National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
F32GM128263
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
DP2GM123496
米国
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)
1R01DK106009
米国
引用
ジャーナル: Nat Commun / 年: 2022 タイトル: Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes. 著者: Susheel 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 / ...著者: Susheel 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 / 要旨: 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 ...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.
凍結剤: ETHANE / チャンバー内湿度: 100 % / チャンバー内温度: 295.15 K / 装置: FEI VITROBOT MARK IV 詳細: 2 microliter drop size, manual wait time of 2 seconds, blot force of 1, 3 second blot time.
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電子顕微鏡法
顕微鏡
FEI TALOS ARCTICA
撮影
フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 平均電子線量: 51.59 e/Å2