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, 8 (1), 10183

Preventive Treatment With Liraglutide Protects Against Development of Glucose Intolerance in a Rat Model of Wolfram Syndrome

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Preventive Treatment With Liraglutide Protects Against Development of Glucose Intolerance in a Rat Model of Wolfram Syndrome

Maarja Toots et al. Sci Rep.

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.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
WS development in Wfs1 deficient rat. Based on Plaas et al..
Figure 2
Figure 2
Repeated liraglutide effect on glucose intolerant 5-month-old Wfs1 KO rats. (a) IPGTT (2 g/kg) before and after 8-day chronic administration of 0.4 mg/kg liraglutide to 5-month-old male Wfs1 KO and control rats. (b) Decrease in IPGTT (2 g/kg) area under curve before and after chronic liraglutide treatment for 8 days. Glucose-stimulated increases in blood (c) insulin and (d) C-peptide levels before and 30 minutes after glucose administration. The data were compared using repeated measures ANOVA followed by Tukey’s HSD tests; £££p < 0.001 compared to WT AUC during same IPGTT. ***p < 0.001 compared to baseline of the same genotype during the same IPGTT. ##p < 0.01 compared to WT animals in the same timepoint during the same IPGTT. ¤p < 0.05 compared to WT saline animals in the same timepoint during the first IPGTT. The data are presented as the mean ± SEM, n = 6–8.
Figure 3
Figure 3
Development of glucose intolerance over 19 weeks of liraglutide treatment. (a) Weight change over 19 weeks of liraglutide administration. Blood glucose profile after glucose challenge during liraglutide treatment (b) before, (c) 7 weeks, (d) 14 weeks and (e) 19 weeks after the beginning of liraglutide treatment. (f) Area under curve analyses for IPGTT results at different timepoints. (g) Langerhans islet mass and (h) Langerhans islet mass/body weight ratio after 19 weeks of liraglutide treatment. (i) Insulin tolerance test with 1U/kg human insulin after 18 weeks of liraglutide treatment. The data were compared using repeated measures ANOVA or one-way ANOVA followed by Tukey’s HSD tests; *p < 0.05, **p < 0.01, ***p < 0.001 compared to (same-age) WT saline-treated animals. ###p < 0.001 compared to same-age Wfs1 KO liraglutide-treated animals. The data are presented as the mean ± SEM, n = 12–15 (weight and IPGTT), n = 6–8 (ITT), n = 4–6 (islet measurements).
Figure 4
Figure 4
Serum insulin, C-peptide, and glucagon levels before and 30 minutes after glucose administration. (ad) Insulin levels after various time on liraglutide treatment, (e) C-peptide and (f) glucagon levels after 19 weeks on liraglutide treatment. The data were compared using repeated measures ANOVA followed by Tukey’s HSD tests; *p < 0.05, **p < 0.01, ***p < 0.001 compared to the baseline of the same animals; #p < 0.05, ##p < 0.01, ###p < 0.001 compared to WT animals of same treatment at the same timepoint; ¤p < 0.05, ¤¤¤p < 0.001 compared to saline treatment of the same GT at the same timepoint. The data are presented as the mean ± SEM, n = 12–15.
Figure 5
Figure 5
Langerhans islet gene expression analyses after 19 weeks of liraglutide treatment compared to WT saline group. Gene expression of (a) Wolframin1; (b) GLP-1 receptor; ER stress markers (c) Grp78 and (d) Xbp1 splicing; inflammation marker (e) IP10; proliferation marker (f) Ki67. The data were compared using factorial ANOVA followed by Tukey’s HSD tests; *p < 0.05, **p < 0.01, ***p < 0.001 compared to WT animals of the same treatment; #p < 0.05, ##p < 0.01 compared to saline animals of the same GT. The data are presented as the mean ± SEM, n = 4–8.

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References

    1. Barrett TG, Poulton K, Bundey S. DIDMOAD syndrome; further studies and muscle biochemistry. J Inherit Metab Dis. 1995;18:218–220. doi: 10.1007/BF00711771. - DOI - PubMed
    1. Barrett TG, Bundey SE. Wolfram (DIDMOAD) syndrome. J Med Genet. 1997;34:838–841. doi: 10.1136/jmg.34.10.838. - DOI - PMC - PubMed
    1. Inoue H. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome) Nat Genet. 1998;20:143–148. doi: 10.1038/2441. - DOI - PubMed
    1. Urano F. Wolfram Syndrome: Diagnosis, Management, and Treatment. Curr Diab Rep. 2016;16:6. doi: 10.1007/s11892-015-0702-6. - DOI - PMC - PubMed
    1. Vilsboll T. The effects of glucagon-like peptide-1 on the beta cell. Diabetes Obes Metab. 2009;11(Suppl 3):11–18. doi: 10.1111/j.1463-1326.2009.01073.x. - DOI - PubMed

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