S 50131 and S 51434, two novel small molecule glucokinase activators, lack chronic efficacy despite potent acute antihyperglycaemic activity in diabetic mice

Autor:	Perron-Sierra Françoise, Audrey Caliez, Solo Goldstein, Catherine Ilic, Jean-Olivier Rolin, Alain Ktorza, Elizabeth Harley, Frédéric De Ceuninck, Yves Charton, Catherine Kargar, Marjorie Sadlo, Cédric Vinson
Rok vydání:	2013
Předmět:	Pharmacology medicine.medical_specialty Glycogen Glucokinase Pancreatic islets Insulin medicine.medical_treatment Biology medicine.disease Intestinal absorption chemistry.chemical_compound Endocrinology medicine.anatomical_structure chemistry Internal medicine medicine biology.protein Glucose homeostasis Steatosis Glycogen synthase
Zdroj:	British Journal of Pharmacology. 169:999-1010
ISSN:	0007-1188
DOI:	10.1111/bph.12172
Popis:	Background and Purpose Small molecule glucokinase activators (GKAs) have been associated with potent antidiabetic efficacy and hepatic steatosis in rodents. This study reports the discovery of S 50131 and S 51434, two novel GKAs with an original scaffold and an atypical pharmacological profile. Experimental Approach Activity of the compounds was assessed in vitro by measuring activation of recombinant glucokinase, stimulation of glycogen synthesis in rat hepatocytes and increased insulin secretion from rat pancreatic islets of Langerhans. Efficacy and safety in vivo were evaluated after oral administration in db/db mice by measuring glycaemia, HbA1c and dyslipidaemia-associated events. Key Results S 50131 and S 51434 activated GK and stimulated glycogen synthesis in hepatocytes and insulin secretion from pancreatic islets. Unexpectedly, while both compounds effectively lowered glycaemia after acute oral administration, they did not decrease HbA1c after a 4-week treatment in db/db mice. This lack of antidiabetic efficacy was associated with increased plasma free fatty acids (FFAs), contrasting with the effect of GKA50 and N00236460, two GKAs with sustained HbA1c lowering activity but neutral regarding plasma FFAs. S 50131, but not S 51434, also induced hepatic steatosis, as did GKA50 and N00236460. However, a shorter, 4-day treatment resulted in increased hepatic triglycerides without changing the plasma FFA levels, demonstrating dynamic alterations in the lipid profile over time. Conclusions and Implications In addition to confirming the occurrence of dyslipidaemia with GKAs, these findings provide new insights into understanding how such compounds may sustain or lose efficacy over time.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::1c41e8dab1ccb5dc6132412fd6ea96ac https://doi.org/10.1111/bph.12172 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.