1332-P: Lactation Improves Glucose Homeostasis by Enhancing ß-Cell Mass and Function through Serotonin Production

Parous women who did not lactate have increased risk of diabetes compared to nulliparous women, but this risk is normalized by lactating for >3 months. However, the mechanism of the beneficial effects of lactation has not been elucidated. Therefore, we compared metabolic phenotypes including β cell characteristics in lactating and non-lactating humans and mice. For the human study, we recruited gestational diabetes and gestational impaired glucose tolerance women, and performed 75 g oral glucose tolerance test at postpartum 2 months and annually thereafter. Both lactating and non-lactating women showed normal glucose tolerance after 2 months of lactation. However, after a mean 3.6 years from delivery, lactated women maintained similar glucose tolerance whereas glucose tolerance deteriorated over time in non-lactated women. The Disposition index was improved in previously lactated women, suggesting improved β cell function after several years of delivery. For the mouse study, nine-week-old female C57BL/6J mice were mated to give birth and pups were either left (Lactating) or removed (Non-lactating) from the cage at the day of delivery. At 3 weeks after delivery, lactating mice had improved glucose tolerance and increased β cell mass compared to non-lactating mice. Lactating mice maintained high serum prolactin levels, which induced serotonin production in β cell via PRLR-STAT5-TPH1 cascade. Serotonin facilitated β cell proliferation and enhanced β cell function in lactating mice. Amelioration of glucose tolerance and β cell function were maintained for several months after the cessation of lactation in mice. These beneficial effects of lactation, however, were diminished in β cell-specific Tph1 knockout mice. We demonstrated a novel mechanism of 5-HT derivatives acting as a direct anti-oxidant to enhance β cell survival upon oxidative stress.

In conclusion, serotonin contributes to the beneficial metabolic effects of lactation by enhancing β cell mass and function.