Anti-inflammatory effects of exendin-4, a glucagon-like peptide-1 analog, on human peripheral lymphocytes in patients with type 2 diabetes

Aims/Introduction: Type 2 diabetes is characterized by dysregulation of immunity, oxidative stress and reduced incretin effects. Experimental studies suggest that glucagon-like peptide (GLP-1) might have immunomodulating effects. We hypothesize that GLP-1 receptor agonist, exendin-4, might reduce inflammatory response in type 2 diabetes. Materials and Methods: Using peripheral blood mononuclear cells (PBMC) sampled from 10 type 2 diabetes and 10 sex-and age-matched control subjects and supernatants from PBMC culture, the expression of phospho-mitogen activated protein kinase (MAPK) signaling pathways in CD4+ T helper lymphocytes and monocytes was analyzed using flow cytometry. Cytokines/chemokines and superoxide anion before and after treatment with exendin-4 were measured by cytometric bead array and chemiluminesence assay, respectively. Results: Compared with control subjects, PBMC from type 2 diabetes patients showed activated MAPK (P38, c-Jun NH2-terminal protein kinase and extracellular signal-regulated kinase) signaling pathway, elevated superoxide anion, increased pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6) and chemokines (CCL5/regulated on activation normal T-cell expressed and secreted and CXCL10/interferon-gamma-induced protein 10). These changes were attenuated by exendin-4, possibly through the suppression of p38 MAPK. Conclusions: These results suggest that exendin-4 might downregulate pro-inflammatory responses and reduce oxidative stress by suppressing MAPK signaling pathways in type 2 diabetes.