidase inhibition by nitric oxide.

A high-sucrose, low-copper-diet (HSD) induces inhibition of glucose-sensitive rats (CDs) but not Cohen diabetes-resistant rats (CDr). Copper-supplemented HSD increased activity of the copper-dependent mitochondrial respiratory chain enzyme cytochrome c oxidase (COX) and reversed hyperglycemia. This study examined the mechanism by which interleukin-1β modulates GSIS and the role of COX in this process.

Is there a role for neuronal nitric oxide synthase (nNOS) in cytokine toxicity to pancreatic beta cells?

Nitric oxide (NO), produced by the action of the inducible NO synthase, plays a crucial role in cytokine toxicity to pancreatic beta cells during type 1 diabetes development. It was the aim of this study to analyze the role of the neuronal NOS (nNOS) in proinflammatory cytokine-mediated beta cell toxicity. Expression of different isoforms of nitric oxide synthase in insulin-secreting INS1E cells and rat islets was analyzed by quantitative real-time PCR and Western blotting.

Effects of the novel mitochondrial protein mimitin in insulin-secreting cells.

Mimitin, a novel mitochondrial protein, has been shown to act as a molecular chaperone for the mitochondrial complex I and to regulate ATP synthesis. During Type 1 diabetes development, pro-inflammatory cytokines induce mitochondrial damage in pancreatic β-cells, inhibit ATP synthesis and reduce glucose-induced insulin secretion. Mimitin was expressed in rat pancreatic islets including β-cells and decreased by cytokines.

Mechanism of prostacyclin-induced potentiation of glucose-induced insulin secretion.

Arachidonic acid metabolites are crucial mediators of inflammation in diabetes. Although eicosanoids are established modulators of pancreatic β-cell function, the role of prostacyclin (prostaglandin I2) is unknown. Therefore, this study aimed to analyze the role of prostacyclin in β-cell function.

Induction of the intrinsic apoptosis pathway in insulin-secreting cells is dependent on oxidative damage of mitochondria but independent of caspase-12 activation.

Pro-inflammatory cytokine-mediated beta cell apoptosis is activated through multiple signaling pathways involving mitochondria and endoplasmic reticulum. Activation of organelle-specific caspases has been implicated in the progression and execution of cell death. This study was therefore performed to elucidate the effects of pro-inflammatory cytokines on a possible cross-talk between the compartment-specific caspases 9 and 12 and their differential contribution to beta cell apoptosis.

Differential effects of proinflammatory cytokines on cell death and ER stress in insulin-secreting INS1E cells and the involvement of nitric oxide.

Proinflammatory cytokines produced by immune cells destroy pancreatic beta cells in type 1 diabetes. The aim of this study was to investigate the cytokine network and its effects in insulin-secreting cells. INS1E cells were exposed to different combinations of proinflammatory cytokines.

Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stress-induced hydroxyl radical formation in mitochondria.

Although nitric oxide (NO) and oxidative stress both contribute to proinflammatory cytokine toxicity in pancreatic β-cells during type 1 diabetes mellitus (T1DM) development, the interactions between NO and reactive oxygen species (ROS) in cytokine-mediated β-cell death have not been clarified. Exposure of insulin-producing RINm5F cells to IL-1β generated NO, while exposure to a combination of IL-1β, TNF-α, and IFN-γ, which simulates T1DM conditions, generated both NO and ROS. In theory, two reactions between NO and ROS are possible, one with the superoxide radical yielding peroxynitrite, and the other with hydrogen peroxide (H(2)O(2)) yielding hydroxyl radicals.

Protection against cytokine toxicity through endoplasmic reticulum and mitochondrial stress prevention by prostacyclin synthase overexpression in insulin-producing cells.

Proinflammatory cytokines play a crucial role in the pathogenesis of type 1 diabetes mellitus. One of the cytokine-regulated pathways mediating inflammation in this autoimmune disease is the arachidonic acid metabolism pathway, comprising both the induction of cyclooxygenases and the production of different prostaglandins. Cytokine toxicity is mediated in many cell types, including pancreatic beta cells through this pathway.

Protection of insulin-producing cells against toxicity of dexamethasone by catalase overexpression.

Pancreatic beta cells are very sensitive to reactive oxygen species (ROS) and this might play an important role in beta cell death in diabetes. Dexamethasone is a synthetic diabetogenic glucocorticoid, which impairs pancreatic beta cell function. Therefore we investigated the toxicity of dexamethasone in RINm5F insulin-producing cells and its dependence on the expression level of the antioxidant enzyme catalase, which inactivates hydrogen peroxide.

Interaction between pro-inflammatory and anti-inflammatory cytokines in insulin-producing cells.

Pro-inflammatory cytokines cause beta-cell dysfunction and death. The aim of this study was to investigate the interactions between different pro- and anti-inflammatory cytokines and their effects on apoptotic beta-cell death pathways. Insulin-producing RINm5F cells were exposed to different combinations of cytokines.