Pharmacology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
Diabetes Obes Metab. 2010 Mar;12(3):224-33. doi: 10.1111/j.1463-1326.2009.01156.x.
Alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and voglibose, an alpha-glucosidase inhibitor, have different but complementary mechanisms of action on glucagon-like peptide-1 (GLP-1) regulation and glucose-lowering effects. The present study evaluated the chronic effects of combination treatment with alogliptin and voglibose in prediabetic db/db mice.
Alogliptin (0.03%) and voglibose (0.001%) alone or in combination were administered in the diet to prediabetic db/db mice.
After 3 weeks, voglibose treatment increased GLP-1 secretion (voglibose alone, 1.6-fold; alogliptin plus voglibose, 1.5-fold), while it decreased plasma glucose-dependent insulinotropic polypeptide (GIP) (voglibose alone, -30%; alogliptin plus voglibose, -29%). Alogliptin, voglibose and combination treatment decreased plasma DPP-4 activity by 72, 15 and additively by 80%, respectively, and increased plasma active GLP-1 levels by 4.5-, 1.8- and synergistically by 9.1-fold respectively. Combination treatment increased plasma insulin by 3.6-fold (alogliptin alone, 1.3-fold; voglibose alone, 1.8-fold), decreased plasma glucagon by 30% (alogliptin alone, 11%; voglibose alone, 8%), and prevented the development of diabetes, much more effectively than either agent alone. After 4 weeks, alogliptin, voglibose and combination treatment increased pancreatic insulin content by 1.6-, 3.4- and synergistically by 8.5-fold respectively. Furthermore, combination treatment resulted in an increased expression of insulin, pancreatic and duodenal homeobox 1 (PDX1) and glucose transporter 2 (GLUT2), and maintenance of normal beta/alpha-cell distribution in the pancreatic islet.
Chronic treatment with alogliptin in combination with voglibose concurrently increased active GLP-1 circulation, increased insulin secretion, decreased glucagon secretion, prevented the onset of the disease, and preserved pancreatic beta-cells and islet structure in prediabetic db/db mice.
阿格列汀（一种二肽基肽酶-4[DPP-4]抑制剂）和伏格列波糖（一种α-葡萄糖苷酶抑制剂）对胰高血糖素样肽-1（GLP-1）的调节和降血糖作用具有不同但互补的作用机制。本研究评估了在糖尿病前期 db/db 小鼠中联合应用阿格列汀和伏格列波糖的慢性作用。
将阿格列汀（0.03%）和伏格列波糖（0.001%）单独或联合添加到饮食中用于治疗糖尿病前期 db/db 小鼠。
3 周后，伏格列波糖治疗增加了 GLP-1 的分泌（伏格列波糖单独使用时为 1.6 倍；阿格列汀加伏格列波糖联合使用时为 1.5 倍），同时降低了血浆葡萄糖依赖性胰岛素释放肽（GIP）（伏格列波糖单独使用时为-30%；阿格列汀加伏格列波糖联合使用时为-29%）。阿格列汀、伏格列波糖和联合治疗分别使血浆 DPP-4 活性降低 72%、15%和相加降低 80%，并使血浆活性 GLP-1 水平分别增加 4.5 倍、1.8 倍和协同增加 9.1 倍。联合治疗使血浆胰岛素增加 3.6 倍（阿格列汀单独使用时为 1.3 倍；伏格列波糖单独使用时为 1.8 倍），使血浆胰高血糖素降低 30%（阿格列汀单独使用时为 11%；伏格列波糖单独使用时为 8%），并能更有效地预防糖尿病的发生，比单独使用任何一种药物都有效。4 周后，阿格列汀、伏格列波糖和联合治疗分别使胰腺胰岛素含量增加 1.6 倍、3.4 倍和协同增加 8.5 倍。此外，联合治疗还导致胰岛素、胰腺十二指肠同源盒 1（PDX1）和葡萄糖转运蛋白 2（GLUT2）的表达增加，并维持了糖尿病前期 db/db 小鼠胰岛内正常的β/α 细胞分布。
糖尿病前期 db/db 小鼠长期联合应用阿格列汀和伏格列波糖可同时增加循环活性 GLP-1、增加胰岛素分泌、减少胰高血糖素分泌、预防疾病发生，并维持胰腺β细胞和胰岛结构。
