Finally, we demonstrated in C57Bl/6J mice and in Glu-Venus mice that diet-induced obesity reinforced basal ER-mitochondria interactions in colonic L cells and blocked their ability to respond to oral glucose in terms of both GLP-1 secretion and MAM upregulation.<h4>Conclusions/interpretation</h4>These results point to a new role for ER-mitochondria calcium coupling in glucose-induced GLP-1 secretion in L cells of the gut, which is impaired in obesity and type 2 diabetes, providing a novel target for the modulation of GLP-1 secretion. This evidence concerns the gene GCG and type 2 diabetes mellitus.