Modulatory effect of insulin on T cell receptor mediated calcium signaling is blunted in long lasting type 1 diabetes mellitus

Abstract

Insulin significantly influences Ca(2+) signals evoked by various stimulants. In type 1 recent onset diabetes mellitus the proliferative response of T cells is significantly decreased. The number of clinical trials exploring the role of anti-CD3 monoclonal antibodies (mAb) as a therapeutic agent in recent onset diabetes mellitus type 1 is increasing last years. Therefore, a better understanding of the interplay between T cell receptor (TCR) dependent Ca(2+) increase, and insulin is of vital clinical significance. The aim of the study was to assess the effect of insulin on TCR evoked Ca(2+) responses in T lymphocytes obtained from healthy volunteers and patients suffering from long lasting diabetes mellitus type 1. Analysis was performed with use of the flow cytometer. We demonstrated that T cells ability to mobilize Ca(2+) was significantly reduced in long lasting diabetes mellitus type 1. Ca(2+) decrease achieved by the long term incubation with anti-CD3 mAb in T cells from healthy volunteers was restored by insulin. Strong interrelationship between baseline Ca(2+) level and plateau phase response to TCR stimulation was observed in the cytoplasm of cells pre-incubated with insulin from both healthy subjects and diabetic patients (r = 0.95, p < 0.0001 and r = 0.94, p < 0.0001, respectively). We postulate the existence of the interplay between TCR mediated activation and insulin. The TCR-insulin interplay is blunted in long lasting diabetes mellitus type 1. These observations may have an important implication for future therapeutic options in diabetes.

Calcium Signaling in T Cells and Chronic Inflammatory Disorders of the Oral Cavity

“…Diabetes is associated with an increased susceptibility to infections and impaired wound healing. Significant changes in Ca 2+ homeostasis are observed in both type I and type II diabetes (Demkow et al 2012;Wang et al 2018). Type I diabetes is major autoimmune disease.…”

T Cell Calcium Signaling Regulation by the Co-Receptor CD5

“…Thus, impaired Ca 2+ mobilization affects T cell development, activation, differentiation, and function [ 42 , 43 ]. Examples of diseases with impaired Ca 2+ signaling in T cells include systemic lupus erythematosus, type 1 diabetes mellitus, and others [ 44 , 45 ].…”

Regulatory T Cells with Effector Memory Phenotype and Glycaemic Control in Adult Type 1 Diabetes Mellitus

“…Recent studies in humans provide evidence for an altered immune balance between the expansion of proinflammatory Th17 cells and defects in regulatory T (Treg) cell-mediated suppression [4,5]. Nevertheless, human data interpretation is problematic because 1) T cells are always in adynamic state of differentiation, 2) literature shows a wide range in terms of patients' age and disease duration, 3) chronological changes of T cell subsets that occur in recent onset and long lasting diabetes are unknown, but the modulatory effect of insulin on T cell receptor mediated calcium signalling has been found blunted in long-term type 1 diabetes [6], 4) finally, metabolism is a fundamental determinant of T cell fate and redox-metabolic remodelling regulate immune responses by Treg cells [7,8]. Initial reports on impaired frequency or function of Treg cells in type 1 diabetes have not been confirmed, and to date there is controversy or little information about their absolute number, frequency, and status of homing markers [5].…”