期刊
DIABETES
卷 68, 期 4, 页码 709-723出版社
AMER DIABETES ASSOC
DOI: 10.2337/db18-0557
关键词
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资金
- Swedish Research Council [2016-01082, VR521-201-2571, 2016-02179, 2013-765, 2014-2603]
- Swedish Cancer Society [2015/238]
- Knut and Alice Wallenberg Foundation [KAW 2013.0026, KAW 2014.0293, KAW 2015.0063]
- Stockholm County Council [20170022]
- Spanish Ministerio of Economia y Competitividad [BFU2016-77634-R, RYC-2014-15792]
- Diabetesfonden
- Alicia Koplowitz Foundation
- Karolinska Institutet
- Swedish Research Council [2016-01082, 2016-02179] Funding Source: Swedish Research Council
Thioredoxin-interacting protein (TXNIP) is an -arrestin that can bind to and inhibit the antioxidant protein thioredoxin (TXN). TXNIP expression is induced by glucose and promotes -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.
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