Watanabe Hitoshi, Du Wen, Son Jinsook, Sui Lina, Asahara Shun-Ichiro, Kurland Irwin J, Kuo Taiyi, Kitamoto Takumi, Miyachi Yasutaka, de Cabo Rafael, Accili Domenico
Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Sci Transl Med. 2023 Feb;15(681):eabq4126. doi: 10.1126/scitranslmed.abq4126. Epub 2023 Feb 1.
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.
磺脲类药物（SUs）是有效且经济实惠的抗糖尿病药物。然而，长期使用会导致继发性失效，限制了它们的应用。在此，我们确定细胞色素b5还原酶3（Cyb5r3）下调是继发性SU失效的一种机制，并成功将其逆转。在体内小鼠和离体小鼠胰岛中，长期暴露于SU会降低Cyb5r3丰度并减少胰岛葡萄糖利用。Cyb5r3β细胞特异性敲除小鼠表现出与SU失效相似的症状。Cyb5r3参与一种葡萄糖依赖性相互作用，该相互作用可稳定葡萄糖激酶（Gck）以维持葡萄糖利用。因此，Gck激活剂可规避Cyb5r3依赖性SU失效。一种Cyb5r3激活剂在体内挽救了小鼠的继发性SU失效，并在离体人胰岛中恢复了胰岛素分泌。我们得出结论，Cyb5r3是SU继发性失效的关键因素及其预防的潜在靶点，这可能会恢复SU在糖尿病治疗中的应用。
