Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes

• Published in: Nature communications 2022-02, Vol.13 (1), p.784-784, Article 784
• Main Authors: Gunasekar, Susheel K., Xie, Litao, Kumar, Ashutosh, Hong, Juan, Chheda, Pratik R., Kang, Chen, Kern, David M., My-Ta, Chau, Maurer, Joshua, Heebink, John, Gerber, Eva E., Grzesik, Wojciech J., Elliot-Hudson, Macaulay, Zhang, Yanhui, Key, Phillip, Kulkarni, Chaitanya A., Beals, Joseph W., Smith, Gordon I., Samuel, Isaac, Smith, Jessica K., Nau, Peter, Imai, Yumi, Sheldon, Ryan D., Taylor, Eric B., Lerner, Daniel J., Norris, Andrew W., Klein, Samuel, Brohawn, Stephen G., Kerns, Robert, Sah, Rajan
• Format: Article
• Language: English
• Subjects: 101/28; 13; 13/95; 14; 14/19; 38/90; 42/109; 45/88; 49/88; 631/154/309/2420; 631/443/319/1557; 64; 64/60; 692/163/2743/2037; 82/29; 9/74; 96/1; 96/106; 96/44; Ablation; Adipose Tissue - metabolism; Animals; Beta cells; Cryoelectron Microscopy; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 2 - metabolism; Electron microscopy; Endothelium; Fatty liver; Glucose - metabolism; Glycemic Control - methods; Humanities and Social Sciences; Injury prevention; Insulin; Insulin - metabolism; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells - metabolism; Liver; Liver - metabolism; Liver diseases; Male; Membrane proteins; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membrane trafficking; Metabolism; Mice; Mice, Inbred C57BL; Modulators; Molecular docking; Molecular Docking Simulation; multidisciplinary; Muscles; Non-alcoholic Fatty Liver Disease - metabolism; Protein transport; Proteins; Science; Science (multidisciplinary); Secretion; Sensitivity enhancement; Signal Transduction; Signaling; Skeletal muscle; Steatosis; Transcriptome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28435-0

Type 2 diabetes is associated with insulin resistance, impaired pancreatic β-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs β-cell insulin secretion and glycemic control. Here, we show that I Cl,SWELL and SWELL1 protein are reduced in adipose and β-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease. Type 2 diabetes is associated with insulin resistance, impaired insulin secretion and liver steatosis. Here the authors report a proof-of-concept study for small molecule SWELL1 modulators as a therapeutic approach to treat diabetes and associated liver steatosis by enhancing systemic insulin-sensitivity and insulin secretion in mice.