Lactational Programming of Offspring Glucose Homeostasis and Body Composition by Early Postnatal Metformin Exposure

Abstract

Background: The early postnatal period is a critical window for programming of long-term metabolic health. Our previous studies have shown that gestational metformin exposure increases pancreatic beta-cell fraction at birth and improves glucose homeostasis in adulthood. Hypothesis: We hypothesized that metformin administration to dams during the critical window of lactation would alter neonatal nutrient exposure and the acquisition of the gut microbiome from the mother leading to a permanent change in offspring metabolic tissues. Methods: We used C57BL/6J mice for the developmental programming studies in this experiment. Metformin was delivered in drinking water to dams from postnatal day 1 (P1) and continued through the lactation period to P21 (Met PN group). Offspring were examined during lactation and as adults. Dams were examined during lactation and upon weaning. Gut microbe composition was determined by 16s sequencing in dams and offspring. Results: Dams on metformin showed improved glucose tolerance at weaning. Met PN pups had lower body weights that began during the first 3 weeks of life and persisted to 6 months. On intraperitoneal glucose tolerance testing male but not female offspring had improved glucose responses at 2 months and increased glucose stimulated insulin secretion. Met PN offspring had a lower body fat percentage at necropsy. Stool microbiome studies showed that Met PN pups had an altered intestinal colonization that persisted into adulthood with an increase in the bacteroidetes:firmicutes ratio at the time the lower weight trajectory was established. A lower bacteroidetes:firmicutes ratio has been associated with obesity. Conclusions: These findings suggest that limited early postnatal exposure to a dam on metformin results in long-term programming of offspring weight, insulin secretion and intestinal microbiome. Disclosure B. Gregg: None.