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

• Published in: Diabetes care Vol. 40; no. 8; pp. 1090 - 1095
• Main Authors: Espes, Daniel, Singh, Kailash, Sandler, Stellan, Carlsson, Per-Ola
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.08.2017
• Subjects: Adult; Beta cells; Blood circulation; Blood levels; C-Peptide - blood; Case-Control Studies; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell Differentiation; Cells; Cytokines; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - blood; Differentiation; Enzyme-linked immunosorbent assay; Female; Foxp3 protein; Humans; Immunologi; Immunology; Immunoregulation; Insulin; Insulin - blood; Insulin-Secreting Cells - metabolism; Interleukin-17 - blood; Interleukins; Interleukins - blood; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Lymphocytes; Lymphocytes T; Male; Middle Aged; Patients; Peptides; Peripheral blood mononuclear cells; Research design; T-Lymphocytes, Regulatory - metabolism; Th17 Cells - metabolism
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc16-2121

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. 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. 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 CD8 Foxp3 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. 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.