Activation of GLP-1 receptor signalling alleviates cellular stresses and improves beta cell function in a mouse model of Wolfram syndrome
Loss of functional beta cells results in a gradual progression of insulin insufficiency in Wolfram syndrome caused by recessive WFS1 mutations. However, beta cell dysfunction in Wolfram syndrome has yet to be fully characterised, and there are also no specific treatment recommendations. In this study, we aimed to characterise beta cell secretory defects and to examine the potential effects of a glucagon-like peptide-1 (GLP-1) receptor agonist on diabetes in Wolfram syndrome.
Insulin secretory function was assessed by the pancreatic perfusion method in mice used as a model of Wolfram syndrome. In addition, granule dynamics in living beta cells were examined using total internal reflection fluorescence microscopy. Acute and chronic effects of exendin-4 (Ex-4) on glucose tolerance and insulin secretion were examined in young Wfs1−/− mice without hyperglycaemia. Molecular events associated with Ex-4 treatment were investigated using pancreatic sections and isolated islets. In addition, we retrospectively observed a woman with Wolfram syndrome who had been treated with liraglutide for 24 weeks.
Treatment with liraglutide ameliorated our patient’s glycaemic control and resulted in a 20% reduction of daily insulin dose along with an off-drug elevation of fasting C-peptide immunoreactivity. Glucose-stimulated first-phase insulin secretion and potassium-stimulated insulin secretion decreased by 53% and 59%, respectively, in perfused pancreases of 10-week-old Wfs1−/− mice compared with wild-type (WT) mice. The number of insulin granule fusion events in the first phase decreased by 41% in Wfs1−/− beta cells compared with WT beta cells. Perfusion with Ex-4 increased insulin release in the first and second phases by 3.9-fold and 5.6-fold, respectively, in Wfs1−/− mice compared with perfusion with saline as a control. The physiological relevance of the effects of Ex-4 was shown by the fact that a single administration potentiated glucose-stimulated insulin secretion and improved glucose tolerance in Wfs1−/− mice. Four weeks of administration of Ex-4 resulted in an off-drug amelioration of glucose excursions after glucose loading in Wfs1−/− mice, with insulin secretory dynamics that were indistinguishable from those in WT mice, despite the fact that there was no alteration in beta cell mass. In association with the functional improvements, Ex-4 treatment reversed the increases in phosphorylated eukaryotic initiation factor (EIF2α) and thioredoxin interacting protein (TXNIP), and the decrease in phosphorylated AMP-activated kinase (AMPK), in the beta cells of the Wfs1−/− mice. Furthermore, Ex-4 treatment modulated the transcription of oxidative and endoplasmic reticulum stress-related markers in isolated islets, implying that it was able to mitigate the cellular stresses resulting from Wfs1 deficiency.
Our study provides deeper insights into the pathophysiology of beta cell dysfunction caused by WFS1 deficiency and implies that activation of the GLP-1 receptor signal may alleviate insulin insufficiency and aid glycaemic control in Wolfram syndrome.
KeywordsDiabetes mellitus Endoplasmic reticulum stress Glucagon-like peptide-1 Insulin secretion Pancreatic beta cell Wolfram syndrome
Vacuolar-type H+-ATPase V1A
Eukaryotic initiation factor 2α
Glucose-stimulated insulin secretion
Secretory units of islets in transplantation
Total internal reflection fluorescence microscopy
Thioredoxin interacting protein
Wolfram syndrome 1 protein
The authors would like to thank members of the division of Yamaguchi University Graduate School of Medicine for their helpful discussion with preparing the manuscript.
All authors participated substantially in the investigations reported here as indicated. KT and YT conceived and designed experimental studies, collected, analysed and interpreted data, and drafted and critically revised the manuscript. MK designed the study, conducted experiments, collected, analysed and interpreted data and wrote and revised the manuscript. KA-S, MH, TM, and HT designed experimental studies and collected, analysed and interpreted data; they also critically reviewed the manuscript and gave valuable suggestions for its revision. SS and YY assisted in the design of the study and contributed significantly to data interpretation, critical reading and revision of the manuscript. All authors carefully read and approved the final version to be published. YT is the guarantor of this work.
KT is supported by a Grant-in-Aid for Scientific Research (grant number 16K09752). YT is supported by a Grant-in-Aid for Scientific Research (grant numbers 23390080 and 15H04849) and by Takeda Science Foundation. KA-S is supported by a Grant-in-Aid for Scientific Research (grant number 15K21198), a Japan Diabetes Society Junior Scientist Development Grant supported by Novo Nordisk Pharma Ltd., a Grant for Front Runner of Future Diabetes Research, and Grants for young researchers from the Japan Association for Diabetes Education and Care and from Banyu Life Science Foundation International. MH is supported by a Grant-in-Aid for Scientific Research (grant number 15K09390).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.