scholarly journals The B55α-containing PP2A holoenzyme dephosphorylates FOXO1 in islet β-cells under oxidative stress

2012 ◽  
Vol 444 (2) ◽  
pp. 239-247 ◽  
Author(s):  
Ling Yan ◽  
Shuangli Guo ◽  
Marie Brault ◽  
Jamie Harmon ◽  
R. Paul Robertson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Cell Death ◽  
Pancreatic Islet ◽  
Transcriptional Activation ◽  
Nuclear Import ◽  
Nuclear Translocation ◽  
Regulatory Subunit ◽  
Β Cells

The FOXO1 (forkhead box O1) transcription factor influences many key cellular processes, including those important in metabolism, proliferation and cell death. Reversible phosphorylation of FOXO1 at Thr24 and Ser256 regulates its subcellular localization, with phosphorylation promoting cytoplasmic localization, whereas dephosphorylation triggers nuclear import and transcriptional activation. In the present study, we used biochemical and molecular approaches to isolate and link the serine/threonine PP2A (protein phosphatase 2A) holoenzyme containing the B55α regulatory subunit, with nuclear import of FOXO1 in pancreatic islet β-cells under oxidative stress, a condition associated with cellular dysfunction in Type 2 diabetes. The mechanism of FOXO1 dephosphorylation and nuclear translocation was investigated in pancreatic islet INS-1 and βTC-3 cell lines subjected to oxidative stress. A combined chemical cross-linking and MS strategy revealed the association of FOXO1 with a PP2A holoenzyme composed of the catalytic C, structural A and B55α regulatory subunits. Knockdown of B55α in INS-1 cells reduced FOXO1 dephosphorylation, inhibited FOXO1 nuclear translocation and attenuated oxidative stress-induced cell death. Furthermore, both B55α and nuclear FOXO1 levels were increased under hyperglycaemic conditions in db/db mouse islets, an animal model of Type 2 diabetes. We conclude that B55α-containing PP2A is a key regulator of FOXO1 activity in vivo.

scholarly journals Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

2021 ◽  
Vol 22 (3) ◽  
pp. 1059
Author(s):  
Bodo C. Melnik
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Dopaminergic Neurons ◽  
Vagal Nerve ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
The Brain

Epidemiological studies associate milk consumption with an increased risk of Parkinson’s disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded α-syn. In T2D, α-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic β-cells. Prion-like vagal nerve-mediated propagation of exosomal α-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of α-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb α-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic β-cells may enhance miRNA-148a/DNMT1-dependent overexpression of α-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of α-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic α-syn may spread to dopaminergic neurons and pancreatic β-cells linking the pathogenesis of PD and T2D.

scholarly journals Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3328
Author(s):  
Eloisa Aparecida Vilas-Boas ◽  
Davidson Correa Almeida ◽  
Leticia Prates Roma ◽  
Fernanda Ortis ◽  
Angelo Rafael Carpinelli
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Nadph Oxidase ◽  
Er Stress ◽  
Cell Function ◽  
Caloric Intake ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

A high caloric intake, rich in saturated fats, greatly contributes to the development of obesity, which is the leading risk factor for type 2 diabetes (T2D). A persistent caloric surplus increases plasma levels of fatty acids (FAs), especially saturated ones, which were shown to negatively impact pancreatic β-cell function and survival in a process called lipotoxicity. Lipotoxicity in β-cells activates different stress pathways, culminating in β-cells dysfunction and death. Among all stresses, endoplasmic reticulum (ER) stress and oxidative stress have been shown to be strongly correlated. One main source of oxidative stress in pancreatic β-cells appears to be the reactive oxygen species producer NADPH oxidase (NOX) enzyme, which has a role in the glucose-stimulated insulin secretion and in the β-cell demise during both T1 and T2D. In this review, we focus on the acute and chronic effects of FAs and the lipotoxicity-induced β-cell failure during T2D development, with special emphasis on the oxidative stress induced by NOX, the ER stress, and the crosstalk between NOX and ER stress.

scholarly journals Relationship Between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues

2019 ◽  
Vol 8 (9) ◽  
pp. 1385 ◽  
Author(s):  
Burgos-Morón ◽  
Abad-Jiménez ◽  
Marañón ◽  
Iannantuoni ◽  
Escribano-López ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Current Knowledge ◽  
Β Cells ◽  
The Relationship ◽  
And Oxidative Stress

Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia and insulin resistance in which oxidative stress is thought to be a primary cause. Considering that mitochondria are the main source of ROS, we have set out to provide a general overview on how oxidative stress is generated and related to T2D. Enhanced generation of reactive oxygen species (ROS) and oxidative stress occurs in mitochondria as a consequence of an overload of glucose and oxidative phosphorylation. Endoplasmic reticulum (ER) stress plays an important role in oxidative stress, as it is also a source of ROS. The tight interconnection between both organelles through mitochondrial-associated membranes (MAMs) means that the ROS generated in mitochondria promote ER stress. Therefore, a state of stress and mitochondrial dysfunction are consequences of this vicious cycle. The implication of mitochondria in insulin release and the exposure of pancreatic β-cells to hyperglycemia make them especially susceptible to oxidative stress and mitochondrial dysfunction. In fact, crosstalk between both mechanisms is related with alterations in glucose homeostasis and can lead to the diabetes-associated insulin-resistance status. In the present review, we discuss the current knowledge of the relationship between oxidative stress, mitochondria, ER stress, inflammation, and lipotoxicity in T2D.

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

2019 ◽  
Vol 31 (10) ◽  
pp. 722-751 ◽  
Author(s):  
Petr Ježek ◽  
Martin Jabůrek ◽  
Lydie Plecitá-Hlavatá
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Β Cells ◽  
Pancreatic Β Cells

A defect in Nrf2 signaling constitutes a mechanism for cellular stress hypersensitivity in a genetic rat model of type 2 diabetes

2011 ◽  
Vol 301 (6) ◽  
pp. E1119-E1129 ◽  
Author(s):  
Milad S. Bitar ◽  
Fahd Al-Mulla
Keyword(s):  
Type 2 Diabetes ◽  
Transcriptional Activation ◽  
Adaptive Response ◽  
Nuclear Translocation ◽  
Redox Status ◽  
Dermal Fibroblasts ◽  
Nuclear Accumulation ◽  
Cell Extracts ◽  
Gsk 3Β

Nrf2 regulates the expression and coordinated induction of a battery of antioxidant phase 2 genes that protect cells against the cumulative damaging effects of oxidative stress (OS), a major contributor in the development of chronic diabetic complications. Using cultured dermal fibroblasts from rats with type 2 diabetes (DFs), we investigated the intracellular redox status and the adaptive response to OS, in which Nrf2 plays a central role. Our data confirmed that the generation of superoxide by NADPH oxidase and the mitochondria was enhanced in DFs compared with corresponding controls. This was associated with a decrease in the antioxidant capacity and an increase in the sensitivity of these DFs to hydrogen peroxide-induced necrotic cell death. Nrf2 levels in total cell extracts were diminished, and this abnormality appears to stem from a diabetes-related decrease in Nrf2 protein stability. Endogenous (oligomycin) and exogenous ( tert-butylhydroquinone) induction of OS enhanced the nuclear translocation of Nrf2 and increased the mRNA expression of Nrf2-sensitive genes in control but not DFs. The activity of the GSK-3β/Fyn axis was increased markedly in DFs when compared with the corresponding controls. Chemical inhibition of GSK-3β mitigated the diabetes-related suppression of the OS-induced nuclear accumulation of Nrf2 and the transcriptional activation of the genes downstream of Nrf2. Overall, these findings suggest that an augmentation in GSK-3β/Fyn signaling during diabetes contributes to a deficit in both the cellular redox state and the Nrf2-based adaptive response to OS. Moreover, they may also offer a new perspective in the understanding and treatment of nonhealing diabetic wounds.

scholarly journals 4Pi microscopy reveals an impaired three-dimensional mitochondrial network of pancreatic islet β-cells, an experimental model of type-2 diabetes

2010 ◽  
Vol 1797 (6-7) ◽  
pp. 1327-1341 ◽  
Author(s):  
Andrea Dlasková ◽  
Tomáš Špaček ◽  
Jitka Šantorová ◽  
Lydie Plecitá-Hlavatá ◽  
Zuzana Berková ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Experimental Model ◽  
Pancreatic Islet ◽  
Three Dimensional ◽  
Mitochondrial Network ◽  
Β Cells ◽  
4Pi Microscopy

scholarly journals Exendin-4 Improves β-Cell Function in Autophagy-Deficient β-Cells

Endocrinology ◽  
2013 ◽  
Vol 154 (12) ◽  
pp. 4512-4524 ◽  
Author(s):  
Hiroko Abe ◽  
Toyoyoshi Uchida ◽  
Akemi Hara ◽  
Hiroki Mizukami ◽  
Koji Komiya ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Death ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Apoptotic Cell ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

Autophagy is cellular machinery for maintenance of β-cell function and mass. The implication of autophagy failure in β-cells on the pathophysiology of type 2 diabetes and its relation to the effect of treatment of diabetes remains elusive. Here, we found increased expression of p62 in islets of db/db mice and patients with type 2 diabetes mellitus. Treatment with exendin-4, a glucagon like peptide-1 receptor agonist, improved glucose tolerance in db/db mice without significant changes in p62 expression in β-cells. Also in β-cell-specific Atg7-deficient mice, exendin-4 efficiently improved blood glucose level and glucose tolerance mainly by enhanced insulin secretion. In addition, we found that exendin-4 reduced apoptotic cell death and increased proliferating cells in the Atg7-deficient islets, and that exendin-4 counteracted thapsigargin-induced cell death of isolated islets augmented by autophagy deficiency. Our results suggest the potential involvement of reduced autophagy in β-cell dysfunction in type 2 diabetes. Without altering the autophagic state in β-cells, exendin-4 improves glucose tolerance associated with autophagy deficiency in β-cells. This is mainly achieved through augmentation of insulin secretion. In addition, exendin-4 prevents apoptosis and increases the proliferation of β-cells associated with autophagy deficiency, also without altering the autophagic machinery in β-cells.

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.

Protection of Curcumin against Streptozocin-Induced Pancreatic Cell Destruction in T2D Rats

Planta Medica ◽  
2019 ◽  
Vol 86 (02) ◽  
pp. 113-120 ◽  
Author(s):  
Li Qihui ◽  
Deng Shuntian ◽  
Zhou Xin ◽  
Yu Xiaoxia ◽  
Chen Zhongpei
Keyword(s):  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Signaling Pathway ◽  
Pancreatic Islet ◽  
Rat Model ◽  
Fasting Blood Glucose ◽  
Tissue Destruction ◽  
Β Cells ◽  
Pancreatic Cell

AbstractAs a kind of traditional Chinese medicine extract, curcumin has been proven to be effective in inhibiting inflammation and apoptosis in pancreatic islet β cells in the streptozotocin-induced diabetes mellitus rat model, although the underlying mechanism has not yet been clarified. To examine the effect of curcumin on inflammation and apoptosis in pancreatic islet β cells, we established a type 2 diabetes rat model by feeding the animals a high-fat diet and intraperitoneally injecting streptozotocin. The curcumin was administered by intraperitoneal injection. The rat body weight, fasting blood glucose, intraperitoneal glucose tolerance tests, and insulin tolerance tests were recorded and analyzed. Hematoxylin and eosin staining was used for morphological analysis, and a TUNEL assay was performed to detect the apoptotic cells. The expression levels of proteins related to oxidative stress, inflammation and apoptosis were detected by Western blotting and ELISA. Curcumin administration significantly decreased fasting blood glucose and promoted recovery of pancreas function in type 2 diabetes rats. In curcumin-treated rats, the pancreatic tissue destruction and apoptosis index were reduced. The expression of IL-1β, IL-6, TNF-α, caspase-3, Bax, and malondialdehyde were significantly reduced, and Bcl-2, superoxide dismutase 2, and glutathione peroxidase were significantly increased. Curcumin inhibited the expression of phosphorylated JNK and NF-κB proteins to block the RAGE/JNK/NF-κB signaling pathway. In conclusion, these results indicate that curcumin blocks the phosphorylation of JNK and NF-κB protein to inhibit this signaling pathway, thereby further inhibiting inflammation and apoptosis in pancreatic islet β cells. Curcumin has potential value for the treatment of diabetes.

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