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UBC Theses and Dissertations

Caloric restriction in the context of reduced insulin Dionne, Derek Alcide


Therapeutic benefits of caloric restriction (CR) on clinical outcomes in the treatment of neurodegenerative disease, cancer, cardiovascular disease, and diabetes have been found. Studies indicate the positive health outcomes produced by CR may involve cellular nutrient-sensing pathways including insulin/insulin-like growth factor 1 signalling. CR has been reported to have significant effects on glucose metabolism and body composition: lowering fasting blood glucose and insulin, improving glucose tolerance, insulin sensitivity and decreasing energy expenditure and body fat. However, it is not clear which, if any, of the effects of CR are due to the lowering of circulating insulin. To determine which CR effects are a function of circulating insulin-dependent mechanisms we placed female Ins1+/-:Ins2-/- mice and Ins1+/+:Ins2-/- littermate controls on either a chow diet ad libitum (AL) or on a CR diet where they were fed 60% of what their genotype-matched littermate controls ate daily. All mice were singly housed and CR mice fed at night. With the onset of CR, body mass in both genotypes fell and reached a new equilibrium by 20 weeks of age. As expected, mice on CR had lower fasting, fed plasma glucose and improved glucose tolerance when compared to AL controls. We observed a more rapid return to baseline glucose post-insulin injection in mice on CR and no difference in glucose-stimulated insulin secretion compared to AL littermates. CR was able to prevent an age-dependent decline in fasting insulin of Ins1+/-:Ins2-/- mice. Ins1+/+:Ins2-/- and Ins1+/-:Ins2-/- on CR also exhibited increased plasma leptin, glucose-dependent insulinotropic peptide, subcutaneous white and intrascapular brown adipose tissue size compared to the AL controls. The endocrine milieu created in these very low insulin mice appears to disrupt several well-established effects of CR on body composition, insulin and insulin sensitivity.

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