TITLE:
DPP-4 Inhibition Ameliorates Pancreatic β-Cell Failure and Improves Glucose Tolerance in the Mouse Model of Wolfram Syndrome
AUTHORS:
Yasuhiro Tanji, Suguru Yamaguchi, Yasushi Ishigaki, Hideki Katagiri, Yoshitomo Oka, Hisamitsu Ishihara
KEYWORDS:
Diabetes, Incretin, Endoplasmic Reticulum Stress, WFS1, Wolframin
JOURNAL NAME:
Journal of Diabetes Mellitus,
Vol.5 No.2,
May
4,
2015
ABSTRACT: Wolfram syndrome, an autosomal recessive
disorder associated with diabetes and optic atrophy, is caused by mutations in
the WFS1 gene encoding wolframin, an endoplasmic reticulum membrane protein.
Recent development of incretin-based drugs demonstrates promising outcomes for
treatment of diabetes mellitus. The aim of this study is to evaluate whether
dipeptidyl peptidase-4 inhibition is effective for treating endoplasmic
reticulum stress-mediated β-dell failure and impaired glucose tolerance in WFS1-deficient mice (Wfs1－/－). Wfs1－/－ mice were orally administrated with
vildagliptin (50 mg/kg), a dipeptidyl peptidase-4 inhibitor, twice a day for 4
weeks. The pancreases of these mice were subjected to morphological and
biochemical analyses and their glucose tolerance was studied. Electron
microscopic studies revealed that vildagliptin reduced number of β-cell containing
swollen endoplasmic reticulum in Wfs1－/－mice. Vildagliptin treatment increased
pancreatic insulin content by 30% in Wfs1－/－ mice. Oral and intraperitoneal
glucose tolerance tests showed improved glucose tolerance in
vildagliptin-treated Wfs1－/－ mice with increased glucose responsiveness of
insulin secretion as compared with vehicle-treated mutant mice. These effects
by dipeptidyl peptidase-4 inhibition were partly prevented by glucagon-like
peptide-1 receptor blockade. These findings provide evidence that activation of
the incretin system by dipeptidyl peptidase-4 inhibition plays a protective
role against β-cell failure in wolframin-deficiency. Our data suggest that
diabetes in patients affected with Wolfram syndrome could be treated by incretin-based
drugs. Furthermore, since WFS1 dysfunction could be involved in common forms of
type 2 diabetes mellitus, our results strengthen the mechanistic rational of
using this drug for the disease.