The discovery of a new pathology of genetic origin is reported. Deficiency in the TXNIP protein reveals new mechanisms of regulation of metabolism. These studies could potentially lead to new therapeutic targets for diabetes
The advent of new technologies and tools for genetic analysis is enabling the discovery of new pathologies of genetic origin previously unknown. These discoveries not only allow us to gain deeper insight into human physiology, but may also contribute to the development of new therapeutic approaches.
A research team from Universidad Autónoma de Madrid at the Centro de Biología Molecular “Severo Ochoa”, in collaboration with researchers from the Karolinska Institute (Sweden) have used state-of-the-art technologies for genetic analysis to investigate a family in which three siblings displayed abnormal levels of select parameters in blood, including excessive levels of lactic acid and unusually low concentrations of the amino acid methionine. Immediate clinical treatment allowed to lower lactic acid in the patients, thus preventing further tissue damage. However, the cause of these abnormalities remained unknown.
Deep genetic analyses conducted by the researchers led to the identification of a mutation in the gene encoding the protein TXNIP (“Thioredoxin Interacting Protein”). This mutation, which had not previously been described in humans, leads to a complete absence of the protein. In fact, previous studies on TXNIP in experimental animal models suggested that TXNIP could be a potentially interesting target for the treatment of diabetes, as high levels of TXNIP correlate with issues in the management of sugar levels in blood.
TXNIP has mostly been studied by its connection with the thioredoxin system, one of the main cellular systems for protection against oxidative stress, and also necessary for synthesis and maintenance of new genetic material, or DNA. In this study, the researchers used cells isolated directly from patients to examine in detail the different components of the thioredoxin system, as well as their metabolic capacity to use sugar.
The analysis of these cells confirmed that the identified mutation led to the complete absence of TXNIP. In addition, the results also showed that the absence of TXNIP led to a severe defect in sugar metabolism. Specifically, the researchers performed detailed examination of the function of mitochondria, the so-called “power plants of the cells”. Their results clearly demonstrated that the absence of TXNIP rendered cells unable to metabolize pyruvate correctly, an essential intermediate product of sugar metabolism.
In summary, this study shows for the first time the importance of TXNIP in the regulation of whole-body metabolism in humans. The results obtained from cells isolated from patients that lack TXNIP explain many of the symptoms displayed by the patients. Interestingly, these studies also show that it is possible to live with complete absence of TXNIP, albeit special care needs to be taken to preserve health of the patients. Together with previous studies, the present work suggests that partial inhibition of TXNIP could contribute to modulate sugar metabolism in diabetic patients, as long as lactic acid levels in blood are adequately managed. However, it is important to be extremely cautious given that there is still much work to do to fully understand the precise role of TXNIP in human metabolism. Therefore, further studies are required to determine whether TXNIP could be a therapeutic target for diabetes.
The researchers next want to conduct further research in order to understand why the children also have low levels of methionine in their blood, and how the metabolism of methionine might be linked to sugar metabolism.
These studies were led by Alfredo Giménez-Cassina (http://www.cbm.uam.es/joomla-rl/index.php/en/research/scientific-departments/molecular-neuropathology?id=473), from Universidad Autónoma de Madrid and Centro de Biología Molecular “Severo Ochoa”, and Elias Arnér (https://ki.se/en/people/eliarn) and Anna Wedell (https://ki.se/en/people/annwed), both from the Karolinska Institute (Sweden).
Further information: https://ki.se/en/news/newly-discovered-disease-opens-for-future-diabetes-treatment
Bibliographic reference:
Yurika Katsu-Jiménez, Carmela Vázquez-Calvo, Camilla Maffezzini, Maria Halldin, Xiaoxiao Peng, Christoph Freyer, Anna Wredenberg, Alfredo Giménez-Cassina, Anna Wedell and Elias S.J. Arnér. Absence of TXNIP in human gives lactic acidosis and low serum methionine linked to deficient respiration on pyruvate. Diabetes. Doi: 10.2337/db18-0557
