Metabolic determinants of the diabetogenic interferon response in pancreatic beta-cells

Introduction

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β-cells, leading to significant insulin deficiency and persistent hyperglycemia. Type I interferon (IFN-I) responses to double-stranded RNA (dsRNA) play a key role in early T1D development, though a viral cause remains unproven. This raises the possibility that endogenous dsRNA, typically edited by the Adar enzyme, triggers an aberrant IFN-I response when editing is deficient. Supporting this, a recent genetic studies linked reduced RNA editing to autoimmune diseases, including T1D.

Our work shows that Adar inactivation in beta-cells (beta-AdarKO) activates a robust dsRNA-driven IFN-I response, replicating early T1D features such as insulitis, targeted beta-cell failure and death, eventually resulting in diabetes. Interestingly, increased glucose metabolism through calcium influx amplifies the IFN-I response, both by boosting dsRNA-triggered IFN-I production in beta-AdarKO islets and enhancing responses to exogenous IFN-I in wild-type islets (Knebel et al., 2024). While beta-cell workload has been linked to increased toxicity, its role in modulating inflammation in T1D is novel.

Materials and Methods

We used pharmacological tools targeting the calcineurin-NFAT axis to further investigate the pathway by which glucose affects the IFN-I response in beta-AdarKO islets. Additionally, we employed the S961 insulin receptor antagonist and dapagliflozin, an SGLT2 inhibitor, as well as insulin pellets to manipulate blood glucose levels—either increasing or reducing them—and assessed the impact of beta-cell metabolic activity on insulitis in vivo.

Results and Discussion

Using modulators of the calcium signaling pathway, we reveal NFAT as a critical transcription factor connecting beta-cell metabolic activity to pro-inflammatory responses. While NFAT inhibitors target adaptive immunity, their role in the regulation of innate immunity remains unexplored.

We also identify a potential feed-forward loop where hyperglycemia, induced by the S961 insulin receptor antagonist, exacerbates islet inflammation in beta-AdarKO mice. Surprisingly, lowering glucose levels does not mitigate the inflammatory phenotype, pointing to a more intricate effect of glucose on the interplay between immune and beta-cells in vivo.

Conclusions

Understanding how beta-cell metabolism drives islet inflammation could unveil therapeutic targets to protect beta-cells from inflammatory damage. These insights hold promise for developing interventions to prevent or treat T1D.