A significant reduction of beta cell mass has been described during the post partum period in the endocrine rat pancreas. We examined the mechanisms of this involution in Sprague Dawley rats by analyzing beta cell mass, beta cell replication, and beta cell size at end of pregnancy and 4 and 10 days after delivery. beta cell replication was significantly decreased at 4 days post partum but had returned back to nonpregnant levels by 10 days post partum. Similarly, beta cell size was significantly decreased at 4 and 10 days post partum as compared with the end of pregnancy, and at 10 days post partum was significantly decreased as compared with controls. At 4-6 days post partum, DNA fragmentation characteristic of apoptosis (programmed cell death) was detected in pancreatic islets, as assessed by in situ terminal deoxynucleotidyl transferase and nick translation assay. Only occasional cells were labeled with this assay in nonpregnant rats and at other time points after delivery. Condensed chromatin and apoptotic bodies, the morphological characteristics of apoptosis, were detected in beta cells of pancreatic islet at 3 and 4 days after delivery by electron microscopic analysis, confirming the occurrence of apoptosis in involuting islets. The expression of TRPM 2 and TGF beta 1, often enhanced in models of apoptosis, were studied during the post partum period by Northern blot analysis and immunohistochemistry. Levels of TRPM 2 gene and its protein, clusterin, were not different from controls; however, the TGF beta 1 gene and its protein expression were enhanced at 3 days post partum. Our study confirms the capability of beta cells to down-regulate their mass using the mechanisms of changes in rates of beta cell replication and of beta cell death, and changes in beta cell size to achieve homeostasis of the functional endocrine tissue.