| Literature DB >> 35145074 |
Susheel K Gunasekar1, Litao Xie1, Ashutosh Kumar1, Juan Hong1, Pratik R Chheda2, Chen Kang1, David M Kern3,4, Chau My-Ta5, Joshua Maurer1, John Heebink1, Eva E Gerber3,4, Wojciech J Grzesik6, Macaulay Elliot-Hudson7, Yanhui Zhang8, Phillip Key1, Chaitanya A Kulkarni2, Joseph W Beals9, Gordon I Smith9, Isaac Samuel10, Jessica K Smith10, Peter Nau10, Yumi Imai7, Ryan D Sheldon11, Eric B Taylor11, Daniel J Lerner12, Andrew W Norris6, Samuel Klein9, Stephen G Brohawn3,4, Robert Kerns2, Rajan Sah13.
Abstract
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 ICl,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.Entities:
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Year: 2022 PMID： 35145074 PMCID： PMC8831520 DOI： 10.1038/s41467-022-28435-0
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 17.694