Emerging Roles of Dipeptidyl Peptidase-4 Inhibitors in Delaying the Progression of Type 1 Diabetes Mellitus

Abstract

Type 1 diabetes mellitus (T1DM) results from the immune cell-mediated destruction of functional pancreatic β-cells. In the presymptomatic period, T1DM is characterized by the presence of two or more autoantibodies against the islet cells in patients without glycemic decompensation. Therapeutic strategies that can modify the autoimmune process could slow the progression of T1DM. Dipeptidyl peptidase-4 (DPP-4) or CD26, a multifunctional serine protease with a dual function (regulatory protease and binding protein), can modulate inflammation and immune cell-mediated β-cell destruction. CD26 is involved in T-cell costimulation, migration, memory development, thymic maturation, and emigration patterns. DPP-4 degrades the peptide hormones GLP-1 and GIP. In addition to regulating glucose metabolism, DPP-4 exerts anti-apoptotic, regenerative, and proliferative effects to promote βcell mass expansion. GLP-1 receptor signaling may regulate murine lymphocyte proliferation and maintenance of peripheral regulatory T-cells. In patients with T1DM, the serum DPP-4 activity is upregulated. Several studies have suggested that the upregulated DPP-4 activity is correlated with T1DM pathophysiology. DPP-4, which is preferentially expressed on the Th1 surface, can promote the polarization of Th1 immunity, a prerequisite for T1DM development. CD26 inhibition can suppress T-cell proliferation and Th1 cytokine production and stimulate tumor growth factor beta-1 (TGF-β1) secretion, which plays an important role in the regulation of autoimmunity in T1DM. Studies on humans or animal models of T1DM have suggested that DPP-4 inhibitors can improve β-cell function and attenuate autoimmunity in addition to decreasing insulin dependence. This review summarizes the emerging roles of DPP-4 inhibitors in potentially delaying the progression of T1DM.

Role of genetic variants and host polymorphisms on COVID‐19: From viral entrance mechanisms to immunological reactions

“… 138 DPP4 blockers were used to treat type 2 diabetes mellitus (T2DM) because they enhance the half‐life of glucagon‐like peptide 1 (GLP‐1). 139 Given that diabetes and obesity are essential determinants for COVID‐19 development and disease severity, studying DPP4 protein in these individuals may offer valuable information. According to another research, individuals hospitalized with COVID‐19 had lower levels of DPP4 than a control group.…”

Potential Effect of DPP-4 Inhibitors Towards Hepatic Diseases and Associated Glucose Intolerance

“…Although it is unclear whether the DPP-4 inhibitor is directly involved in the regression of HCC, a significant invasion of CD8+ T-cells around the HCC tissue was observed, suggesting that the DPP-4 inhibitor may have improved the immune response, which has been compromised by chronic HCV infection. 169 Whereas treatment with exogenous insulin or sulfonylureas raises the risk of HCC, 85 treatment with a DPP-4 inhibitor had no tumor-promoting effects in mice. 170 As a result, a DPP-4 inhibitor may have a safe effect on HCV-related HCC through modulating immunity.…”

Glucose-Lowering Therapy beyond Insulin in Type 1 Diabetes: A Narrative Review on Existing Evidence from Randomized Controlled Trials and Clinical Perspective

“…The rationale for using DPP4i in T1D is based on the reduction of postprandial glucagon secretion, exerting a positive impact on glucose control. On the other hand, DPP4i are believed to possess immunomodulatory and other pleiotropic features, potentially improving insulitis and delay β-cell destruction in newly diagnosed persons with T1D who are still able to produce endogenous insulin [108].…”