Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action

Thielen, Lance; Chen, Junqin; Gu, Jie; Moukha-Chafiq, Omar; Xu, Guanlan; Jo, Seongho; Grayson, Truman; Lu, Brian; Li, Peng; Augelli‐Szafran, Corinne E.; Suto, Mark J.; Kanke, Matt; Sethupathy, Praveen; Kim, Jason K.; Shalev, Anath

doi:10.1016/j.cmet.2020.07.002

Cited by 63 publications

(47 citation statements)

References 39 publications

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“…Independent of redox regulation, TXNIP also functions as a regulator of glucose metabolism [ 82 ]. Finally, the recent report that TXNIP levels are increased in diabetes is consistent with the enhanced susceptibility of LS patients to develop type 2 diabetes mellitus [ 83 ].…”

Section: Identification Of Thioredoxin-interacting Protein As a Nesupporting

confidence: 64%

Laron Syndrome Research Paves the Way for New Insights in Oncological Investigation

Werner

Sarfstein

Nagaraj

et al. 2020

Cells

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Laron syndrome (LS) is a rare genetic endocrinopathy that results from mutation of the growth hormone receptor (GH-R) gene and is typically associated with dwarfism and obesity. LS is the best characterized entity under the spectrum of the congenital insulin-like growth factor-1 (IGF1) deficiencies. Epidemiological analyses have shown that LS patients do not develop cancer, whereas heterozygous family members have a cancer prevalence similar to the general population. To identify genes and signaling pathways differentially represented in LS that may help delineate a biochemical and molecular basis for cancer protection, we have recently conducted a genome-wide profiling of LS patients. Studies were based on our collection of Epstein–Barr virus (EBV)-immortalized lymphoblastoid cell lines derived from LS patients, relatives and healthy controls. Bioinformatic analyses identified differences in gene expression in several pathways, including apoptosis, metabolic control, cytokine biology, Jak-STAT and PI3K-AKT signaling, etc. Genes involved in the control of cell cycle, motility, growth and oncogenic transformation are, in general, down-regulated in LS. These genetic events seem to have a major impact on the biological properties of LS cells, including proliferation, apoptosis, response to oxidative stress, etc. Furthermore, genomic analyses allowed us to identify novel IGF1 downstream target genes that have not been previously linked to the IGF1 signaling pathway. In summary, by ‘mining’ genomic data from LS patients, we were able to generate clinically-relevant information in oncology and, potentially, related disciplines.

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Section: Identification Of Thioredoxin-interacting Protein As a Nesupporting

confidence: 64%

Laron Syndrome Research Paves the Way for New Insights in Oncological Investigation

Werner

Sarfstein

Nagaraj

et al. 2020

Cells

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“…Thielen L.A. et al recently identified a small-molecule inhibitor, SRI-37330, that effectively suppresses TXNIP expression in rats, mice, and human pancreatic islets. In addition, treatment with SRI-37330 reduces glucagon secretion and hepatic glucose production and reverses streptozotocin-induced diabetes [ 154 ]. Nonetheless, further studies are warranted to determine the therapeutic window for clinical trials.…”

Section: Txnip Is a Potential Therapeutic Targetmentioning

confidence: 99%

Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook

Qayyum

Haseeb

Kim

et al. 2021

IJMS

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Thioredoxin-interacting protein (TXNIP), widely known as thioredoxin-binding protein 2 (TBP2), is a major binding mediator in the thioredoxin (TXN) antioxidant system, which involves a reduction-oxidation (redox) signaling complex and is pivotal for the pathophysiology of some diseases. TXNIP increases reactive oxygen species production and oxidative stress and thereby contributes to apoptosis. Recent studies indicate an evolving role of TXNIP in the pathogenesis of complex diseases such as metabolic disorders, neurological disorders, and inflammatory illnesses. In addition, TXNIP has gained significant attention due to its wide range of functions in energy metabolism, insulin sensitivity, improved insulin secretion, and also in the regulation of glucose and tumor suppressor activities in various cancers. This review aims to highlight the roles of TXNIP in the field of diabetology, neurodegenerative diseases, and inflammation. TXNIP is found to be a promising novel therapeutic target in the current review, not only in the aforementioned diseases but also in prolonged microvascular and macrovascular diseases. Therefore, TXNIP inhibitors hold promise for preventing the growing incidence of complications in relevant diseases.

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“…Interestingly, after a screen of more than 300,000 molecules, Thielen and co-workers recently identified a compound that downregulates TxNIP in mouse and human pancreatic islets. When given orally to mice, this small molecule (SRI-37330) lowered serum levels of glucagon, prevented fatty liver, and inhibited glucose production by the liver ( Thielen et al., 2020 ). In this context, TxNIP continues to generate significant interest as a potential therapeutic target for the management of diabetes and other metabolic disorders ( Yoshihara, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, owing to its diverse array of functions in glucose and lipid metabolism in several cell types, TxNIP has been considered as a novel candidate drug target for type 2 diabetes ( Thielen and Shalev, 2018 ). Interestingly, a study recently identified a novel anti-diabetic small molecule SRI-37330 that inhibits TxNIP expression and signaling in mouse and human islets ( Thielen et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Dual regulation of TxNIP by ChREBP and FoxO1 in liver

et al. 2021

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Summary TxNIP (Thioredoxin-interacting protein) is considered as a potential drug target for type 2 diabetes. Although TxNIP expression is correlated with hyperglycemia and glucotoxicity in pancreatic β cells, its regulation in liver cells has been less investigated. In the current study, we aim at providing a better understanding of Txnip regulation in hepatocytes in response to physiological stimuli and in the context of hyperglycemia in db/db mice. We focused on regulatory pathways governed by ChREBP (Carbohydrate Responsive Element Binding Protein) and FoxO1 (Forkhead box protein O1), transcription factors that play central roles in mediating the effects of glucose and fasting on gene expression, respectively. Studies using genetically modified mice reveal that hepatic TxNIP is up-regulated by both ChREBP and FoxO1 in liver cells and that its expression strongly correlates with fasting, suggesting a major role for this protein in the physiological adaptation to nutrient restriction.

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Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action

Cited by 63 publications

References 39 publications

Laron Syndrome Research Paves the Way for New Insights in Oncological Investigation

Laron Syndrome Research Paves the Way for New Insights in Oncological Investigation

Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook

Dual regulation of TxNIP by ChREBP and FoxO1 in liver

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