Yamada Tomoko, Sugimoto Hikaru, Hironaka Ken-Ichi, Morita Yasuko, Miura Hiroshi, Otowa-Suematsu Natsu, Okada Yuko, Hirota Yushi, Sakaguchi Kazuhiko, Kuroda Shinya, Ogawa Wataru
Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan.
Department of Biochemistry and Molecular Biology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
J Endocr Soc. 2024 Apr 8;8(6):bvae067. doi: 10.1210/jendso/bvae067. eCollection 2024 Apr 6.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels by promoting urinary glucose excretion, but their overall effects on hormonal and metabolic status remain unclear.
We here investigated the roles of insulin and glucagon in the regulation of glycemia in individuals treated with an SGLT2 inhibitor using mathematical model analysis.
Hyperinsulinemic-euglycemic clamp and oral glucose tolerance tests were performed in 68 individuals with type 2 diabetes treated with the SGLT2 inhibitor dapagliflozin. Data previously obtained from such tests in 120 subjects with various levels of glucose tolerance and not treated with an SGLT2 inhibitor were examined as a control. Mathematical models of the feedback loops connecting glucose and insulin (GI model) or glucose, insulin, and glucagon (GIG model) were generated.
Analysis with the GI model revealed that the disposition index, which is defined as the product of insulin sensitivity and insulin secretion divided by the square of insulin clearance and represents the glucose-handling ability of insulin, was significantly correlated with glycemia in subjects not taking an SGLT2 inhibitor but not in those taking dapagliflozin. Analysis with the GIG model revealed that a metric defined as the product of glucagon sensitivity and glucagon secretion divided by glucagon clearance (designated production index) was significantly correlated with blood glucose level in subjects treated with dapagliflozin.
Treatment with an SGLT2 inhibitor alters the relation between insulin effect and blood glucose concentration, and glucagon effect may account for variation in glycemia among individuals treated with such drugs.
钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂通过促进尿糖排泄来降低血糖水平，但其对激素和代谢状态的总体影响仍不明确。
我们在此使用数学模型分析研究了胰岛素和胰高血糖素在SGLT2抑制剂治疗个体血糖调节中的作用。
对68例接受SGLT2抑制剂达格列净治疗的2型糖尿病患者进行了高胰岛素-正常血糖钳夹试验和口服葡萄糖耐量试验。将先前在120例不同糖耐量水平且未接受SGLT2抑制剂治疗的受试者中进行此类试验获得的数据作为对照进行检查。建立了连接葡萄糖和胰岛素的反馈回路（GI模型）或葡萄糖、胰岛素和胰高血糖素的反馈回路（GIG模型）的数学模型。
GI模型分析显示，处置指数定义为胰岛素敏感性与胰岛素分泌的乘积除以胰岛素清除率的平方，代表胰岛素的葡萄糖处理能力，在未服用SGLT2抑制剂的受试者中与血糖显著相关，但在服用达格列净的受试者中则不然。GIG模型分析显示，一个定义为胰高血糖素敏感性与胰高血糖素分泌的乘积除以胰高血糖素清除率的指标（称为生成指数）在接受达格列净治疗的受试者中与血糖水平显著相关。
SGLT2抑制剂治疗改变了胰岛素效应与血糖浓度之间的关系，胰高血糖素效应可能是此类药物治疗个体血糖差异的原因。
