Effects of novel flame retardants tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPhP) on function and homeostasis in human and rat pancreatic beta-cell lines
Language English Country Germany Media print-electronic
Document type Journal Article
Grant support
Cooperatio METD
Univerzita Karlova v Praze
PubMed
39192017
PubMed Central
PMC11489283
DOI
10.1007/s00204-024-03841-z
PII: 10.1007/s00204-024-03841-z
Knihovny.cz E-resources
- Keywords
- Beta-cells, Diabetes, Insulin, Metabolic disease, TDCIPP, TPhP,
- MeSH
- Insulin-Secreting Cells * drug effects metabolism MeSH
- Cell Line MeSH
- Homeostasis * drug effects MeSH
- Insulin * metabolism MeSH
- Rats MeSH
- Humans MeSH
- Organophosphates toxicity MeSH
- Organophosphorus Compounds * toxicity MeSH
- Proinsulin metabolism MeSH
- Flame Retardants * toxicity MeSH
- Insulin Secretion drug effects MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Insulin * MeSH
- Organophosphates MeSH
- Organophosphorus Compounds * MeSH
- Proinsulin MeSH
- Flame Retardants * MeSH
- triphenyl phosphate MeSH Browser
- tris(1,3-dichloro-2-propyl)phosphate MeSH Browser
Despite the fact that environmental pollution has been implicated in the global rise of diabetes, the research on the impact of emerging pollutants such as novel flame retardants remains limited. In line with the shift towards the use of non-animal approaches in toxicological testing, this study aimed to investigate the effects of two novel flame retardants tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPhP) in rat (INS1E) and human (NES2Y) pancreatic beta-cell lines. One-week exposure to 1 μM and 10 μM TDCIPP and TPhP altered intracellular insulin and proinsulin levels, but not the levels of secreted insulin (despite the presence of a statistically insignificant trend). The exposures also altered the protein expression of several factors involved in beta-cell metabolic pathways and signaling, including ATP citrate lyase, isocitrate dehydrogenase 1, perilipins, glucose transporters, ER stress-related factors, and antioxidant enzymes. This study has brought new and valuable insights into the toxicity of TDCIPP and TPhP on beta-cell function and revealed alterations that might impact insulin secretion after more extended exposure. It also adds to the scarce studies using in vitro pancreatic beta-cells models in toxicological testing, thereby promoting the development of non-animal testing strategy for identifying pro-diabetic effects of chemical pollutants.
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Aghelan Z, Kiani S, Nasiri A, Sadeghi M, Farrokhi A, Khodarahmi R (2020) Factors influencing mitochondrial function as a key mediator of glucose-induced insulin release: highlighting nicotinamide nucleotide transhydrogenase. Int J Mol Cell Med 9:107–122 PubMed PMC
Bailey MJ, Naik NN, Wild LE, Patterson WB, Alderete TL (2020) Exposure to air pollutants and the gut microbiota: a potential link between exposure, obesity, and type 2 diabetes. Gut Microbes 11:1188–1202 PubMed PMC
Bajard L, Melymuk L, Blaha L (2019) Prioritization of hazards of novel flame retardants using the mechanistic toxicology information from ToxCast and adverse outcome pathways. Environ Sci Eur 31:19
Bajard L, Negi CK, Mustieles V, Melymuk L, Jomini S, Barthelemy-Berneron J, Fernandez MF, Blaha L (2021) Endocrine disrupting potential of replacement flame retardants-Review of current knowledge for nuclear receptors associated with reproductive outcomes. Environ Int 153:12 PubMed
Baranano DE, Rao M, Ferris CD, Snyder SH (2002) Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci U S A 99:16093–16098 PubMed PMC
Bauchle CJ, Rohli KE, Boyer CK, Pal V, Rocheleau JV, Liu SM, Imai Y, Taylor EB, Stephens SB (2021) Mitochondrial efflux of citrate and isocitrate is fully dispensable for glucose-stimulated insulin secretion and pancreatic islet beta-cell function. Diabetes 70:1717–1728 PubMed PMC
Benner C, van der Meulen T, Caceres E, Tigyi K, Donaldson CJ, Huising MO (2014) The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression. BMC Genomics 15:16 PubMed PMC
Blum A, Behl M, Birnbaum L, Diamond ML, Phillips A, Singla V, Sipes NS, Stapleton HM, Venier M (2019a) Organophosphate ester flame retardants: are they a regrettable substitution for polybrominated diphenyl ethers? Environ Sci Technol Lett 6(11):638–649 PubMed PMC
Blum A, Behl M, Birnbaum LS, Diamond ML, Phillips A, Singla V, Sipes NS, Stapleton HM, Venier M (2019b) Organophosphate ester flame retardants: are they a regrettable substitution for polybrominated diphenyl ethers? Environ Sci Technol Lett 6:638–649 PubMed PMC
Bresson SE, Isom S, Jensen ET, Huber S, Oulhote Y, Rigdon J, Lovato J, Liese AD, Pihoker C, Dabelea D, Ehrlich S, Ruzzin J (2022) Associations between persistent organic pollutants and type 1 diabetes in youth. Environ Int 163:11 PubMed PMC
Burgos-Morón E, Abad-Jiménez Z, de Marañón AM, Iannantuoni F, Escribano-López I, López-Domènech S, Salom C, Jover A, Mora V, Roldan I, Solá E, Rocha M, Víctor VM (2019) Relationship between oxidative stress, ER stress, and inflammation in type 2 diabetes: the battle continues. J Clin Med 8:22 PubMed PMC
Campbell JE, Newgard CB (2021) Mechanisms controlling pancreatic islet cell function in insulin secretion. Nat Rev Mol Cell Biol 22:142–158 PubMed PMC
Cano-Sancho G, Smith A, La Merrill MA (2017) Triphenyl phosphate enhances adipogenic differentiation, glucose uptake and lipolysis via endocrine and noradrenergic mechanisms. Toxicol Vitro 40:280–288 PubMed PMC
Chen E, Tsai TH, Li L, Saha P, Chan L, Chang BHJ (2017) PLIN2 is a key regulator of the unfolded protein response and endoplasmic reticulum stress resolution in pancreatic beta cells. Sci Rep 7:12 PubMed PMC
Chen Y, Fang J, Ren L, Fan R, Zhang J, Liu G, Zhou L, Chen D, Yu Y, Lu S (2018) Urinary metabolites of organophosphate esters in children in South China: concentrations, profiles and estimated daily intake. Environ Pollut. 10.1016/j.envpol.2017.12.092 PubMed
Cnop M, Toivonen S, Igoillo-Esteve M, Salpea P (2017) Endoplasmic reticulum stress and eIF2alpha phosphorylation: The Achilles heel of pancreatic beta cells. Mol Metab 6:1024–1039 PubMed PMC
Demirtepe H, Melymuk L, Diamond ML, Bajard L, Vojta S, Prokes R, Sanka O, Klanova J, Palkovicova Murinova L, Richterova D, Rasplova V, Trnovec T (2019) Linking past uses of legacy SVOCs with today’s indoor levels and human exposure. Environ Int 127:653–663 PubMed
Ding J, Liu W, Zhang H, Zhu L, Zhu L, Feng J (2021) Liver-based probabilistic risk assessment of exposure to organophosphate esters via dust ingestion using a physiologically based toxicokinetic (PBTK) model. Int J Environ Res Public Health 18(23):12496 PubMed PMC
Dishaw LV, Macaulay LJ, Roberts SC, Stapleton HM (2014) Exposures, mechanisms, and impacts of endocrine-active flame retardants. Curr Opin Pharmacol 19:125–133 PubMed PMC
Ferdaoussi M, Dai X, Jensen MV, Wang R, Peterson BS, Huang C, Ilkayeva O, Smith N, Miller N, Hajmrle C, Spigelman AF, Wright RC, Plummer G, Suzuki K, Mackay JP, van de Bunt M, Gloyn AL, Ryan TE, Norquay LD, Brosnan MJ, Trimmer JK, Rolph TP, Kibbey RG, Manning Fox JE, Colmers WF, Shirihai OS, Neufer PD, Yeh ET, Newgard CB, MacDonald PE (2015) Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional beta cells. J Clin Invest 125:3847–3860 PubMed PMC
Flamez D, Berger V, Kruhoffer M, Orntoft T, Pipeleers D, Schuit FC (2002) Critical role for cataplerosis via citrate in glucose-regulated insulin release. Diabetes 51:2018–2024 PubMed
Fonseca SG, Urano F, Burcin M, Gromada J (2010) Stress hypERactivation in the β-cell. Islets 2:1–9 PubMed
Gómez-Lechón MJ, Tolosa L, MT, D., (2014) Cell-based models to predict human hepatotoxicity of drugs. Rev Toxicol 31:149–156
Gong J, Wang XZ, Wang T, Chen JJ, Xie XY, Hu H, Yu F, Liu HL, Jiang XY, Fan HD (2017) Molecular signal networks and regulating mechanisms of the unfolded protein response. J Zhejiang Univ-SCI B. 18(1):1–14 PubMed PMC
Groothuis FA, Timmer N, Opsahl E, Nicol B, Droge STJ, Blaauboer BJ, Kramer NI (2019) Influence of in vitro assay setup on the apparent cytotoxic potency of benzalkonium chlorides. Chem Res Toxicol 32:1103–1114 PubMed PMC
Guillam MT, Dupraz P, Thorens B (2000) Glucose uptake, utilization, and signaling in GLUT2-null islets. Diabetes 49:1485–1491 PubMed
Guo C, Li R, Zheng N, Xu L, Liang T, He Q (2013) Anti-diabetic effect of ramulus mori polysaccharides, isolated from Morus alba L., on STZ-diabetic mice through blocking inflammatory response and attenuating oxidative stress. Int Immunopharmacol 16:93–99 PubMed
Hao ZL, Zhang ZJ, Lu DZ, Ding B, Shu L, Zhang Q, Wang C (2019) Organophosphorus flame retardants impair intracellular lipid metabolic function in human hepatocellular cells. Chem Res Toxicol 32:1250–1258 PubMed
He R, Li Y, Xiang P, Li C, Zhou C, Zhang S, Cui X, Ma LQ (2016) Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: bioaccessibility and risk assessment. Chemosphere 150:528–535 PubMed
Hoffmann S, Kleinstreuer N, Alepee N, Allen D, Api AM, Ashikaga T, Clouet E, Cluzel M, Desprez B, Gellatly N, Goebel C, Kern PS, Klaric M, Kuhnl J, Lalko JF, Martinozzi-Teissier S, Mewes K, Miyazawa M, Parakhia R, van Vliet E, Zang Q, Petersohn D (2018) Non-animal methods to predict skin sensitization (I): the Cosmetics Europe database<sup/>. Crit Rev Toxicol 48:344–358 PubMed
Hoyeck MP, Matteo G, MacFarlane EM, Perera I, Bruin JE (2022) Persistent organic pollutants and beta-cell toxicity: a comprehensive review. Am J Physiol Endocrinol Metab 322:E383–E413 PubMed PMC
Hu WX, Kang QY, Zhang CH, Ma HJ, Xu CK, Wan Y, Hu JY (2020) Triphenyl phosphate modulated saturation of phospholipids: Induction of endoplasmic reticulum stress and inflammation. Environ Pollut 263:7 PubMed
Jiang CX, Wang YP, Guo M, Long Y, Chen J, Fan F, Tang S, Xu Y (2021) PCB118 induces inflammation of islet beta cells via activating ROS-NLRP3 inflammasome signaling. Biomed Res Int 2021:8 PubMed PMC
Kim YA, Kim HY, Oh YJ, Kwon WY, Lee MH, Bae JY, Woo MS, Kim JM, Yoo YH (2018) Polychlorinated biphenyl 138 exposure-mediated lipid droplet enlargement endows adipocytes with resistance to TNF-alpha-induced cell death. Toxicol Lett 292:55–62 PubMed
Kim YA, Park JB, Woo MS, Lee SY, Kim HY, Yoo YH (2019) Persistent organic pollutant-mediated insulin resistance. Int J Environ Res Public Health 16:14 PubMed PMC
Kleinstreuer NC, Hoffmann S, Alepee N, Allen D, Ashikaga T, Casey W, Clouet E, Cluzel M, Desprez B, Gellatly N, Gobel C, Kern PS, Klaric M, Kuhnl J, Martinozzi-Teissier S, Mewes K, Miyazawa M, Strickland J, van Vliet E, Zang Q, Petersohn D (2018) Non-animal methods to predict skin sensitization (II): an assessment of defined approaches. Crit Rev Toxicol 48:359–374 PubMed PMC
Klemen MS, Dolensek J, Rupnik MS, Stozer A (2017) The triggering pathway to insulin secretion: functional similarities and differences between the human and the mouse cells and their translational relevance. Islets 9:109–139 PubMed PMC
Krewski D, Acosta D Jr, Andersen M, Anderson H, Bailar JC 3rd, Boekelheide K, Brent R, Charnley G, Cheung VG, Green S Jr, Kelsey KT, Kerkvliet NI, Li AA, McCray L, Meyer O, Patterson RD, Pennie W, Scala RA, Solomon GM, Stephens M, Yager J, Zeise L (2010) Toxicity testing in the 21st century: a vision and a strategy. J Toxicol Environ Health B Crit Rev 13:51–138 PubMed PMC
Krumm EA, Patel VJ, Tillery TS, Yasrebi A, Shen JL, Guo GL, Marco SM, Buckley BT, Roepke TA (2018) Organophosphate flame-retardants alter adult mouse homeostasis and gene expression in a sex-dependent manner potentially through interactions with ERα. Toxicol Sci 162:212–224 PubMed PMC
Ku HC, Cheng CF (2020) Master regulator activating transcription factor 3 (ATF3) in metabolic homeostasis and cancer. Front Endocrinol 11:556 PubMed PMC
Langley G, Evans T, Holgate ST, Jones A (2007) Replacing animal experiments: choices, chances and challenges. BioEssays 29:918–926 PubMed
Law E, Lu S, Kieffer TJ, Warnock GL, Ao Z, Woo M, Marzban L (2010) Differences between amyloid toxicity in alpha and beta cells in human and mouse islets and the role of caspase-3. Diabetologia 53:1415–1427 PubMed
Lee YM, Jacobs DR, Lee DH (2018) Persistent organic pollutants and type 2 diabetes: a critical review of review articles. Front Endocrinol 9:9 PubMed PMC
Lenzen S (2017) Chemistry and biology of reactive species with special reference to the antioxidative defence status in pancreatic beta-cells. Biochim Biophys Acta-Gen Subj 1861:1929–1942 PubMed
Li W, Wang Y, Asimakopoulos AG, Covaci A, Gevao B, Johnson-Restrepo B, Kumosani TA, Malarvannan G, Moon HB, Nakata H, Sinha RK, Tran TM, Kannan K (2019) Organophosphate esters in indoor dust from 12 countries: concentrations, composition profiles, and human exposure. Environ Int. 10.1016/j.envint.2019.105178 PubMed
Loiola RA, dos Anjos FM, Shimada AL, Cruz WS, Drewes CC, Rodrigues SF, Cardozo KHM, Carvalho VM, Pinto E, Farsky SH (2016) Long-term <i>in vivo</i> polychlorinated biphenyl 126 exposure induces oxidative stress and alters proteomic profile on islets of Langerhans. Sci Rep 6:12 PubMed PMC
Marroqui L, Tudurí E, Alonso-Magdalena P, Quesada I, Nadal A, dos Santos RS (2018) Mitochondria as target of endocrine-disrupting chemicals: implications for type 2 diabetes. J Endocrinol 239:R27–R45 PubMed
McCulloch LJ, van de Bunt M, Braun M, Frayn KN, Clark A, Gloyn AL (2011) GLUT2 (SLC2A2) is not the principal glucose transporter in human pancreatic beta cells: implications for understanding genetic association signals at this locus. Mol Genet Metab 104:648–653 PubMed
Morikawa S, Urano F (2023) The role of ER stress in diabetes: exploring pathological mechanisms using wolfram syndrome. Int J Mol Sci 24:13 PubMed PMC
Mueckler M, Thorens B (2013) The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med 34:121–138 PubMed PMC
Mullerova D, Pesta M, Cedikova M, Dvorakova J, Kulda V, Srbecka K, Muller L, Dvorak P, Kripnerova M, Kralickova M, Babuska V, Kuncova J (2016) DDE downregulates PLIN2 expression during differentiation of mesenchymal stem cells into adipocytes in lipid-enriched medium. J Appl Biomed 14:113–117
Muscogiuri G, Salmon AB, Aguayo-Mazzucato C, Li M, Balas B, Guardado-Mendoza R, Giaccari A, Reddick RL, Reyna SM, Weir G, Defronzo RA, Van Remmen H, Musi N (2013) Genetic disruption of SOD1 gene causes glucose intolerance and impairs beta-cell function. Diabetes 62:4201–4207 PubMed PMC
Nagaoka Y, Iuchi Y, Ikeda Y, Fujii J (2004) Glutathione reductase is expressed at high levels in pancreatic islet cells. Redox Rep 9:321–324 PubMed
Najjar A, Punt A, Wambaugh J, Paini A, Ellison C, Fragki S, Bianchi E, Zhang F, Westerhout J, Mueller D, Li H, Shi Q, Gant TW, Botham P, Bars R, Piersma A, van Ravenzwaay B, Kramer NI (2022) Towards best use and regulatory acceptance of generic physiologically based kinetic (PBK) models for in vitro-to-in vivo extrapolation (IVIVE) in chemical risk assessment. Arch Toxicol 96(12):3407–3419 PubMed PMC
Negi CK, Bajard L, Kohoutek J, Blaha L (2021) An adverse outcome pathway based in vitro characterization of novel flame retardants-induced hepatic steatosis. Environ Pollut 289:11 PubMed
Park CM, Kim KT, Rhyu DY (2020) Low-concentration exposure to organochlorine pesticides (OCPs) in L6 myotubes and RIN-m5F pancreatic beta cells induces disorders of glucose metabolism. Toxicol in Vitro 65:104767 PubMed
Pasecnaja E, Perkons I, Bartkevics V, Zacs D (2021) Legacy and alternative brominated, chlorinated, and organophosphorus flame retardants in indoor dust-levels, composition profiles, and human exposure in Latvia. Environ Sci Pollut Res 28(20):25493–25502 PubMed
Pavlikova N, Smetana P, Halada P, Kovar J (2015) Effect of prolonged exposure to sublethal concentrations of DDT and DDE on protein expression in human pancreatic beta cells. Environ Res 142:257–263 PubMed
Pavlikova N, Daniel P, Sramek J, Jelinek M, Sramkova V, Nemcova V, Balusikova K, Halada P, Kovar J (2019) Upregulation of vitamin D-binding protein is associated with changes in insulin production in pancreatic beta-cells exposed to p, p’-DDT and p, p’-DDE. Sci Rep 9:18026 PubMed PMC
Pavlikova N, Sramek J, Jacek M, Kovar J, Nemcova V (2023) Targets for pollutants in rat and human pancreatic beta-cells: The effect of prolonged exposure to sub-lethal concentrations of hexachlorocyclohexane isomers on the expression of function- and survival-related proteins. Environ Toxicol Pharmacol 104:104299 PubMed
Plichta V, Steinwider J, Vogel N, Weber T, Kolossa-Gehring M, Murinova LP, Wimmerova S, Tratnik JS, Horvat M, Koppen G, Govarts E, Gilles L, Rodriguez Martin L, Schoeters G, Covaci A, Fillol C, Rambaud L, Jensen TK, Rauscher-Gabernig E (2022) Risk assessment of dietary exposure to organophosphorus flame retardants in children by using HBM-Data. Toxics 10(5):234 PubMed PMC
Pratt EPS, Harvey KE, Salyer AE, Hockerman GH (2019) Regulation of cAMP accumulation and activity by distinct phosphodiesterase subtypes in INS-1 cells and human pancreatic beta-cells. PLoS ONE 14:e0215188 PubMed PMC
Saillenfait AM, Ndaw S, Robert A, Sabate JP (2018) Recent biomonitoring reports on phosphate ester flame retardants: a short review. Archives Toxicol 92:2749–2778 PubMed
Sedlak TW, Snyder SH (2004) Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle. Pediatrics 113:1776–1782 PubMed
Sramek J, Nemcova-Furstova V, Kovar J (2021) Molecular mechanisms of apoptosis induction and its regulation by fatty acids in pancreatic beta-cells. Int J Mol Sci 22(8):4285 PubMed PMC
Tinant G, Neefs I, Das K, Rees JF, Larondelle Y, Debier C (2021) Methylmercury displays pro-adipogenic properties in rainbow trout preadipocytes. Chemosphere 263:11 PubMed
Tong X, Liu SM, Stein R, Imai Y (2022) Lipid droplets’ role in the regulation of beta-cell function and beta-cell demise in type 2 diabetes. Endocrinology 163:11 PubMed PMC
van der Schyff V, Kalina J, Govarts E, Gilles L, Schoeters G, Castano A, Esteban-Lopez M, Kohoutek J, Kukucka P, Covaci A, Koppen G, Andryskova L, Piler P, Klanova J, Jensen TK, Rambaud L, Riou M, Lamoree M, Kolossa-Gehring M, Vogel N, Weber T, Goen T, Gabriel C, Sarigiannis DA, Sakhi AK, Haug LS, Murinova LP, Fabelova L, Tratnik JS, Mazej D, Melymuk L (2023) Exposure to flame retardants in European children - results from the HBM4EU aligned studies. Int J Hygiene Environ Health. 10.1016/j.ijheh.2022.114070 PubMed PMC
Walley SN, Krumm EA, Yasrebi A, Kwiecinski J, Wright V, Baker C, Roepke TA (2021) Maternal organophosphate flame-retardant exposure alters offspring energy and glucose homeostasis in a sexually dimorphic manner in mice. J Appl Toxicol 41:572–586 PubMed PMC
Wang XD, Vatamaniuk MZ, Wang SK, Roneker CA, Simmons RA, Lei XG (2008) Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice. Diabetologia 51:1515–1524 PubMed
Wang J, Yang X, Zhang JJ (2016) Bridges between mitochondrial oxidative stress, ER stress and mTOR signaling in pancreatic β cells. Cell Signal 28:1099–1104 PubMed
Wang D, Yan S, Yan J, Teng M, Meng Z, Li R, Zhou Z, Zhu W (2019) Effects of triphenyl phosphate exposure during fetal development on obesity and metabolic dysfunctions in adult mice: Impaired lipid metabolism and intestinal dysbiosis. Environ Pollut 246:630–638 PubMed
Xiao X, Erukainure OL, Islam MS (2023) Red honeybush tea mitigates oxidative imbalance and hyperlipidemia, while improving glucose homeostasis in type 2 diabetic rats. Food Sci Hum Well 12:2029–2039
Xu J, Fan X, Zhu M, Zhao Z, Qi X, Gao H, Liu Y, Shi Y, Zhang C (2023) Ginsenoside Rg3 protects mouse islet beta-cells injured by high glucose. Indian J Microbiol 63:173–180 PubMed PMC
Yang BY, Fan SJ, Thiering E, Seissler J, Nowak D, Dong GH, Heinrich J (2020) Ambient air pollution and diabetes: a systematic review and meta-analysis. Environ Res 180:11 PubMed
Yao X, Geng S, Zhu L, Jiang H, Wen J (2023) Environmental pollutants exposure and gestational diabetes mellitus: evidence from epidemiological and experimental studies. Chemosphere 332:138866 PubMed
Yue J, Sun X, Duan X, Sun C, Chen H, Sun H, Zhang L (2023) Triphenyl phosphate proved more potent than its metabolite diphenyl phosphate in inducing hepatic insulin resistance through endoplasmic reticulum stress. Environ Int 172:107749 PubMed
Zhang GF, Jensen MV, Gray SM, El K, Wang Y, Lu DH, Becker TC, Campbell JE, Newgard CB (2021) Reductive TCA cycle metabolism fuels glutamine- and glucose-stimulated insulin secretion. Cell Metab 33(4):804-817.e5 PubMed PMC
Zhao JY, Zhan ZX, Lu MJ, Tao FB, Wu D, Gao H (2022) A systematic scoping review of epidemiological studies on the association between organophosphate flame retardants and neurotoxicity. Ecotoxicol Environ Saf 243:113973 PubMed
Zheng XF, Ho QWC, Chua M, Stelmashenko O, Yeo XY, Muralidharan S, Torta F, Chew EGY, Lian MM, Foo JN, Jung S, Wong SH, Tan NS, Tong NW, Rutter GA, Wenk MR, Silver DL, Berggren PO, Ali Y (2022) Destabilization of beta Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes. Proc Natl Acad Sci U S A 119:10 PubMed PMC
Zhu YX, Zhang XY, Zhang L, Zhang ML, Li L, Luo D, Zhong Y (2019) Perilipin5 protects against lipotoxicity and alleviates endoplasmic reticulum stress in pancreatic beta-cells. Nutr Metab 16:14 PubMed PMC
Zhu YX, Ren CX, Zhang ML, Zhong Y (2020) Perilipin 5 reduces oxidative damage associated with lipotoxicity by activating the PI3K/ERK-mediated Nrf2-ARE signaling pathway in INS-1 pancreatic beta-cells. Front Endocrinol 11:14 PubMed PMC
Zmuda EJ, Qi L, Zhu MX, Mirmira RG, Montminy MR, Hai T (2010) The Roles of ATF3, an adaptive-response gene, in high-fat-diet-induced diabetes and pancreatic beta-cell dysfunction. Mol Endocrinol 24:1423–1433 PubMed PMC