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Absence of TXNIP in Humans Leads to Lactic Acidosis and Low Serum Methionine Linked to Deficient Respiration on Pyruvate
Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Stockholm, Sweden.
Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Stockholm, Sweden;Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden.
Karolinska Inst, Div Mol Metab, Dept Med Biochem & Biophys, Stockholm, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
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2019 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, no 4, p. 709-723Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER DIABETES ASSOC , 2019. Vol. 68, no 4, p. 709-723
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-381116DOI: 10.2337/db18-0557ISI: 000462053100004PubMedID: 30755400OAI: oai:DiVA.org:uu-381116DiVA, id: diva2:1302572
Funder
Swedish Research Council, 2016-01082Swedish Research Council, VR521-201-2571Swedish Research Council, 2016-02179Swedish Research Council, 2013-765Swedish Research Council, 2014-2603Knut and Alice Wallenberg Foundation, KAW 2013.0026Knut and Alice Wallenberg Foundation, KAW 2014.0293Knut and Alice Wallenberg Foundation, KAW 2015.0063Swedish Cancer Society, 2015/238Stockholm County Council, 20170022Swedish Diabetes AssociationThe Karolinska Institutet's Research FoundationAvailable from: 2019-04-05 Created: 2019-04-05 Last updated: 2019-04-05Bibliographically approved

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