Metabolic effects of short-term caloric restriction in mice with reduced insulin gene dosage

Caloric restriction (CR) is the only environmental intervention with robust evidence that it extends lifespan and delays the symptoms of ageing, but its mechanisms are incompletely understood. Based on the prolonged longevity of knockout models, it was hypothesized that the insulin-IGF pathway could be a target for developing a CR mimic. This study aimed to test whether CR has additive effects on glucose homeostasis and beta-cell function in mice with reduced insulin gene dosage. To study models with a range of basal insulin levels, wildtype C57BL/6J and mice on an Ins2-/-background, were put on 8 weeks of 40% CR. Both male and female mice rapidly lost weight due to a reduced WAT mass. Interestingly, absolute BAT mass was increased in female Ins2-/-mice, suggesting the possibility of increased thermogenic capacity. Glucose tolerance was improved and fasting glucose levels were reduced by CR in both wildtype and 45 and 70 week-old Ins2-/-mice. The effects of CR and reduced insulin on glucose tolerance were non-additive in 20 week-old mice. Interestingly, mice on CR generally exhibited an inability to further depress blood glucose after insulin injection, pointing to possible alterations in insulin sensitivity. In conclusion, our results demonstrate that CR can cause weight loss in the context of reduced insulin production, but that CR-improved glucose homeostasis does not occur near the 'insulin floor' in young mice. Collectively, these data shed further light on the relationships between caloric restriction, insulin and glucose homeostasis.