SUMMARY During pregnancy, maternal metabolism goes through a series of adaptations to meet the constant nutrient demand from the fetal compartment and prepare lactation. Failure of maternal metabolic adaptation causes gestational diabetes mellitus (GDM) and other complications. There is a significant increase in islet mass and insulin production during normal pregnancy. The pancreatic α-cells are the second primary endocrine cells in islets and regulate glucose metabolism mainly through the endocrine effects of glucagon. Although studies have reported that pregnancy may increase α-cell mass and maternal blood glucagon concentrations, there is a knowledge gap about the role of α-cells in controlling maternal metabolic adaptation. Our most recent study demonstrated the essential role of α-cells in maternal insulin production during pregnancy. First, we ablated α-cells in adult mice using an inducible genetic approach. Despite no significant change in fasting and randomly fed blood glucose concentrations, α-cell ablation improved glucose tolerance in non-pregnant mice. In contrast, a significant elevation of blood glucose concentrations and low insulin secretion were observed in α-null dams. Second, we treated pregnant mice with a glucagon receptor antibody during pregnancy to determine the contribution of glucagon in maternal metabolic adaptation. Surprisingly, glucagon receptor antagonism did not alter maternal blood glucose and insulin levels. Besides glucagon, α- cells also secret glucagon-like protein 1 (GLP-1). It is known that intraislet GLP-1 plays an important role in augmenting glucose-induced insulin production under metabolic stress conditions. Our study showed that GLP-1 receptor agonist restored insulin production and glucose metabolism in α-null dams. Therefore, we hypothesize that α-cells play a vital role in regulating maternal metabolic adaptation through the intraislet paracrine effects on insulin production. We will use the α cell-specific Pcsk1 gene, which directs GLP-1 production, knockout dams, and glucagon or GLP-1 reconstitution to verify this hypothesis. Mouse models with α cell-specific prolactin receptor (Prlr) gene knockout will be employed to verify the role of PL/PRLR in regulating α-cell adaptation to pregnancy and intraislet GLP-1 production. We will use the RNAseq approach to compare gene expression profiles in sorted α-cells from pregnant mice and hormone-treated human islets to determine how α-cell adapt to pregnancy. The success of this project will reveal a new underlying mechanism of maternal metabolic adaptation. It will significantly impact the research of both reproductive medicine and GDM.