Increased Interleukin-35 Levels in Patients With Type 1 Diabetes With Remaining C-Peptide

Objective: Many patients with long-standing type 1 diabetes have remaining functional β-cells. This study investigated immunological differences between patients with or without measurable remaining endogenous insulin production after ≥10 years duration of disease.

Research Design And Methods: Patients ( = 113; ≥18 years of age) with type 1 diabetes and with disease duration of ≥10 years were recruited at Uppsala University Hospital. Residual β-cell function was determined with an ultrasensitive C-peptide ELISA. Circulating cytokines, including interleukin-35 (IL-35), were determined in plasma. Additional blood samples were collected from 14 of the identified C-peptide-positive patients and 12 of the C-peptide-negative patients, as well as from 15 healthy control subjects, and were used for immediate investigation of peripheral blood mononuclear cells.

Results: The blood concentration of the cytokine IL-35 was markedly lower in C-peptide-negative patients, and this was associated with a simultaneous decrease in the proportion of IL-35 regulatory T cells (Tregs), IL-35 regulatory B cells, and IL-35-producing CD8Foxp3 cells. IL-35 has previously been shown to maintain the phenotype of Tregs, block the differentiation of T-helper 17 cells, and thereby dampen immune assaults to β-cells. We found that the proportions of IL-17a cells among the Tregs, CD4 T cells, and CD8 T cells were lower in the C-peptide-positive patients.

Conclusions: Patients with remaining endogenous β-cell function after >10 years duration of type 1 diabetes differ immunologically from other patients with long-standing type 1 diabetes. In particular, they have a much higher IL-35 production.