Tyk2 Inhibition Prevents Islet Inflammation and Delays Type 1 Diabetes Development in Mice

New study findings published in eBioMedicine highlight a potential strategy for preventing or slowing disease progression for type 1 diabetes (T1D) by focusing on a specific inflammation-related protein known to play a key role in its development. Researchers at the Indiana University School of Medicine suggest the findings could influence the repurposing of an existing FDA-approved psoriasis drug as a novel treatment for T1D, potentially leading to new clinical trials.^1,2

Image credit: VadimGuzhva | stock.adobe.com

According to previous evidence, T1D is a direct result of autoimmune destruction of insulin-producing pancreatic β cells. Additionally, polymorphisms in tyrosine protein kinase 2 (TYK2), a member of the Janus kinase (JAK) family, relate to a reduced risk of several autoimmune diseases, such as T1D, ulcerative colitis, and rheumatoid arthritis.² 

In the current study, researchers used 3 in vitro human model systems and 2 in vivo preclinical mouse models to assess whether the pharmacological inhibition of TYK2 facilitates crosstalk between the immune system and β cells in T1D.¹

In the study, rat insulin promoter-lymphocytic choriomeningitis virus-glycoprotein (RIP-LCMV-GP) mice were pre-treated with a TYK2 inhibitor or a control substance before lymphocytic choriomeningitis virus inoculation. The study authors noted that the inhibitor was administered daily, and blood glucose levels were monitored to track diabetes development. Similarly, female non-obese diabetic (NOD) mice received the TYK2 inhibitor or a control for 6 weeks, and their blood glucose was tracked for 24 weeks to observe diabetes onset. Additionally, pancreases from a subset of NOD mice were examined after 6 weeks of treatment to assess insulitis.¹

The results demonstrated that applying a molecular method to block inflammation signaling through the TYK2 protein reduced harmful inflammation in the pancreas, according to investigators.^1,2

"Our study showed that targeting TYK2 could be a powerful way to protect insulin-producing beta cells while calming inflammation in the immune system at the same time," Carmella Evans-Molina, MD, PhD, co-author of the study and director of the Indiana Diabetes Research Center and the Eli Lilly and Company Professor of Pediatric Diabetes at the IU School of Medicine, said in a news release. "This finding is exciting because there is already a drug on the market that does this for psoriasis, which could help us move more quickly toward testing it for Type 1 diabetes.²

Further results demonstrated that the treatment also affected the location within the cell of key ISG messenger RNAs, notably increasing cytoplasmic CD274 mRNA, suggesting that inflammation reduction might influence mRNA localization. Additionally, PD-L1 protein levels in islets were initially lower in treated mice but became similar to control mice later in the study in both models.^1,2

"Our preclinical models suggest that the treatment might work in people as well," Farooq Syed, PhD, lead author of the study and assistant professor in the Department of Diabetes-Immunology at the Arthur-Riggs Diabetes and Metabolic Research Institute of the City of Hope, said in a news release. "The next step is to initiate translational studies to evaluate the impact of TYK2 inhibition alone or in combination with other already approved drugs in individuals at risk or with recent-onset type 1 diabetes."^1,2

REFERENCES

1. Syed F., Ballew O., Lee C., Rana Jyoti., Preethi K., Castela A. Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice. May 6, 2025. Accessed May 9, 2025. https://www.thelancet.com/journals/EBIOM/article/PIIS2352-3964(25)00178-1/fulltext

2. Dual-action approach targeting inflammation shows potential as Type 1 diabetes treatment. EuerkAlert!. News release. May 7, 2025. Accessed May 9, 2025. https://www.eurekalert.org/news-releases/1083048