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This DPPIV inhibitor was ineffective in βSENP1+/- or βSENP1- / - mice. Finally, we confirm impaired exocytotic responses of β-cells and reduced insulin secretion from islets of βSENP1- / - mice and show that the ability of Exendin 4 to enhance exocytosis is lost in these cells. Thus, an impaired ability of glucose to amplify insulin exocytosis results in a deficient effect of DPPIV inhibition to improve in vivo insulin responses and glucose tolerance. © 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behal