Le Lay Aurélie, Philippe Erwann, Roth Fanny, Sanchez-Archidona Ana Rodriguez, Mehl Florence, Denom Jessica, Prasad Rashmi, Asplund Olof, Hansson Ola, Ibberson Mark, Andreelli Fabrizio, Santoro Lyse, Amouyal Paul, Amouyal Gilles, Brechot Christian, Jamot Laure, Cruciani-Guglielmacci Céline, Magnan Christophe
The Healthy Aging Company, Incubateur Paris Biotech Santé, F-75014 Paris, France.
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
Heliyon. 2022 Jul 16;8(7):e09944. doi: 10.1016/j.heliyon.2022.e09944. eCollection 2022 Jul.
The aim of our study was to test the hypothesis that administration of Regenerating islet-derived protein 3α (Reg3α), a protein described as having protective effects against oxidative stress and anti-inflammatory activity, could participate in the control of glucose homeostasis and potentially be a new target of interest in the treatment of type 2 diabetes. To that end the recombinant human Reg3α protein was administered for one month in insulin-resistant mice fed high fat diet. We performed glucose and insulin tolerance tests, assayed circulating chemokines in plasma and measured glucose uptake in insulin sensitive tissues. We evidenced an increase in insulin sensitivity during an oral glucose tolerance test in ALF-5755 treated mice vs controls and decreased the pro-inflammatory cytokine C-X-C Motif Chemokine Ligand 5 (CXCL5). We also demonstrated an increase in glucose uptake in skeletal muscle. Finally, correlation studies using human and mouse muscle biopsies showed negative correlation between intramuscular Reg3α mRNA expression (or its murine isoform Reg3γ) and insulin resistance. Thus, we have established the proof of concept that Reg3α could be a novel molecule of interest in the treatment of T2D by increasing insulin sensitivity via a skeletal muscle effect.
给予再生胰岛衍生蛋白3α（Reg3α），一种被描述为具有抗氧化应激保护作用和抗炎活性的蛋白质，可能参与葡萄糖稳态的调控，并有可能成为治疗2型糖尿病的新靶点。为此，将重组人Reg3α蛋白给予喂食高脂饮食的胰岛素抵抗小鼠一个月。我们进行了葡萄糖和胰岛素耐量试验，检测血浆中的循环趋化因子，并测量胰岛素敏感组织中的葡萄糖摄取。我们发现，与对照组相比，接受ALF-5755治疗的小鼠在口服葡萄糖耐量试验期间胰岛素敏感性增加，促炎细胞因子C-X-C基序趋化因子配体5（CXCL5）减少。我们还证明了骨骼肌中葡萄糖摄取增加。最后，使用人和小鼠肌肉活检的相关性研究表明，肌肉内Reg3α mRNA表达（或其小鼠异构体Reg3γ）与胰岛素抵抗呈负相关。因此，我们已经建立了概念验证，即Reg3α可能是通过骨骼肌效应增加胰岛素敏感性来治疗2型糖尿病的新型分子。
