Improved glucose tolerance with DPPIV inhibition requires β‐cell SENP1 amplification of glucose‐stimulated insulin secretion

Pancreatic islet insulin secretion is amplified by both metabolic and receptor‐mediated signaling pathways. The incretin‐mimetic and DPPIV inhibitor anti‐diabetic drugs increase insulin secretion, but in humans this can be variable both in vitro and in vivo. We examined the correlation of GLP‐1 induced insulin secretion from human islets with key donor characteristics, glucose‐responsiveness, and the ability of glucose to augment exocytosis in β‐cells. No clear correlation was observed between several donor or organ processing parameters and the ability of Exendin 4 to enhance insulin secretion. The ability of glucose to facilitate β‐cell exocytosis was, however, significantly correlated with responses to Exendin 4. We therefore studied the effect of impaired glucose‐dependent amplification of insulin exocytosis on responses to DPPIV inhibition (MK‐0626) in vivo using pancreas and β‐cell specific sentrin‐specific protease‐1 (SENP1) mice which exhibit impaired metabolic amplification of insulin exocytosis. Glucose tolerance was improved, and plasma insulin was increased, following either acute or 4 week treatment of wild‐type (βSENP1(+/+)) mice with MK‐0626. 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.