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Aug 8, 2012

Missing Link Points to New Diabetes Target

  • Scientists suggest that a protein known as thioredoxin-interacting protein (TXNIP) could represent a new target for diabetes and potentially other human diseases such as Wolfram syndrome that are associated with endoplasmic reticulum stress (ER stress). The researchers, headed by a University of Massachusetts (UMass) Medical School team, have found that TXNIP effectively triggers cell inflammatory responses as a result of ER stress caused by chronic high glucose levels, which leads directly to the death of insulin-producing β cells in the pancreas.

    Recent evidence suggests that crosstalk between inflammation and ER stress plays a role in the loss of β cells during the progression of type 1 and type 2 diabetes and Wolfram syndrome, a genetic form of diabetes and neurodegeneration. ER stress caused by cellular disturbances is associated with a buildup of unfolded proteins in the endoplasmic reticulum, which can lead to cell death if the cells' unfolded protein response (UPR) repair mechanism can't correct the problem. However, a key molecule that links ER stress to inflammation hasn’t yet been identified.

    To try and find this link the UMass researchers built on experimental results indicating that TXNIP plays a role in β cell death in diabetes. They looked at mouse pancreatic tissue to see whether the protein was actually produced by β cells and determine its signalling pattern. They initially confirmed that TXNIP was highly expressed in insulin-producing β cells, and that subjecting the cells to chemical ER stress inducers or high levels of glucose, which also causes ER stress, triggered even higher levels of TXNIP mRNA expression. Importantly, TXNIP mRNA expression was increased in human primary islets following treatment with chemical ER stress inducers.

    Subsequent analysis of TXNIP-related pathways showed that expression of the protein was induced by ER stress as part of the resulting UPR, leading to the production of interleukin 1β and subsequently β cell death. The results indicated that TXNIP production is induced by ER stress through the PERK and IRE1 pathways, leading to IL-1β mRNA transcription, activation of IL-1β production by the NLRP3 inflammasome, and thus eventually ER stress-mediated β cell death.

    In essence, the team suggests, a range of stress-signalling pathways appear to converge at TXNIP, leading to inflammasome activation and IL-1β production, which has catastrophic effects on the β cell. “Our findings unexpectedly revealed that the UPR regulates IL-1β production through TXNIP,” write Fumihiko Urano, M.D., and colleagues in Cell Metabolism. “We propose that during diabetes, TXNIP expression is induced through the UPR and leads to β cell inflammation and apoptosis... Our data combined with recent findings indicate that there exists a tight link between ER stress, oxidative stress, glucose toxicity, and inflammation, suggesting that a therapeutic strategy that aims to target the common molecular processes that are altered in stressed β cells might be effective.”

    Dr. Urano, et al describe their findings in a paper titled “Thioredoxin-Interacting Protein Mediates ER Stress-Induced β Cell Death through Initiation of the Inflammasome.”


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