Doctor of Philosophy
Physiology and Pharmacology
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.
Summary for Lay Audience
Diabetes occurs when there is a loss or dysfunction of insulin-producing β-cells in the pancreas, leading to elevated blood sugar levels. Diabetes is often classified as either being type 1 or type 2. However, gestational diabetes mellitus (GDM) is another type of diabetes that first presents during pregnancy and is becoming increasingly prevalent. Although human pancreas samples during GDM are scarce, it is believed that β-cell dysfunction is a major driver of GDM pathogenesis. In this thesis, I sought to develop a mouse model that can be used to better understand the reasons for suboptimal pancreas adaptations in GDM. First, I established the mouse model using a dietary insult (low protein) during early life, which results in suboptimal pancreas development in the offspring. As is diagnosed in humans, these animals presented with GDM identified during late gestation (which in mice is around gestational day 18.5) due to impairments in β-cell number and the capacity for insulin release. Since many women go on to develop type 2 diabetes mellitus after delivery, I also presented evidence that these impairments in the pancreas are still present following birth and contribute to high blood sugar levels until at least one month postpartum. Using our mouse model, I demonstrated that diabetes develops not only due to impairments in β-cells, but also due to abnormalities in pancreatic α-cells, which work antagonistically with β-cells to secrete glucagon. Finally, I identified a therapeutic effect in GDM where there was a reversal of diabetes in animals treated with a chemical that likely damages the gut equivalent to transient fasting. This thesis characterized a novel mouse model of GDM and provides new information about mechanisms of suboptimal pancreas adaptations that can be used to explore methods of treatment.
Szlapinski, Sandra K., "Mechanisms of beta-cell deficiency in gestational diabetes and strategies to reverse hyperglycemia" (2020). Electronic Thesis and Dissertation Repository. 7217.
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