Distinct Levels of Reactive Oxygen Species Coordinate Metabolic Activity with Beta-cell Mass Plasticity

Alfar, Ezzaldin Ahmed; Kirova, Dilyana Georgieva; Konantz, Judith; Birke, Sarah; Mansfeld, Jörg; Ninov, Nikolay

doi:10.1038/s41598-017-03873-9

Cited by 48 publications

(27 citation statements)

References 44 publications

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“…In turn, manipulations leading to decreases in cellular ROS levels prevented normal β-cell differentiation. Moderate increases in cytosolic H 2 O 2 were found to promote β-cell proliferation in zebrafish, whereas high H 2 O 2 levels can stimulate differentiation of new β-cells from progenitors (8). It has been hypothesized that the moderate H 2 O 2 levels are necessary for β-cell proliferation.…”

Section: Impaired Biogenesis Of Pancreatic β-Cellsmentioning

confidence: 99%

Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes

Ježek

Jabůrek

Plecitá–Hlavatá

2019

Antioxidants & Redox Signaling

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Significance: Type 2 diabetes development involves multiple changes in β-cells, related to the oxidative stress and impaired redox signaling, beginning frequently by sustained overfeeding due to the resulting lipotoxicity and glucotoxicity. Uncovering relationships among the dysregulated metabolism, impaired β-cell “well-being,” biogenesis, or cross talk with peripheral insulin resistance is required for elucidation of type 2 diabetes etiology. Recent Advances: It has been recognized that the oxidative stress, lipotoxicity, and glucotoxicity cannot be separated from numerous other cell pathology events, such as the attempted compensation of β-cell for the increased insulin demand and dynamics of β-cell biogenesis and its “reversal” at dedifferentiation, that is, from the concomitantly decreasing islet β-cell mass (also due to transdifferentiation) and low-grade islet or systemic inflammation. Critical Issues: At prediabetes, the compensation responses of β-cells, attempting to delay the pathology progression—when exaggerated—set a new state, in which a self-checking redox signaling related to the expression of Ins gene expression is impaired. The resulting altered redox signaling, diminished insulin secretion responses to various secretagogues including glucose, may lead to excretion of cytokines or chemokines by β-cells or excretion of endosomes. They could substantiate putative stress signals to the periphery. Subsequent changes and lasting glucolipotoxicity promote islet inflammatory responses and further pathology spiral. Future Directions: Should bring an understanding of the β-cell self-checking and related redox signaling, including the putative stress signal to periphery. Strategies to cure or prevent type 2 diabetes could be based on the substitution of the “wrong” signal by the “correct” self-checking signal.

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Section: Impaired Biogenesis Of Pancreatic β-Cellsmentioning

confidence: 99%

Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes

Ježek

Jabůrek

Plecitá–Hlavatá

2019

Antioxidants & Redox Signaling

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“…Interestingly, ROS is known to increase apoptosis and in high concentrations induce cell cycle arrest. However, in low to moderate concentrations, ROS have been found to stimulate cell proliferation (Boonstra and Post, 2004; Ahmed Alfar et al, 2017). In addition, experimental studies have shown that mitochondrial ROS play an important role in beta-cell proliferation (Ahmed Alfar et al, 2017) and in the establishment of beta-cell mass during development (Zeng et al, 2017).…”

Section: Adaptive Changes Of Beta-cell Mass In Obesity and Type 2 Diamentioning

confidence: 99%

“…However, in low to moderate concentrations, ROS have been found to stimulate cell proliferation (Boonstra and Post, 2004; Ahmed Alfar et al, 2017). In addition, experimental studies have shown that mitochondrial ROS play an important role in beta-cell proliferation (Ahmed Alfar et al, 2017) and in the establishment of beta-cell mass during development (Zeng et al, 2017). The loss of beta-cell mass in T2D can be explained by the increased apoptosis rate observed in islets from T2D patients (Butler et al, 2003; Rahier et al, 2008; Hanley et al, 2010) and the lack of increased beta-cell proliferation (Butler et al, 2003).…”

Section: Adaptive Changes Of Beta-cell Mass In Obesity and Type 2 Diamentioning

confidence: 99%

Heterogeneity of Metabolic Defects in Type 2 Diabetes and Its Relation to Reactive Oxygen Species and Alterations in Beta-Cell Mass

et al. 2019

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Type 2 diabetes (T2D) is a complex and heterogeneous disease which affects millions of people worldwide. The classification of diabetes is at an interesting turning point and there have been several recent reports on sub-classification of T2D based on phenotypical and metabolic characteristics. An important, and perhaps so far underestimated, factor in the pathophysiology of T2D is the role of oxidative stress and reactive oxygen species (ROS). There are multiple pathways for excessive ROS formation in T2D and in addition, beta-cells have an inherent deficit in the capacity to cope with oxidative stress. ROS formation could be causal, but also contribute to a large number of the metabolic defects in T2D, including beta-cell dysfunction and loss. Currently, our knowledge on beta-cell mass is limited to autopsy studies and based on comparisons with healthy controls. The combined evidence suggests that beta-cell mass is unaltered at onset of T2D but that it declines progressively. In order to better understand the pathophysiology of T2D, to identify and evaluate novel treatments, there is a need for in vivo techniques able to quantify beta-cell mass. Positron emission tomography holds great potential for this purpose and can in addition map metabolic defects, including ROS activity, in specific tissue compartments. In this review, we highlight the different phenotypical features of T2D and how metabolic defects impact oxidative stress and ROS formation. In addition, we review the literature on alterations of beta-cell mass in T2D and discuss potential techniques to assess beta-cell mass and metabolic defects in vivo .

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“…Inhibiting islet inflammation has emerged as an important objective for the protection of β-cells (Campbell-Thompson et al, 2016; Eizirik et al, 2009; Nordmann et al, 2017). It has been suggested that hyperglycemia in T2DM enhances the metabolic load on β-cells, causing an increase in the production of reactive oxygen species (ROS), in part, due to the oxidative nature of insulin protein folding and glucose metabolism (Ahmed Alfar et al, 2017). β-cell oxidative stress could promote inflammasome and caspase-1 activation, which can lead to the production and release of low levels of mature interleukin-1β (IL-1β).…”

Section: Introductionmentioning

confidence: 99%

Modelling pancreatic β-cell inflammation in zebrafish identifies the natural product wedelolactone for human islet protection

Delgadillo-Silva

Tsakmaki

Akhtar

et al. 2019

Disease Models &Amp; Mechanisms

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Islet inflammation and cytokine production are implicated in pancreatic β-cell dysfunction and diabetes pathogenesis. However, we lack therapeutics to protect the insulin-producing β-cells from inflammatory damage. Closing this clinical gap requires the establishment of new disease models of islet inflammation to facilitate screening efforts aimed at identifying new protective agents. Here, we have developed a genetic model of Interleukin-1β (Il-1β)-driven islet inflammation in zebrafish, a vertebrate that allows for non-invasive imaging of β-cells and in vivo drug discovery. Live imaging of immune cells and β-cells in our model revealed dynamic migration, increased visitation and prolonged macrophage retention in the islet, together with robust activation of NF-κB signalling in β-cells. We find that Il-1β-mediated inflammation does not cause β-cell destruction but, rather, it impairs β-cell function and identity. In vivo, β-cells exhibit impaired glucose-stimulated calcium influx and reduced expression of genes involved in function and maturity. These defects are accompanied by α-cell expansion, glucose intolerance and hyperglycemia following a glucose challenge. Notably, we show that a medicinal plant derivative (wedelolactone) is capable of reducing the immune-cell infiltration while also ameliorating the hyperglycemic phenotype of our model. Importantly, these anti-diabetic properties in zebrafish are predictive of wedelolactone's efficacy in protecting rodent and human islets from cytokine-induced apoptosis. In summary, this new zebrafish model of diabetes opens a window to study the interactions between immune and β-cells in vivo, while also allowing the identification of therapeutic agents for protecting β-cells from inflammation.

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Distinct Levels of Reactive Oxygen Species Coordinate Metabolic Activity with Beta-cell Mass Plasticity

Cited by 48 publications

References 44 publications

Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes

Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes

Heterogeneity of Metabolic Defects in Type 2 Diabetes and Its Relation to Reactive Oxygen Species and Alterations in Beta-Cell Mass

Modelling pancreatic β-cell inflammation in zebrafish identifies the natural product wedelolactone for human islet protection

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