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Des-Aspartate-Angiotensin I Exerts Hypoglycemic Action via Glucose Transporter-4 Translocation in Type 2 Diabetic KKAy Mice and GK Rats

Departments of Pharmacology (M.-K.S., X.-G.X., Y.-C.W., S.-Z.S.) and Department of Medicine (K.-O.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Address all correspondence and requests for reprints to: Meng-Kwoon Sim, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. E-mail: phcsimmk{at}nus.edu.sg.

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 angiotensin converting enzyme 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 nmol/kg·d for 4 and 6 wk, 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 killed, and the levels of plasma membrane glucose transporter-4 and cytosolic tyrosine-phosphorylated insulin receptor substrate-1 in hind limb skeletal muscles were determined by Western blot in insulin-challenged and nonchallenged 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 wk of treatment, respectively. At the maximal effective dose of 600 nmol/kg, insulin induced a significant increase in plasma membrane glucose transporter-4 and cytosolic tyrosine-phosphorylated insulin receptor substrate-1. These findings show that DAA-I is not an insulin secretagogue and exerts hypoglycemic action by attenuating insulin resistance, the first such demonstration indicating that the nonapeptide is involved in glycemic regulation.