We investigated the effects of exendin-4 (Ex4) treatment on expression of clusterin and beta cell regeneration in the endocrine pancreas in neonatal streptozotocin (nSTZ) diabetic rats. Three groups were used: (1) n2-STZ group; on the second day after birth 100 mg/kg STZ was given i.p. to two groups of newborn rats, (2) n2-STZ+Ex4 group; 3 mu g/kg/day Ex4 was given for 5 days starting on the third day, and (3) control group. In situ hybridization for mRNAs of insulin and clusterin, double immunostaining for insulin/clusterin and insulin/BrdU were carried out. Immunostaining for insulin, glucagon, somatostatin, clusterin, synaptophysin and pdx-1 was performed. In the n2-STZ + Ex4 group, BrdU/insulin and insulin/clusterin immunopositive cells were significantly increased in the islets of Langerhans in comparison to the other groups. The areas occupied by the insulin mRNA and peptide positive cells and also pdx-1 immunopositive cells were decreased in the n2-STZ diabetic group compared with the other groups. The clusterin mRNA and protein positive cells, and also the glucagon and somatostatin cells, were significantly increased in the islets of the n2-STZ and the n2-STZ + Ex4 groups compared with the control group. The results show that Ex4 treatment induces new beta cell clusters via up-regulation of clusterin, which might be effective on beta-cell proliferation and neogenesis. (C) 2012 Elsevier GmbH. All rights reserved.