Objectives: N-AcGIP is a potent and dipeptidylpeptidasc IV-resistant analogue of glucose -dependent insulinotropic polypeptide with significantly improved antidiabetic actions in type 2 diabetes. The present study investigated the effects of subchronic treatment with N-AcGIP on glucose homeostasis in a type I model, namely, streptozotocin (STZ)-induced diabetic mice. Methods: Swiss TO mice given a single intraperitoneal injection of STZ (150 mg/kg body weight) received once-daily injection of N-AcGIP (25 nmol/kg body weight) or saline for 20 days and effects on metabolic parameters and islet architecture assessed. Results: Daily injection of N-AcGlP for 20 days did not significantly alter the characteristic STZ-induced changes of pancreatic insulin content, body weight, food intake, glucose, and,glycated hemoglobin levels. Glucose tolerance and insulin sensitivity were also unchanged by N-AcGIP treatment. Circulating insulin was undetectable, and the number of intact islets and insulin expression was greatly reduced in both groups. Some proliferative activity was identified by 5-bromo-2-deoxyuridine staining in the pancreas, but this and expression of glucagon and somatostatin were similar in the 2 groups. Conclusions: These data indicate that subchronic treatment with the Iona-acting glucose-dependent insulinotropic polypeptide receptor agonist, N-AcGIP, does not have beneficial effects in insulin-deficient STZ-diabetic mice. This supports the primary antidiabetic action of this analogue in type 2 diabetes as stimulation of P-cell function and insulin secretion.