Targeting SWELL1 Signaling to Treat Obesity-Induced Type 2 Diabetes

Project Summary Abstract TypediabetesT Dis characterized by both a loss of insulin sensitivity of target tissuesfatskeletal muscleliverand ultimatelyimpaired insulin secretion from the pancreaticcellWe have identified a novel SWELLmediated signaling pathway that regulates both insulin sensitivity and insulin secretionwhereby SWELLloss of function can both negatively regulate insulin signaling in target tissuesand insulin secretion from the pancreaticcellinducing a state of glucose intoleranceWe have also identified a small molecule modulatorSmodas a lead compound that acutely inhibits SWELLmediated ICl SWELLandgtinhibitionand induces compensatory SWELLprotein up regulationfoldSmodmediated SWELLupregulation is associated with augmented adipocyte insulin signalingfoldand enhancedcell insulin secretionup tofoldin vitroSmodnormalizes both glucose tolerance and insulin sensitivity in obeseglucose intolerant mice and in the polygenic KKAy Typediabetes mouse modelWe propose that small molecule SWELLmodulators may represent afirst in classtherapeutic approach to treat obesityinduced insulin resistance and Typediabetes by augmenting both insulin sensitivity and secretion to improve glycemic control in diabetic patientsImportantlySmodhas no to very mild effects on non obese euglycemic miceemphasizing a very low risk of hypoglycemic events typically associated with other commonly used anti diabetic therapiesincluding sulfonylureasGLPreceptor agonistsand insulinFinallyvery infrequent Smoddosingi e once a monthmay be sufficient to normalize systemic glycaemia in diabetic patientsThe objectives of the current proposal areto establish the proof of concept of modulating SWELLsignaling as a novel therapeutic approach for the treatment of T DandTo begin to develop a pipeline of SWELLmodulators to treat T DAIMCharacterize the therapeutic effect of Smodin augmenting insulin sensitivity and secretion in T D mouse models AIMExplore Smodfunctional chemistry by characterizing Smodstructural variants for modulation of SWELLactivity in vitro and in vivoAIMPerform AbsorptionDistributionMetabolismEliminationand Toxicity studiesADMETstudies on Smodand bioactive derivativesThe results of Phasewill provide proof of concept for the pharmacological modulation of SWELLsignaling for the treatment of T Dand will provide an initial class of drug like small molecules for further development of candidate molecules to ultimately take into humans in the form of a clinical trial for efficacy in T D patientsWe anticipate PhaseSBIR funding of drug development efforts as guided by success of the Phasestudies hereProject Narrative Diabetes and associated diseases are major health concerns in todayandapos s societyThe proposed research is relevant to the mission of the NIDDK because it examines the therapeutic tractability of SWELLmodulators for the treatment of TypediabetesExploring this therapeutic approach and testing a series of SWELLmodulators will expand our understanding of novel therapeutic avenues and delineate an innovative target for the treatment and prevention of diabetes