GLP-1 Receptor Agonist Improves Metabolic Disease in a Pre-clinical Model of Lipodystrophy

Abstract

ABSTRACTIndividuals with lipodystrophies typically suffer from significant metabolic disease linked to adipose tissue dysfunction including severe insulin resistance and lipoatrophic diabetes, hepatic steatosis and hyperphagia. Current treatment options are limited and beter therapies for affected individuals are urgently needed. No systematic, detailed analyses exist of the effects of glucagon like peptide-1 receptor (GLP-1R) agonists in the treatment of lipoatrophic diabetes. Here we examined the effects of the GLP-1R agonist liraglutide in seipin knockout mice, a pre-clinical model of generalised lipodystrophy. Acute liraglutide treatment of seipin knockout mice significantly improved insulin, glucose and pyruvate tolerance. Once-daily injection of seipin knockout mice with liraglutide for 14 days led to a modest reduction in food intake but significant improvements in hepatomegaly associated with steatosis and significantly reduced markers of liver fibrosis. Detailed examination of the pancreas revealed that liraglutide enhanced insulin secretion in response to glucose challenge with concomitantly improved glucose control. Thus, GLP-1R agonist liraglutide significantly improved multiple aspects of lipoatrophic diabetes and hepatic steatosis in mice with congenital 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.