Absence of TXNIP in Humans Leads to Lactic Acidosis and Low Serum Methionine Linked to Deficient Respiration on Pyruvate.

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

Diabetes

journal_title

Diabetes

authors

Katsu-Jiménez Y,Vázquez-Calvo C,Maffezzini C,Halldin M,Peng X,Freyer C,Wredenberg A,Giménez-Cassina A,Wedell A,Arnér ESJ

doi

10.2337/db18-0557

subject

Has Abstract

pub_date

2019-04-01 00:00:00

pages

709-723

issue

4

eissn

0012-1797

issn

1939-327X

pii

db18-0557

journal_volume

68

pub_type

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