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Antihyperglycemic action of guanidinoalkanoic acids: 3- guanidinopropionic acid ameliorates hyperglycemia in diabetic KKAy and C57BL6Job/ob mice and increases glucose disappearance in rhesus monkeys

MD Meglasson, JM Wilson, JH Yu, DD Robinson, BM Wyse and CJ de Souza

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.

Volume 266, Issue 3, pp. 1454-1462, 09/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1993 by the American Society for Pharmacology and Experimental Therapeutics.