Novel, non-peptidic somatostatin receptor subtype 5 antagonists improve glucose tolerance in rodents.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Sprecher
Urs
U
Discovery Research, Chemistry and Non-Clinical Safety, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
Mohr
Peter
P
Martin
Rainer E
RE
Maerki
Hans Peter
HP
Sanchez
Rubén Alvarez
RA
Binggeli
Alfred
A
Künnecke
Basil
B
Christ
Andreas D
AD
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D009765:Obesity / Q000097:blood / Q000188:drug therapy*; D051381:Rats; D011924:Rats, Zucker; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D017481:Receptors, Somatostatin; D014280:Triglycerides; C094573:somatostatin receptor 5