Strikingly, the impairments in glucose tolerance apparent in both male and female βVps13cKO mice vs. littermate controls at this age were abolished after maintenance on HFD. These findings demonstrate an interesting interaction between the inheritance of a genetic factor influencing risk, and age [as observed in human T2D, (87)] as well as sex and diet. The reasons for the difference in penetrance between the effects of Vps13c deletion observed here between male and female mice remain unknown but may reflect interactions with sex hormones at the level of the individual β-cell (46) or, alternatively, subtle differences in insulin sensitivity between the sexes that go on to influence the effect of perturbations in the β-cell on overall glucose homeostasis.