Pyrazinoylguanidine (PZG) is a new antihyperglycemic, antihyperlipidemic drug. The current study reports on the development of an animal model in which the favorable metabolic effects of PZG, previously described in diabetic patients, could be reproduced and investigated. Adult* male as well as female Sprague-Dawley rats received a single intraperitoneal dose (50 mg/kg) of streptozotocin (STZ). One week later, they received PZG (50 mg/kg i.p.) twice daily for a week. Compared to vehicle (saline-treated controls), PZG reduced plasma concentrations of glucose by 33–70%, triglycerides by 50–70%, nonesterified fatty acids by 17–27%, cholesterol by 10–50%, and glucagon by 18–20%. Hydrochlorothiazide given in a dose of 20 mg/kg i.p. b.i.d for 1 week induced metabolic effects opposite to those of PZG. In the Zucker fatty rat, PZG also lowered plasma glucose and lipid concentrations. These results indicate that PZG ameliorated the abnormalities of plasma glucose and lipid that characterize STZ-diabetic and Zucker fatty rats.

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