Objective: Teneligliptin, a newer DPP-4 inhibitor provides a narrative clinical efficacy and oral tolerability with a unique chemical structure amongst currently available DPP-4 inhibitors. Herein we investigated the direct effect of Teneligliptin, on beta-cell function and survival in response to high glucose conditions. Methods: We subjected INS-cells and human 1.1b4 pancreatic beta cells to high glucose (30mM) for 48 hours in the absence or presence of DPP-4 inhibitor Teneligliptin. Insulin secretion was assessed by Millipore ELISA Kit. P66Shc mitochondrial translocation was measured by western blot and immunofluorescent analysis. Apoptosis was determined by TUNEL In-Situ cell death detection kit. SERCA2B ubiquitination in response to high glucose was assessed by western blot analysis. Results: Exposure of INS-1 cells or human 1.1b4 pancreatic beta cells to high glucose (30 mM) downregulated GLP1R expression and induce beta cell apoptosis. Interestingly, Teneligliptin treatment stabilized GLP1R protein and increased the intracellular cAMP production (p < 0.005) and potentiate glucose stimulated insulin secretion (GSIS) (p < 0.05). In parallel, Teneligliptin treatment correlated with the up-regulation of Sirt1 expression. Further, Teneligliptin treatment significantly decreased the high glucose induced reactive oxygen species (ROS) production (p < 0.05) and reduce the JNK mediated p66Shc serine 36 phosphorylation and its mitochondrial translocation and cleaved caspase-3 activation. Moreover, Teneligliptin counteracted the high glucose induced ubiquitination of SERCA2b and lowers the ER stress markers. Interestingly, cAMP pathway inhibition by H89 (PKA inhibitor) blocked the teneligliptin protective effects against the high glucose induced beta cell apoptosis. Conclusion: Teneligliptin stabilizes GLP1R protein and increase the cAMP dependent antioxidant response (Sirt1 activation) and its downstream signaling lead to β-cell function (GSIS) and survival under high glucose conditions. Teneligliptin ameliorates high glucose-induced endoplasmic reticulum stress by reducing the ubiquitination of SERCA2b. Collectively, our results unveil a direct effect of Teneligliptin on beta-cell function and survival.