Endocrine Abstracts

The KINGS mouse harbours a mutant Ins2 which drives beta cell ER stress, however only males develop diabetes. Since diabetes incidence is lower in women and ER stress is implicated in human diabetes, we investigated the influence of oestrogen and testosterone in mediating sex differences in the KINGS mouse. To investigate the influence oestrogen (E2) and testosterone removal on glycaemic control, male (n =4-6) and female (n =9) KINGS mice underwent pre- or post-puberty gonadectomies. In a separate study, KINGS males were administered oestrogen from 3-weeks (n =5-7). Glycaemic control was measured through non-fasted blood glucose (NFBG) measurements. Direct beta cell effects of sex hormone removal/administration were investigated through insulin secretion assays using isolated islets and assessing beta cell ER stress using immunofluorescence. Female KINGS ovariectomy mildly increased NFBG but did not cause diabetes, despite increasing beta cell ER stress (10wk BiP fluorescence (AU): Ovariectomy:29.1±1.2, Sham:21.9±1.7, P<0.05) and impairing islet glucose stimulated insulin secretion (ng/islet/h at 20mM glucose: Ovariectomy:0.10±0.03, Sham: 0.15±0.05, P<0.05). Oestrogen administration in KINGS males prevented diabetes (6-week NFBG: E2:11.2mM±1.0, Vehicle:17.5mM±2.3, P<0.05) and was found to reduce beta cell ER stress (BiP fluorescence (AU): E2:40.6±1.7, Vehicle:48.7±1.8, P<0.05) and improve islet glucose stimulated insulin secretion (ng/islet/h at 20mM glucose: E2:0.02±0.003, Vehicle: 0.004±0.001, P<0.05). Orchidectomy in male mice similarly prevented the development of overt diabetes (10-week NFBG: Orchidectomy:10.4mM±1.1, Sham:25.7mM±2.2, P<0.05). Oestrogen was found to have protective effects on the beta cell through reducing beta cell ER stress and improving glucose stimulated insulin secretion. Whilst oestrogen administration rescued male KINGS mice from developing diabetes, ovariectomy was not associated with overt diabetes in female KINGS mice. This suggests that oestrogen is not solely responsible for driving sex differences in diabetes, and indeed testosterone also seems to be involved.