Higher Serum DPP-4 Enzyme Activity and Decreased Lymphocyte CD26 Expression in Type 1 Diabetes

Abstract

Dipeptidyl peptidase-4 (DPP-4) is involved in the metabolism of peptide hormones, T-cell activation and proliferation. In type 1 diabetes mellitus (T1DM) β-cell destruction involves a number of dysregulated T-cells. Our aim was to assess the serum DPP-4 activity and the lymphocyte membrane bound CD26 expression in patients with type 1 diabetes and healthy controls. Ninety-eight (T1DM: 48, F/M = 20/28, mean age: 34.4y; control: 50, F/M = 39/11 mean age: 32,4y) individuals were included. Fasting serum DPP-4 enzymatic activity, plasma glucose (FPG), CD26 expression on CD3+, CD4+ and CD8+ lymphocytes, HbA1c and body mass index (BMI) were assessed. ICA and GAD antibodies were assessed in the T1DM group. DPP-4 enzymatic activity was determined by kinetic enzyme assay, ICA and GAD were assessed by ELISA. Determination of the CD26 expression on CD3+, CD4+ and CD8+ lymphocytes was performed by flow-cytometric analysis. We found higher serum DPP-4 activity (Mean: T1DM: 30.069 U/L, control: 22.62 U/L, p < 0.0001) and decreased CD26 lymphocyte expression on all lymphocyte subpopulations in T1DM. Fasting serum DPP-4 activity was independent from the ICA or GAD status of patients with T1DM. Here we first present that the serum DPP-4 activity is increased and the lymphocyte membrane bound CD26 expression is decreased in type 1 diabetes. Decreased lymphocyte membrane bound CD26 expression in T1DM might be a novel part of the T-lymphocyte regulatory dysfunction observed in type 1 diabetes mellitus. These results might provide some basis for the clinical implication of DPP-4 inhibition in patients with T1DM.

Persons with latent autoimmune diabetes in adults express higher dipeptidyl peptidase-4 activity compared to persons with type 2 and type 1 diabetes

“…However, we also showed that DPP-4 activity correlates with GAD autoantibody titre which might confirm its meaning in the pathophysiological background of the disease. This is partially in accordance with the study of Iwbuchi et al (2013) [25] as well as with Varga et al (2010) who demonstrated a significantly higher DPP-4 activity in the AI form of diabetes,a strong correlation with anthropometric parameters and glycaemic control [24]. We could explain this with the fact that AI diabetes is a T-cell mediated organspecific disease, initiated by the imbalance between pathogenic and regulatory T-lymphocytes.…”

“…DPP-4 is ubiquitously distributed, predominantly found on endothelial and epithelial cells throughout the body [21,22]. A fraction of soluble DPP-4 however, originates from the immune system cells which explain its altered abundance and the circulating activity in various immune mediated conditions [23] including T1DM [24]. Recent data suggest that DPP-4 activity is higher in persons with T1DM compared to healthy controls independently of islet-cell antibody status, C-peptide concentration, disease duration or HbA1c level [24] and in an inverse correlation with body mass index (BMI) and insulin sensitivity [24,25].…”

“…A fraction of soluble DPP-4 however, originates from the immune system cells which explain its altered abundance and the circulating activity in various immune mediated conditions [23] including T1DM [24]. Recent data suggest that DPP-4 activity is higher in persons with T1DM compared to healthy controls independently of islet-cell antibody status, C-peptide concentration, disease duration or HbA1c level [24] and in an inverse correlation with body mass index (BMI) and insulin sensitivity [24,25]. This is in accordance with our study results because patophysiology of LADA comprises an autoimmune component while its phenotype usually resembles T2DM.…”

“…We could explain this with the fact that AI diabetes is a T-cell mediated organspecific disease, initiated by the imbalance between pathogenic and regulatory T-lymphocytes. DPP-4 is the lymphocyte cell surface protein CD26, critical in T-cell biology as a marker of Tcell activation [24,26]. DPP-4 inhibition increased regulatory T-cells and reversed recent-onset diabetes in a non-obese mouse model of AI diabetes [27].…”

Circulating Dipeptidyl Peptidase-4 Activity is Associated with Diabetic Retinopathy in Type 1 Diabetic Patients

“…The clinical characteristics and the fasting serum DPP4 activity of total 44 T1DM patients included in this cross-sectional study are detailed described in Table 1 showing beneficial pleiotropic effect beyond glycaemic control for this class of drugs [14,20] and simultaneously growing body of evidence about increased serum DPP4 activity in T1DM patients [12,13], this cross-sectional study was designed primarily in order to elucidate the possible association of serum DPP4 activity and DR as most 7 frequent microvascular complication in diabetes [3,4]. Metabolic and anthropometric variables and fasting serum DPP4 activity were assessed in two groups of T1DM patients according to the DR prevalence.…”