Abstract:
:Thioredoxin-interacting protein (TXNIP) is an α-arrestin that can bind to and inhibit the antioxidant protein thioredoxin (TXN). TXNIP expression is induced by glucose and promotes β-cell apoptosis in the pancreas, and deletion of its gene in mouse models protects against diabetes. TXNIP is currently studied as a potential new target for antidiabetic drug therapy. In this study, we describe a family with a mutation in the TXNIP gene leading to nondetectable expression of TXNIP protein. Symptoms of affected family members include lactic acidosis and low serum methionine levels. Using patient-derived TXNIP-deficient fibroblasts and myoblasts, we show that oxidative phosphorylation is impaired in these cells when given glucose and pyruvate but normalized with malate. Isolated mitochondria from these cells appear to have normal respiratory function. The cells also display a transcriptional pattern suggestive of a high basal activation of the Nrf2 transcription factor. We conclude that a complete lack of TXNIP in human is nonlethal and leads to specific metabolic distortions that are, at least in part, linked to a deficient respiration on pyruvate. The results give important insights into the impact of TXNIP in humans and thus help to further advance the development of antidiabetic drugs targeting this protein.
journal_name
Diabetesjournal_title
Diabetesauthors
Katsu-Jiménez Y,Vázquez-Calvo C,Maffezzini C,Halldin M,Peng X,Freyer C,Wredenberg A,Giménez-Cassina A,Wedell A,Arnér ESJdoi
10.2337/db18-0557subject
Has Abstractpub_date
2019-04-01 00:00:00pages
709-723issue
4eissn
0012-1797issn
1939-327Xpii
db18-0557journal_volume
68pub_type
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