Potentiation Of TRPM5 Leads To Increased Taste Perception And Insulin Secretion

Abstract

TRPM5 is a monovalent cation selective ion channel that is activated by raises in the intracellular Ca2+ concentration. This ion channel is functionally expressed in the type II taste receptor cells in the tongue, where it has an essential role in taste signal transduction. TRPM5‐expression is also present in the insulin secreting beta‐cells in the pancreas, where TRPM5 has a regulating role in glucose‐induced insulin secretion. There are currently no good pharmacological tools available to assess the potential of TRPM5 to modulate taste signalling or stimulate insulin secretion.We show a new class of natural compounds with TRPM5‐potentiating activity. We show potentiation of TRPM5‐mediated current in a heterologous expression system. We observe increased glucose‐induced calcium activity in isolated pancreatic islets of Langerhans when potentiating TRPM5. There is increased insulin secretion in the presence of our potentiator and WT but not TRPM5‐KO mice respond with an increased glucose tolerance during acute and long‐term treatment. Administration of a TRPM5‐potentiator to mice on a high fat diet leads to a healthier glycemic profile and delays or largely prevents the onset of diet‐induced type II diabetes.In a murine animal model we show stimulation of sweet bitter and umami taste perception. In a two bottle preference test with WT, TRPM5‐KO and sweet receptor‐KO mice, we show that specific potentiation of TRPM5 increases the preferences for sweet solution, without increasing the sugar load.Our work shows a novel class of compounds to potentiate TRPM5. Stimulating TRPM5 in taste leads to increased perception of nutrients and can lead do a decrease of the calorie intake. We further confirm TRPM5 as a valid pharmacological target in the battle against diabetes to potentiate the physiological profile of glucose induced insulin secretion.