Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; Kansai Electric Power Medical Research Institute, 1-5-6 Minatojimaminamimachi, Chuo-ku, Kobe 650-0047, Japan.
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Eur J Pharmacol. 2018 Jun 5;828:52-59. doi: 10.1016/j.ejphar.2018.03.025. Epub 2018 Mar 16.
The dynamics of insulin secretion stimulated by repaglinide, a glinide, and the combinatorial effects of repaglinide and incretin were investigated. At 4.4 mM glucose, repaglinide induced insulin secretion with a gradually increasing first phase, showing different dynamics from that induced by glimepiride, a sulfonylurea. In the presence of glucagon-like peptide-1 (GLP-1), insulin secretion by repaglinide was augmented significantly but to lesser extent and showed different dynamics from that by glimepiride. At 4.4 mM glucose, the intracellular Ca level was gradually increased by repaglinide alone or repaglinide plus GLP-1, which differs from the Ca dynamics by glimepiride alone or glimepiride plus GLP-1, suggesting that the difference in Ca dynamics contributes to the difference in the dynamics of insulin secretion. At a higher concentration (8.8 mM) of glucose, the dynamics of insulin secretion stimulated by repaglinide was similar to that by glimepiride. Combination of repaglinide and GLP-1 significantly augmented insulin secretion, the amount of which was comparable to that by the combination of glimepiride and GLP-1. The Ca dynamics was similar for repaglinide and glimepiride at 8.8 mM glucose. Our data indicate that repaglinide has characteristic properties in its effects on the dynamics of insulin secretion and intracellular Ca and that the combination of repaglinide and GLP-1 stimulates insulin secretion more effectively than the combination of glimepiride and GLP-1 at a high concentration of glucose, providing a basis for its use in clinical settings.
我们研究了瑞格列奈（一种格列奈类药物）刺激胰岛素分泌的动力学以及瑞格列奈与肠降血糖素的组合效应。在 4.4mM 葡萄糖的情况下，瑞格列奈诱导的胰岛素分泌具有逐渐增加的第一相，其动力学与磺酰脲类药物格列美脲不同。在胰高血糖素样肽-1（GLP-1）存在的情况下，瑞格列奈诱导的胰岛素分泌显著增强，但程度较小，且动力学与格列美脲不同。在 4.4mM 葡萄糖的情况下，瑞格列奈单独或瑞格列奈加 GLP-1 可逐渐增加细胞内 Ca 水平，这与格列美脲单独或格列美脲加 GLP-1 的 Ca 动力学不同，表明 Ca 动力学的差异导致了胰岛素分泌动力学的差异。在更高的葡萄糖浓度（8.8mM）下，瑞格列奈刺激的胰岛素分泌动力学与格列美脲相似。瑞格列奈与 GLP-1 的组合可显著增强胰岛素分泌，其分泌量与格列美脲与 GLP-1 的组合相当。在 8.8mM 葡萄糖时，瑞格列奈和格列美脲的 Ca 动力学相似。我们的数据表明，瑞格列奈在其对胰岛素分泌动力学和细胞内 Ca 的影响方面具有特征性，并且在高葡萄糖浓度下，瑞格列奈与 GLP-1 的组合比格列美脲与 GLP-1 的组合更有效地刺激胰岛素分泌，为其在临床环境中的应用提供了依据。
