Angiotensin II Type 2 Receptor Activation With Compound 21 Augments Islet Function and Regeneration in Streptozotocin-Induced Neonatal Rats and Human Pancreatic Progenitor Cells

OBJECTIVES: We investigated the effects of compound 21 (C21), a nonpeptide angiotensin II type 2 receptor agonist, on islet cell function and survival in streptozotocin (STZ)-treated neonatal rats and human pancreatic progenitor cells. METHODS: Neonatal rats were randomized into 5 groups, including a control, an STZ (100 mg/kg, intraperitoneally), and 3 STZ + C21 (0.25, 0.5, and 1 mg/kg per day for 7 days, intraperitoneally) groups. Body weight and blood glucose were monitored daily. On the last experimental day, serum insulin levels and glucose tolerance were assessed, and the rat pups' pancreata were extracted for examination of islet cell function/mass and involvement of signaling pathways. RESULTS: The C21-treated STZ rats, particularly in the 0.5- and 1 mg/kg-dosage groups, had significantly decreased blood glucose, increased serum insulin concentrations, higher glucose-stimulated insulin secretion activity, and greater islet-cell mass and up-regulated expression of insulin and Ngn3 in the pancreas than did the control groups; these rats also demonstrated increased β-cell proliferation, lower superoxide levels and enhanced SOD1 expression, and up-regulated phospho-AKT expression; consistently, similar results were also observed in human pancreatic progenitor cells. CONCLUSIONS: These data suggest that C21 has a beneficial effect on islet cell function and regeneration, probably via proliferative and antioxidative pathways.