Effects of Maternal Metformin Exposure during Lactation on Mouse Offspring Metabolic Health

Presentation Number: SUN 584
Date of Presentation: April 2nd, 2017

Brigid Gregg*1, Joshua Donnelly Brill2, Nathalie Botezatu3, Hannah Hafner4, Allen Zhu4 and Ernesto Bernal-Mizrachi5
1University of Michigan, Ann Arbor, MI, 2Albany Medical College, NY, 3Michigan State University Medical School, MI, 4University of Michigan, MI, 5University of Miami, Miami, FL

Abstract

Background: Metformin administration during pregnancy has become more accepted as a treatment for gestational diabetes. Clinical trials are underway to investigate the potential benefits of metformin use during lactation to improve milk output in mothers at high risk of lactation failure. The early postnatal period is a critical window for programming of long-term metabolic health. Our previous studies have shown that metformin exposure during gestation increases pancreatic beta-cell fraction at birth.

Hypothesis: We hypothesized that metformin administration during the critical window of early postnatal life would have a permanent impact on long-term offspring metabolic health and programming of pancreatic beta-cells.

Methods: We used a rodent model of 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 throughout the lactation period to P21 (Met PN group). The metformin exposure ceased at the time of weaning. Offspring were examined during lactation and as adults for pancreas morphology and glucose homeostasis. Mothers were examined during lactation and upon weaning.

Results: Dams given metformin from day 1 of life showed no change in milk output in estimated milk volume experiments but had a modest decrease in milk protein. Metformin exposed pups had decreased body weight during the first 3 weeks of life. The pups also demonstrated an increase in pancreatic beta-cell mass at postnatal day 11 (P11). In vitro islet studies showed no difference in insulin secretion or content at this time point. On intraperitoneal glucose tolerance testing male offspring exhibited improved glucose tolerance at 2 months of age and an increase in glucose stimulated insulin secretion. Offspring body weight in this experiment was lower than control pups and remained so throughout young adulthood. Stool microbiome studies demonstrated an altered intestinal colonization that persisted into adulthood.

Conclusions: These findings suggest that metformin may have an impact on milk nutrient composition. This early postnatal treatment of dams with metformin also results in long-term programming of offspring metabolic health and intestinal microbial community.

 

Nothing to Disclose: BG, JDB, NB, HH, AZ, EB