Moritoh Yusuke, Takeuchi Koji, Asakawa Tomoko, Kataoka Osamu, Odaka Hiroyuki
Pharmacology Research Laboratories I, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
Eur J Pharmacol. 2009 Jan 14;602(2-3):448-54. doi: 10.1016/j.ejphar.2008.11.017. Epub 2008 Nov 17.
The combination of two agents with different but complementary mechanisms of action is a logical approach for treating patients with type 2 diabetes. Thus, we evaluated chronic combination therapy with alogliptin, a highly selective dipeptidyl peptidase-4 inhibitor that enhances the action of incretins, and pioglitazone, a thiazolidinedione that improves peripheral and hepatic insulin sensitivity. Studies were designed to investigate the chronic metabolic and pancreatic effects of alogliptin (0.03%) plus pioglitazone (0.003%) combination treatment in obese ob/ob mice. After 4-5 weeks of treatment, alogliptin significantly increased plasma active glucagon-like peptide-1 levels up to 4.1-fold and decreased plasma glucagon up to 25%, whereas pioglitazone significantly increased plasma adiponectin up to 1.3-fold. Combination treatment exhibited a complementary effect, increasing plasma insulin levels by 3.2-fold (alogliptin alone, 1.6-fold; pioglitazone alone, 1.5-fold) and decreasing glycosylated hemoglobin by 2.3% (alogliptin alone, 1.0%; pioglitazone alone, 1.5%), and non-fasting and fasting plasma glucose by 37% and 62% (alogliptin alone, 17% and 24%; pioglitazone alone, 30% and 45%), respectively. Combination treatment also decreased plasma triglycerides by 67% and non-esterified fatty acids by 25% (alogliptin alone, 24% and 11%; pioglitazone alone, 54% and 8%). Moreover, combination treatment increased pancreatic insulin content by 2.2-fold (alogliptin alone, 1.3-fold; pioglitazone alone, 1.6-fold), with no significant changes in body weight. These results indicate that combination treatment with alogliptin and pioglitazone improved glycemic control, lipid profiles and increased pancreatic insulin content in ob/ob mice by preventing incretin inactivation and improving insulin resistance. These results provide a strong argument for using alogliptin in combination with pioglitazone.
联合使用两种作用机制不同但互补的药物是治疗2型糖尿病患者的合理方法。因此，我们评估了阿格列汀（一种增强肠促胰岛素作用的高选择性二肽基肽酶-4抑制剂）与吡格列酮（一种改善外周和肝脏胰岛素敏感性的噻唑烷二酮类药物）的长期联合治疗效果。研究旨在调查阿格列汀（0.03%）加吡格列酮（0.003%）联合治疗对肥胖ob/ob小鼠的长期代谢和胰腺影响。治疗4-5周后，阿格列汀可使血浆活性胰高血糖素样肽-1水平显著升高至4.1倍，使血浆胰高血糖素降低25%，而吡格列酮可使血浆脂联素显著升高至1.3倍。联合治疗表现出互补效应，使血浆胰岛素水平升高3.2倍（单独使用阿格列汀为1.6倍；单独使用吡格列酮为1.5倍），糖化血红蛋白降低2.3%（单独使用阿格列汀为1.0%；单独使用吡格列酮为1.5%），非空腹和空腹血糖分别降低37%和62%（单独使用阿格列汀为17%和24%；单独使用吡格列酮为30%和45%）。联合治疗还使血浆甘油三酯降低67%，非酯化脂肪酸降低25%（单独使用阿格列汀为24%和11%；单独使用吡格列酮为54%和8%）。此外，联合治疗使胰腺胰岛素含量增加2.2倍（单独使用阿格列汀为1.3倍；单独使用吡格列酮为1.6倍），体重无显著变化。这些结果表明，阿格列汀与吡格列酮联合治疗通过防止肠促胰岛素失活和改善胰岛素抵抗，改善了ob/ob小鼠的血糖控制、血脂水平并增加了胰腺胰岛素含量。这些结果为阿格列汀与吡格列酮联合使用提供了有力依据。
