ANTIHYPERGLYCEMIC ACTION OF GUANIDINOALKANOIC ACIDS - 3-GUANIDINOPROPIONIC ACID AMELIORATES HYPERGLYCEMIA IN DIABETIC KKA(Y) AND C57BL6JOB OB MICE AND INCREASES GLUCOSE DISAPPEARANCE IN RHESUS-MONKEYS/

To evaluate the long-held concept that acidic guanidines lack glycemic effects, guanidinoalkanoic acids and the biguanide metformin (positiv e control) were administered to KKA(y) mice, a model of noninsulin-dep endent diabetes. Two acidic guanidines, 3-guanidinopropionic acid (3-G PA) and guanidinoacetic acid, decreased the plasma glucose level; othe r compounds were ineffective. 3-GPA was more potent than even metformi n. Insulin suppression tests in KKA(y) mice indicated that improved in sulin sensitivity was the mode of action for 3-GPA. Glycemic effects i n KKA(y) mice resulted from increased glucose disposal whereas glucone ogenesis, hepatic glycogen content and intestinal glucose absorption w ere unchanged. 3-GPA's glycemic effect was corroborated in two other m odels of noninsulin-dependent diabetes. In ob/ob mice, the compound re duced hyperglycemia, polyuria, glycosuria and hyperinsulinemia. In ins ulin-resistant rhesus monkeys, it increased the disappearance of i.v. glucose. The glycemic action of 3-GPA required the presence of some ci rculating insulin as well as hyperglycemia because the compound was in effective in normoglycemic mice, insulinopenic Chinese hamsters and st reptozotocin-diabetic rats. These data indicate that acidic guanidine derivatives can ameliorate hyperglycemia in animal models of noninsuli n-dependent diabetes. Because acidic derivatives uniquely lack the pro pensity of guanidine compounds for inducing lactic acidosis, our findi ng suggests a new approach for developing improved antidiabetes compou nds from this chemical class.