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/
Md. Meglasson et al., 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/, The Journal of pharmacology and experimental therapeutics, 266(3), 1993, pp. 1454-1462
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.