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Nat Commun ; 13(1): 784, 2022 02 10.
Article in English | MEDLINE | ID: mdl-35145074

ABSTRACT

Type 2 diabetes is associated with insulin resistance, impaired pancreatic ß-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs ß-cell insulin secretion and glycemic control. Here, we show that ICl,SWELL and SWELL1 protein are reduced in adipose and ß-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.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Glycemic Control/methods , Membrane Proteins/genetics , Membrane Proteins/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Adipose Tissue/metabolism , Animals , Cryoelectron Microscopy , Diabetes Mellitus, Experimental/metabolism , Glucose/metabolism , Insulin/metabolism , Insulin Resistance , Insulin Secretion , Insulin-Secreting Cells/metabolism , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Signal Transduction , Transcriptome
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