Journal article
Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes
Nature communications, Vol.13(1), pp.784-784
02/10/2022
DOI: 10.1038/s41467-022-28435-0
PMCID: PMC8831520
PMID: 35145074
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
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.
Details
- Title: Subtitle
- Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes
- Creators
- Susheel K Gunasekar - Washington University in St. LouisLitao Xie - Washington University in St. LouisAshutosh Kumar - Washington University in St. LouisJuan Hong - Washington University in St. LouisPratik R Chheda - University of IowaChen Kang - Washington University in St. LouisDavid M Kern - University of California, BerkeleyChau My-Ta - Northwestern UniversityJoshua Maurer - Washington University in St. LouisJohn Heebink - Washington University in St. LouisEva E Gerber - University of California, BerkeleyWojciech J Grzesik - University of IowaMacaulay Elliot-Hudson - University of IowaYanhui Zhang - Xiamen UniversityPhillip Key - Washington University in St. LouisChaitanya A Kulkarni - University of IowaJoseph W Beals - Washington University in St. LouisGordon I Smith - Washington University in St. LouisIsaac Samuel - University of IowaJessica K Smith - University of IowaPeter Nau - University of IowaYumi Imai - University of IowaRyan D Sheldon - University of IowaEric B Taylor - University of IowaDaniel J Lerner - Senseion Therapeutics Inc, BioGenerator Labs, St Louis, MO, USA.Andrew W Norris - University of IowaSamuel Klein - Washington University in St. LouisStephen G Brohawn - University of California, BerkeleyRobert Kerns - University of IowaRajan Sah - Washington University in St. Louis
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.13(1), pp.784-784
- DOI
- 10.1038/s41467-022-28435-0
- PMID
- 35145074
- PMCID
- PMC8831520
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Grant note
- R01 DK106009 / NIDDK NIH HHS T32 HL130357 / NHLBI NIH HHS I01 BX005072 / BLRD VA DP2 GM123496 / NIGMS NIH HHS UL1 TR002345 / NCATS NIH HHS UL1 TR000448 / NCATS NIH HHS T32 GM008365 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS R44 DK126600 / NIDDK NIH HHS R01 DK126068 / NIDDK NIH HHS R01 DK127080 / NIDDK NIH HHS T32 HL007344 / NHLBI NIH HHS R43 DK121598 / NIDDK NIH HHS R01 DK115791 / NIDDK NIH HHS P30 DK020579 / NIDDK NIH HHS F32 GM128263 / NIGMS NIH HHS P30 DK056341 / NIDDK NIH HHS
- Language
- English
- Date published
- 02/10/2022
- Academic Unit
- Molecular Physiology and Biophysics; Endocrinology and Diabetes; Stead Family Department of Pediatrics; Pharmaceutical Sciences and Experimental Therapeutics; Surgery; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Medicinal and Natural Products Chemistry; Internal Medicine
- Record Identifier
- 9984288732702771
Metrics
62 Record Views