Abstract
Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations in the WFS1 (Wolframin1) gene. The syndrome first manifests as diabetes mellitus, followed by optic nerve atrophy, deafness, and neurodegeneration. The underlying mechanism is believed to be a dysregulation of endoplasmic reticulum (ER) stress response, which ultimately leads to cellular death. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to normalize ER stress response in several in vitro and in vivo models. Early chronic intervention with the GLP-1 receptor agonist liraglutide starting before the onset of metabolic symptoms prevented the development of glucose intolerance, improved insulin and glucagon secretion control, reduced ER stress and inflammation in Langerhans islets in Wfs1 mutant rats. Thus, treatment with GLP-1 receptor agonists might be a promising strategy as a preventive treatment for human WS patients.
Highlights
Wolfram syndrome (WS) is a rare neurodegenerative disorder caused by biallelic mutations of the Wolframin[1] (WFS1) gene and whose main symptoms are diabetes mellitus, optic nerve atrophy, hearing loss, and neurodegeneration in the brainstem[1,2,3]
Glucose-stimulated insulin secretion (Fig. 2c) was significantly weaker in KO animals 30 minutes after glucose challenge (F(1,23) = 6.07, p < 0.05; F(1,23) = 17.38, p < 0.001; F(1,23) = 6.84, p < 0.05). Both in wild-type (WT) and Wfs[1] KO rats, the basal insulin levels were decreased and glucose-stimulated insulin secretion increased after liraglutide treatment (F(1,23) = 0.051, p = 0.82; F(1,23) = 0.14, p = 0.71; F(1,23) = 9.01, p < 0.01; F(1,25) = 0.17, p = 0.686)
In this study we evaluated the effects of short-term and long-term treatments with glucagon-like peptide-1 (GLP-1) receptor agonist on blood glucose control in Wfs[1] KO rats
Summary
Wolfram syndrome (WS) is a rare neurodegenerative disorder caused by biallelic mutations of the Wolframin[1] (WFS1) gene and whose main symptoms are diabetes mellitus, optic nerve atrophy, hearing loss, and neurodegeneration in the brainstem[1,2,3]. Intervention with the GLP-1 receptor agonist liraglutide improved glucose tolerance and beta cell apoptosis in prediabetic Gato-Kakizaki rats[10]. Considering these results, treatment with GLP-1 agonists appears to be an efficient way to reduce elevated ER stress in vitro and in vivo. The progressive development of diabetes mellitus and other WS symptoms makes the Wfs1-ex5-KO232 rat a good tool to study treatment options. The aim of the present study was to investigate the effect of chronic treatment with GLP-1 receptor agonist on the progression of glucose intolerance in a Wfs[1] mutant rat
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