Metabolic Diseases Research, Upjohn Company, Kalamazoo, Michigan.
To evaluate the long-held concept that acidic guanidines lack glycemic effects, guanidinoalkanoic acids and the biguanide metformin (positive control) were administered to KKAy mice, a model of noninsulin-dependent diabetes. Two acidic guanidines, 3-guanidinopropionic acid (3-GPA) and guanidinoacetic acid, decreased the plasma glucose level; other compounds were ineffective. 3-GPA was more potent than even metformin. Insulin suppression tests in KKAy mice indicated that improved insulin sensitivity was the mode of action for 3-GPA. Glycemic effects in KKAy mice resulted from increased glucose disposal whereas gluconeogenesis, hepatic glycogen content and intestinal glucose absorption were unchanged. 3-GPA's glycemic effect was corroborated in two other models of noninsulin-dependent diabetes. In ob/ob mice, the compound reduced hyperglycemia, polyuria, glycosuria and hyperinsulinemia. In insulin-resistant rhesus monkeys, it increased the disappearance of i.v. glucose. The glycemic action of 3-GPA required the presence of some circulating insulin as well as hyperglycemia because the compound was ineffective in normoglycemic mice, insulinopenic Chinese hamsters and streptozotocin-diabetic rats. These data indicate that acidic guanidine derivatives can ameliorate hyperglycemia in animal models of noninsulin-dependent diabetes. Because acidic derivatives uniquely lack the propensity of guanidine compounds for inducing lactic acidosis, our finding suggests a new approach for developing improved antidiabetes compounds from this chemical class.