Adaptive Changes in Glucose Homeostasis and Islet Function During Pregnancy: A Targeted Metabolomics Study in Mice

OBJECTIVE: Pregnancy is a dynamic state involving multiple metabolic adaptions in various tissues including the endocrine pancreas. However, a detailed characterization of the maternal islet metabolome in relation to islet function and the ambient circulating metabolome during pregnancy has not been established. METHODS: A timed-pregnancy mouse model was studied, and age-matched non-pregnant mice were used as controls. Targeted metabolomics was applied to fasting plasma and purified islets during each trimester of pregnancy. Glucose homeostasis and islet function was assessed. Bioinformatic analyses were performed to reveal the metabolic adaptive changes in plasma and islets, and to identify key metabolic pathways associated with pregnancy. RESULTS: Fasting glucose and insulin were found to be significantly lower in pregnant mice compared to non-pregnant controls, throughout the gestational period. Additionally, pregnant mice had superior glucose excursions and greater insulin response to an oral glucose tolerance test. Interestingly, both alpha and beta cell proliferation were significantly enhanced in early to mid-pregnancy, leading to significantly increased islet size seen in mid to late gestation. When comparing the plasma metabolome of pregnant and non-pregnant mice, phospholipid and fatty acid metabolism pathways were found to be upregulated throughout pregnancy, whereas amino acid metabolism initially decreased in early through mid pregnancy, but then increased in late pregnancy. Conversely, in islets, amino acid metabolism was consistently enriched throughout pregnancy, with glycerophospholid and fatty acid metabolism was only upregulated in late pregnancy. Specific amino acids (glutamate, valine) and lipids (acyl-alkyl-PC, diacyl-PC, and sphingomyelin) were found to be significantly differentially expressed in islets of the pregnant mice compared to controls, which was possibly linked to enhanced insulin secretion and islet proliferation. CONCLUSION: Beta cell proliferation and function are elevated during pregnancy, and this is coupled to the enrichment of islet metabolites and metabolic pathways primarily associated with amino acid and glycerophospholipid metabolism. This study provides insight into metabolic adaptive changes in glucose homeostasis and islet function seen during pregnancy, which will provide a molecular rationale to further explore the regulation of maternal metabolism to avoid the onset of pregnancy disorders, including gestational diabetes.