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TitleSmall molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 784, Year 2022
Publish dateFeb 10, 2022
AuthorsSusheel K Gunasekar / Litao Xie / Ashutosh Kumar / Juan Hong / Pratik R Chheda / Chen Kang / David M Kern / Chau My-Ta / Joshua Maurer / John Heebink / Eva E Gerber / Wojciech J Grzesik / Macaulay Elliot-Hudson / Yanhui Zhang / Phillip Key / Chaitanya A Kulkarni / Joseph W Beals / Gordon I Smith / Isaac Samuel / Jessica K Smith / Peter Nau / Yumi Imai / Ryan D Sheldon / Eric B Taylor / Daniel J Lerner / Andrew W Norris / Samuel Klein / Stephen G Brohawn / Robert Kerns / Rajan Sah /
PubMed AbstractType 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 ...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 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.
External linksNat Commun / PubMed:35145074 / PubMed Central
MethodsEM (single particle)
Resolution3.65 - 3.69 Å
Structure data

23614

7m17

EMDB-23614, PDB-7m17:
SN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-1)
Method: EM (single particle) / Resolution: 3.65 Å

23616

7m19

EMDB-23616, PDB-7m19:
SN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2)
Method: EM (single particle) / Resolution: 3.69 Å

Chemicals

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM / Discrete optimized protein energy

ChemComp-YNJ:
7-{[(2S)-2-butyl-6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-inden-5-yl]oxy}heptanoic acid

Source
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / Ion channel / Inhibitor

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