Endocrine Abstracts

Background: The Ins2^+/G32S mutation in the KINGS mouse drives beta-cell endoplasmic reticulum (ER) stress. The result of this is sexually dimorphic; males develop overt diabetes by 5-weeks (>16.7mM) whilst females remain normoglycemic. Previous studies have shown that high-fat feeding increases beta-cell ER stress, whilst GLP1-receptor agonists reduce this. We investigated whether altering ER stress could promote diabetes development in female KINGS mice or prevent it in males.

Methods: Female KINGS and WT mice were fed normal chow (NC) or a high-fat-high-sucrose (HFHS) diet from 3-weeks until 20-weeks. Blood glucose concentrations were monitored, and glucose tolerance tests performed. Western blotting was used to investigate ER stress in islets isolated from these mice. Male KINGS mice were injected daily with 200ug/kg liraglutide or PBS from 3-weeks until 6-weeks and daily blood glucose concentrations were measured and monitored for 2-weeks post-treatment.

Results: HFHS feeding increased several ER stress markers in the KINGS females compared to NC including BiP (expression fold WT-NC: HFHS-KINGS:3.236, NC-KINGS:1.769). Despite worsened glucose tolerance and a trend for increased non-fasted blood glucose concentrations (20-weeks: HFHS-KINGS:16.4mM± 7.2, NC-KINGS: 9.1mM± 1.6), HFHS-KINGS mice did not develop overt diabetes. Moreover, their fasted blood glucose concentrations were unchanged and non-fasted concentrations were substantially lower than those in age-matched NC-KINGS males (33.0mM± 5.0). Liraglutide significantly lowered blood glucose concentrations and prevented diabetes development in KINGS males (6-weeks:KINGS-Liraglutide:12.33mM± 1.7, KINGS-PBS:22.43mM± 3.1). However, treatment cessation resulted in increased blood glucose concentrations comparable to the KINGS-PBS group by 49-days.

Conclusions: HFHS feeding increased islet ER stress in the KINGS females but did not induce overt diabetes. Liraglutide prevented the development of diabetes in KINGS males, however this effect was not sustained post-treatment. This indicates that female KINGS mice can adapt to beta-cell ER stress whereas males cannot. In conclusion, sex differences remain despite manipulation of beta-cell ER stress levels.