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Ozili, Peterson K. "Non-performing loans in European systemic and non-systemic banks." Journal of Financial Economic Policy 12, no. 3 (September 30, 2019): 409–24. http://dx.doi.org/10.1108/jfep-02-2019-0033.
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Purpose The distinction between systemic banks (GSIBs) and non-systemic banks (non-GSIBs) is driven by policy reasons. This study aims to examine the behaviour of non-performing loans in European GSIBs and non-GSIBs from 2004 to 2013. Design/methodology/approach The author uses regression methodology to analyse the association between non-performing loans (NPLs) and the state of the economy. Findings The author finds that more profitable banks witness higher NPLs regardless of them being systemic or non-systemic. Secondly, GSIBs have fewer NPLs during economic booms and during periods of increased lending, while non-GSIBs experience higher NPLs during periods of increased lending. The author also observes that European non-GSIBs that exceed regulatory capital requirement also experience higher NPLs. In the post-crisis period, there is a significant and negative relationship between NPLs and the economic cycle for GSIBs in the post-financial crisis period and a significant and positive relationship between NPLs, loan supply and bank profitability for GSIBs in the post-financial crisis period; on the other hand, there is a significant and negative relationship between NPLs and regulatory capital ratios for non-GSIBs in the post-financial crisis period and a significant and positive relationship between NPLs and bank profitability for non-GSIBs in the post-financial crisis period. The findings have implications. Originality/value To the best of the author’s knowledge, the literature on the determinants of NPL has not empirically examined the behaviour of NPLs in European GSIBs and non-GSIBs. This paper examines this issue to provide insights to help policymakers and academics understand the peculiarities of NPLs in Europe.
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Prefontaine, Jacques. "Implications Of Basel III For Capital, Liquidity, Profitability, And Solvency Of Global Systematically Important Banks." Journal of Applied Business Research (JABR) 29, no. 1 (December 27, 2012): 157. http://dx.doi.org/10.19030/jabr.v29i1.7563.
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The objective of this paper is to study the profitability and solvency implications of the proposed Basel III capital and liquidity requirements in the global banking context. The intent is to improve our understanding on how the Basel III capital and liquidity requirements impact upon the functioning of global systematically important banks (GSIBs), and how this knowledge could prove to be useful in answering questions of policy relevance like financial stability in economics. A longer-term perspective is taken in order to link capital and liquidity requirements with the notion of systemic risk within the evolution of the international financial and monetary system. Of special interest is the interaction between macroeconomic policy - including monetary, exchange rate and combined micro-macro-prudential policy within the setting of present-day Basel III regulatory and supervisory reforms. More specifically, the paper addresses two related issues: first, it studies and presents several financial indicators that GSIBs disclose; second, it examines how these same indicators could be related to GSIBs profitability and solvency.
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Beltran, Daniel O., Hannah Bensen, Amy Kvien, Erin McDevitt, Monica V. Sanz, and Pinar Uysal. "What are Large Global Banks Doing About Climate Change?" International Finance Discussion Paper, no. 1368 (January 2023): 1–28. http://dx.doi.org/10.17016/ifdp.2023.1368.
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We review the "climate action plans" of Global Systemically Important Banks (GSIBs) and the progress they are making toward achieving them. G-SIBs have identified the drivers of climate risk and their transmission channels to credit and other risks. Additionally, some have started to measure and model these risks. While most GSIBs have committed to fully offsetting their emissions by mid-century, they are only beginning to measure financed emissions resulting from their loans and investments, which comprise the vast majority of their emissions. G-SIBs have also committed to increase green finance and have started to do so. All told, despite some progress by large global banks to address climate change considerations, much work lies ahead to properly measure and disclose climate-related risks, and to better align financing activities with their net-zero targets.
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Vasilakopoulos, Konstantinos, Christos Tzovas, and Apostolos Ballas. "Banks’ risk and the impact of audit quality on income smoothing." Journal of Accounting and Management Information Systems 20, no. 3 (September 1, 2021): 425–53. http://dx.doi.org/10.24818/jamis.2021.03003.
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Research question: This paper investigates the impact that specific audit quality dimensions have upon European Union Banks’ income smoothing behavior. Motivation: Although previous studies have investigated the characteristics of audit quality, little is known about the audit quality in the banking sector. Excessive risk taking and business complexity may further impair auditors’ work and an audit’s outcome may be conditioned upon banks’ risk. Idea: We examine whether auditors’ independence influences bank managers’ decision to smooth income and whether this attribute depends on bank risk and systemic importance. We investigate the association between auditors’ industry specialization and auditors’ tenure with the level of Loan Loss Provisions Data: We use a sample of 133 banks from 26 European Union countries for the period 2006-2013. Tools: Similar to previous research, we use ordinary least squares analysis to test the results. Findings: Empirical findings provide evidence that the auditors’ industry expertise limits management’s discretion of high-risk banks to a greater extent relative to low risk banks. In contrast, our results imply that banks that retain the same auditor for a consecutive fiscal year are more likely to engage in income smoothing through LLPs. Furthermore, our study examines whether audit quality dimensions have different outcomes on income smoothing decisions between globally systemically important banks (GSIBs) and the rest of banks. Our results provide evidence that the impact of industry specialization and auditor tenure on EU banks accounting policy decisions differs between GSIBs and non-GSIBs. Contribution: Our analysis contributes in the existing body of research by focusing on the impact of audit quality on managements’ accounting discretion and the influence of banks’ special attributes on the audit process.
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Tok, Evren, and Abdurahman Jemal Yesuf. "Embedding Value-Based Principles in the Culture of Islamic Banks to Enhance Their Sustainability, Resilience, and Social Impact." Sustainability 14, no. 2 (January 14, 2022): 916. http://dx.doi.org/10.3390/su14020916.
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Value-based banks strive to build a self-sustaining banking model with inclusive and transparent governance that is sustainable and resilient to external disturbances. Initiatives for value-based intermediation in Islamic finance started in Malaysia. The growth in VBIBs is accompanied by claims about its relative resilience to crisis and efficiency compared to VBBs and conventional banks. However, little empirical evidence is available to support such claims. This study aims to analyze the resilience and efficiency of VBIBs compared to the VBBs and GSIBs. It highlights the role of value-based strategy in developing a sound and resilient Islamic banking system to overcome future crises and further strengthen the impacts of Islamic banks. The study used quantitative and content analysis research methods, with data collected from the annual reports of 10 VBIBs from 2017 to 2020. The empirical results show that VBIBs have better risk-adjusted capital levels and asset quality, enabling them to be more resilient during crises. They provide more satisfactory returns compared to the VBBs and GSIBs. However, VBBs have a better asset structure and growth rate, which contributes to the real economy. The overall findings suggest that adopting value-based strategies in Islamic banking improve banks’ sustainability, resilience, and social impacts by concentrating resources on value-based activities that provide economic resiliency and enhance inclusive and sustainable economic growth. The study fills gaps in the current Islamic finance literature concerning empirical studies on value-based Islamic banking. It also helps practitioners to understand the relative efficiency, resilience, and social impact of VBIBs.
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Tabor, Dale R., Cynthia H. Larry, and Richard F. Jacobs. "Differential Induction of Macrophage GSIB4 -Binding Activity." Journal of Leukocyte Biology 45, no. 5 (May 1989): 452–57. http://dx.doi.org/10.1002/jlb.45.5.452.
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Wang, Zhongshan, Xiaokun Xia, Meixian Zhang, Jiawei Fang, Yanqiang Li, and Meng Zhang. "Purification and Characterization of Glutathione Binding Protein GsiB from Escherichia coli." BioMed Research International 2018 (November 1, 2018): 1–7. http://dx.doi.org/10.1155/2018/3429569.
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Objectives. To purify and characterize the glutathione binding protein GsiB of glutathione importer (GSI) in Escherichia coli (E. coli). Results. The coding sequence of GsiB was cloned from E. coli MG1655 and expressed in BL21(DE3). GsiB protein was expressed and purified to homogeneity using Ni-affinity and gel filtration chromatography. SDS-PAGE of purified GsiB showed a single protein band of molecular mass 56 kDa, while native gel showed two bands around 56 kDa and 110 kDa. Gene knockout showed that GsiB was essential for GSI mediated glutathione import. Interactions of GsiA, B, C, and D were determined using bacterial two-hybrid method. Without glutathione, GsiB showed no direct interaction with the other three proteins. However, GsiB could interact with GsiC and GsiD when using glutathione as sole sulfur source. Conclusions. GsiB functions in E. coli was characterized which could help elucidate the glutathione import mechanism in gram-negative bacteria.
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Wilson, Bridget S., Xiangbing Meng, Tomas Mazel, Cheryl L. Willman, Susan Atlas, Richard Harvey, I.-Ming Chen, Stephen P. Hunger, Janet M. Oliver, and Stuart S. Winter. "Select γ-Secretase Inhibitors Induce Apoptosis in Pre-B ALL Cells and Disrupt the Balance Between Constitutive Notch Signaling and Repression." Blood 112, no. 11 (November 16, 2008): 1917. http://dx.doi.org/10.1182/blood.v112.11.1917.1917.
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Abstract Several γ secretase inhibitors (GSIs) were tested for the ability to induce apoptosis in precursor B acute lymphoblastic leukemia (pre-B ALL) cells. Of five GSI’s tested, treatment with two compounds resulted in effective killing of both pre-B lymphoblasts and cells from multiple pre-B ALL lines. Since Notch receptors represent an important group of γ secretase targets, we evaluated expression and activation status of Notch receptors in CD19+ lymphoblasts from pediatric pre-B ALL patients, as well as cultured pre-B ALL cells. We found that, unlike T-ALL where activating mutations are common, pre-B ALL cells appear to drive constitutive Notch signaling through autocrine signals. Blasts from 11 patients expressed 3 Notch receptors and multiple Notch counter-ligands. Expression of Notch pathway genes was also confirmed by microarray analysis of genes expressed in 207 children with high risk B precursor ALL. GSI treatment of pre-B ALL cells led to dephosphorylation of AKT and Foxo3, Bim expression and caspase activation. GSI treatment also blocked cleavage of Notch 1 and 2 to their active forms and inhibited expression of Notch targets, Hey2 and Myc. In contrast, increased expression of Hes1 and Hey1 was correlated with GSI-induced loss of the co-repressor, SMRT. GSI treatment appears to induce precursor B cell death by disrupting the balance between constitutive Notch signaling and repression.
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Weksler-Zangen, Sarah, Genya Aharon-Hananel, Carmit Mantzur, Tzemach Aouizerat, Ewa Gurgul-Convey, Itamar Raz, and Ann Saada. "IL-1β hampers glucose-stimulated insulin secretion in Cohen diabetic rat islets through mitochondrial cytochrome c oxidase inhibition by nitric oxide." American Journal of Physiology-Endocrinology and Metabolism 306, no. 6 (March 15, 2014): E648—E657. http://dx.doi.org/10.1152/ajpendo.00451.2013.
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A high-sucrose, low-copper-diet (HSD) induces inhibition of glucose-sensitive rats (CDs) but not Cohen diabetes-resistant rats (CDr). Copper-supplemented HSD increased activity of the copper-dependent mitochondrial respiratory chain enzyme cytochrome c oxidase (COX) and reversed hyperglycemia. This study examined the mechanism by which interleukin-1β modulates GSIS and the role of COX in this process. We measured COX activity, ATP content, GSIS, iNOS expression, and nitrite production with and without IL-1β, Nω-nitro-l-arginine, copper, or potassium cyanide in isolated islets of CDs and CDr fed different diets. We found reduced COX activity, ATP content, and GSIS in isolated islets of CDs rats fed a regular diet. These were severely reduced following HSD and were restored to regular diet levels on copper-supplemented HSD ( P < 0.01 vs. CDr islets). Potassium cyanide chemically reduced COX activity, decreasing GSIS and thus reinforcing the link between islet COX activity and GSIS. Interleukin-1β (2.5 U/ml) reduced GSIS and COX activity in CDs islets. Exposure to 10 U/ml interleukin-1β decreased GSIS and COX activity in both CDs and CDr islets, inducing a similar nitrite production. Nevertheless, the effect on GSIS was more marked in CDs islets. A significant iNOS expression was detected in CDs on the HSD diet, which was reduced by copper supplementation. Nω-nitro-l-arginine and copper prevented the deleterious effect of interleukin-1β on COX activity and GSIS. We conclude that reduced islet COX activity renders vulnerability to GSIS inhibition on low-copper HSD through two interrelated pathways: 1) by further reducing the activity of COX that is essential for β-cell ATP-production and insulin secretion and 2) by inducing the expression of iNOS and nitric oxide-mediated COX inhibition. We suggest that islet COX activity must be maintained above a critical threshold to sustain adequate GSIS with exposure to low-copper HSD.
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Kristinsson, Hjalti, David M. Smith, Peter Bergsten, and Ernest Sargsyan. "FFAR1 Is Involved in Both the Acute and Chronic Effects of Palmitate on Insulin Secretion." Endocrinology 154, no. 11 (November 1, 2013): 4078–88. http://dx.doi.org/10.1210/en.2013-1352.
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Free fatty acids (FFAs) have pleiotropic effects on the pancreatic β-cell. Although acute exposure to FFAs stimulates glucose-stimulated insulin secretion (GSIS), prolonged exposure impairs GSIS and causes apoptosis. FFAs exert their effects both via intracellular metabolism and interaction with the FFA receptor 1 (FFAR1/GPR40). Here we studied the role of FFAR1 in acute and long-term effects of palmitate on GSIS and insulin content in isolated human islets by using the FFAR1 agonist TAK-875 and the antagonist ANT203. Acute palmitate exposure potentiated GSIS approximately 3-fold, whereas addition of the antagonist decreased this potentiation to approximately 2-fold. In the absence of palmitate, the agonist caused a 40% increase in GSIS. Treatment with palmitate for 7 days decreased GSIS to 70% and insulin content to 25% of control level. These negative effects of long-term exposure to palmitate were ameliorated by FFAR1 inhibition and further aggravated by additional stimulation of the receptor. In the absence of extracellularly applied palmitate, long-term treatment with the agonist caused a modest increase in GSIS. The protective effect of FFAR1 inhibition was verified by using FFAR1-deficient MIN6 cells. Improved β-cell function by the antagonist was paralleled by the decreased apoptosis and lowered oxidation of palmitate, which may represent the potential mechanisms of protection. We conclude that FFAR1 in the pancreatic β-cell plays a substantial role not only in acute potentiation of GSIS by palmitate but also in the negative long-term effects of palmitate on GSIS and insulin content.
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Slepchenko, Kira G., Kathryn L. Corbin, and Craig S. Nunemaker. "Comparing methods to normalize insulin secretion shows the process may not be needed." Journal of Endocrinology 241, no. 2 (May 2019): 149–59. http://dx.doi.org/10.1530/joe-18-0542.
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Glucose-stimulated insulin secretion (GSIS) is a well-accepted method to investigate the physiological and pathophysiological function of islets. However, there is little consensus about which method is best for normalizing and presenting GSIS data. In this study, we evaluated the sufficiency of islet area, total protein, total DNA and total insulin content as parameters to normalize GSIS data. First, we tested if there is a linear correlation between each parameter and the number of islets (10, 20, 30 and 40 islets). Islet area, total protein and insulin content produced excellent linear correlations with islet number (R 2 > 0.9 for each) from the same islet material. Insulin secretion in 11 mM glucose also correlated reasonably well for islet area (R 2 = 0.69), protein (R 2 = 0.49) and insulin content (R 2 = 0.58). DNA content was difficult to reliably measure and was excluded from additional comparisons. We next measured GSIS for 18 replicates of 20 islets each, measuring 3 mM and 11 mM glucose to calculate the stimulation index and to compare each normalization parameter. Using these similar islet masses for each replicate, none of the parameters produced linear correlations with GSIS (R 2 < 0.05), suggesting that inherent differences in GSIS dominate small differences in islet mass. We conclude that when comparing GSIS for islets of reasonably similar size (<50% variance), normalization does not improve the representation of GSIS data. Normalization may be beneficial when substantial differences in islet mass are involved. In such situations, we suggest that using islet cross-sectional area is superior to other commonly used techniques for normalizing GSIS data.
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Hewison, Tim J., David R. Doelling, Constantine Lukashin, David Tobin, Viju O. John, Sauli Joro, and Bojan Bojkov. "Extending the Global Space-Based Inter-Calibration System (GSICS) to Tie Satellite Radiances to an Absolute Scale." Remote Sensing 12, no. 11 (June 1, 2020): 1782. http://dx.doi.org/10.3390/rs12111782.
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The Global Space-based Inter-Calibration System (GSICS) routinely monitors the calibration of various channels of Earth-observing satellite instruments and generates GSICS Corrections, which are functions that can be applied to tie them to reference instruments. For the infrared channels of geostationary imagers GSICS algorithms are based on comparisons of collocated observations with hyperspectral reference instruments; whereas Pseudo Invariant Calibration Targets are currently used to compare the counterpart channels in the reflected solar band to multispectral reference sensors. This paper discusses how GSICS products derived from both approaches can be tied to an absolute scale using specialized satellite reference instruments with SI-traceable calibration on orbit. This would provide resilience against gaps between reference instruments and drifts in their calibration outside their overlap period and allow construction of robust and harmonized data records from multiple satellite sources to build Fundamental Climate Data Records, as well as more uniform environmental retrievals in both space and time, thus improving inter-operability.
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Feng, Yue, Xiao-Ming Guan, Jing Li, Joseph M. Metzger, Yonghua Zhu, Kirstine Juhl, Bei B. Zhang, Nancy A. Thornberry, Marc L. Reitman, and Yun-Ping Zhou. "Bombesin Receptor Subtype-3 (BRS-3) Regulates Glucose-Stimulated Insulin Secretion in Pancreatic Islets across Multiple Species." Endocrinology 152, no. 11 (August 30, 2011): 4106–15. http://dx.doi.org/10.1210/en.2011-1440.
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Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, and BRS-3 agonism is being explored as a possible therapy for obesity. Here we study the role of BRS-3 in the regulation of glucose-stimulated insulin secretion (GSIS) and glucose homeostasis. We quantified BRS-3 mRNA in pancreatic islets from multiple species and examined the acute effects of Bag-1, a selective BRS-3 agonist, on GSIS in mouse, rat, and human islets, and on oral glucose tolerance in mice. BRS-3 is highly expressed in human, mouse, rhesus, and dog (but not rat) pancreatic islets and in rodent insulinoma cell lines (INS-1 832/3 and MIN6). Silencing BRS-3 with small interfering RNA or pharmacological blockade with a BRS-3 antagonist, Bantag-1, reduced GSIS in 832/3 cells. In contrast, the BRS-3 agonist (Bag-1) increased GSIS in 832/3 and MIN6 cells. The augmentation of GSIS by Bag-1 was completely blocked by U73122, a phospholipase C inhibitor. Bag-1 also enhanced GSIS in islets isolated from wild-type, but not Brs3 knockout mice. In vivo, Bag-1 reduced glucose levels during oral glucose tolerance test in a BRS-3-dependent manner. BRS-3 agonists also increased GSIS in human islets. These results identify a potential role for BRS-3 in islet physiology, with agonism directly promoting GSIS. Thus, in addition to its potential role in the treatment of obesity, BRS-3 may also regulate blood glucose levels and have a role in the treatment of diabetes mellitus.
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Suh, Y.-H., S.-Y. Kim, H.-Y. Lee, B. C. Jang, J. H. Bae, J.-N. Sohn, J.-H. Bae, et al. "Overexpression of short heterodimer partner recovers impaired glucose-stimulated insulin secretion of pancreatic β-cells overexpressing UCP2." Journal of Endocrinology 183, no. 1 (October 2004): 133–44. http://dx.doi.org/10.1677/joe.1.05675.
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The short heterodimer partner (SHP) (NR0B2) is an orphan nuclear receptor whose function in pancreatic β-cells is unclear. Mitochondrial uncoupling protein (UCP2) in β-cells is upregulated in obesity-related diabetes, causing impaired glucose-stimulated insulin secretion (GSIS). We investigated whether SHP plays a role in UCP2-induced GSIS impairment. We overexpressed SHP in normal islet cells and in islet cells overexpressing UCP2 by an adenovirus-mediated infection technique. We found that SHP overexpression enhanced GSIS in normal islets, and restored GSIS in UCP2-overexpressing islets. SHP overexpression increased the glucose sensitivity of ATP-sensitive K+ (KATP) channels and enhanced theATP/ADP ratio. A peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, GW9662, did not block the SHP effect on GSIS. SHP overexpression also corrected the impaired sensitivity of UCP2-overexpressing β-cells to methylpyruvate, another energy fuel that bypasses glycolysis and directly enters the Krebs cycle. KATP channel inhibition mediated by dihydroxyacetone, which gives reducing equivalents directly to complex II of the electron transport system, was similar in Ad-Null-, Ad-UCP2- and Ad-UCP2+Ad-SHP-infected cells. The mitochondrial metabolic inhibitor sodium azide totally blocked the effect of SHP overexpression on GSIS. These results suggest that SHP positively regulates GSIS in β-cells and restores glucose sensitivity in UCP2-overexpressing β-cells by enhancing mitochondrial glucose metabolism, independent of PPARγ activation.
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Gerst, Felicia, Christine Singer, Katja Noack, Dunia Graf, Gabriele Kaiser, Madhura Panse, Marketa Kovarova, et al. "Glucose Responsiveness of β-Cells Depends on Fatty Acids." Experimental and Clinical Endocrinology & Diabetes 128, no. 10 (April 15, 2019): 644–53. http://dx.doi.org/10.1055/a-0884-2919.
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AbstractGlucose-stimulated insulin secretion (GSIS) is the gold standard for β-cell function. Both experimental and clinical diabetology, i. e., preceding transplantation of isolated human islets, depend on functional testing. However, multiple factors influence GSIS rendering the comparison of different in vitro tests of glucose responsiveness difficult. This study examined the influence of bovine serum albumin (BSA)-coupled fatty acids on GSIS. Isolated islet preparations of human donors and of 12-months old mice displayed impaired GSIS in the presence of 0.5% FFA-free BSA compared to 0.5% BSA (fraction V, not deprived from fatty acids). In aged INS-1E cells, i. e. at a high passage number, GSIS became highly sensitive to FFA-free BSA. Readdition of 30 µM palmitate or 30 µM oleate to FFA-free BSA did not rescue GSIS, while the addition of 100 µM palmitate and the raise of extracellular Ca2+from 1.3 to 2.6 mM improved glucose responsiveness. A high concentration of palmitate (600 µM), which fully activates FFA1, largely restored insulin secretion. The FFA1-agonist TUG-469 also increased insulin secretion but to a lesser extent than palmitate. Glucose- and TUG-induced Ca2+oscillations were impaired in glucose-unresponsive, i. e., aged INS-1E cells. These results suggest that fatty acid deprivation (FFA-free BSA) impairs GSIS mainly through an effect on Ca2+sensitivity.
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Ghanbari-Movahed, Maryam, Zahra Ghanbari-Movahed, Saeideh Momtaz, Kaitlyn L. Kilpatrick, Mohammad Hosein Farzaei, and Anupam Bishayee. "Unlocking the Secrets of Cancer Stem Cells with γ-Secretase Inhibitors: A Novel Anticancer Strategy." Molecules 26, no. 4 (February 12, 2021): 972. http://dx.doi.org/10.3390/molecules26040972.
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The dysregulation of Notch signaling is associated with a wide variety of different human cancers. Notch signaling activation mostly relies on the activity of the γ-secretase enzyme that cleaves the Notch receptors and releases the active intracellular domain. It is well-documented that γ-secretase inhibitors (GSIs) block the Notch activity, mainly by inhibiting the oncogenic activity of this pathway. To date, several GSIs have been introduced clinically for the treatment of various diseases, such as Alzheimer’s disease and various cancers, and their impacts on Notch inhibition have been found to be promising. Therefore, GSIs are of great interest for cancer therapy. The objective of this review is to provide a systematic review of in vitro and in vivo studies for investigating the effect of GSIs on various cancer stem cells (CSCs), mainly by modulation of the Notch signaling pathway. Various scholarly electronic databases were searched and relevant studies published in the English language were collected up to February 2020. Herein, we conclude that GSIs can be potential candidates for CSC-targeting therapy. The outcome of our study also indicates that GSIs in combination with anticancer drugs have a greater inhibitory effect on CSCs.
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Ishida, Yuuki, and Sadafumi Yoshida. "Simulation Studies on Giant Step Bunching Accompanying Trapezoid-Shape Defects in 4H-SiC Epitaxial Layer." Materials Science Forum 778-780 (February 2014): 222–25. http://dx.doi.org/10.4028/www.scientific.net/msf.778-780.222.
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Trapezoid-shape (T-S) defects on epilayer surfaces, which include two kinds of the giant step bunching (GSB), are one of killer defects for MOSFETs. We have investigated the generation mechanism of the two GSBs using "step kinetics simulator" we developed. The simulator has reproduced the behavior of the GSBs. Based on results from the simulation, we have discussed the generation mechanism of the two GSBs.
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Kong, Xiangchen, Dan Yan, Jiangming Sun, Xuerui Wu, Hindrik Mulder, Xianxin Hua, and Xiaosong Ma. "Glucagon-Like Peptide 1 Stimulates Insulin Secretion via Inhibiting RhoA/ROCK Signaling and Disassembling Glucotoxicity-Induced Stress Fibers." Endocrinology 155, no. 12 (December 1, 2014): 4676–85. http://dx.doi.org/10.1210/en.2014-1314.
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Chronic hyperglycemia leads to pancreatic β-cell dysfunction characterized by diminished glucose-stimulated insulin secretion (GSIS), but the precise cellular processes involved are largely unknown. Here we show that pancreatic β-cells chronically exposed to a high glucose level displayed substantially increased amounts of stress fibers compared with β-cells cultured at a low glucose level. β-Cells at high glucose were refractory to glucose-induced actin cytoskeleton remodeling and insulin secretion. Importantly, F-actin depolymerization by either cytochalasin B or latrunculin B restored glucotoxicity-diminished GSIS. The effects of glucotoxicity on increasing stress fibers and reducing GSIS were reversed by Y-27632, a Rho-associated kinase (ROCK)-specific inhibitor, which caused actin depolymerization and enhanced GSIS. Notably, glucagon-like peptide-1-(7–36) amide (GLP-1), a peptide hormone that stimulates GSIS at both normal and hyperglycemic conditions, also reversed glucotoxicity-induced increase of stress fibers and reduction of GSIS. In addition, GLP-1 inhibited glucotoxicity-induced activation of RhoA/ROCK and thereby resulted in actin depolymerization and potentiation of GSIS. Furthermore, this effect of GLP-1 was mimicked by cAMP-increasing agents forskolin and 3-isobutyl-1-methylxanthine as well as the protein kinase A agonist 6-Bnz-cAMP-AM whereas it was abolished by the protein kinase A inhibitor Rp-Adenosine 3′,5′-cyclic monophosphorothioate triethylammonium salt. To establish a clinical relevance of our findings, we examined the association of genetic variants of RhoA/ROCK with metabolic traits in homeostasis model assessment index of insulin resistance. Several single-nucleotide polymorphisms in and around RHOA were associated with elevated fasting insulin and homeostasis model assessment index of insulin resistance, suggesting a possible role in metabolic dysregulation. Collectively these findings unravel a novel mechanism whereby GLP-1 potentiates glucotoxicity-diminished GSIS by depolymerizing F-actin cytoskeleton via protein kinase A-mediated inhibition of the RhoA-ROCK signaling pathway.
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Cornell, Deborah, Satomi Miwa, Merilin Georgiou, Scott James Anderson, Minna Honkanen-Scott, James A. M. Shaw, and Catherine Arden. "Pseudoislet Aggregation of Pancreatic β-Cells Improves Glucose Stimulated Insulin Secretion by Altering Glucose Metabolism and Increasing ATP Production." Cells 11, no. 15 (July 29, 2022): 2330. http://dx.doi.org/10.3390/cells11152330.
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Appropriate glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells is an essential component of blood glucose homeostasis. Configuration of β-cells as 3D pseudoislets (PI) improves the GSIS response compared to 2D monolayer (ML) culture. The aim of this study was to determine the underlying mechanisms. MIN6 β-cells were grown as ML or PI for 5 days. Human islets were isolated from patients without diabetes. Function was assessed by GSIS and metabolic capacity using the Seahorse bioanalyser. Connexin 36 was downregulated using inducible shRNA. Culturing MIN6 as PI improved GSIS. MIN6 PI showed higher glucose-stimulated oxygen consumption (OCR) and extracellular acidification (ECAR) rates. Further analysis showed the higher ECAR was, at least in part, a consequence of increased glycolysis. Intact human islets also showed glucose-stimulated increases in both OCR and ECAR rates, although the latter was smaller in magnitude compared to MIN6 PI. The higher rates of glucose-stimulated ATP production in MIN6 PI were consistent with increased enzyme activity of key glycolytic and TCA cycle enzymes. There was no impact of connexin 36 knockdown on GSIS or ATP production. Configuration of β-cells as PI improves GSIS by increasing the metabolic capacity of the cells, allowing higher ATP production in response to glucose.
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Suzuki, Kengo, Yoshifumi Sato, Shinichi Kai, Kenichiro Nishi, Takehiko Adachi, Yoshiyuki Matsuo, and Kiichi Hirota. "Volatile anesthetics suppress glucose-stimulated insulin secretion in MIN6 cells by inhibiting glucose-induced activation of hypoxia-inducible factor 1." PeerJ 3 (December 10, 2015): e1498. http://dx.doi.org/10.7717/peerj.1498.
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Proper glycemic control is one of the most important goals in perioperative patient management. Insulin secretion from pancreaticβ-cells in response to an increased blood glucose concentration plays the most critical role in glycemic control. Several animal and human studies have indicated that volatile anesthetics impair glucose-stimulated insulin secretion (GSIS). A convincing GSIS model has been established, in which the activity of ATP-dependent potassium channels (KATP) under the control of intracellular ATP plays a critical role. We previously reported that pimonidazole adduct formation and stabilization of hypoxia-inducible factor-1α(HIF-1α) were detected in response to glucose stimulation and that MIN6 cells overexpressing HIF-1αwere resistant to glucose-induced hypoxia. Genetic ablation of HIF-1αor HIF-1βsignificantly inhibited GSIS in mice. Moreover, we previously reported that volatile anesthetics suppressed hypoxia-induced HIF activationin vitroandin vivo.To examine the direct effect of volatile anesthetics on GSIS, we used the MIN6 cell line, derived from mouse pancreaticβ-cells. We performed a series of experiments to examine the effects of volatile anesthetics (sevoflurane and isoflurane) on GSIS and demonstrated that these compounds inhibited the glucose-induced ATP increase, which is dependent on intracellular hypoxia-induced HIF-1 activity, and suppressed GSIS at a clinically relevant dose in these cells.
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Ganiron, Tomas Jr. "Forensic Investigation of Abandoned GSIS Building in Manila." International Journal of Disaster Recovery and Business Continuity 4 (November 30, 2013): 23–34. http://dx.doi.org/10.14257/ijdrbc.2013.4.03.
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Holness, Mark J., Gemma K. Greenwood, Nicholas D. Smith, and Mary C. Sugden. "PPARα activation and increased dietary lipid oppose thyroid hormone signaling and rescue impaired glucose-stimulated insulin secretion in hyperthyroidism." American Journal of Physiology-Endocrinology and Metabolism 295, no. 6 (December 2008): E1380—E1389. http://dx.doi.org/10.1152/ajpendo.90700.2008.
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The aim of the study was to investigate the impact of hyperthyroidism on the characteristics of the islet insulin secretory response to glucose, particularly the consequences of competition between thyroid hormone and peroxisome proliferator-activated receptor (PPAR)α in the regulation of islet adaptations to starvation and dietary lipid-induced insulin resistance. Rats maintained on standard (low-fat/high-carbohydrate) diet or high-fat/low-carbohydrate diet were rendered hyperthyroid (HT) by triiodothyronine (T3) administration (1 mg·kg body wt−1·day−1 sc, 3 days). The PPARα agonist WY14643 (50 mg/kg body wt ip) was administered 24 h before sampling. Glucose-stimulated insulin secretion (GSIS) was assessed during hyperglycemic clamps or after acute glucose bolus injection in vivo and with step-up and step-down islet perifusions. Hyperthyroidism decreased the glucose responsiveness of GSIS, precluding sufficient enhancement of insulin secretion for the degree of insulin resistance, in rats fed either standard diet or high-fat diet. Hyperthyroidism partially opposed the starvation-induced increase in the glucose threshold for GSIS and decrease in glucose responsiveness. WY14643 administration restored glucose tolerance by enhancing GSIS in fed HT rats and relieved the impact of hyperthyroidism to partially oppose islet starvation adaptations. Competition between thyroid hormone receptor (TR) and PPARα influences the characteristics of GSIS, such that hyperthyroidism impairs GSIS while PPARα activation (and increased dietary lipid) opposes TR signaling and restores GSIS in the fed hyperthyroid state. Increased islet PPARα signaling and decreased TR signaling during starvation facilitates appropriate modification of islet function.
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Heart, Emma, Gary W. Cline, Leon P. Collis, Rebecca L. Pongratz, Joshua P. Gray, and Peter J. S. Smith. "Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion." American Journal of Physiology-Endocrinology and Metabolism 296, no. 6 (June 2009): E1354—E1362. http://dx.doi.org/10.1152/ajpendo.90836.2008.
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Pyruvate cycling has been implicated in glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. The operation of some pyruvate cycling pathways is proposed to necessitate malate export from the mitochondria and NADP+-dependent decarboxylation of malate to pyruvate by cytosolic malic enzyme (ME1). Evidence in favor of and against a role of ME1 in GSIS has been presented by others using small interfering RNA-mediated suppression of ME1. ME1 was also proposed to account for methyl succinate-stimulated insulin secretion (MSSIS), which has been hypothesized to occur via succinate entry into the mitochondria in exchange for malate and subsequent malate conversion to pyruvate. In contrast to rat, mouse β-cells lack ME1 activity, which was suggested to explain their lack of MSSIS. However, this hypothesis was not tested. In this report, we demonstrate that although adenoviral-mediated overexpression of ME1 greatly augments GSIS in rat insulinoma INS-1 832/13 cells, it does not restore MSSIS, nor does it significantly affect GSIS in mouse islets. The increase in GSIS following ME1 overexpression in INS-1 832/13 cells did not alter the ATP-to-ADP ratio but was accompanied by increases in malate and citrate levels. Increased malate and citrate levels were also observed after INS-1 832/13 cells were treated with the malate-permeable analog dimethyl malate. These data suggest that although ME1 overexpression augments anaplerosis and GSIS in INS-1 832/13 cells, it is not likely involved in MSSIS and GSIS in pancreatic islets.
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Mieczkowski, Grzegorz, Dariusz Szpica, Andrzej Borawski, Mohamed M. Awad, Ahmed Elgarayhi, and Mohammed Sallah. "Investigation of the Near-Tip Stress Field of a Notch Terminating at a Bi-Material Interface." Materials 14, no. 16 (August 9, 2021): 4466. http://dx.doi.org/10.3390/ma14164466.
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The article deals with the problem of a sharp corner, the tip of which is located on the bi-material interface. The paper presents a qualitative and quantitative description of singular stress fields occurring in the tip area of such a stress concentrator. The qualitative description was obtained by solving the problem of the plane theory of elasticity with appropriately defined boundary conditions. To obtain a quantitative description, it was necessary to determine the values of generalised stress intensity factors (GSIFs). The GSIFs were determined using the developed analytical-numerical method. The calculations were made for various load variants (uniaxial/biaxial tension load, shear load) and notch positions (single/double edge-notched plate, centre-notched plate). Additionally, the impact of notch geometry (height and opening angle) and relative stiffness (Young’s moduli ratio of both components of bi-material) on GSIFs was investigated. It has been noticed that with a decrease in the relative stiffness and an increase in the notch angle or its height, the normalised GSIFs values increased. The obtained results were compared with the data available in the literature and their satisfactory agreement with those presented by other scientists was found.
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Surnam, B. Y. R. "Use of Materials in Green and Sustainable Buildings in Mauritius." Advanced Materials Research 905 (April 2014): 226–29. http://dx.doi.org/10.4028/www.scientific.net/amr.905.226.
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With the launching of the Mauritius Sustainable Island project in Mauritius for sustainable development, Green and Sustainable Buildings are being constructed in Mauritius. The use of materials has an impact on the design of these buildings. A survey was consequently performed to find the materials presently used in the country, materials that are being used in GSBs and the prospects of GSBs in Mauritius. Apart from the use of concrete and steel, other novel materials are being used, especially those that can be used in sustainable buildings. As for GSBs, there are presently only two in Mauritius. However, all the stakeholders in the construction sector are very optimistic of an average to rapid movement towards GSBs in the next 10 years.
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Ho, Chan, Chan Kin-yan Kenneth, Ip Ka-chun, and Li Wilson. "Open Transcervical Fracture of Femur Resulted from Gunshot Injury: A Case Report." Journal of Orthopaedics, Trauma and Rehabilitation 25, no. 1 (June 1, 2018): 87–90. http://dx.doi.org/10.1016/j.jotr.2018.03.001.
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Gunshot injury (GSI) is rare in Hong Kong, and local experience on the management of GSIs is limited. There is yet a worldwide consensus on the classification system or management guidelines for the management of GSIs. We report a case of open transcervical fracture of right femur resulting from a GSI. The management of GSIs, including the classification of these injuries, corresponding fracture and soft tissue management, the indications of bullet removal and antibiotics use will be discussed.
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Mizgier, Maria L., Luis R. Cataldo, Juan Gutierrez, José L. Santos, Mariana Casas, Paola Llanos, Ariel E. Contreras-Ferrat, Cedric Moro, Karim Bouzakri, and Jose E. Galgani. "Effect of Human Myotubes-Derived Media on Glucose-Stimulated Insulin Secretion." Journal of Diabetes Research 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/1328573.
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Fasting to postprandial transition requires a tight adjustment of insulin secretion to its demand, so tissue (e.g., skeletal muscle) glucose supply is assured while hypo-/hyperglycemia are prevented. High muscle glucose disposal after meals is pivotal for adapting to increased glycemia and might drive insulin secretion through muscle-released factors (e.g., myokines). We hypothesized that insulin influences myokine secretion and then increases glucose-stimulated insulin secretion (GSIS). In conditioned media from human myotubes incubated with/without insulin (100 nmol/L) for 24 h, myokines were qualitatively and quantitatively characterized using an antibody-based array and ELISA-based technology, respectively. C57BL6/J mice islets and Wistar rat beta cells were incubated for 24 h with control and conditioned media from noninsulin- and insulin-treated myotubes prior to GSIS determination. Conditioned media from insulin-treated versus nontreated myotubes had higher RANTES but lower IL6, IL8, and MCP1 concentration. Qualitative analyses revealed that conditioned media from noninsulin- and insulin-treated myotubes expressed 32 and 23 out of 80 myokines, respectively. Islets incubated with conditioned media from noninsulin-treated myotubes had higher GSIS versus control islets(p<0.05). Meanwhile, conditioned media from insulin-treated myotubes did not influence GSIS. In beta cells, GSIS was similar across conditions. In conclusion, factors being present in noninsulin-stimulated muscle cell-derived media appear to influence GSIS in mice islets.
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Basarab, I., U. Drachuk, B. Halukh, H. Koval, I. Simonova, and N. Herez. "Using of non-traditional raw materials in the technology of cooked sausages with functional purposes." Scientific Messenger of LNU of Veterinary Medicine and Biotechnologies 23, no. 95 (April 9, 2021): 65–71. http://dx.doi.org/10.32718/nvlvet-f9511.
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In modern conditions of meat production, one of the priorities of the meat processing industry is the production of products with improved consumer properties. To perform this task, it is necessary to include in the industrial circulation of physiologically functional ingredients of plant origin, which will provide the body with nutrients and expand the range of functional foods. The paper covers the issues of partial replacement of raw materials of animal origin with germinated sea-buckthorn seeds (GSBS) flour as a functional ingredient in the production of sausages. The chemical and vitamin composition of the physiologically functional ingredient has been studied. Three experimental recipes for sausages from GSBS flour has been developed. The positive influence of GSBS flour on functional-technological and physical-chemical properties of the received forcemeat is proved. Organoleptic parameters of sausages from GSBS flour are determined. The use of GSBS flour as a functional ingredient in the technology of sausages affects the appearance, taste, smell. It is established that the increase in the amount of GSBS flour introduction leads to an increase in pH by 0.4–0.8 % and finished products by 6.8 %. The improvement of functional and technological properties of experimental minced meat of sausages based on the use of GSBS flour is proved. The optimal amount of replacement of the main raw material with a physiologically functional ingredient, which is characteristic of the experimental sample № 2. The changes in the qualitative characteristics of the developed sample of sausages, which where within the regulatory requirements. The addition of 10 % GSBS flour to the minced meat of sausages leads to a slight increase in protein with a significant reduction in lipid content by 4.4 % in the finished product. As a result, the caloric content of Altaiska functional sausage is reduced by 13.2 % compared to traditional products. Production of such products will allow to expand the domestic range of functional products. Consumption of such sausages allows to consider them as foodstuff with essentially new functional properties which would correspond to modern requirements concerning food.
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Okatani, Takaki, Hiroaki Tanaka, Yuki Kurisu, Hidetoshi Nakajima, and Keisuke Katsuta. "Geospatial Information Authority of Japan’s (GSI’s) support for geography education." Abstracts of the ICA 1 (July 15, 2019): 1–2. http://dx.doi.org/10.5194/ica-abs-1-280-2019.
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<p><strong>Abstract.</strong> In Japan, the National Courses of Study was revised in 2016 and 2017. One of the most extensive discussions is on enhancing geography education in primary and secondary levels in this era of globalization. Further, it is argued how the Geospatial Information Authority of Japan (GSI), the national organization within the Japanese government for the production and coordination of basic geospatial information, should play a more important role in this process to support the promotion of geography education. In addition to these actions, GSI had started discussion with specialists for geography education and high-school teachers about supports for geography education expected to GSI. This presentation discusses the role of GSI in the promotion of geography education.</p>
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Tabor, Dale R., Joseph W. Thompson, Cynthia H. Lary, and Richard F. Jacobs. "Fc-γ Receptor-Ligand Interactions Enhance Macrophage GSIB4 -Binding Activity." Journal of Leukocyte Biology 48, no. 6 (December 1990): 482–87. http://dx.doi.org/10.1002/jlb.48.6.482.
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Pradhan, Geetali, Jong Han Lee, Chia-Shan Wu, Hongying Wang, Ligen Lin, Taraka Donti, Brett H. Graham, et al. "Mechanistic Investigation of GHS-R Mediated Glucose-Stimulated Insulin Secretion in Pancreatic Islets." Biomolecules 12, no. 3 (March 6, 2022): 407. http://dx.doi.org/10.3390/biom12030407.
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Ghrelin receptor, a growth hormone secretagogue receptor (GHS-R), is expressed in the pancreas. Emerging evidence indicates that GHS-R is involved in the regulation of glucose-stimulated insulin secretion (GSIS), but the mechanism by which GHS-R regulates GSIS in the pancreas is unclear. In this study, we investigated the role of GHS-R on GSIS in detail using global Ghsr−/− mice (in vivo) and Ghsr-ablated pancreatic islets (ex vivo). GSIS was attenuated in both Ghsr−/− mice and Ghsr-ablated islets, while the islet morphology was similar between WT and Ghsr−/− mice. To elucidate the mechanism underpinning Ghsr-mediated GSIS, we investigated the key steps of the GSIS signaling cascade. The gene expression of glucose transporter 2 (Glut2) and the glucose-metabolic intermediate—glucose-6-phosphate (G6P) were reduced in Ghsr-ablated islets, supporting decreased glucose uptake. There was no difference in mitochondrial DNA content in the islets of WT and Ghsr−/− mice, but the ATP/ADP ratio in Ghsr−/− islets was significantly lower than that of WT islets. Moreover, the expression of pancreatic and duodenal homeobox 1 (Pdx1), as well as insulin signaling genes of insulin receptor (IR) and insulin receptor substrates 1 and 2 (IRS1/IRS2), was downregulated in Ghsr−/− islets. Akt is the key mediator of the insulin signaling cascade. Concurrently, Akt phosphorylation was reduced in the pancreas of Ghsr−/− mice under both insulin-stimulated and homeostatic conditions. These findings demonstrate that GHS-R ablation affects key components of the insulin signaling pathway in the pancreas, suggesting the existence of a cross-talk between GHS-R and the insulin signaling pathway in pancreatic islets, and GHS-R likely regulates GSIS via the Akt-Pdx1-GLUT2 pathway.
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Wang, Baile, Huige Lin, Xiaomu Li, Wenqi Lu, Jae Bum Kim, Aimin Xu, and Kenneth K. Y. Cheng. "The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic β-cells." Proceedings of the National Academy of Sciences 117, no. 45 (October 29, 2020): 28307–15. http://dx.doi.org/10.1073/pnas.2016997117.
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Filamentous actin (F-actin) cytoskeletal remodeling is critical for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells, and its dysregulation causes type 2 diabetes. The adaptor protein APPL1 promotes first-phase GSIS by up-regulating solubleN-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein expression. However, whether APPL2 (a close homology of APPL1 with the same domain organization) plays a role in β-cell functions is unknown. Here, we show that APPL2 enhances GSIS by promoting F-actin remodeling via the small GTPase Rac1 in pancreatic β-cells. β-cell specific abrogation of APPL2 impaired GSIS, leading to glucose intolerance in mice. APPL2 deficiency largely abolished glucose-induced first- and second-phase insulin secretion in pancreatic islets. Real-time live-cell imaging and phalloidin staining revealed that APPL2 deficiency abolished glucose-induced F-actin depolymerization in pancreatic islets. Likewise, knockdown of APPL2 expression impaired glucose-stimulated F-actin depolymerization and subsequent insulin secretion in INS-1E cells, which were attributable to the impairment of Ras-related C3 botulinum toxin substrate 1 (Rac1) activation. Treatment with the F-actin depolymerization chemical compounds or overexpression of gelsolin (a F-actin remodeling protein) rescued APPL2 deficiency-induced defective GSIS. In addition, APPL2 interacted with Rac GTPase activating protein 1 (RacGAP1) in a glucose-dependent manner via the bin/amphiphysin/rvs-pleckstrin homology (BAR-PH) domain of APPL2 in INS-1E cells and HEK293 cells. Concomitant knockdown of RacGAP1 expression reverted APPL2 deficiency-induced defective GSIS, F-actin remodeling, and Rac1 activation in INS-1E cells. Our data indicate that APPL2 interacts with RacGAP1 and suppresses its negative action on Rac1 activity and F-actin depolymerization thereby enhancing GSIS in pancreatic β-cells.
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Kim, Hyo-Seon, Dahae Lee, Young-Hye Seo, Seung-Mok Ryu, A.-Yeong Lee, Byeong-Cheol Moon, Wook-Jin Kim, Ki-Sung Kang, and Jun Lee. "Chemical Constituents from the Roots of Angelica reflexa That Improve Glucose-Stimulated Insulin Secretion by Regulating Pancreatic β-Cell Metabolism." Pharmaceutics 15, no. 4 (April 13, 2023): 1239. http://dx.doi.org/10.3390/pharmaceutics15041239.
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The aim of this study was to discover bioactive constituents of Angelica reflexa that improve glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. Herein, three new compounds, namely, koseonolin A (1), koseonolin B (2), and isohydroxylomatin (3), along with 28 compounds (4–31) were isolated from the roots of A. reflexa by chromatographic methods. The chemical structures of new compounds (1–3) were elucidated through spectroscopic/spectrometric methods such as NMR and HRESIMS. In particular, the absolute configuration of the new compounds (1 and 3) was performed by electronic circular dichroism (ECD) studies. The effects of the root extract of A. reflexa (KH2E) and isolated compounds (1–31) on GSIS were detected by GSIS assay, ADP/ATP ratio assay, and Western blot assay. We observed that KH2E enhanced GSIS. Among the compounds 1–31, isohydroxylomatin (3), (−)-marmesin (17), and marmesinin (19) increased GSIS. In particular, marmesinin (19) was the most effective; this effect was superior to treatment with gliclazide. GSI values were: 13.21 ± 0.12 and 7.02 ± 0.32 for marmesinin (19) and gliclazide at a same concentration of 10 μM, respectively. Gliclazide is often performed in patients with type 2 diabetes (T2D). KH2E and marmesinin (19) enhanced the protein expressions associated with pancreatic β-cell metabolism such as peroxisome proliferator-activated receptor γ, pancreatic and duodenal homeobox 1, and insulin receptor substrate-2. The effect of marmesinin (19) on GSIS was improved by an L-type Ca2+ channel agonist and K+ channel blocker and was inhibited by an L-type Ca2+ channel blocker and K+ channel activator. Marmesinin (19) may improve hyperglycemia by enhancing GSIS in pancreatic β-cells. Thus, marmesinin (19) may have potential use in developing novel anti-T2D therapy. These findings promote the potential application of marmesinin (19) toward the management of hyperglycemia in T2D.
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Saleh, Monique C., Michael B. Wheeler, and Catherine B. Chan. "Endogenous islet uncoupling protein-2 expression and loss of glucose homeostasis in ob/ob mice." Journal of Endocrinology 190, no. 3 (September 2006): 659–67. http://dx.doi.org/10.1677/joe.1.06715.
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We hypothesized that the loss of glucose homeostasis in ob/ob mice is associated with upregulation of islet uncoupling protein-2 (UCP2) expression, leading to impaired glucose-stimulated insulin secretion (GSIS). Changes in glucose homeostasis in lean and ob/ob mice from 5 to 16 weeks were assessed by fasting blood glucose, plasma insulin, oral glucose tolerance, and tissue insulin sensitivity. In vitro GSIS and ATP content were assayed in isolated islets, while UCP2 expression was determined by quantitative real-time PCR and immunoblotting. Short-term reduction of UCP2 expression was achieved through transfection of islets with specific small interfering RNA. Insulin resistance was detected in 5-week-old ob/ob mice, but GSIS and blood glucose levels remained normal. By 8 weeks of age, ob/ob mice displayed fasting hyperglycemia, hyperinsulinemia and glucose intolerance, and also had elevated non-esterified fatty acid concentration in plasma. In vitro, GSIS and ATP generation were impaired in ob/ob islets. Islet UCP2 expression was elevated at 5 and 8 weeks of age. Short-term knockdown of islet UCP2 increased GSIS in islets of lean mice, but had no effect in islets from ob/ob mice. Loss of glucose homeostasis and impairment of insulin secretion from isolated islets at 8 weeks in ob/ob mice is preceded by an increase in UCP2 expression in islets. Moreover, the glucolipotoxic conditions observed are predicted to increase UCP2 activity, contributing to lower islet ATP and GSIS.
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Kim, Hyo-Eun, Sung-E. Choi, Soo-Jin Lee, Ji-Hyun Lee, Youn-Jung Lee, Sang Sun Kang, Jaesun Chun, and Yup Kang. "Tumour necrosis factor-α-induced glucose-stimulated insulin secretion inhibition in INS-1 cells is ascribed to a reduction of the glucose-stimulated Ca2+ influx." Journal of Endocrinology 198, no. 3 (July 1, 2008): 549–60. http://dx.doi.org/10.1677/joe-08-0131.
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The present study was undertaken to determine how tumour necrosis factor-α (TNF-α) elicits the inhibition of glucose-stimulated insulin secretion (GSIS) in rat insulinoma cells (INS)-1 β-cells. TNF-α pretreatment did not change the expression levels of insulin, PDX-1, glucose transporter 2, glucokinase, KATP channels, Ca2+ channels, and exocytotic molecules and, furthermore, did not reduce the glucose-stimulated ATP level. On the other hand, TNF-α reduced the glucose-stimulated influx of Ca2+. The TNF-α treatment was thought to activate c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and NF-κB inflammatory signals, since TNF-α increased phospho-JNK and phospho-p38 and reduced IκB levels. Inhibitors of these signaling pathways prevented the TNF-α-induced reduction of the Ca2+ influx and GSIS. Overexpression of MEKK3, a possible mediator from the TNF-α receptor to the JNK/p38 and NK-κB signaling cascade, increased the levels of phospho-JNK, phospho-p38, and NF-κB, and reduced the glucose-stimulated Ca2+ influx and GSIS. The reduction of the Ca2+ influx and GSIS in MEKK3-overexpressing INS-1 cells was also prevented by inhibitors of JNK, p38, and NF-κB. These data demonstrate that TNF-α inhibits GSIS by reducing the glucose-stimulated Ca2+ influx, possibly through the activation of JNK and p38 MAPK and NF-κB inflammatory signals. Thus, our findings suggest that the activation of stress and inflammatory signals can contribute to the inhibition of GSIS in the development of diabetes.
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Boehmer, Brit H., Peter R. Baker, Laura D. Brown, Stephanie R. Wesolowski, and Paul J. Rozance. "Leucine acutely potentiates glucose-stimulated insulin secretion in fetal sheep." Journal of Endocrinology 247, no. 1 (October 2020): 115–26. http://dx.doi.org/10.1530/joe-20-0243.
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A 9-day infusion of leucine into fetal sheep potentiates fetal glucose-stimulated insulin secretion (GSIS). However, there were accompanying pancreatic structural changes that included a larger proportion of β-cells and increased vascularity. Whether leucine can acutely potentiate fetal GSIS in vivo before these structural changes develop is unknown. The mechanisms by which leucine acutely potentiates GSIS in adult islets and insulin-secreting cell lines are well known. These mechanisms involve leucine metabolism, including leucine oxidation. However, it is not clear if leucine-stimulated metabolic pathways are active in fetal islets. We hypothesized that leucine would acutely potentiate GSIS in fetal sheep and that isolated fetal islets are capable of oxidizing leucine. We also hypothesized that leucine would stimulate other metabolic pathways associated with insulin secretion. In pregnant sheep we tested in vivo GSIS with and without an acute leucine infusion. In isolated fetal sheep islets, we measured leucine oxidation with a [1-14C] l-leucine tracer. We also measured concentrations of other amino acids, glucose, and analytes associated with cellular metabolism following incubation of fetal islets with leucine. In vivo, a leucine infusion resulted in glucose-stimulated insulin concentrations that were over 50% higher than controls (P < 0.05). Isolated fetal islets oxidized leucine. Leucine supplementation of isolated fetal islets also resulted in significant activation of metabolic pathways involving leucine and other amino acids. In summary, acute leucine supplementation potentiates fetal GSIS in vivo, likely through pathways related to the oxidation of leucine and catabolism of other amino acids.
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Cataldo, L. R., M. L. Mizgier, D. Busso, P. Olmos, J. E. Galgani, R. Valenzuela, D. Mezzano, E. Aranda, V. A. Cortés, and J. L. Santos. "Serotonin- and Dopamine-Related Gene Expression indb/dbMice Islets and in MIN6β-Cells Treated with Palmitate and Oleate." Journal of Diabetes Research 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/3793781.
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High circulating nonesterified fatty acids (NEFAs) concentration, often reported in diabetes, leads to impaired glucose-stimulated insulin secretion (GSIS) through not yet well-defined mechanisms. Serotonin and dopamine might contribute to NEFA-dependentβ-cell dysfunction, since extracellular signal of these monoamines decreases GSIS. Moreover, palmitate-treatedβ-cells may enhance the expression of the serotonin receptor Htr2c, affecting insulin secretion. Additionally, the expression of monoamine-oxidase type B (Maob) seems to be lower in islets from humans and mice with diabetes compared to nondiabetic islets, which may lead to increased monoamine concentrations. We assessed the expression of serotonin- and dopamine-related genes in islets fromdb/dband wild-type (WT) mice. In addition, the effect of palmitate and oleate on the expression of such genes, 5HT content, and GSIS in MIN6β-cell was determined. Lower Maob expression was found in islets fromdb/dbversus WT mice and in MIN6β-cells in response to palmitate and oleate treatment compared to vehicle. Reduced 5HT content and impaired GSIS in response to palmitate (−25%;p<0.0001) and oleate (−43%;p<0.0001) were detected in MIN6β-cells. In conclusion, known defects of GSIS in islets fromdb/dbmice and MIN6β-cells treated with NEFAs are accompanied by reduced Maob expression and reduced 5HT content.
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Holness, Mark J., Nicholas D. Smith, Gemma K. Greenwood, and Mary C. Sugden. "PPARα activation reverses adverse effects induced by high-saturated-fat feeding on pancreatic β-cell function in late pregnancy." American Journal of Physiology-Endocrinology and Metabolism 292, no. 4 (April 2007): E1087—E1094. http://dx.doi.org/10.1152/ajpendo.00375.2006.
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We examined whether the additional demand for insulin secretion imposed by dietary saturated fat-induced insulin resistance during pregnancy is accommodated at late pregnancy, already characterized by insulin resistance. We also assessed whether effects of dietary saturated fat are influenced by PPARα activation or substitution of 7% of dietary fatty acids (FAs) with long-chain ω-3 FA, manipulations that improve insulin action in the nonpregnant state. Glucose tolerance at day 19 of pregnancy in the rat was impaired by high-saturated-fat feeding throughout pregnancy. Despite modestly enhanced glucose-stimulated insulin secretion (GSIS) in vivo, islet perifusions revealed an increased glucose threshold and decreased glucose responsiveness of GSIS in the saturated-fat-fed pregnant group. Thus, insulin resistance evoked by dietary saturated fat is partially countered by augmented insulin secretion, but compensation is compromised by impaired islet function. Substitution of 7% of saturated FA with long-chain ω-3 FA suppressed GSIS in vivo but did not modify the effect of saturated-fat feeding to impair GSIS by perifused islets. PPARα activation (24 h) rescued impaired islet function that was identified using perifused islets, but GSIS in vivo was suppressed such that glucose tolerance was not improved, suggesting modification of the feedback loop between insulin action and secretion.
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Huang, Yan. "GSiB: PSE infrastructure for dynamic service-oriented Grid applications." Future Generation Computer Systems 21, no. 6 (June 2005): 868–77. http://dx.doi.org/10.1016/j.future.2003.12.022.
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Nie, Jia, Chao Sun, Zhijie Chang, Nicolas Musi, and Yuguang Shi. "SAD-A Promotes Glucose-Stimulated Insulin Secretion Through Phosphorylation and Inhibition of GDIα in Male Islet β Cells." Endocrinology 159, no. 8 (June 4, 2018): 3036–47. http://dx.doi.org/10.1210/en.2017-03243.
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Abstract Rho GDP-dissociation inhibitor (GDIα) inhibits glucose-stimulated insulin secretion (GSIS) in part by locking Rho GTPases in an inactive GDP-bound form. The onset of GSIS causes phosphorylation of GDIα at Ser174, a critical inhibitory site for GDIα, leading to the release of Rho GTPases and their subsequent activation. However, the kinase regulator(s) that catalyzes the phosphorylation of GDIα in islet β cells remains elusive. We propose that SAD-A, a member of AMP-activated protein kinase–related kinases that promotes GSIS as an effector kinase for incretin signaling, interacts with and inhibits GDIα through phosphorylation of Ser174 during the onset GSIS from islet β cells. Coimmunoprecipitation and phosphorylation analyses were carried out to identify the physical interaction and phosphorylation site of GDIα by SAD-A in the context of GSIS from INS-1 β cells and primary islets. We identified GDIα directly binds to SAD-A kinase domain and phosphorylated by SAD-A on Ser174, leading to dissociation of Rho GTPases from GDIα complexes. Accordingly, overexpression of SAD-A significantly stimulated GDIα phosphorylation at Ser174 in response to GSIS, which is dramatically potentiated by glucagonlike peptide-1, an incretin hormone. Conversely, SAD-A deficiency, which is mediated by short hairpin RNA transfection in INS-1 cells, significantly attenuated endogenous GDIα phosphorylation at Ser174. Consequently, coexpression of SAD-A completely prevented the inhibitory effect of GDIα on insulin secretion in islets. In summary, glucose and incretin stimulate insulin secretion through the phosphorylation of GDIα at Ser174 by SAD-A, which leads to the activation of Rho GTPases, culminating in insulin exocytosis.
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Gray, Joshua P., Delaine Zayasbazan Burgos, Tao Yuan, Navindra Seeram, Rebecca Rebar, Rebecca Follmer, and Emma A. Heart. "Thymoquinone, a bioactive component ofNigella sativa, normalizes insulin secretion from pancreatic β-cells under glucose overload via regulation of malonyl-CoA." American Journal of Physiology-Endocrinology and Metabolism 310, no. 6 (March 15, 2016): E394—E404. http://dx.doi.org/10.1152/ajpendo.00250.2015.
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Thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone) is a major bioactive component of Nigella sativa, a plant used in traditional medicine to treat a variety of symptoms, including elevated blood glucose levels in type 2 diabetic patients. Normalization of elevated blood glucose depends on both glucose disposal by peripheral tissues and glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. We employed clonal β-cells and rodent islets to investigate the effects of thymoquinone (TQ) and Nigella sativa extracts (NSEs) on GSIS and cataplerotic metabolic pathways implicated in the regulation of GSIS. TQ and NSE regulated NAD(P)H/NAD(P)+ratios via a quinone-dependent redox cycling mechanism. TQ content was positively correlated with the degree of redox cycling activity of NSE extracts, suggesting that TQ is a major component engaged in mediating NSE-dependent redox cycling. Both acute and chronic exposure to TQ and NSE enhanced GSIS and were associated with the ability of TQ and NSE to increase the ATP/ADP ratio. Furthermore, TQ ameliorated the impairment of GSIS following chronic exposure of β-cells to glucose overload. This protective action was associated with the TQ-dependent normalization of chronic accumulation of malonyl-CoA, elevation of acetyl-CoA carboxylase (ACC), fatty acid synthase, and fatty acid-binding proteins following chronic glucose overload. Together, these data suggest that TQ modulates the β-cell redox circuitry and enhances the sensitivity of β-cell metabolic pathways to glucose and GSIS under normal conditions as well as under hyperglycemia. This action is associated with the ability of TQ to regulate carbohydrate-to-lipid flux via downregulation of ACC and malonyl-CoA.
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Marrano, Nicola, Rosaria Spagnuolo, Giuseppina Biondi, Angelo Cignarelli, Sebastio Perrini, Leonardo Vincenti, Luigi Laviola, Francesco Giorgino, and Annalisa Natalicchio. "Effects of Extra Virgin Olive Oil Polyphenols on Beta-Cell Function and Survival." Plants 10, no. 2 (February 3, 2021): 286. http://dx.doi.org/10.3390/plants10020286.
Full textAbstract:
Extra virgin olive oil (EVOO) is a major component of the Mediterranean diet and is appreciated worldwide because of its nutritional benefits in metabolic diseases, including type 2 diabetes (T2D). EVOO contains significant amounts of secondary metabolites, such as phenolic compounds (PCs), that may positively influence the metabolic status. In this study, we investigated for the first time the effects of several PCs on beta-cell function and survival. To this aim, INS-1E cells were exposed to 10 μM of the main EVOO PCs for up to 24 h. Under these conditions, survival, insulin biosynthesis, glucose-stimulated insulin secretion (GSIS), and intracellular signaling activation (protein kinase B (AKT) and cAMP response element-binding protein (CREB)) were evaluated. Hydroxytyrosol, tyrosol, and apigenin augmented beta-cell proliferation and insulin biosynthesis, and apigenin and luteolin enhanced the GSIS. Conversely, vanillic acid and vanillin were pro-apoptotic for beta-cells, even if they increased the GSIS. In addition, oleuropein, p-coumaric, ferulic and sinapic acids significantly worsened the GSIS. Finally, a mixture of hydroxytyrosol, tyrosol, and apigenin promoted the GSIS in human pancreatic islets. Apigenin was the most effective compound and was also able to activate beneficial intracellular signaling. In conclusion, this study shows that hydroxytyrosol, tyrosol, and apigenin foster beta-cells’ health, suggesting that EVOO or supplements enriched with these compounds may improve insulin secretion and promote glycemic control in T2D patients.
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Weksler-Zangen, Sarah, Anne Jörns, Limor Tarsi-Chen, Fiona Vernea, Genya Aharon-Hananel, Ann Saada, Sigurd Lenzen, and Itamar Raz. "Dietary copper supplementation restores β-cell function of Cohen diabetic rats: a link between mitochondrial function and glucose-stimulated insulin secretion." American Journal of Physiology-Endocrinology and Metabolism 304, no. 10 (May 15, 2013): E1023—E1034. http://dx.doi.org/10.1152/ajpendo.00036.2013.
Full textAbstract:
β-Cell mitochondrial dysfunction as well as proinflammatory cytokines have been suggested to contribute to reduced glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. We recently demonstrated that Cohen diabetic sensitive (CDs) rats fed a high-sucrose, low-copper diet (HSD) developed hyperglycemia and reduced GSIS in association with peri-islet infiltration of fat and interleukin (IL)-1β-expressing macrophages, whereas CD resistant (CDr) rats remained normoglycemic on HSD. We examined: 1) the correlation between copper concentration in the HSD and progression, prevention, and reversion of hyperglycemia in CDs rats, 2) the relationship between activity of the copper-dependent, respiratory-chain enzyme cytochrome c oxidase (COX), infiltration of fat, IL-1β-expressing macrophages, and defective GSIS in hyperglycemic CDs rats. CDs and CDr rats were fed HSD or copper-supplemented HSD before and during hyperglycemia development. Blood glucose and insulin concentrations were measured during glucose tolerance tests. Macrophage infiltration and IL-1β expression were evaluated in pancreatic sections by electron-microscopy and immunostaining. COX activity was measured in pancreatic sections and isolated islets. In CDs rats fed HSD, GSIS and islet COX activity decreased, while blood glucose and infiltration of fat and IL-1β-expressing macrophages increased with time on HSD ( P < 0.01 vs. CDr-HSD rats, all parameters, respectively). CDs rats maintained on copper-supplemented HSD did not develop hyperglycemia, and in hyperglycemic CDs rats, copper supplementation restored GSIS and COX activity, reversed hyperglycemia and infiltration of fat and IL-1β-expressing macrophages ( P < 0.01 vs. hyperglycemic CDs-HSD rats, all parameters, respectively). We provide novel evidence for a critical role of low dietary copper in diminished GSIS of susceptible CDs rats involving the combined consequence of reduced islet COX activity and pancreatic low-grade inflammation.
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Kim, Min Joo, Se Hee Min, Seon Young Shin, Mi Na Kim, Hakmo Lee, Jin Young Jang, Sun-Whe Kim, Kyong Soo Park, and Hye Seung Jung. "Attenuation of PERK enhances glucose-stimulated insulin secretion in islets." Journal of Endocrinology 236, no. 3 (March 2018): 125–36. http://dx.doi.org/10.1530/joe-17-0497.
Full textAbstract:
PERK is a pancreatic endoplasmic reticulum (ER) kinase. Its complete deletion in pancreatic β cells induces insulin deficiency; however, the effects of partial Perk suppression are unclear. We investigated the effect of partial PERK suppression using the specific PERK inhibitors GSK2606414 and GSK2656157. Low-dose GSK2606414 treatment for 24 h enhanced glucose-stimulated insulin secretion (GSIS), islet insulin content and calcium transit in mouse (at 40 nM) and human (at 50–100 nM) pancreatic islets. GSK2606414 also induced the expression of the ER chaperone BiP and the release of calcium from the ER. When Bip expression was inhibited using a Bip siRNA, the GSK2606414-induced augmentation of the ER calcium level, islet insulin contents, glucose-stimulated cytosolic calcium transit and GSIS were abrogated. In both wild-type and insulin-deficient Atg7-knockout mice, 8 weeks of GSK2656157 treatment enhanced GSIS and improved hyperglycemia without affecting body weight. In conclusion, partial PERK inhibition induced BiP expression in islets, increased glucose-stimulated calcium transit and islet insulin contents and enhanced GSIS, suggesting that low-dose PERK inhibitors could potentially be used to treat insulin deficiency.
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Zhang, Ye, Zhifang Xie, Guangdi Zhou, Hai Zhang, Jian Lu, and Weiping J. Zhang. "Fructose-1,6-Bisphosphatase Regulates Glucose-Stimulated Insulin Secretion of Mouse Pancreatic β-Cells." Endocrinology 151, no. 10 (August 18, 2010): 4688–95. http://dx.doi.org/10.1210/en.2009-1185.
Full textAbstract:
Pancreatic β-cells can precisely sense glucose stimulation and accordingly adjust their insulin secretion. Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme, but its physiological significance in β-cells is not established. Here we determined its physiological role in regulating glucose sensing and insulin secretion of β-cells. Considerable FBPase mRNA was detected in normal mouse islets and β-cell lines, although their protein levels appeared to be quite low. Down-regulation of FBP1 in MIN6 cells by small interfering RNA could enhance the glucose-stimulated insulin secretion (GSIS), whereas FBP1-overexpressing MIN6 cells exhibited decreased GSIS. Inhibition of FBPase activity in islet β-cells by its specific inhibitor MB05032 led to significant increase of their glucose utilization and cellular ATP to ADP ratios and consequently enhanced GSIS in vitro. Pretreatment of mice with the MB05032 prodrug MB06322 could potentiate GSIS in vivo and improve their glucose tolerance. Therefore, FBPase plays an important role in regulating glucose sensing and insulin secretion of β-cells and serves a promising target for diabetes treatment.
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Srinivasan, Malathi, Cheol S. Choi, Pushpankur Ghoshal, Lioudmila Pliss, Jignesh D. Pandya, David Hill, Gary Cline, and Mulchand S. Patel. "β-Cell-specific pyruvate dehydrogenase deficiency impairs glucose-stimulated insulin secretion." American Journal of Physiology-Endocrinology and Metabolism 299, no. 6 (December 2010): E910—E917. http://dx.doi.org/10.1152/ajpendo.00339.2010.
Full textAbstract:
Glucose-stimulated insulin secretion (GSIS) by β-cells requires the generation of ATP from oxidation of pyruvate as well as generation of coupling factors involving three different pyruvate cycling shuttles. The roles of several key enzymes involved in pyruvate cycling in β-cells have been documented using isolated islets and β-cell clonal lines. To investigate the role of the pyruvate dehydrogenase (PDH) complex (PDC) in GSIS, a murine model of β-cell-specific PDH deficiency (β-PDHKO) was created. Pancreatic insulin content was decreased in 1-day-old β-PDHKO male pups and adult male mice. The plasma insulin levels were decreased and blood glucose levels increased in β-PDHKO male mice from neonatal life onward. GSIS was reduced in isolated islets from β-PDHKO male mice with about 50% reduction in PDC activity. Impairment in a glucose tolerance test and in vivo insulin secretion during hyperglycemic clamp was evident in β-PDHKO adults. No change in the number or size of islets was found in pancreata from 4-wk-old β-PDHKO male mice. However, an increase in the mean size of individual β-cells in islets of these mice was observed. These findings show a key role of PDC in GSIS by pyruvate oxidation. This β-PDHKO mouse model represents the first mouse model in which a mitochondrial oxidative enzyme deletion by gene knockout has been employed to demonstrate an altered GSIS by β-cells.
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Heisel, Marnin, and Gordon Flett. "ASSESSING THE PSYCHOMETRIC PROPERTIES OF THE GERIATRIC SUICIDE IDEATION SCALE (GSIS) IN MIDDLE-AGED AND OLDER MEN." Innovation in Aging 6, Supplement_1 (November 1, 2022): 372. http://dx.doi.org/10.1093/geroni/igac059.1470.
Full textAbstract:
Abstract Middle-aged and older men have high rates of suicide, necessitating focused risk detection. We developed the Geriatric Suicide Ideation Scale (GSIS; Heisel & Flett, 2006) as an age-specific, multidimensional suicide risk assessment tool. The GSIS has shown strong psychometric properties in clinical, community, and residential samples (see Heisel & Flett, 2016), yet research has lagged investigating its utility with middle-aged and older men. The purpose of the present study was thus to assess the psychometric properties of the GSIS administered to 82 men, 55 years and older (M=63.3, SD=4.6 years), who participated in a meaning-centered psychological intervention group for those concerned about or struggling with the transition to retirement (Heisel et al., 2020). Psychometric analyses included investigation of participant response characteristics, internal consistency, and construct validity. Findings demonstrated acceptable internal consistency for GSIS totals (α =.88) and for its Suicide Ideation, Death Ideation, Loss of Personal and Social Worth, and Perceived Meaning in Life subscales (α =.62-.81). Positive associations between the GSIS and negative psychological factors (depression, anxiety, hopelessness, loneliness, perceived lack of mattering to others, and history of suicidal behavior; r =.30 to .51) and negative associations with positive factors (life satisfaction, psychological well-being, perceived support, and meaning in life; r = -.21 to -.51) supported its construct validity. These and other findings will be discussed in the broader context of upstream population level approaches to suicide risk detection and prevention.
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Wyss, Jean-Christophe, Rajesh Kumar, Josip Mikulic, Manfred Schneider, Johannes D. Aebi, Lucienne Juillerat-Jeanneret, and Dela Golshayan. "Targeted γ-secretase inhibition of Notch signaling activation in acute renal injury." American Journal of Physiology-Renal Physiology 314, no. 5 (May 1, 2018): F736—F746. http://dx.doi.org/10.1152/ajprenal.00414.2016.
Full textAbstract:
The Notch pathway has been reported to control tissue damage in acute kidney diseases. To investigate potential beneficial nephroprotective effects of targeting Notch, we developed chemically functionalized γ-secretase inhibitors (GSIs) targeting γ-glutamyltranspeptidase (γ-GT) and/or γ-glutamylcyclotransferase (γ-GCT), two enzymes overexpressed in the injured kidney, and evaluated them in in vivo murine models of acute tubular and glomerular damage. Exposure of the animals to disease-inducing drugs together with the functionalized GSIs improved proteinuria and, to some extent, kidney dysfunction. The expression of genes involved in the Notch pathway, acute inflammatory stress responses, and the renin-angiotensin system was enhanced in injured kidneys, which could be downregulated upon administration of functionalized GSIs. Immunohistochemistry staining and Western blots demonstrated enhanced activation of Notch1 as detected by its cleaved active intracellular domain during acute kidney injury, and this was downregulated by concomitant treatment with the functionalized GSIs. Thus targeted γ-secretase-based prodrugs developed as substrates for γ-GT/γ-GCT have the potential to selectively control Notch activation in kidney diseases with subsequent regulation of the inflammatory stress response and the renin-angiotensin pathways.
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Marçal, A. C., J. P. G. Camporez, T. M. Lima-Salgado, D. E. Cintra, E. H. Akamine, L. M. Ribeiro, F. N. Almeida, et al. "Changes in food intake, metabolic parameters and insulin resistance are induced by an isoenergetic, medium-chain fatty acid diet and are associated with modifications in insulin signalling in isolated rat pancreatic islets." British Journal of Nutrition 109, no. 12 (November 27, 2012): 2154–65. http://dx.doi.org/10.1017/s0007114512004576.
Full textAbstract:
Long-chain fatty acids are capable of inducing alterations in the homoeostasis of glucose-stimulated insulin secretion (GSIS), but the effect of medium-chain fatty acids (MCFA) is poorly elucidated. In the present study, we fed a normoenergetic MCFA diet to male rats from the age of 1 month to the age of 4 months in order to analyse the effect of MCFA on body growth, insulin sensitivity and GSIS. The 45 % MCFA substitution of whole fatty acids in the normoenergetic diet impaired whole body growth and resulted in increased body adiposity and hyperinsulinaemia, and reduced insulin-mediated glucose uptake in skeletal muscle. In addition, the isolated pancreatic islets from the MCFA-fed rats showed impaired GSIS and reduced protein kinase Bα (AKT1) protein expression and extracellular signal-related kinase isoforms 1 and 2 (ERK1/2) phosphorylation, which were accompanied by increased cellular death. Furthermore, there was a mildly increased cholinergic sensitivity to GSIS. We discuss these findings in further detail, and advocate that they might have a role in the mechanistic pathway leading to the compensatory hyperinsulinaemic status found in this animal model.
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Yajima, Ken, Hiroshi Hirose, Haruhisa Fujita, Yoshiko Seto, Hiroshi Fujita, Kaname Ukeda, Kiichi Miyashita, et al. "Combination therapy with PPARγ and PPARα agonists increases glucose-stimulated insulin secretion in db/dbmice." American Journal of Physiology-Endocrinology and Metabolism 284, no. 5 (May 1, 2003): E966—E971. http://dx.doi.org/10.1152/ajpendo.00149.2002.
Full textAbstract:
Although peroxisome proliferator-activated receptor (PPAR)γ agonists ameliorate insulin resistance, they sometimes cause body weight gain, and the effect of PPAR agonists on insulin secretion is unclear. We evaluated the effects of combination therapy with a PPARγ agonist, pioglitazone, and a PPARα agonist, bezafibrate, and a dual agonist, KRP-297, for 4 wk in male C57BL/6J mice and db/db mice, and we investigated glucose-stimulated insulin secretion (GSIS) by in situ pancreatic perfusion. Body weight gain in db/db mice was less with KRP-297 treatment than with pioglitazone or pioglitazone + bezafibrate treatment. Plasma glucose, insulin, triglyceride, and nonesterified fatty acid levels were elevated in untreated db/db mice compared with untreated C57BL/6J mice, and these parameters were significantly ameliorated in the PPARγ agonist-treated groups. Also, PPARγ agonists ameliorated the diminished GSIS and insulin content, and they preserved insulin and GLUT2 staining in db/db mice. GSIS was further increased by PPARγ and -α agonists. We conclude that combination therapy with PPARγ and PPARα agonists may be more useful with respect to body weight and pancreatic GSIS in type 2 diabetes with obesity.