Abstract
Type 1 diabetes (T1D) is largely considered an autoimmune disease leading to the destruction of insulin-producing pancreatic β cells. Further, patients with T1D have 3–4-fold increased risk of developing micro- and macrovascular complications. However, the contribution of immune-related factors contributing to these diabetes complications are poorly understood. Individuals with long-term T1D who do not progress to vascular complications offer a great potential to evaluate end-organ protection. The aim of the present study was to investigate the association of inflammatory protein levels with vascular complications (retinopathy, nephropathy, cardiovascular disease) in individuals with long-term T1D compared to individuals who rapidly progressed to complications. We studied a panel of inflammatory markers in plasma of patients with long-term T1D with (n = 81 and 26) and without (n = 313 and 25) vascular complications from two cross-sectional Scandinavian cohorts (PROLONG and DIALONG) using Luminex technology. A subset of PROLONG individuals (n = 61) was screened for circulating immune cells using multicolor flow cytometry. We found that elevated plasma levels of soluble interleukin-2 receptor alpha (sIL-2R) were positively associated with the complication phenotype. Risk carriers of polymorphisms in the IL2RA and PTPN2 gene region had elevated plasma levels of sIL-2R. In addition, cell surface marker analysis revealed a shift from naïve to effector T cells in T1D individuals with vascular complications as compared to those without. In contrast, no difference between the groups was observed either in IL-2R cell surface expression or in regulatory T cell population size. In conclusion, our data indicates that IL2RA and PTPN2 gene variants might increase the risk of developing vascular complications in people with T1D, by affecting sIL-2R plasma levels and potentially lowering T cell responsiveness. Thus, elevated sIL-2R plasma levels may serve as a biomarker in monitoring the risk for developing diabetic complications and thereby improve patient care.
Highlights
Type 1 diabetes (T1D) is characterised by T cell mediated autoimmune destruction of insulin-producing pancreatic b cells [1, 2], causing T1D individuals to become insulin-dependent throughout their life [3]
The present study revealed that plasma soluble interleukin-2 receptor alpha (sIL-2R) levels are reproducibly elevated in individuals with long-term T1D with severe vascular complications as compared to those who remained free from to vascular complications despite more than 30 years of diabetes duration
Plasma levels of sIL-2R were associated with SNPs in the IL2RA and PTPN2 gene regions, which might suggest underlying genetic determinants and possibly biological causal inference
Summary
Type 1 diabetes (T1D) is characterised by T cell mediated autoimmune destruction of insulin-producing pancreatic b cells [1, 2], causing T1D individuals to become insulin-dependent throughout their life [3]. Vascular complications in T1D individuals are a common cause of mortality related to end-organ damage as compared to the nondiabetic population [4, 7]. Few patients with T1D do not progress to these vascular complications despite long disease duration and chronic hyperglycaemia, and exert great potential to evaluate end-organ protection [8]. T1D individuals with complications show considerable derangement in immunological processes like having elevated concentrations of C-reactive protein (CRP), a marker of inflammation, proinflammatory cytokines interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-a) as compared to individuals without complications [9], the extent of contribution of immunological factors to the development of vascular complications in patients with T1D is poorly understood
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