Wolfram syndrome(WS)is a rare autosomal rece s s i ve disease characte r i zed by the development of diabetes insipidus,diabetes mellitus,optic atrophy,and deafness(often referred to as DIDMOAD),and overall severe neu...Wolfram syndrome(WS)is a rare autosomal rece s s i ve disease characte r i zed by the development of diabetes insipidus,diabetes mellitus,optic atrophy,and deafness(often referred to as DIDMOAD),and overall severe neurodegenerative fallback.The global prevalence of this disease is estimated at 1 in 770,000(Lee et al.,2023).It is most commonly caused by biallelic(point)mutations in the Wolframin endoplasmic reticulum(ER)transmembrane glycoprotein(WFS1)gene(in case of WS type 1),but mutations in the CDGSH Iron Sulfur Domain 2(CISD2)are also linked to WS(type 2).The latter,however,often present with less severe pathological manifestations(Lee et al.,2023).WFS1 is located on chromosome 4p16.1 and spans over 33 kilobases.Many mutation variants have been identified in WFS1,encompassing missense,nonsense,and frameshift mutations.These mutations are spread across the coding region of WFS1,but certain regions,such as exon 8,the largest exon,appear particularly mutation-prone and associated with the classical WS type 1 phenotype(Lee et al.,2023).展开更多
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 o...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.展开更多
基金Research into Wolfram syndrome in the De Groef team has been supported by the Eye Hope Foundation(Belgium),Wolfram UK(UK)and The Snow Foundation(USA).
文摘Wolfram syndrome(WS)is a rare autosomal rece s s i ve disease characte r i zed by the development of diabetes insipidus,diabetes mellitus,optic atrophy,and deafness(often referred to as DIDMOAD),and overall severe neurodegenerative fallback.The global prevalence of this disease is estimated at 1 in 770,000(Lee et al.,2023).It is most commonly caused by biallelic(point)mutations in the Wolframin endoplasmic reticulum(ER)transmembrane glycoprotein(WFS1)gene(in case of WS type 1),but mutations in the CDGSH Iron Sulfur Domain 2(CISD2)are also linked to WS(type 2).The latter,however,often present with less severe pathological manifestations(Lee et al.,2023).WFS1 is located on chromosome 4p16.1 and spans over 33 kilobases.Many mutation variants have been identified in WFS1,encompassing missense,nonsense,and frameshift mutations.These mutations are spread across the coding region of WFS1,but certain regions,such as exon 8,the largest exon,appear particularly mutation-prone and associated with the classical WS type 1 phenotype(Lee et al.,2023).
文摘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.
