Sprecher Urs, Mohr Peter, Martin Rainer E, Maerki Hans Peter, Sanchez Rubén Alvarez, Binggeli Alfred, Künnecke Basil, Christ Andreas D
Discovery Research, Chemistry and Non-Clinical Safety, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
Regul Pept. 2010 Jan 8;159(1-3):19-27. doi: 10.1016/j.regpep.2009.09.006.
Somatostatin regulates numerous endocrine processes, including glucose homeostasis. The contribution and effects of the 5 somatostatin receptors are still unclear, in part due to the lack of suitable subtype specific receptor antagonists. We explored the effects of two novel, non-peptidic, orally bioavailable somatostatin receptor subtype 5 antagonists named Compound A and Compound B on glycemia in animal models of type 2 diabetes after an initial in vitro characterization.
Compound A led to a dose-dependent decrease in glucose and insulin excursions during an OGTT in Zucker (fa/fa) rats after single treatment by up to 17% and 49%, respectively. Diet-induced obese mice showed after three weeks treatment with compounds A and B a dose-dependent decrease of the glucose excursion of up to 45% and 37%, respectively. In contrast to the acute effect observed in Zucker rats, Compound A showed a dose-dependent insulin increase by up to 72%, whereas body weight, liver triglycerides, ALT and AST were dose-dependently decreased.
SSTR5 antagonists have the potential for short- and long-term improvements of the glucose homeostasis in rodent models of type 2 diabetes. Further work on the mechanism and the relevance for human disease is warranted.
生长抑素调节多种内分泌过程，包括葡萄糖稳态。5种生长抑素受体的作用和影响仍不清楚，部分原因是缺乏合适的亚型特异性受体拮抗剂。在初步体外表征后，我们研究了两种新型、非肽类、口服生物可利用的生长抑素受体亚型5拮抗剂化合物A和化合物B对2型糖尿病动物模型血糖的影响。
单次治疗后，化合物A使 Zucker（fa/fa）大鼠口服葡萄糖耐量试验（OGTT）期间的血糖和胰岛素波动分别剂量依赖性降低高达17%和49%。饮食诱导的肥胖小鼠在接受化合物A和B治疗三周后，血糖波动分别剂量依赖性降低高达45%和37%。与在 Zucker 大鼠中观察到的急性效应相反，化合物A使胰岛素剂量依赖性增加高达72%，而体重、肝脏甘油三酯、谷丙转氨酶（ALT）和谷草转氨酶（AST）则剂量依赖性降低。
生长抑素受体5拮抗剂具有改善2型糖尿病啮齿动物模型短期和长期葡萄糖稳态的潜力。有必要进一步研究其作用机制以及与人类疾病的相关性。
