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.
METHODS:
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.
RESULTS: 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.
CONCLUSIONS/INTERPRETATION: