Mechanisms of beta-cell deficiency in gestational diabetes and strategies to reverse hyperglycemia

Gestational diabetes mellitus (GDM) is an increasingly prevalent form of diabetes that first appears during pregnancy, and reverses after parturition in most cases. Nonetheless, GDM is associated with adverse maternal and fetal health outcomes. There is currently no reliable method of intervention for GDM and a limited understanding of the mechanisms of impaired endocrine adaptability in GDM. In this thesis, I aimed to address these knowledge gaps by establishing a mouse model for the study of suboptimal endocrine adaptations during pregnancy. This was accomplished using a dietary low protein (LP) insult during fetal and neonatal development, which programs for suboptimal pancreas development in the offspring, and performing histomorphometric analyses on fixed pancreas tissues. Female offspring displayed glucose intolerance during their own pregnancy that was apparent by gestational day (GD) 18.5 and characterized by reduced β-cell mass (BCM) and α-cell mass (ACM) relative to control-fed animals. Using this model, I provided evidence that pancreatic maladaptations at GD18.5 persisted at postpartum day 7.5, contributing to glucose intolerance until 1 month after parturition. To provide mechanistic insights of reduced BCM expansion in GDM, I investigated the contribution of α- to β-cell transdifferentiation via immunofluorescence cell counting analysis of fixed pancreas tissues. I identified maladaptations of α-cell plasticity in glucose-intolerant mice, as demonstrated by reduced α-cell proliferation, leading to reduced ACM expansion relative to controls. Additionally, these animals presented with hyperglucagonemia. These findings demonstrated that, in addition to β-cells, insufficient pancreatic α-cell adaptations can also contribute to GDM pathogenesis. Although there were differences in the percentages of bihormonal (Insulin+Glucagon+) cells in LP vs. control pregnancy, genetic lineage tracing in control pregnancy using Glucagon-Cre/Rosa26-eYFP mice revealed a negligible amount of α- to β-cell transdifferentiation contributing to BCM expansion. Finally, I used the animal model to test a therapeutic intervention for GDM through the attempted manipulation of BCM using the artemisinin, artesunate. Artesunate-treated animals had improved glucose tolerance, although the glucose-lowering effect was attributed to the acetone vehicle. Collectively, this thesis has identified mechanisms of impaired endocrine pancreas adaptability in GDM and has established a mouse model that can be used to explore novel therapeutics