Age increases the prevalence of type 2 diabetes (T2D) and insulin resistance (IR) accelerates the appearance of senescent β-cells, one of the hallmarks of aging. This suggests that senescence could contribute to the development of T2D and be a novel therapeutic target. In addition to improving blood glucose levels, exercise has been shown to attenuate all hallmarks of aging. However, the effects of exercise upon β-cell senescence remain to be determined. Our hypothesis is that exercise can decrease β-cell senescence and we aim to verify the effects of exercise upon senescence prevention and reversibility under control and IR conditions. Retired breeder male C57Bl/6 mice (6-8 months of age) were randomly assigned into groups (n=5/group): sedentary, exercised (treadmill running, 1 h, 5 times per week, for 2 weeks, at 17 cm/s and 5% incline) and IR (S961, 40nM/week for 2 weeks); exercise was performed at the same time, before or after IR to assess prevention and reversibility. ANOVA Brown-Forsythe and Welch were used to compare groups. Under control conditions, exercise decreased β-cell senescent markers (-58.1% p21Cip1 mRNA and -29% β-Galactosidase activity through FACS sorting), improved glucose tolerance (-13.6% in total area under the curve during intraperitoneal glucose tolerance test) and preserved suppression of basal insulin secretion when compared to sedentary (+39.3% insulin). Exercise performed before and during IR decreased mRNA levels of senescence marker and effector p16Ink4a by 41.7% and 80% respectively. Basal insulin secretion was decreased, and glucose-stimulated insulin secretion restored. When performed after IR, exercise decreased p16Ink4a mRNA by 62.4% and restored basal insulin secretion with no change in the stimulation index.
In conclusion, exercise decreased the load of senescent cells in insulin resistant animals. Its effects were more effective before and during IR but it was also able to reverse some of the deleterious effects of IR converting it into a novel β-cell anti-aging strategy.
P. Carapeto: None. C. Aguayo-mazzucato: Consultant; Self; eGenesis.
Joslin Diabetes Center (to C.A-M.); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (to P.C.)