Litter size affects the beta-cell proliferative response during puberty in male rats

Puberty is associated with a transient period of insulin resistance. In children with overweight, insulin resistance persists after puberty leading to an increased risk of type 2 diabetes in adulthood. How beta cells adapt to pubertal insulin resistance is unknown. In a recent study, we observed a loss of insulin sensitivity and a transient increase in beta-cell proliferation in male and female rats during puberty. We further showed in culled litters of male rats (females sacrificed at 8–10 days) that pubertal serum triggers beta-cell proliferation in isolated islets, suggesting the involvement of a circulating factor. However, pubertal serum collected from male and female animals of unreduced litters did not significantly increase beta-cell proliferation. Objective: To evaluate the impact of rat litter size on the ability of pubertal serum to increase beta-cell proliferation in male rat islets. The proliferative effect of pubertal serum (D37) on isolated islets was assessed by flow cytometry for EdU and insulin using serum collected from animals of unreduced litters (males and females) vs reduced litters (males only). Exposure of male pubertal rat islets to 10% pubertal serum from unreduced litters for 72h did not increase beta-cell proliferation compared to weaning serum (D21) (fold change: 1.1±0.2 vs 0.9±0.2 %, n=3, NS). In contrast, exposure of male pubertal rat islets to 10% pubertal serum from reduced litters for 72h increased beta-cell proliferation (fold change: 1.4±0.1 vs 0.9±0.2 %, n=3, p<0.05). The absence of a proliferative effect of pubertal serum in unreduced litters was accompanied by lower body weight at weaning in males compared to the reduced litters (57±6 vs 73±4 g, n=13–19, p<0.0001). Litter size impacts the ability of pubertal serum to stimulate beta-cell proliferation in male rats.