The present study investigated the hypoglycemic action of des-aspartate-angiotensin I (DAA-I), a metabolite of angiotensin I, in two animal models of type 2 diabetes. The rationale was based on our earlier studies demonstrating that DAA-I acts on the angiotensin AT₁ receptor and exerts responses opposing those of angiotensin II, and on recent reports that curtailment of angiotensin II formation by ACE inhibitors and blockade of the AT₁ receptor attenuate hyperglycemia in type 2 diabetics and diabetic animals. Diabetic KKAy mice and GK rats were administered orally (by gavage) one of the following doses of DAA-I: 400, 600 or 800 nmole/kg/day for 4 and 6 weeks, respectively. Control diabetic animals were similarly administered water. Blood glucose of each animal was determined fortnightly by oral glucose tolerance test, and blood insulin on the last day of treatment. Animals were sacrificed and the level of plasma membrane GLUT4, and cytosolic tyrosine phosphorylated IRS-1 in hind limb skeletal muscles were determined by Western blot in insulin-challenged and non-challenged animals. Orally-administered DAA-I had no effect on blood insulin level, but exerted dose-dependent hypoglycemic action in KKAy mice and GK rats after 4 and 6 weeks of treatment, respectively. At the maximum effective dose of 600 nmole/kg, insulin induced a significant increase in plasma membrane GLUT4 and cytosolic tyrosine phosphorylated IRS-1. These findings show that DAA-I is not an insulin secretagogue and exerts hypoglycemic action by attenuating insulin resistance, a first of such a demonstration indicating that the nonapeptide is involved in glycemic regulation.