The potential role of glucokinase activator SHP289-04 in anti-diabetes and hepatic protection

Abstract

Glucokinase was glucose sensor in hepatocytes and islet beta cells. It not only promoted glucose metabolism, but also advanced glucose-stimulated insulin secretion. Glucokinase activators had been reported as one kind of new potential drugs for treatment of type 2 diabetes. Compound 6-(5-(3-fluorobenzyloxy)-2-ethoxybenzamido) pyridine-3-carboxylic acid (SHP289-04) was found to increase glucokinase activity effectively by our lab. In order to demonstrate its effect of anti-diabetes, in vitro, human liver carcinoma cell line HepG2 was used to glucose consumption test, and pancreatic cell line NIT-1 was used to assess insulin secretion in response to different concentration of glucose (5 mmol/l and 20 mmol/l). Type 2 diabetes model KKA^y mice were chose to evaluate the pharmacodynamics of SHP289-04 in vivo. In hepatocytes, SHP289-04 could accelerate glucose consuming. In NIT cell line, it promoted glucose-stimulated insulin secretion at the 20 mmol/l of glucose. Moreover, it normalized oral glucose tolerance test and down-regulated blood lipid level in KKA^y mice. At the same time, it ameliorated function of islets and accelerated the ratio of beta cell/alpha cell mass, and also alleviated the fatty liver of KKA^y mice. Therefore, SHP289-04 as a glucokinase activator had the potential effect of diabetes treatment.

Keywords: Beta cell; Diabetes; Fatty liver; Glucokinase.