Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes
© 2022. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Nature communications - 13(2022), 1 vom: 10. Feb., Seite 784 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gunasekar, Susheel K [VerfasserIn] |
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| Links: |
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| Themen: |
Glucose |
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| Anmerkungen: |
Date Completed 03.03.2022 Date Revised 28.03.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-022-28435-0 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Gunasekar, Susheel K |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes |
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| 520 | |a © 2022. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Hong, Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Chheda, Pratik R |e verfasserin |4 aut | |
| 700 | 1 | |a Kang, Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Kern, David M |e verfasserin |4 aut | |
| 700 | 1 | |a My-Ta, Chau |e verfasserin |4 aut | |
| 700 | 1 | |a Maurer, Joshua |e verfasserin |4 aut | |
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| 700 | 1 | |a Gerber, Eva E |e verfasserin |4 aut | |
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| 700 | 1 | |a Elliot-Hudson, Macaulay |e verfasserin |4 aut | |
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