Glucose homeostasis is critically dependent on insulin release from pancreatic beta cells, which is strictly regulated by glucose-induced simultaneously oscillations in membrane potential (V_m) and cytosolic calcium concentrations [Ca²⁺]_cyt. We propose that TRPM5, a Ca²⁺-activated monovalent cation channel, is a positive regulator of glucose-induced insulin release. Micro-array screening and immunostaining reveal high and selective expression of TRPM5 in pancreatic islets. Whole cell current measurements demonstrate a Ca²⁺-activated non-selective cation current with a bell-shaped dependency on intracellular Ca²⁺ in WT pancreatic islet cells. This current is significantly reduced in Trpm5^-/- cells. Ca²⁺-imaging and electrophysiological analysis show that glucose-induced oscillations of V_m and [Ca²⁺]_cyt have a reduced frequency in Trpm5^-/- islets, due to a lack of fast oscillations. Fast oscillations in V_m show a shorter burst interval, due to a higher slope of depolarization towards the threshold potential for burst initiation. Our results indicate that TRPM5 accelerates the depolarization during the interburst interval, initiating rapid oscillations and higher insulin release. As a consequence, glucose-induced insulin release from Trpm5^-/- pancreatic isletsis significantly reduced, resulting in an impaired glucose tolerance in these mice. Pharmacological modulation of TRPM5 activity may represent a novel means to adjust insulin release in diabetic patients.