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.

Effects of palmitate on ER and cytosolic Ca2+ homeostasis in β-cells

2009 ◽  
Vol 296 (4) ◽  
pp. E690-E701 ◽  
Author(s):  
Kamila S. Gwiazda ◽  
Ting-Lin B. Yang ◽  
Yalin Lin ◽  
James D. Johnson
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Free Fatty Acids ◽  
Cell Function ◽  
Fluorescent Protein ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

There are strong links between obesity, elevated free fatty acids, and type 2 diabetes. Specifically, the saturated fatty acid palmitate has pleiotropic effects on β-cell function and survival. In the present study, we sought to determine the mechanism by which palmitate affects intracellular Ca2+, and in particular the role of the endoplasmic reticulum (ER). In human β-cells and MIN6 cells, palmitate rapidly increased cytosolic Ca2+ through a combination of Ca2+ store release and extracellular Ca2+ influx. Palmitate caused a reversible lowering of ER Ca2+, measured directly with the fluorescent protein-based ER Ca2+ sensor D1ER. Using another genetically encoded indicator, we observed long-lasting oscillations of cytosolic Ca2+ in palmitate-treated cells. In keeping with this observed ER Ca2+ depletion, palmitate induced rapid phosphorylation of the ER Ca2+ sensor protein kinase R-like ER kinase (PERK) and subsequently ER stress and β-cell death. We detected little palmitate-induced insulin secretion, suggesting that these Ca2+ signals are poorly coupled to exocytosis. In summary, we have characterized Ca2+-dependent mechanisms involved in altered β-cell function and survival induced by the free fatty acid palmitate. We present the first direct evidence that free fatty acids reduce ER Ca2+ and shed light on pathways involved in lipotoxicity and the pathogenesis of type 2 diabetes.

Probucol preserves pancreatic β-cell function through reduction of oxidative stress in type 2 diabetes

2002 ◽  
Vol 57 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Shin-ichi Gorogawa ◽  
Yoshitaka Kajimoto ◽  
Yutaka Umayahara ◽  
Hideaki Kaneto ◽  
Hirotaka Watada ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function

BLX-1002, a novel thiazolidinedione with no PPAR affinity, stimulates AMP-activated protein kinase activity, raises cytosolic Ca2+, and enhances glucose-stimulated insulin secretion in a PI3K-dependent manner

2009 ◽  
Vol 296 (2) ◽  
pp. C346-C354 ◽  
Author(s):  
Fan Zhang ◽  
Deben Dey ◽  
Robert Bränström ◽  
Lars Forsberg ◽  
Ming Lu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
High Glucose ◽  
Cell Function ◽  
Dependent Manner ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Amp Activated Protein Kinase

BLX-1002 is a novel small thiazolidinedione with no apparent affinity to peroxisome proliferator-activated receptors (PPAR) that has been shown to reduce glycemia in type 2 diabetes without adipogenic effects. Its precise mechanisms of action, however, remain elusive, and no studies have been done with respect to possible effects of BLX-1002 on pancreatic β-cells. We have investigated the influence of the drug on β-cell function in mouse islets in vitro. BLX-1002 enhanced insulin secretion stimulated by high, but not low or intermediate, glucose concentrations. BLX-1002 also augmented cytoplasmic free Ca2+ concentration ([Ca2+]i) at high glucose, an effect that was abolished by pretreatment with the Ca2+-ATPase inhibitor thapsigargin. In contrast, BLX-1002 did not interfere with voltage-gated Ca2+ channel or ATP-sensitive K+ channel activities. In addition, cellular NAD(P)H stimulated by glucose was not affected by the drug. The stimulatory effect of BLX-1002 on insulin secretion at high glucose was completely abolished by treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY-294002. Stimulation of the β-cells with BLX-1002 also induced activation of AMP-activated protein kinase (AMPK) at high glucose. Our study suggests that BLX-1002 potentiates insulin secretion only at high glucose in β-cells in a PI3K-dependent manner. This effect of BLX-1002 is associated with an increased [Ca2+]i mediated through Ca2+ mobilization, and an enhanced activation of AMPK. The glucose-sensitive stimulatory impact of BLX-1002 on β-cell function may translate into substantial clinical benefits of the drug in the management of type 2 diabetes, by avoidance of hypoglycemia.

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 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 The pathogenetic role of β-cell mitochondria in type 2 diabetes

2018 ◽  
Vol 236 (3) ◽  
pp. R145-R159 ◽  
Author(s):  
Malin Fex ◽  
Lisa M Nicholas ◽  
Neelanjan Vishnu ◽  
Anya Medina ◽  
Vladimir V Sharoyko ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mitochondrial Dysfunction ◽  
Translational Regulation ◽  
Cell Function ◽  
Rare Condition ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation. Evidence has recently been mounting that mitochondrial dysfunction plays an important role in these processes. Monogenic dysfunction of mitochondria is a rare condition but causes a type 2 diabetes-like syndrome owing to β-cell failure. Here, we describe novel advances in research on mitochondrial dysfunction in the β-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on β-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. We argue that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes.

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 Circulating LncRNAs Analysis in Patients with Type 2 Diabetes Reveals Novel Genes Influencing Glucose Metabolism and Islet β-Cell Function

2018 ◽  
Vol 46 (1) ◽  
pp. 335-350 ◽  
Author(s):  
Yuting Ruan ◽  
Nie Lin ◽  
Qiang Ma ◽  
Rongping Chen ◽  
Zhen Zhang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Diabetic Patients ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Min6 Cells ◽  
Β Cell Function

Background/Aims: The islet is an important endocrine organ to secrete insulin to regulate the metabolism of glucose and maintain the stability of blood glucose. Long noncoding RNAs (lncRNAs) are involved in a variety of biological functions and play key roles in many diseases, including type 2 diabetes (T2D). The aim of this study was to determine whether lncRNA-p3134 is associated with glucose metabolism and insulin signaling in pancreatic β cells. Methods: LncRNA microarray technology was used to identify the differentially expressed circulating lncRNAs in T2D patients. RT-PCR analyses were performed to determine the expression of lncRNA-p3134 in 30 pairs of diabetic and non-diabetic patients. The correlation of lncRNA-p3134 to clinical data from T2D patients was analyzed. LncRNA-p3134 was overexpressed in Min6 cells and db/db mice by adenovirus-mediated technology. CCK-8, TUNEL, Western blot, glucose-stimulated insulin secretion (GSIS), ELISAs and immunochemistry were performed to determine the effect of lncRNA-p3134 on proliferation, apoptosis and insulin secretion both in vitro and vivo. Results: The circulating level of lncRNA-p3134 was higher in diabetic patients than in non-diabetic controls and was correlated with fasting blood glucose and HOMA-β levels. The lncRNA-p3134 had risen by 4 times in serum exosomes but nearly unchanged in exosome-free samples. The secretion of lncRNA-p3134 was dynamically modulated by glucose in both Min6 cells and isolated mouse islet cells. LncRNA-p3134 positively regulate GSIS through promoting of key regulators (Pdx-1, MafA, GLUT2 and Tcf7l2) in β cells. In addition, the overexpression of lncRNA-p3134 resulted in a decreased apoptosis ratio and partially reversed the glucotoxicity effects on GSIS function in Min6 cells. The restoration of insulin synthesis and secretion the increase of the insulin positive cells areas by upregulation of lncRNA-p3134 in db/db mice confirmed the compensatory role of lncRNA-p3134 to preserve β-cell function. Furthermore, a protective effect of lncRNA-p3134 on GSIS by positive modulation of PI3K/Akt/mTOR signaling was also confirmed. After blocking the PI3K/AKT signals with their specific inhibitor, the effect of overexpressed lncRNA-p3134 on insulin secretion was obviously attenuated. Conclusion: Taken together, the results of this study provide new insights into lncRNA-p3134 regulation in pancreatic β cells and provide a better understanding of novel mechanism of glucose homeostasis.

scholarly journals H3K4 Methylation in β-cells Prevents Transcriptional Downregulation and Variance Associated with Type 2 Diabetes

2021 ◽  
Author(s):  
Ben Vanderkruk ◽  
Nina Maeshima ◽  
Daniel J Pasula ◽  
Meilin An ◽  
Priya Suresh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Cell Function ◽  
H3k4 Methylation ◽  
Β Cells ◽  
Β Cell ◽  
Genetic Mouse Model ◽  
Expression Of Genes ◽  
Β Cell Function

SummaryHistone 3 lysine 4 trimethylation (H3K4me3) is associated with promoters of actively expressed genes, with genes important for cell identity frequently having exceptionally broad H3K4me3-enriched domains at their TSS. While H3K4 methylation is implicated in contributing to transcription, maintaining transcriptional stability, facilitating enhancer-promoter interactions, and preventing irreversible silencing, some studies suggest it has little functional impact. Therefore, the function of H3K4 methylation is not resolved. Insufficient insulin release by β-cells is the primary etiology in type 2 diabetes (T2D) and is associated with the loss of expression of genes essential to normal β-cell function. We find that H3K4me3 is reduced in islets from mouse models of diabetes and from human donors with T2D. Using a genetic mouse model to impair H3K4 methyltransferase activity of TrxG complexes, we find that reduction of H3K4 methylation significantly reduces insulin production and glucose-responsiveness and increases transcriptional entropy, indicative of a loss of β-cell maturity. Genes that are downregulated by reduction to H3K4 methylation are concordantly downregulated in T2D. Loss of H3K4 methylation causes global dilution of epigenetic complexity but does not generally reduce gene expression – instead, genes related to β-cell function and/or in particular chromatin environments are specifically affected. While neither H3K4me3 nor H3K4me1 are strictly required for the expression of many genes, the expression of genes with critical roles in β-cell function becomes destabilized, with increased variance and decreased overall expression. Our data further suggests that, in absence of H3K4me3, promoter-associated H3K4me1 is sufficient to maintain expression. Together, these data implicate H3K4 methylation dysregulation as destabilizing β-cell gene expression and contributing to β-cell dysfunction in T2D.

Sign in / Sign up

Export Citation Format

Share Document