Sex steroids influence pancreatic islet hypertrophy and subsequent autoimmune infiltration in nonobese diabetic (NOD) and NDDscid mice

Female nonobese diabetic (NOD) mice more frequently develop autoimmune diab etes than NOD males. Orchidectomy of the latter aggravates insulitis and di abetes. Because clear differences in immune function have not been observed between prediabetic females and males, before or after castration, we hypo thesized that sex-related differences in diabetes incidence are related to target organ-specific actions of sex steroids. Previously, we showed that p rediabetic NOD females develop hyperinsulinemia and subsequently mega-islet s. Infiltration of the first inflammatory leukocytes is predominantly assoc iated with these mega-islets. Here, we determined the relationship between sex hormones, mega-islet formation, and infiltrating cells in NOD and nonob ese diabetic/severe combined immune-deficient (NODscid) mice. Mega-islet fo rmation was reduced in NOD males compared with NOD females, and orchidectom y increased it, indicating a relationship between androgen levels and mega- islet formation. Moreover, enhanced mega-islet formation in castrated NOD m ales was associated with increased numbers of infiltrating leukocytes. Cast rated NODscid males also exhibited increased mega-islet formation and dendr itic cell infiltration, indicating that lymphocytes are not required for ca stration-induced effects. In conclusion, we show that androgens influence p ancreatic islets and autoimmune infiltration in NOD and NODscid mice. This suggests that the gender difference in diabetes incidence in NOD mice is re lated to target organ-specific androgen effects.