Background Clinical evidence connects hyperinsulinemia with obesity, and development of type 2 diabetes (T2D). However, its role in autoimmune conditions was questioned. We investigated consequences of hyperinsulinemia for development of T2D and CD4 T cell function in rheumatoid arthritis (RA).

Methods Incident T2D was prospectively studied in two independent RA cohorts and in gout patients matched to RA by age and gender, for 10 years. Effect of hyperinsulinemia and JAK-STAT signaling inhibition (JAKi) in CD4 T cells was studied by integrating transcriptional sequencing with direct effect of insulin, and JAKi on cell proliferation, DNA enrichment, and cytokine production.

Results T2D was 3.2-2.5 times less prevalent in RA compared to gout, particularly in females. Hyperinsulinemia predicted the development of T2D, regardless of metabolic parameters and insulin resistance. Additionally, hyperinsulinemia correlated with the senescence-associated high serum levels of IL6, IL8, and VEGF.

Hyperinsulinemia, along with ex-vivo exposure of CD4 cells to insulin, inhibited cell cycle progression and induced DNA enrichment through the suppression of the PI3K-Src kinases and cell cycle promoting genes. It also reduced IFNγ production. JAKi-treated CD4+ cells regained insulin sensitivity, which activated glucose metabolism and facilitated senescence. This insulin-dependent mechanism promoted the accumulation of naïve CD4 cells in JAKi-treated patients.

Conclusions This study shows that insulin has important immunosuppressive ability controlling the adaptive immunity by suppressing IFNγ production and inducing senescence in the effector CD4 T cells. Inhibition of JAK-STAT signaling enhances insulin sensitivity and rejuvenates CD4 cell population in RA patients.

The authors have declared no competing interest.

This work has been funded by grants from the Swedish Research Council (MB, 2017-03025 and 2017-00359), the Swedish Association against Rheumatism (MB, R-566961, R-751351 and R-860371; MD, R-968867; RP, R-969562, R-862061), the King Gustaf V:s 80-year Foundation (MB, FAI-2018-0519, FAI-2020-0653, FAI-2022-0882), the Regional agreement on medical training and clinical research between the Western Gotaland county council and the University of Gothenburg (MB, ALFGBG-717681, ALFGBG-965623; RP, ALFGBG-965012, ALFGBG-926621; MD, ALFGBG-888321), the University of Gothenburg. The authors declare that the funding sources have no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The included swedish RA study is approved by the Swedish Ethical Review Authority and was registered at the Clinical Trials.gov with ID NCT03449589. The data collection of gout patients and their comorbidities was approved by the Ethical Review Board of Gothenburg, Sweden.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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This study includes publically available transcriptional data which is deposited at the Gene Expression Omnibus at the National Centre for Biotechnology Information, accession numbers GSE201669 and GSE138747. Other data from the present study are available upon request to the authors

https://www.ncbi.nlm.nih.gov/geo/