Effect of acute and sub-chronic administration of the imidazoline compoundS 22068 on in vivo glucose and insulin responses in normal lean CBA/Ca mice

Acute S 22068 (24 mg/kg po) improved glucose tolerance and increased insuli n sensitivity, assessed as the acute blood glucose response to exogenous in sulin. The same acute dose did not stimulate insulin secretion or induce hy poglycemia in fed animals. Comparison of acute S 22068 to equipotent doses (with respect to effect on glucose tolerance) of gliclazide (2 mg/kg) and m etformin (60 mg/kg) found S 22068 to be similar to metformin with respect t o its effects on basal glucose levels (BGL) and insulin sensitivity. This a lso suggests that S 22068 acts by a mechanism which does not involve insuli n release. Acute or sub-chronic S 22068 (14 days at 25 mg/day) had no effec t on brown adipose tissue (BAT) or white adipose tissue (WAT) lipogenesis, an insulin-sensitive metabolic pathway. Sub-chronic treatment with S 22068 did not alter body weight (BW) or food intake, and resulted in tolerance to its effects on glucose metabolism and insulin sensitivity. These findings suggest that S 22068 is similar in effect to metformin, and is not insulino genic, in contrast to the sulfonylureas or putative I-3 imidazoline site li gands. (C) 2000 Elsevier Science Inc. All rights reserved.