Antihyperglycemic action of guanidinoalkanoic acids: 3-guanidinopropionic acid ameliorates hyperglycemia in diabetic KKAy 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 (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.
Metabolic Diseases Research, Upjohn Company, Kalamazoo, Michigan.
M D
MD
Meglasson
J M
JM
Wilson
J H
JH
Yu
D D
DD
Robinson
B M
BM
Wyse
C J
CJ
de Souza
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000493:pharmacokinetics*; D006003:Glycogen / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance; D007408:Intestinal Absorption; D008112:Liver Glycogen / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009132:Muscles / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001786:Blood Glucose; D006146:Guanidines; D007328:Insulin; D008112:Liver Glycogen; D011422:Propionates; D006003:Glycogen; D008687:Metformin; D005947:Glucose; C005775:guanidinopropionic acid