Dipeptidyl peptidase-4 (DPP-4) inhibitors were available in Japan since the end of 2009, and incretin-based therapies including glucagon-like peptide-1(GLP-1) mimetics are currently expected to be effective to Japanese patients with type 2 diabetes. Recently, there are a few reports that DPP-4 inhibitors cause severe hypoglycemia when combined with sulfonylureas although no major hypoglycemic episodes were reported in clinical studies. We discuss the mechanism of hypoglycemia by combination therapy, based on our islet studies about ATP-sensitive K+ channel inhibition by sulfonylureas and novel effects and mechanism of incretin.