Nycomed: a Takeda company, Nycomed GmbH, Institute of Pharmacology and Preclinical Drug Safety, Department RDP/LP, Haidkrugsweg 1, 22885, Barsbüttel, Germany.
Nycomed, Konstanz, Germany.
Diabetologia. 2012 Oct;55(10):2779-2788. doi: 10.1007/s00125-012-2632-z. Epub 2012 Jul 13.
AIMS/HYPOTHESIS: The cAMP-degrading phosphodiesterase 4 (PDE4) enzyme has recently been implicated in the regulation of glucagon-like peptide-1 (GLP-1), an incretin hormone with glucose-lowering properties. We investigated whether the PDE4 inhibitor roflumilast elevates GLP-1 levels in diabetic db/db mice and whether this elevation is accompanied by glucose-lowering effects.
Plasma GLP-1 was determined in db/db mice after single oral administration of roflumilast or its active metabolite roflumilast-N-oxide. Diabetes-relevant variables including HbA(1c), blood glucose, serum insulin, body weight, food and water intake, and pancreas morphology were determined in db/db mice treated daily for 28 days with roflumilast or roflumilast-N-oxide. Pharmacokinetic/pharmacodynamic analysis clarified the contribution of roflumilast vs its metabolite. In addition, the effect of roflumilast-N-oxide on insulin release was investigated in primary mouse islets.
Single treatment of db/db mice with 10 mg/kg roflumilast or roflumilast-N-oxide enhanced plasma GLP-1 2.5- and fourfold, respectively. Chronic treatment of db/db mice with roflumilast or roflumilast-N-oxide at 3 mg/kg showed prevention of disease progression. Roflumilast-N-oxide abolished the increase in blood glucose, reduced the increment in HbA(1c) by 50% and doubled fasted serum insulin compared with vehicle, concomitant with preservation of pancreatic islet morphology. Furthermore, roflumilast-N-oxide amplified forskolin-induced insulin release in primary islets. Roflumilast-N-oxide showed stronger glucose-lowering effects than its parent compound, consistent with its greater effect on GLP-1 secretion and explainable by pharmacokinetic/pharmacodynamic modelling.
CONCLUSIONS/INTERPRETATION: Our results suggest that roflumilast and roflumilast-N-oxide delay the progression of diabetes in db/db mice through protection of pancreatic islet physiology potentially involving GLP-1 and insulin activities.
目的/假设：环磷酸腺苷（cAMP）降解磷酸二酯酶 4（PDE4）酶最近被牵连到胰高血糖素样肽-1（GLP-1）的调节中，GLP-1 是一种具有降低血糖作用的肠促胰岛素。我们研究了 PDE4 抑制剂罗氟司特是否能提高糖尿病 db/db 小鼠的 GLP-1 水平，以及这种升高是否伴有降血糖作用。
在 db/db 小鼠单次口服罗氟司特或其活性代谢物罗氟司特-N-氧化物后，测定血浆 GLP-1 水平。用罗氟司特或罗氟司特-N-氧化物每日治疗 28 天，测定与糖尿病相关的变量，包括 HbA（1c）、血糖、血清胰岛素、体重、食物和水的摄入以及胰腺形态。药代动力学/药效学分析阐明了罗氟司特与其代谢物的贡献。此外，还研究了罗氟司特-N-氧化物对原代小鼠胰岛胰岛素释放的影响。
单次给予 10mg/kg 罗氟司特或罗氟司特-N-氧化物可使 db/db 小鼠血浆 GLP-1 分别增加 2.5 倍和 4 倍。3mg/kg 罗氟司特或罗氟司特-N-氧化物慢性治疗 db/db 小鼠可预防疾病进展。与载体相比，罗氟司特-N-氧化物可消除血糖升高，使 HbA（1c）增加减少 50%，空腹血清胰岛素增加一倍，同时保持胰腺胰岛形态。此外，罗氟司特-N-氧化物可增强原代胰岛中 forskolin 诱导的胰岛素释放。罗氟司特-N-氧化物的降血糖作用强于其母体化合物，与其对 GLP-1 分泌的更强作用一致，并可通过药代动力学/药效学模型解释。
结论/解释：我们的研究结果表明，罗氟司特和罗氟司特-N-氧化物通过保护胰腺胰岛生理功能，可能涉及 GLP-1 和胰岛素活性，延缓 db/db 小鼠糖尿病的进展。
