Oxidative stress: the vulnerable β-cell

2008 ◽  
Vol 36 (3) ◽  
pp. 343-347 ◽  
Author(s):  
Sigurd Lenzen
Keyword(s):  
Type 2 Diabetes ◽  
Reactive Oxygen ◽  
Reactive Species ◽  
Β Cells ◽  
Β Cell ◽  
Subsequent Formation ◽  
Redox Imbalance ◽  
Cell Dysfunction

Antioxidative defence mechanisms of pancreatic β-cells are particularly weak and can be overwhelmed by redox imbalance arising from overproduction of reactive oxygen and reactive nitrogen species. The consequences of this redox imbalance are lipid peroxidation, oxidation of proteins, DNA damage and interference of reactive species with signal transduction pathways, which contribute significantly to β-cell dysfunction and death in Type 1 and Type 2 diabetes mellitus. Reactive oxygen species, superoxide radicals (O2•−), hydrogen peroxide (H2O2) and, in a final iron-catalysed reaction step, the most reactive and toxic hydroxyl radicals (OH•) are produced during both pro-inflammatory cytokine-mediated β-cell attack in Type 1 diabetes and glucolipotoxicity-mediated β-cell dysfunction in Type 2 diabetes. In combination with NO•, which is toxic in itself, as well as through its reaction with the O2•− and subsequent formation of peroxynitrite, reactive species play a central role in β-cell death during the deterioration of glucose tolerance in the development of diabetes.

scholarly journals Does epigenetic dysregulation of pancreatic islets contribute to impaired insulin secretion and type 2 diabetes?

2015 ◽  
Vol 93 (5) ◽  
pp. 511-521 ◽  
Author(s):  
Tasnim Dayeh ◽  
Charlotte Ling
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Impaired Insulin Secretion ◽  
Expression Of Genes ◽  
Impaired Insulin

β cell dysfunction is central to the development and progression of type 2 diabetes (T2D). T2D develops when β cells are not able to compensate for the increasing demand for insulin caused by insulin resistance. Epigenetic modifications play an important role in establishing and maintaining β cell identity and function in physiological conditions. On the other hand, epigenetic dysregulation can cause a loss of β cell identity, which is characterized by reduced expression of genes that are important for β cell function, ectopic expression of genes that are not supposed to be expressed in β cells, and loss of genetic imprinting. Consequently, this may lead to β cell dysfunction and impaired insulin secretion. Risk factors that can cause epigenetic dysregulation include parental obesity, an adverse intrauterine environment, hyperglycemia, lipotoxicity, aging, physical inactivity, and mitochondrial dysfunction. These risk factors can affect the epigenome at different time points throughout the lifetime of an individual and even before an individual is conceived. The plasticity of the epigenome enables it to change in response to environmental factors such as diet and exercise, and also makes the epigenome a good target for epigenetic drugs that may be used to enhance insulin secretion and potentially treat diabetes.

scholarly journals Role for Activating Transcription Factor 3 in Stress-Induced β-Cell Apoptosis

2004 ◽  
Vol 24 (13) ◽  
pp. 5721-5732 ◽  
Author(s):  
Matthew G. Hartman ◽  
Dan Lu ◽  
Mi-Lyang Kim ◽  
Gary J. Kociba ◽  
Tala Shukri ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Cell Apoptosis ◽  
Activating Transcription Factor 3 ◽  
Β Cells ◽  
Β Cell ◽  
Activating Transcription Factor

ABSTRACT Activating transcription factor 3 (ATF3) is a stress-inducible gene and encodes a member of the ATF/CREB family of transcription factors. However, the physiological significance of ATF3 induction by stress signals is not clear. In this report, we describe several lines of evidence supporting a role of ATF3 in stress-induced β-cell apoptosis. First, ATF3 is induced in β cells by signals relevant to β-cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate. Second, induction of ATF3 is mediated in part by the NF-κB and Jun N-terminal kinase/stress-activated protein kinase signaling pathways, two stress-induced pathways implicated in both type 1 and type 2 diabetes. Third, transgenic mice expressing ATF3 in β cells develop abnormal islets and defects secondary to β-cell deficiency. Fourth, ATF3 knockout islets are partially protected from cytokine- or nitric oxide-induced apoptosis. Fifth, ATF3 is expressed in the islets of patients with type 1 or type 2 diabetes, and in the islets of nonobese diabetic mice that have developed insulitis or diabetes. Taken together, our results suggest ATF3 to be a novel regulator of stress-induced β-cell apoptosis.

scholarly journals The Anna Karenina model of β cell maturation in development and their dedifferentiation in type 1 and type 2 diabetes

2021 ◽  
Author(s):  
Sutichot D. Nimkulrat ◽  
Zijian Ni ◽  
Jared Brown ◽  
Christina Kendziorski ◽  
Barak Blum
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Lineage Tracing ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dedifferentiation ◽  
Anna Karenina ◽  
Β Cell Function

AbstractLoss of mature β cell function and identity, or β cell dedifferentiation, is seen in all types of diabetes mellitus. Two competing models explain β cell dedifferentiation in diabetes. In the first model, β cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated β cells resemble β cell progenitors. In the second model, β cell dedifferentiation depends on the type of diabetogenic stress. This model, which we call the “Anna Karenina” model, predicts that in each type of diabetes, β cells dedifferentiate in their own way, depending on how their mature identity is disrupted by any particular diabetogenic stress. We directly tested the two models using a β cell-specific lineage-tracing system coupled with RNA-sequencing in mice. We constructed a multidimensional map of β cell transcriptional trajectories during the normal course of β cell postnatal development and during their dedifferentiation in models of both type 1 diabetes (NOD) and type 2 diabetes (BTBR-Lepob/ob). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated β cells, β cells dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between different types of diabetes.

scholarly journals Longitudinal Intravital Imaging of Biosensor-labeled In Situ Islet Beta Cells

2019 ◽  
Author(s):  
Christopher A. Reissaus ◽  
Ashley N. Twigg ◽  
Kara S. Orr ◽  
Abass M. Conteh ◽  
Michelle M. Martinez ◽  
...  
Keyword(s):  
Β Cells ◽  
Dynamic Nature ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Longitudinal Measurements ◽  
Ros Accumulation

AbstractImpaired function and apoptosis of insulin-secreting islet β-cells is central to disease progression in both type 1 and type 2 diabetes. Oxidative damage resulting from excess reactive oxygen species (ROS) is a central factor in β-cell dysfunction and death, but the dynamic nature of ROS accumulation and its depletion pose a problem for mechanistic studies in vivo. Biosensors, including the redox-sensitive GFP (roGFPs), coupled with intravital microscopy provide a sensitive and dynamic solution to this problem. Here, we utilize a virally-delivered roGFP2-containing human glutaredoxin-1 (Grx1-roGFP2) to selectively monitor β-cell ROS dynamics in vivo in response to toxic glucose analogs. We paired viral biosensor delivery with implanted abdominal imaging windows over the pancreas, thus allowing longitudinal measurements of β-cell ROS and islet area during and after streptozotocin (STZ) exposure. The studies presented here represent a robust experimental platform that could be readily adapted to various transgenic or physiological mouse models in conjunction with any number of available biosensors, and thus opens a vast realm of potential for discovery in islet biology in vivo.

scholarly journals The Anna Karenina Model of β Cell Maturation in Development and their Dedifferentiation in Type 1 and Type 2 Diabetes

2021 ◽  
Author(s):  
Sutichot D. Nimkulrat ◽  
Matthew N. Bernstein ◽  
Zijian Ni ◽  
Jared Brown ◽  
Christina Kendziorski ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Lineage Tracing ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dedifferentiation ◽  
Anna Karenina ◽  
Β Cell Function

Loss of mature β cell function and identity, or β cell dedifferentiation, is seen in both type 1 and type 2 diabetes. Two competing models explain β cell dedifferentiation in diabetes. In the first model, β cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated β cells resemble β cell progenitors. In the second model, β cell dedifferentiation depends on the type of diabetogenic stress. This model, which we call the “Anna Karenina” model, predicts that in each type of diabetes, β cells dedifferentiate in their own way, depending on how their mature identity is disrupted by any particular diabetogenic stress. We directly tested the two models using a β cell-specific lineage-tracing system coupled with RNA-sequencing in mice. We constructed a multidimensional map of β cell transcriptional trajectories during the normal course of β cell postnatal development and during their dedifferentiation in models of both type 1 diabetes (NOD) and type 2 diabetes (BTBR-<i>Lep<sup>ob/ob</sup></i>). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated β cells, <a>β cells dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between </a>different types of diabetes.

scholarly journals β-Cell Dysfunction, Hepatic Lipid Metabolism, and Cardiovascular Health in Type 2 Diabetes: New Directions of Research and Novel Therapeutic Strategies

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 226
Author(s):  
Ahmad Al-Mrabeh
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Lipid Metabolism ◽  
Cardiovascular Health ◽  
Lipoprotein Metabolism ◽  
Hepatic Lipid Metabolism ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction

Cardiovascular disease (CVD) remains a major problem for people with type 2 diabetes mellitus (T2DM), and dyslipidemia is one of the main drivers for both metabolic diseases. In this review, the major pathophysiological and molecular mechanisms of β-cell dysfunction and recovery in T2DM are discussed in the context of abnormal hepatic lipid metabolism and cardiovascular health. (i) In normal health, continuous exposure of the pancreas to nutrient stimulus increases the demand on β-cells. In the long term, this will not only stress β-cells and decrease their insulin secretory capacity, but also will blunt the cellular response to insulin. (ii) At the pre-diabetes stage, β-cells compensate for insulin resistance through hypersecretion of insulin. This increases the metabolic burden on the stressed β-cells and changes hepatic lipoprotein metabolism and adipose tissue function. (iii) If this lipotoxic hyperinsulinemic environment is not removed, β-cells start to lose function, and CVD risk rises due to lower lipoprotein clearance. (iv) Once developed, T2DM can be reversed by weight loss, a process described recently as remission. However, the precise mechanism(s) by which calorie restriction causes normalization of lipoprotein metabolism and restores β-cell function are not fully established. Understanding the pathophysiological and molecular basis of β-cell failure and recovery during remission is critical to reduce β-cell burden and loss of function. The aim of this review is to highlight the link between lipoprotein export and lipid-driven β-cell dysfunction in T2DM and how this is related to cardiovascular health. A second aim is to understand the mechanisms of β-cell recovery after weight loss, and to explore new areas of research for developing more targeted future therapies to prevent T2DM and the associated CVD events.

scholarly journals The Anna Karenina Model of β Cell Maturation in Development and their Dedifferentiation in Type 1 and Type 2 Diabetes

2021 ◽  
Author(s):  
Sutichot D. Nimkulrat ◽  
Matthew N. Bernstein ◽  
Zijian Ni ◽  
Jared Brown ◽  
Christina Kendziorski ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Lineage Tracing ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dedifferentiation ◽  
Anna Karenina ◽  
Β Cell Function

Loss of mature β cell function and identity, or β cell dedifferentiation, is seen in both type 1 and type 2 diabetes. Two competing models explain β cell dedifferentiation in diabetes. In the first model, β cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated β cells resemble β cell progenitors. In the second model, β cell dedifferentiation depends on the type of diabetogenic stress. This model, which we call the “Anna Karenina” model, predicts that in each type of diabetes, β cells dedifferentiate in their own way, depending on how their mature identity is disrupted by any particular diabetogenic stress. We directly tested the two models using a β cell-specific lineage-tracing system coupled with RNA-sequencing in mice. We constructed a multidimensional map of β cell transcriptional trajectories during the normal course of β cell postnatal development and during their dedifferentiation in models of both type 1 diabetes (NOD) and type 2 diabetes (BTBR-<i>Lep<sup>ob/ob</sup></i>). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated β cells, <a>β cells dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between </a>different types of diabetes.

scholarly journals A focus on the role of Pax4 in mature pancreatic islet β-cell expansion and survival in health and disease

2007 ◽  
Vol 40 (2) ◽  
pp. 37-45 ◽  
Author(s):  
Thierry Brun ◽  
Benoit R Gauthier
Keyword(s):  
Type 2 Diabetes ◽  
Type 1 Diabetes ◽  
Pancreatic Islet ◽  
Cell Expansion ◽  
Cell Mass ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell

Blood glucose homeostasis is achieved by the regulation of insulin and glucagon secretion from the pancreatic islet β- and α-cells. Diabetes mellitus, which comprises a heterogeneous group of hyperglycaemic disorders, results mainly from inadequate mass and function of islet β-cells. Autoimmune destruction of β-cells causes type 1 diabetes, while type 2 is characterized by impaired insulin secretion and is often associated with diminished insulin action on its target tissues. Interestingly, similar to type 1 diabetes, a gradual loss of β-cell mass is observed in type 2 diabetes often requiring insulin therapy. Understanding the molecular mechanism that governs β-cell mass plasticity may provide a means to develop strategies to countera,ct β-cell death while increasing replication. Of particular interest is the islet-specific transcription factor paired box4 (Pax4) that was previously shown to be indispensable for the establishment of the β-cell lineage during development. However, recent accumulating evidence now suggest that Pax4 is also crucial for mature β-cell expansion and survival in response to physiological cues and that mutations or polymorphisms are associated with both type 1 and type 2 diabetes. In contrast, aberrant expression of Pax4 confers protection against apoptosis to insulinomas, whereas it promotes cell growth in lymphocytes. This review summarizes promising new published results supporting the important function of Pax4 in mature islet β-cell physiology and its contribution to pathophysiology when deregulated.

scholarly journals Long-term inhibition of protein tyrosine kinase impairs electrophysiologic activity and a rapid component of exocytosis in pancreatic β-cells

2005 ◽  
Vol 35 (1) ◽  
pp. 49-59 ◽  
Author(s):  
Yu-Feng Zhao ◽  
Damien J Keating ◽  
Maria Hernandez ◽  
Dan Dan Feng ◽  
Yulong Zhu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Protein Tyrosine ◽  
Cell Dysfunction ◽  
Genistein Treatment

Dysfunction of pancreatic β-cells is a fundamental feature in the pathogenesis of type 2 diabetes. As insulin receptor signaling occurs via protein tyrosine kinase (PTK), we investigated the role of PTK activity in the etiology of β-cell dysfunction by inhibiting PTK activity in primary cultured mouse pancreatic β-cells and INS-1 cells with genistein treatment over 24 h. Electrophysiologic recordings showed genistein treatment significantly attenuated ATP-sensitive K+ (KATP) and voltage-dependent Ca2+ currents, and depolarized the resting membrane potential in primary β-cells. When stimulated by high glucose, genistein-treated β-cells exhibited a time delay of both depolarization and Ca2+ influx, and were unable to fire action potentials, as well as displaying a reduced level of Ca2+ influx and a loss of Ca2+ oscillations. Semiquantitative PCR analysis revealed decreased expression of KATP and L-type Ca2+ channel mRNA in genistein-treated islets. PTK inhibition also significantly reduced the rapid component of secretory vesicle exocytosis, as indicated by membrane capacitance measurements, and this is likely to be due to the reduced Ca2+ current amplitude in these cells. These results illustrate that compromised PTK activity contributes to pancreatic β-cell dysfunction and may be involved in the etiology of type 2 diabetes.

scholarly journals Pancreatic β-Cell Mass as a Pharmacologic Target in Diabetes

2020 ◽  
Vol 12 (2) ◽  
Author(s):  
Stephen Hanley
Keyword(s):  
Type 2 Diabetes ◽  
Cell Expansion ◽  
Cell Mass ◽  
Basic Research ◽  
Cell Loss ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Prevalence Of Diabetes Mellitus

While the prevalence of maternal While the prevalence of diabetes mellitus reaches epidemic proportions, most available treatments still focus on the symptoms of the disease, rather than the underlying pathology. Types 1 and 2 diabetes have in common a deficit in β-cell mass. In type 1 diabetes, auto-immune β-cell destruction leads to an absolute deficit in β-cells, while in type 2 diabetes, insulin resistance and β-cell dysfunction cause a functional deficit. More recently, however, it has been suggested that type 2 diabetes is also marked by an absolute deficit in β-cell mass, although a causal relationship has not yet been established. Overall β-cell mass reflects the balance between the dynamic processes of β-cell expansion, through proliferation and neogenesis, and β-cell loss via apoptosis. Given that β-cell mass can be modified significantly by altering the rate of any of these mechanisms, therapies that modulate β-cell expansion and loss have garnered recent interest. We review herein the current therapeutics under investigation as modulators of β-cell mass dynamics, and the basic research that supports these novel therapeutic targets.

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