RGD Reference Report - Cystine accumulation attenuates insulin release from the pancreatic ß-cell due to elevated oxidative stress and decreased ATP levels. - Rat Genome Database

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Cystine accumulation attenuates insulin release from the pancreatic ß-cell due to elevated oxidative stress and decreased ATP levels.

Authors: McEvoy, Bernadette  Sumayao, Rodolfo  Slattery, Craig  McMorrow, Tara  Newsholme, Philip 
Citation: McEvoy B, etal., J Physiol. 2015 Dec 1;593(23):5167-82. doi: 10.1113/JP271237. Epub 2015 Nov 18.
RGD ID: 12910938
Pubmed: (View Article at PubMed) PMID:26482480
DOI: Full-text: DOI:10.1113/JP271237

The pancreatic ß-cell 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-stage renal disease. Following kidney transplant, cystine accumulation in other organs including the pancreas leads to multi-organ dysfunction. In this study, a Ctns gene knockdown model of cystinosis was developed in the BRIN-BD11 rat clonal pancreatic ß-cell line using Ctns-targeting siRNA. Additionally there was reduced cystinosin expression, while cell cystine levels were similarly elevated to the cystinotic state. Decreased levels of chronic (24 h) and acute (20 min) nutrient-stimulated 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-sensitive transcription factor NF-κB were increased in cells with silenced Ctns. From this study, the cystinotic-like pancreatic ß-cell model demonstrated that the altered oxidative status of the cell, resulted in depressed mitochondrial function and pathways of ATP production, causing reduced nutrient-stimulated insulin secretion.


Objects Annotated

Genes (Rattus norvegicus)
Ctns  (cystinosin, lysosomal cystine transporter)

Additional Information