Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes
Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes
复制标题
DOI：
10.1126/scitranslmed.abq4126
复制
发表时间：
2023-02
影响因子：
17.1
通讯作者：
H. Watanabe;Wen-Liang Du;J. Son;Lina Sui;Shun-ichiro Asahara;I. Kurland;T. Kuo;T. Kitamoto;Yasutaka Miyachi;R. de Cabo;D. Accili
中科院分区：
文献类型：
--
作者：
H. Watanabe;Wen-Liang Du;J. Son;Lina Sui;Shun-ichiro Asahara;I. Kurland;T. Kuo;T. Kitamoto;Yasutaka Miyachi;R. de Cabo;D. Accili
磺酰脲类药物是一种有效且价格低廉的抗糖尿病药物。然而，长期使用会导致继发性失效，限制了它们的利用。在这里，我们确定细胞色素b5还原酶3（Cyb 5 r3）下调作为继发性SU失败的机制，并成功地扭转it. Chronic暴露于SU降低Cyb 5 r3丰度和减少胰岛葡萄糖利用率在小鼠体内和离体小鼠胰岛。Cyb 5 r3 β细胞特异性敲除小鼠表型模仿SU失败。Cyb 5 r3参与葡萄糖依赖性相互作用，稳定葡萄糖激酶（Gck）以维持葡萄糖利用。因此，Gck激活剂可以规避Cyb 5 r3依赖性SU故障。Cyb 5 r3激活剂在小鼠体内挽救了继发性SU衰竭，并在离体人胰岛中恢复了胰岛素分泌。我们的结论是，Cyb 5 r3是继发性失败的SU和潜在的目标，其预防，这可能会恢复SU在糖尿病中的使用的关键因素。说明磺酰脲继发性失效是由Cyb 5 r3下调依赖性葡萄糖利用受损引起的。磺酰脲类药物是通过增加胰腺胰岛素分泌而起作用的抗糖尿病药物，但它们在2型糖尿病患者中的疗效通常会随着时间的推移而恶化。Watanabe等人表明，长期暴露于磺酰脲类药物会降低胰腺细胞色素b5还原酶3（Cyb 5 r3）丰度，导致葡萄糖感知受损。CYB 5 R3的药理学激活恢复了小鼠模型和离体人胰岛对磺酰脲类药物治疗的敏感性，突出了恢复这些负担得起的抗糖尿病药物疗效的潜在策略。-CAC
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. Description Sulfonylurea secondary failure is caused by Cyb5r3 down-regulation–dependent impaired glucose utilization. Sensitization to sulfonylureas Sulfonylureas are anti-diabetic drugs that work by increasing pancreatic insulin secretion, but their efficacy in patients with type 2 diabetes commonly deteriorates over time. Watanabe et al. show that chronic exposure to sulfonylureas decreases pancreatic cytochrome b5 reductase 3 (Cyb5r3) abundance, resulting in impaired glucose sensing. Pharmacological activation of CYB5R3 restored sensitivity to sulfonylurea treatment in both a mouse model and ex vivo human pancreatic islets, highlighting a potential strategy to restore efficacy of these affordable antidiabetic drugs. —CAC