scholarly journals Suppression of Peroxisome Proliferator-Activated Receptor γ-Coactivator-1α Normalizes the Glucolipotoxicity-Induced Decreased BETA2/NeuroD Gene Transcription and Improved Glucose Tolerance in Diabetic Rats

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4074-4083 ◽  
Author(s):  
Ji-Won Kim ◽  
Young-Hye You ◽  
Dong-Sik Ham ◽  
Jae-Hyoung Cho ◽  
Seung-Hyun Ko ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Receptor Site ◽  
Diabetic Rats ◽  
Peroxisome Proliferator ◽  
Β Cells ◽  
Β Cell ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cell Dysfunction

Abstract Peroxisome proliferator-activated receptor γ-coactivator-1α (PGC-1α) is significantly elevated in the islets of animal models of diabetes. However, the molecular mechanism has not been clarified. We investigated whether the suppression of PGC-1α expression protects against β-cell dysfunction in vivo and determined the mechanism of action of PGC-1α in β-cells. The studies were performed in glucolipotixicity-induced primary rat islets and INS-1 cells. In vitro and in vivo approaches using adenoviruses were used to evaluate the role of PGC-1α in glucolipotoxicity-associated β-cell dysfunction. The expression of PGC-1α in cultured β-cells increased gradually with glucolipotoxicity. The overexpression of PGC-1α also suppressed the expression of the insulin and β-cell E-box transcription factor (BETA2/NeuroD) genes, which was reversed by PGC-1α small interfering RNA (siRNA). BETA2/NeuroD, p300-enhanced BETA2/NeuroD, and insulin transcriptional activities were significantly suppressed by Ad-PGC-1α but were rescued by Ad-siPGC-1α. PGC-1α binding at the glucocorticoid receptor site on the BETA2/NeuroD promoter increased in the presence of PGC-1α. Ad-siPGC-1α injection through the celiac arteries of 90% pancreatectomized diabetic rats improved their glucose tolerance and maintained their fasting insulin levels. The suppression of PGC-1α expression protects the glucolipotoxicity-induced β-cell dysfunction in vivo and in vitro. A better understanding of the functions of molecules such as PGC-1α, which play key roles in intracellular fuel regulation, could herald a new era of the treatment of patients with type 2 diabetes mellitus by providing protection from glucolipotoxicity, which is an important cause of the development and progression of the disease.

LOX-1 and inflammation: a new mechanism for renal injury in obesity and diabetes

2008 ◽  
Vol 294 (5) ◽  
pp. F1136-F1145 ◽  
Author(s):  
Katherine J. Kelly ◽  
Pengfei Wu ◽  
Carolyn E. Patterson ◽  
Constance Temm ◽  
Jesus H. Dominguez
Keyword(s):  
Oxidized Ldl ◽  
Lipid Peroxides ◽  
Diabetic Rats ◽  
Peroxisome Proliferator ◽  
Tubulointerstitial Injury ◽  
Peroxisome Proliferator Activated Receptor ◽  
Obesity And Diabetes ◽  
Obese Diabetic Rats

The early nephropathy in obese, diabetic, dyslipidemic (ZS) rats is characterized by tubular lipid accumulation and pervasive inflammation, two critically interrelated events. We now tested the hypothesis that proximal tubules from ZS obese diabetic rats in vivo, and proximal tubule cells (NRK52E) exposed to oxidized LDL (oxLDL) in vitro, change their normally quiescent epithelial phenotype into a proinflammatory phenotype. Urine of obese diabetic rats contained more lipid peroxides, and LOX-1, a membrane receptor that internalizes oxidized lipids, was mobilized to luminal sites. Levels of ICAM-1 and focal adhesion kinase, which participate in leukocyte migration and epithelial dedifferentiation, respectively, were also upregulated in tubules. NRK52E cells exposed to oxLDL showed similar modifications, plus suppression of anti-inflammatory transcription factor peroxisome proliferator-activated receptor-δ. In addition, oxLDL impaired epithelial barrier function. These alterations were prevented by an anti-LOX-1 antibody. The data support the concept that tubular LOX-1 activation driven by lipid oxidants in the preurine fluid is critical in the inflammatory changes. We suggest that luminal lipid oxidants and abnormal tubular permeability may be partly responsible for the renal tubulointerstitial injury of obesity, diabetes, and dyslipidemia.

Neonatal growth and regeneration of β-cells are regulated by the Wnt/β-catenin signaling in normal and diabetic rats

2010 ◽  
Vol 298 (2) ◽  
pp. E245-E256 ◽  
Author(s):  
Florence Figeac ◽  
Benjamin Uzan ◽  
Monique Faro ◽  
Noura Chelali ◽  
Bernard Portha ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wnt Pathway ◽  
Diabetic Rats ◽  
Β Cells ◽  
Β Cell ◽  
Ductal Cells ◽  
Gsk 3Β ◽  
Canonical Wnt

Wnt/β-catenin signaling is critical for a variety of fundamental cellular processes. Here, we investigated the implication of the Wnt/β-catenin signaling in the in vivo regulation of β-cell growth and regeneration in normal and diabetic rats. To this aim, TCF7L2, the distal effector of the canonical Wnt pathway, was knocked down in groups of normal and diabetic rats by the use of specific antisense morpholino-oligonucleotides. In other groups of diabetic rats, the Wnt/β-catenin pathway was activated by the inhibition of its negative regulator GSK-3β. GSK-3β was inactivated by either LiCl or anti-GSK-3β oligonucleotides. The β-cell mass was evaluated by morphometry. β-cell proliferation was assessed in vivo and in vitro by BrdU incorporation method. In vivo β-cell neogenesis was estimated by the evaluation of PDX1-positive ductal cells and GLUT2-positive ductal cells and the number of β cells budding from the ducts. We showed that the in vivo disruption of the canonical Wnt pathway resulted in the alteration of normal and compensatory growth of β-cells mainly through the inhibition of β-cell proliferation. Conversely, activation of the Wnt pathway through the inhibition of GSK-3β had a significant stimulatory effect on β-cell regeneration in diabetic rats. In vitro, GSK-3β inactivation resulted in the stimulation of β-cell proliferation. This was mediated by the stabilization of β-catenin and the induction of cyclin D. Taken together, our results demonstrate the involvement of the canonical Wnt signaling in the neonatal regulation of normal and regenerative growth of pancreatic β-cells. Moreover, we provide evidence that activation of this pathway by pharmacological maneuvers can efficiently improve β-cell regeneration in diabetic rats. These findings might have potential clinical applications in the regenerative therapy of diabetes.

scholarly journals Inhibition of Small Maf Function in Pancreatic β-Cells Improves Glucose Tolerance Through the Enhancement of Insulin Gene Transcription and Insulin Secretion

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3570-3580 ◽  
Author(s):  
Hiroshi Nomoto ◽  
Takuma Kondo ◽  
Hideaki Miyoshi ◽  
Akinobu Nakamura ◽  
Yoko Hida ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Cell Function ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

The large-Maf transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) has been found to be crucial for insulin transcription and synthesis and for pancreatic β-cell function and maturation. However, insights about the effects of small Maf factors on β-cells are limited. Our goal was to elucidate the function of small-Maf factors on β-cells using an animal model of endogenous small-Maf dysfunction. Transgenic (Tg) mice with β-cell-specific expression of dominant-negative MafK (DN-MafK) experiments, which can suppress the function of all endogenous small-Mafs, were fed a high-fat diet, and their in vivo phenotypes were evaluated. Phenotypic analysis, glucose tolerance tests, morphologic examination of β-cells, and islet experiments were performed. DN-MafK-expressed MIN6 cells were also used for in vitro analysis. The results showed that DN-MafK expression inhibited endogenous small-Maf binding to insulin promoter while increasing MafA binding. DN-MafK Tg mice under high-fat diet conditions showed improved glucose metabolism compared with control mice via incremental insulin secretion, without causing changes in insulin sensitivity or MafA expression. Moreover, up-regulation of insulin and glucokinase gene expression was observed both in vivo and in vitro under DN-MafK expression. We concluded that endogenous small-Maf factors negatively regulates β-cell function by competing for MafA binding, and thus, the inhibition of small-Maf activity can improve β-cell function.

scholarly journals β-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice

2020 ◽  
Vol 319 (4) ◽  
pp. E805-E813
Author(s):  
Frank K. Huynh ◽  
Brett S. Peterson ◽  
Kristin A. Anderson ◽  
Zhihong Lin ◽  
Aeowynn J. Coakley ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Whole Body ◽  
Β Cells ◽  
Β Cell ◽  
Direct Role ◽  
Normal Glucose

Sirtuins are a family of proteins that regulate biological processes such as cellular stress and aging by removing posttranslational modifications (PTMs). We recently identified several novel PTMs that can be removed by sirtuin 4 (SIRT4), which is found in mitochondria. We showed that mice with a global loss of SIRT4 [SIRT4-knockout (KO) mice] developed an increase in glucose- and leucine-stimulated insulin secretion, and this was followed by accelerated age-induced glucose intolerance and insulin resistance. Because whole body SIRT4-KO mice had alterations to nutrient-stimulated insulin secretion, we hypothesized that SIRT4 plays a direct role in regulating pancreatic β-cell function. Thus, we tested whether β-cell-specific ablation of SIRT4 would recapitulate the elevated insulin secretion seen in mice with a global loss of SIRT4. Tamoxifen-inducible β-cell-specific SIRT4-KO mice were generated, and their glucose tolerance and glucose- and leucine-stimulated insulin secretion were measured over time. These mice exhibited normal glucose- and leucine-stimulated insulin secretion and maintained normal glucose tolerance even as they aged. Furthermore, 832/13 β-cells with a CRISPR/Cas9n-mediated loss of SIRT4 did not show any alterations in nutrient-stimulated insulin secretion. Despite the fact that whole body SIRT4-KO mice demonstrated an age-induced increase in glucose- and leucine-stimulated insulin secretion, our current data indicate that the loss of SIRT4 specifically in pancreatic β-cells, both in vivo and in vitro, does not have a significant impact on nutrient-stimulated insulin secretion. These data suggest that SIRT4 controls nutrient-stimulated insulin secretion during aging by acting on tissues external to the β-cell, which warrants further study.

scholarly journals RIPK3-mediated inflammation is a conserved β cell response to ER stress

2020 ◽  
Vol 6 (51) ◽  
pp. eabd7272
Author(s):  
Bingyuan Yang ◽  
Lisette A. Maddison ◽  
Karolina E. Zaborska ◽  
Chunhua Dai ◽  
Linlin Yin ◽  
...  
Keyword(s):  
Er Stress ◽  
Cell Response ◽  
Dependent Manner ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Proinflammatory Mediators ◽  
Islet Inflammation

Islet inflammation is an important etiopathology of type 2 diabetes; however, the underlying mechanisms are not well defined. Using complementary experimental models, we discovered RIPK3-dependent IL1B induction in β cells as an instigator of islet inflammation. In cultured β cells, ER stress activated RIPK3, leading to NF-kB–mediated proinflammatory gene expression. In a zebrafish muscle insulin resistance model, overnutrition caused islet inflammation, β cell dysfunction, and loss in an ER stress–, ripk3-, and il1b-dependent manner. In mouse islets, high-fat diet triggered the IL1B expression in β cells before macrophage recruitment in vivo, and RIPK3 inhibition suppressed palmitate-induced β cell dysfunction and Il1b expression in vitro. Furthermore, in human islets grafted in hyperglycemic mice, a marked increase in ER stress, RIPK3, and NF-kB activation in β cells were accompanied with murine macrophage infiltration. Thus, RIPK3-mediated induction of proinflammatory mediators is a conserved, previously unrecognized β cell response to metabolic stress and a mediator of the ensuing islet inflammation.

Elevated levels of extracellular heat-shock protein 72 (eHSP72) are positively correlated with insulin resistance in vivo and cause pancreatic β-cell dysfunction and death in vitro

2014 ◽  
Vol 126 (10) ◽  
pp. 739-752 ◽  
Author(s):  
Mauricio Krause ◽  
Kevin Keane ◽  
Josianne Rodrigues-Krause ◽  
Domenico Crognale ◽  
Brendan Egan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Heat Shock ◽  
Chronic Exposure ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Important Mediator

We have demonstrated a positive correlation between eHSP72 and insulin resistance, and that chronic exposure of β-cells to eHSP72 may provoke β-cell dysfunction and thus is potentially an important mediator of β-cell failure.

scholarly journals The mitochondrial Ca2+ uniporter MCU is required for normal glucose-stimulated insulin secretion in vitro and in vivo

2019 ◽  
Author(s):  
Elizabeth Haythorne ◽  
Eleni Georgiadou ◽  
Matthew T. Dickerson ◽  
Livia Lopez-Noriega ◽  
Timothy J. Pullen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Β Cells ◽  
Β Cell ◽  
Compensatory Mechanisms ◽  
Glucose Stimulated Insulin Secretion

AbstractMitochondrial oxidative metabolism is central to glucose-stimulated insulin secretion (GSIS). Whether Ca2+ uptake into pancreatic β-cell mitochondria potentiates or antagonises this process is still a matter of debate. Although the mitochondrial importer (MCU) complex is thought to represent the main route for Ca2+ transport across the inner mitochondrial membrane, its role in β-cells has not previously been examined in vivo. Here, we inactivated the pore-forming subunit MCUa (MCU) selectively in the β-cell in mice using Ins1Cre-mediated recombination. Glucose-stimulated mitochondrial Ca2+ accumulation, ATP production and insulin secretion were strongly (p<0.05 and p<0.01) inhibited in MCU null animals (βMCU-KO) in vitro. Interestingly, cytosolic Ca2+ concentrations increased (p<0.001) whereas mitochondrial membrane depolarisation improved in βMCU-KO animals. Male βMCU-KO mice displayed impaired in vivo insulin secretion at 5 (p<0.001) but not 15 min. post intraperitoneal (IP) injection of glucose while the opposite phenomenon was observed following an oral gavage at 5 min. Unexpectedly, glucose tolerance was improved (p<0.05) in young βMCU-KO (<12 weeks), but not older animals. We conclude that MCU is crucial for mitochondrial Ca2+ uptake in pancreatic β-cells and is required for normal GSIS. The apparent compensatory mechanisms which maintain glucose tolerance in βMCU-KO mice remain to be established.

scholarly journals Enhanced insulin secretion and improved glucose tolerance in mice with homozygous inactivation of the Na+K+2Cl− co-transporter 1

2012 ◽  
Vol 215 (1) ◽  
pp. 59-70 ◽  
Author(s):  
Saeed Alshahrani ◽  
Mauricio Di Fulvio
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Mass ◽  
Chloride Concentration ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell ◽  
Functional Alleles

The intracellular chloride concentration ([Cl−]i) in β-cells plays an important role in glucose-stimulated plasma membrane depolarisation and insulin secretion. [Cl−]i is maintained above equilibrium in β-cells by the action of Cl− co-transporters of the solute carrier family 12 group A (Slc12a). β-Cells express Slc12a1 and Slc12a2, which are known as the bumetanide (BTD)-sensitive Na+-dependent K+2Cl− co-transporters 2 and 1 respectively. We show that mice lacking functional alleles of the Slc12a2 gene exhibit better fasting glycaemia, increased insulin secretion in response to glucose, and improved glucose tolerance when compared with wild-type (WT). This phenomenon correlated with increased sensitivity of β-cells to glucose in vitro and with increased β-cell mass. Further, administration of low doses of BTD to mice deficient in Slc12a2 worsened their glucose tolerance, and low concentrations of BTD directly inhibited glucose-stimulated insulin secretion from β-cells deficient in Slc12a2 but expressing intact Slc12a1 genes. Together, our results suggest for the first time that the Slc12a2 gene is not necessary for insulin secretion and that its absence increases β-cell secretory capacity. Further, impairment of insulin secretion with BTD in vivo and in vitro in islets lacking Slc12a2 genes unmasks a potential new role for Slc12a1 in β-cell physiology.

scholarly journals Jiedu Tongluo Tiaogan Formula Protects Pancreatic Islet Cells Against Dysfunction by Relieving Endoplasmic Reticulum Stress and Excessive Autophagy via Regulating CaMKKβ/AMPK Pathway

2021 ◽  
Author(s):  
Chunli Piao ◽  
Qi Zhang ◽  
Wenqi Jin ◽  
Han Wang ◽  
Cheng Tang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Pancreatic Injury ◽  
Insulin Biosynthesis ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Ampk Pathway ◽  
Glucose Stimulated Insulin Secretion

Abstract Background: Endoplasmic reticulum stress (ERS) and excessive autophagy are increasingly recognized as risk factors associated with development and progression of β-cell dysfunction. Jiedu Tongluo Tiaogan Formula (JTTF) has known anti-glucotoxicity activities, but its pharmacological effects on pancreatic cell are not clearly understood. This study was designed to investigate JTTF effects/mechanisms on in vitro glucotoxicity (HG)-induced ERS and excessive autophagic damage of pancreatic cells in vitro and on in vivo pancreatic injury in db/db mice. Methods: The chemical composition of a JTTF preparation were analyzed using high-performance liquid chromatographic fingerprinting. Meanwhile, cell viability, glucose-stimulated insulin secretion, insulin biosynthesis dysfunction, Ca2+ overload, ERS and excessive autophagy were assessed in JTTF-pretreated pancreatic β-cells with HG-induced injury. Hematoxylin and eosin staining and immunohistochemical analyses of pancreatic tissues revealed effects of in vivo JTTF pretreatment on development of HG-induced pancreatic injury in db/db mice. Results: Five JTTF chemical components were identified. Our results revealed that JTTF treatment protected β-cells from HG injury by increasing insulin biosynthesis and glucose-stimulated insulin secretion (GSIS), while also decreasing Ca2+ overload, ERS and excessive autophagy. Furthermore, protective effects of JTTF treatment against HG-induced β-cell ERS and excessive autophagy were linked to regulation of CaMKKβ/AMPK pathway functions, while JTTF administration as confirmed to reverse pancreatic injury in db/db mice. Conclusions: Collectively, the results presented here indicate that JTTF may prevent islet cell dysfunction in T2DM mice by inhibiting CaMKKβ/AMPK pathway-mediated ERS and excessive autophagy. These findings enhance our understanding of mechanisms underlying beneficial JTTF-induced amelioration of T2DM.

scholarly journals Augmented Rac1 Expression and Activity are Associated with Oxidative Stress and Decline of β Cell Function in Obesity

2015 ◽  
Vol 35 (6) ◽  
pp. 2135-2148 ◽  
Author(s):  
Shutong Zhou ◽  
Dongni Yu ◽  
Shangyong Ning ◽  
Heli Zhang ◽  
Lei Jiang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Insulin Mrna ◽  
Rac1 Expression

Background: The aim of this study was to clarify the relationship among Rac1 expression and activation, oxidative stress and β cell dysfunction in obesity. Methods: In vivo, serum levels of glucose, insulin, oxidative stress markers and Rac1 expression were compared between ob/ob mice and C57BL/6J controls. Then, these variables were rechecked after the administration of the specific Rac1 inhibitor-NSC23766 in ob/ob mice. In vitro, NIT-1 β cells were cultured in a hyperglycemic and/or hyperlipidemic state with or without NSC23766, and the differences of Rac1 expression and translocation, NADPH oxidase(Nox) enzyme activity, reactive oxygen species (ROS) and insulin mRNA were observed. Results: ob/ob mice displayed abnormal glycometabolism, oxidative stress and excessive expression of Rac1 in the pancreas. NSC23766 injection inhibited the expression of Rac1 in the pancreas, along with amelioration of oxidative stress and glycometabolism in obese mice. Under hyperglycemic and/or hyperlipidemic conditions, Rac1 translocated to the cellular membrane, induced activation of the NADPH oxidase enzyme and oxidative stress, and simultaneously reduced the insulin mRNA expression in NIT-1 β cells. Inhibiting Rac1 activity could alleviate oxidative stress and meliorate the decline of insulin mRNA in β cells. Conclusions: Rac1 might contribute to oxidative stress systemically and locally in the pancreas in obesity. The excessive activation and expression of Rac1 in obesity were associated with β cell dysfunction through ROS production.

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