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r 25-Hydroxyvitamin D (25OHD) is a partial agonist of TRPV1 whereby 25OHD can weakly activate TRPV1 yet antagonize the stimulatory effects of the full TRPV1 agonists capsaicin and oleoyl dopamine. r 25OHD binds to TRPV1 within the same vanilloid binding pocket as capsaicin. r 25OHD inhibits the potentiating effects of PKC-mediated TRPV1 activity. r 25OHD reduces T-cell activation and trigeminal neuron calcium signalling mediated by TRPV1 activity. r These results provide evidence that TRPV1 is a novel receptor for the biological actions of vitamin D in addition to the well-documented effects of vitamin D upon the nuclear vitamin D receptor. r The results may have important implications for our current understanding of certain diseases where TRPV1 and vitamin D deficiency have been implicated, such as chronic pain and autoimmune diseases, such as type 1 diabetes.

TRPM5 is a calcium‐activated monovalent cation channel that is expressed in human and murine islets. Ion channels of the TRP family are multimodal sensors and are activated by different stimuli such as voltage, temperature and ligands, including natural compounds. Previous work showed that mice lacking TRPM5 have increased postprandial blood glucose levels and an impaired insulin secretion. There are increased observations of TRPM5 mutations in patients suffering from diabetes or metabolic syndrome. Stevioside or stevia is a sweet‐tasting organic compound isolated from the plant Stevia rebaudiana, and is widely used as a low‐caloric sweetener. Despite the use of stevioside in consumer products, there is limited knowledge about its molecular interaction in the body. It was previously shown in mice that stevioside potentiates TRPM5, which leads to increased insulin secretion and ultimately better glycemic control in diabetic animal models. In this work, we translate these observations to freshly isolated human islets. We show that TRPM5 expression is limited to a subset of the insulin‐expressing beta‐cells in islets from non‐diabetic donors. In islets isolated from diabetic donors, we also see distinct TRPM5 positive cells that are insulin negative. There are substantial differences observed in the microanatomy of the islets and the functional synchronization of calcium signaling in beta cells between mouse and man. In perifusion studies, there is a potentiation of the glucose‐induced insulin secretion with the application of stevioside. These studies provide insight in the molecular mechanism of the action of stevioside in the human islets. Furthermore, we confirm the importance of TRPM5 in modulating the glucose‐stimulated insulin secretion in human islets. Modulating TRPM5 with stevioside constitutes a potential novel

TRPM5 is a calcium‐activated monovalent cation channel expressed in the pancreatic beta‐cells where it is involved in the regulation of glucose‐induced insulin secretion. Screening of a large library of bioactive drug‐like compounds revealed that glimepiride displays TRPM5‐potentiating activity. Glimepiride is a third generation sulfolylurea drug and is used in clinical practice to stimulate insulin secretion in type II diabetic patients. It is an optimized sulfonylurea drug compound with improved pharmacological effects compared to earlier drugs in this class. One of the main advantages of glimepiride is the reduced observation of hypoglycemic events during treatment. The interaction of glimepiride with KATP channels, the bona fide target of sulfonylureas, cannot fully explain the differences in observed effects between glimepiride and earlier sulfonylureas as glyburide and tolbutamide. We used a series of in vitro and in vivo experiments to examine the interaction between glimepiride and TRPM5. We measured the TRPM5 currents evoked by glimepiride in a HEK‐cell overexpression system. In isolated pancreatic islets from WT, Trpm5−/− and KATP functional knockout mice, we measured the changes in intracellular calcium dynamics. Ultimately we observed the effects of glimepiride in vivo. Glimepiride increases TRPM5‐mediated currents in HEK cells. In isolated islets, we observe calcium activity in the presence of glimepiride in a lower concentration range compared to Trpm5−/− islets. Furthermore in islets isolated form KATP pore mutant mice, we observed increased calcium activity in the beta‐cells during application of glimepiride. Ultimately, in Trpm5−/− mice, glimepiride has less antihyperglycemic effects after a glucose injection compared to WT mice, indicating there is an important role for TRPM5 in the signal transduction of glimepiride in the beta‐cells. The action on TRPM5 is downstream of increases in [Ca2+]i, and therefore glucose‐dependent. Our data suggest an explanation for the reduced hypoglycemic effect of glimepiride. Taken together the promiscuity of glimepride leads to a synergetic action on KATP channels and TRPM5 channels to stimulate insulin secretion from pancreatic beta‐cells. This new information confirms the hypothesis that targeting TRPM5 is a valid approach to stimulate insulin secretion and in fact, is unknowingly already widely used. Support or Funding Information Koenraad Philippaert is a FWO [PEGASUS]2 Marie Skłodowska‐Curie Fellow and received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska‐Curie grant agreement (665501) with the Research Foundation Flanders (FWO).