Project Summary/Abstract Type 2 diabetes (T2D) is characterized by both a loss of insulin sensitivity of target tissues (fat, skeletal muscle, liver) and ultimately, impaired insulin secretion from the pancreatic β-cell1-3. We have identified a novel SWELL1-mediated signaling pathway that regulates both insulin sensitivity and insulin secretion, whereby SWELL1 loss-of-function can both negatively regulate insulin signaling in target tissues4, 5 and insulin secretion from the pancreatic β-cell6 – inducing a state of glucose intolerance4, 6 We have also identified a small molecule modulator, Smod1, as a lead compound that acutely inhibits SWELL1-mediated ICl,SWELL (> 90% inhibition) and induces compensatory SWELL1 protein up-regulation (3-fold). Smod1-mediated SWELL1 upregulation is associated with augmented adipocyte insulin signaling (1.5-fold) and enhanced β-cell insulin secretion (up to 2-fold) in vitro. Smod1 normalizes both glucose tolerance and insulin sensitivity in obese, glucose intolerant mice and in the polygenic KKAy Type 2 diabetes mouse model. We propose that small molecule SWELL1 modulators may represent a “first-in-class” therapeutic approach to treat obesity- induced insulin resistance and Type 2 diabetes by augmenting both insulin sensitivity and secretion to improve glycemic control in diabetic patients. Importantly, Smod1 has no to very mild effects on non-obese euglycemic mice – emphasizing a very low risk of hypoglycemic events typically associated with other commonly used anti-diabetic therapies, including sulfonylureas, GLP-1 receptor agonists, and insulin. Finally, very infrequent Smod1 dosing (i.e once a month) may be sufficient to normalize systemic glycaemia in diabetic patients. The objectives of the current proposal are: 1. to establish the proof-of-concept of modulating SWELL1 signaling as a novel therapeutic approach for the treatment of T2D; and 2. To begin to develop a pipeline of SWELL1 modulators to treat T2D. AIM#1: Characterize the therapeutic effect of Smod1 in augmenting insulin sensitivity and secretion in T2D mouse models AIM#2: Explore Smod1 functional chemistry by characterizing Smod1 structural variants for modulation of SWELL1 activity in vitro and in vivo. AIM#3: Perform Absorption, Distribution, Metabolism, Elimination, and Toxicity studies (ADMET) studies on Smod1 and bioactive derivatives   The results of Phase 1 will provide proof of concept for the pharmacological modulation of SWELL1 signaling for the treatment of T2D, and 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 T2D patients. We anticipate Phase 2 SBIR funding of drug development efforts as guided by success of the Phase 1 studies here.  

Project Narrative Diabetes and associated diseases are major health concerns in today's society. The proposed research is relevant to the mission of the NIDDK because it examines the therapeutic tractability of SWELL1 modulators for the treatment of Type 2 diabetes. Exploring this therapeutic approach and testing a series of SWELL1 modulators will expand our understanding of novel therapeutic avenues and delineate an innovative target for the treatment and prevention of diabetes.