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

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 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 secre

SUBMITTER: Gunasekar SK 

PROVIDER: S-EPMC8831520 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature