GLP-1 Receptor Agonist Improves Metabolic Disease in a Pre-clinical Model of Lipodystrophy
GLP-1 Receptor Agonist Improves Metabolic Disease in a Pre-clinical Model of Lipodystrophy
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GLP-1 受体激动剂改善脂肪营养不良临床前模型中的代谢疾病
DOI：
10.1101/2023.09.01.555852
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Roumane A
中科院分区：
文献类型：
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作者：
Roumane A
目的脂肪营养不良患者通常患有与脂肪组织功能障碍相关的代谢疾病，包括脂肪萎缩性糖尿病。在最严重的脂肪营养不良形式，先天性全身性脂肪营养不良，脂肪组织可能几乎完全缺失。迫切需要为受影响的个体提供更好的治疗。在这里，我们首次对胰高血糖素样肽-1受体（GLP-1R）激动剂在脂肪萎缩型糖尿病中的作用进行了详细的研究，研究对象是患有广泛性脂肪营养不良的小鼠。方法用GLP-1R激动剂利拉鲁肽治疗足营养失调型胰岛素抵抗和葡萄糖不耐受赛平敲除小鼠，在胰岛素和葡萄糖耐量分析前急性治疗，或在代谢表型和指数体内研究前慢性治疗。结果急性利拉鲁肽治疗可显著改善胰岛素、葡萄糖和丙酮酸耐量。每天给seipin敲除小鼠注射利拉鲁肽14天，可显著改善与脂肪变性相关的肝肿大，并减少肝纤维化标志物。此外，利拉鲁肽增强胰岛素分泌以应对葡萄糖挑战，同时改善血糖控制。结论glp - 1r激动剂利拉鲁肽能显著改善广泛性脂肪营养不良小鼠的脂肪萎缩性糖尿病和肝脂肪变性。这为GLP-1R激动剂治疗脂肪营养不良的益处提供了重要的见解，为更广泛的使用提供了信息，以改善患有这种疾病的个体的健康。
AimsIndividuals with lipodystrophies typically suffer from metabolic disease linked to adipose tissue dysfunction including lipoatrophic diabetes. In the most severe forms of lipodystrophy, congenital generalised lipodystrophy, adipose tissue may be almost entirely absent. Better therapies for affected individuals are urgently needed. Here we performed the first detailed investigation of the effects of a glucagon like peptide-1 receptor (GLP-1R) agonist in lipoatrophic diabetes, using mice with generalised lipodystrophy.MethodsLipodystrophic insulin resistant and glucose intolerant seipin knockout mice were treated with the GLP-1R agonist liraglutide either acutely preceding analyses of insulin and glucose tolerance or chronically prior to metabolic phenotyping andex vivostudies.ResultsAcute liraglutide treatment significantly improved insulin, glucose and pyruvate tolerance. Once daily injection of seipin knockout mice with liraglutide for 14 days led to significant improvements in hepatomegaly associated with steatosis and reduced markers of liver fibrosis. Moreover, liraglutide enhanced insulin secretion in response to glucose challenge with concomitantly improved glucose control.ConclusionsGLP-1R agonist liraglutide significantly improved lipoatrophic diabetes and hepatic steatosis in mice with generalised lipodystrophy. This provides important insights regarding the benefits of GLP-1R agonists for treating lipodystrophy, informing more widespread use to improve the health of individuals with this condition.