Context/Objective: Hyperinsulinism with islet cell hyperplasia is a frequent complication, of unknown cause, in hemolytic disease of the newborn (HDN), occurring in Rh(D) positive infants of Rh-isoimmunized Rh(D) negative mothers, but not in infants with other hemolytic disorders. We investigated the possibility that trans-placentally acquired anti-D immunoglobulin is the cause of both conditions.

Design: Monolayer cultures of human islet cells, were exposed to sera from Rh-isoimmunized mothers and newborns, where jaundice, hyperinsulinism and hypoglycemia in the infant, had ensued. Parallel cultures with anti-D, specific anti-D monoclonal antibodies, normal human immunoglobulin (15 µg/ml) and serum controls were also undertaken. Islet cell proliferation was determined by ³H-thymidine incorporation. Insulin storage and chronic and acute insulin secretion to glucose were analyzed by radioimmunoassay. Rh(D) surface antigen expression was determined on islet cells by flow cytometric analysis.

Results: Islet cell proliferation and insulin secretion were significantly greater in co-culture with test sera (P < 0.01) (n = 8) and with anti-D (P < 0.001) (n = 8), compared with either controls or immunoglobulin. Following eight days of growth, the static incubation experiment showed a 3.5-fold response to glucose stimulus in all sera. Rh(D) antigen expression was detected on the islet cell surface by flow cytometry, and islet cell morphology was normal. Co-localization of the proliferation marker, Ki67, with insulin by immunofluorescent staining further indicated that Rh(D) antibody promoted islet growth.

Conclusions: The anti-Rh(D) islet cell proliferative effect generates neonatal hyperinsulinism in Rh-isoimmunisation. Anti-Rh(D) may have application for islet cell proliferation in diabetes mellitus treatment for Rh(D)-positive subjects. Further analysis is required.