Abstract
The symptom of hyposalivation associated with hypofunction of the salivary glands is a common feature of diabetes. Inadequate saliva production can cause tissue damage in the mouth, making it susceptible to infections and leading to oral health diseases. Previous studies have highlighted the harmful effects of methylglyoxal (MGO) and MGO-derived advanced glycation end products (AGEs) in diabetes. In this study, we investigated the protective effects of gemigliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, against MGO-induced salivary gland dysfunction. MGO treatment of immortalized human salivary gland acinar cells induced apoptosis via reactive oxygen species (ROS)-mediated pathways, but this effect was mitigated by gemigliptin. In vivo experiments involved the simultaneous administration of MGO (17.25 mg/kg) with aminoguanidine (100 mg/kg) and gemigliptin (10 and 100 mg/kg) daily to rats for two weeks. Gemigliptin increased the saliva volume and amylase levels in MGO-injected rats. Gemigliptin reduced the DPP-4 activity in both the salivary glands and serum of MGO-injected rats. Furthermore, gemigliptin exerted anti-glycation effects by reducing the accumulation of AGEs in the saliva, salivary glands, and serum and suppressing the expression of the receptor for AGEs. These actions protected the salivary gland cells from ROS-mediated apoptosis. Overall, gemigliptin protected the salivary gland cells from ROS-mediated cell death, reduced the accumulation of amylase and mucins in the salivary glands, and enhanced the salivary function by upregulating aquaporin 5 expression, and it exerted protective effects against MGO-induced salivary gland dysfunction by enhancing the anti-glycation, antioxidant, and salivary secretion activities. Our findings suggest gemigliptin as a potential therapeutic for patients with salivary gland dysfunction caused by the complications of diabetes.