Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes.

Hitoshi Watanabe, Wen Du, Jinsook Son, Lina Sui, Shun-Ichiro Asahara, Irwin J Kurland, Taiyi Kuo, Takumi Kitamoto, Yasutaka Miyachi, Rafael de Cabo, Domenico Accili

Science translational medicine 2023 Feb

filter terms:

Sulfonylureas (SUs) are effective and affordable antidiabetic drugs. However, chronic use leads to secondary failure, limiting their utilization. Here, we identify cytochrome b5 reductase 3 (Cyb5r3) down-regulation as a mechanism of secondary SU failure and successfully reverse it. Chronic exposure to SU lowered Cyb5r3 abundance and reduced islet glucose utilization in mice in vivo and in ex vivo murine islets. Cyb5r3 β cell-specific knockout mice phenocopied SU failure. Cyb5r3 engaged in a glucose-dependent interaction that stabilizes glucokinase (Gck) to maintain glucose utilization. Hence, Gck activators can circumvent Cyb5r3-dependent SU failure. A Cyb5r3 activator rescued secondary SU failure in mice in vivo and restored insulin secretion in ex vivo human islets. We conclude that Cyb5r3 is a key factor in the secondary failure to SU and a potential target for its prevention, which might rehabilitate SU use in diabetes.

Citation

Hitoshi Watanabe, Wen Du, Jinsook Son, Lina Sui, Shun-Ichiro Asahara, Irwin J Kurland, Taiyi Kuo, Takumi Kitamoto, Yasutaka Miyachi, Rafael de Cabo, Domenico Accili. Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes. Science translational medicine. 2023 Feb;15(681):eabq4126