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Compound 21 ameliorates type 2 diabetes in Zucker diabetic fatty rats by islet preservation (1108.13)

This study aimed to evaluate the therapeutic potential of Compound 21 (C21), a nonpeptide AT2R agonist, on type 2 diabetes in Zucker Diabetic Fatty (ZDF) rats. Rats received C21 infusion (0.3 mg/rat/day; saline as the control) from the age of 4 weeks to 16 weeks. The blood glucose, water intake, and urine excretion were monitored weekly. At the end of C21 treatment, the islet function, morphology, endoplasmic reticulum (ER) stress markers, beta‐cell proliferation markers, and apoptosis were examined by oral glucose tolerance test, immunofluorescence, western blotting, and TUNEL staining. The serum insulin concentration was measured by ELISA. We found that, compared with control ZDF rats, C21‐treated ZDF rats displayed significantly lower blood glucose, water intake, and urine excretion from the day 7 post C21 treatment. These rats also exhibited significantly less islet destruction, elevated serum insulin level (2.45 ± 0.21 vs 1.24 ± 0.04 ng/ml; P < 0.05), and improved glucose tolerance (peak glucose level: 131.5 ± 1.7 vs 219.0 ± 17.0 mg/dl; P < 0.05). In the islets of these rats, we found lower Bip (17.1 ± 1.24 vs 54.2 ± 3.6 %; P < 0.05) and Chop signals, less apoptosis (21.3 ± 1.07 vs 61.0 ± 5.34 %; P < 0.05), and up‐regulated Ki67 expressions. Our data suggested that C21 treatment ameliorated type 2 diabetes by preserving islets through suppressing ER stress, attenuating apoptosis, and promoting proliferation of beta‐cells.