{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T19:19:15Z","timestamp":1777490355236,"version":"3.51.4"},"reference-count":74,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2015,11,18]],"date-time":"2015-11-18T00:00:00Z","timestamp":1447804800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>In cystinosis, a lysosomal storage disorder, an altered redox state has been suggested as contributing to cellular dysfunction.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>Ctns<\/jats:italic> gene knockdown in a pancreatic \u03b2\u2010cell line caused increased cystine levels.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Attenuated nutrient stimulated insulin secretion was observed after <jats:italic>Ctns<\/jats:italic> knockdown which may have been caused by an increase in oxidative stress.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Oxidative stress may reduce ATP production in pancreatic \u03b2\u2010cells resulting in attenuated insulin release.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The redox\u2010sensitive transcription factor NF\u2010\u03baB was activated after <jats:italic>Ctns<\/jats:italic> knockdown which may contribute to the increased incidence of apoptosis.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>The pancreatic \u03b2\u2010cell has reduced antioxidant defences making it more susceptible to oxidative stress. In cystinosis, a lysosomal storage disorder, an altered redox state may contribute to cellular dysfunction. This rare disease is caused by an abnormal lysosomal cystine transporter, cystinosin, which causes excessive accumulation of cystine in the lysosome. Cystinosis associated kidney damage and dysfunction leads to the Fanconi syndrome and ultimately end\u2010stage renal disease. Following kidney transplant, cystine accumulation in other organs including the pancreas leads to multi\u2010organ dysfunction. In this study, a <jats:italic>Ctns<\/jats:italic> gene knockdown model of cystinosis was developed in the BRIN\u2010BD11 rat clonal pancreatic \u03b2\u2010cell line using <jats:italic>Ctns<\/jats:italic>\u2010targeting siRNA. Additionally there was reduced cystinosin expression, while cell cystine levels were similarly elevated to the cystinotic state. Decreased levels of chronic (24\u00a0h) and acute (20\u00a0min) nutrient\u2010stimulated insulin secretion were observed. This decrease may be due to depressed ATP generation particularly from glycolysis. Increased ATP production and the ATP\/ADP ratio are essential for insulin secretion. Oxidised glutathione levels were augmented, resulting in a lower [glutathione\/oxidised glutathione] redox potential. Additionally, the mitochondrial membrane potential was reduced, apoptosis levels were elevated, as were markers of oxidative stress, including reactive oxygen species, superoxide and hydrogen peroxide. Furthermore, the basal and activated phosphorylated forms of the redox\u2010sensitive transcription factor NF\u2010\u03baB were increased in cells with silenced <jats:italic>Ctns<\/jats:italic>. From this study, the cystinotic\u2010like pancreatic \u03b2\u2010cell model demonstrated that the altered oxidative status of the cell, resulted in depressed mitochondrial function and pathways of ATP production, causing reduced nutrient\u2010stimulated insulin secretion.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp271237","type":"journal-article","created":{"date-parts":[[2015,10,20]],"date-time":"2015-10-20T09:12:00Z","timestamp":1445332320000},"page":"5167-5182","source":"Crossref","is-referenced-by-count":15,"title":["Cystine accumulation attenuates insulin release from the pancreatic \u03b2\u2010cell due to elevated oxidative stress and decreased ATP levels"],"prefix":"10.1113","volume":"593","author":[{"given":"Bernadette","family":"McEvoy","sequence":"first","affiliation":[{"name":"Conway Institute, School of Biomolecular and Biomedical Science University College Dublin  Dublin 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