Cyb5r3 activation rescues secondary failure to sulfonylurea but not β-cell dedifferentiation.
Hitoshi Watanabe, Shun-Ichiro Asahara, Jinsook Son, Wendy M McKimpson, Rafael de Cabo, Domenico Accili
Author Information
Hitoshi Watanabe: Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, United States of America. ORCID
Shun-Ichiro Asahara: Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
Jinsook Son: Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
Wendy M McKimpson: Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
Rafael de Cabo: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
Domenico Accili: Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
Diabetes mellitus is characterized by insulin resistance and β-cell failure. The latter involves impaired insulin secretion and β-cell dedifferentiation. Sulfonylurea (SU) is used to improve insulin secretion in diabetes, but it suffers from secondary failure. The relationship between SU secondary failure and β-cell dedifferentiation has not been examined. Using a model of SU secondary failure, we have previously shown that functional loss of oxidoreductase Cyb5r3 mediates effects of SU failure through interactions with glucokinase. Here we demonstrate that SU failure is associated with partial β-cell dedifferentiation. Cyb5r3 knockout mice show more pronounced β-cell dedifferentiation and glucose intolerance after chronic SU administration, high-fat diet feeding, and during aging. A Cyb5r3 activator improves impaired insulin secretion caused by chronic SU treatment, but not β-cell dedifferentiation. We conclude that chronic SU administration affects progression of β-cell dedifferentiation and that Cyb5r3 activation reverses secondary failure to SU without restoring β-cell dedifferentiation.
References
J Biol Chem. 2016 May 6;291(19):10162-72
[PMID: 26984405]
