Vitamin B6 Deficiency During Pregnancy: A Mouse Model to Study Mechanisms Underlying Gestational Diabetes Mellitus

• Main Author: Fields, Ashley M
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2021
• Subjects: Endocrinology; Medicine; Obstetrics; Public health
• ISBN: 9798708748577

Gestational diabetes mellitus (GDM) is a metabolic disorder characterized by hyperglycemia and glucose intolerance during pregnancy. GDM affects one out of every ten pregnancies and poses significant maternal and fetal health complications. Although risk factors have been associated with GDM, the etiology remains unknown, and thus elucidating the underlying mechanism of GDM would greatly benefit prevention, intervention, and management strategies. Human and mouse studies have demonstrated that failure of pancreatic beta (β)-cell expansion is associated with GDM, and this process is dependent of serotonin signaling via serotonin receptor 2B (HTR2B). During pregnancy, pancreatic islet serotonin synthesis is upregulated via increased tryptophan catabolism, promoting β-cell proliferation, and high β-cell number prevents maternal hyperglycemia. In mice, manipulation of the tryptophan-serotonin pathway reduces both maternal serotonin levels and β-cell number, and these changes are associated with gestational glucose intolerance. Interestingly, the tryptophan-serotonin pathway is highly dependent on vitamin B6 bioavailability, suggesting that maternal vitamin B6 status may adversely influence glucose homeostasis during pregnancy. Although, vitamin B6 deficiency is the leading nutritional deficiency in the United States, affecting ~40% of women of reproductive age and pregnant women, its impact on maternal glucose homeostasis has not been thoroughly investigated. My dissertation investigates the role of vitamin B6 in modulating maternal glucose homeostasis during pregnancy. As part of my thesis work, I developed a novel GDM mouse model via dietary vitamin B6 restriction. This mouse model is translatable because the level of vitamin B6 in these mice reflects a mild vitamin B6 deficiency status in the human population. My work shows that vitamin B6 deficient mice develop maternal hyperglycemia and glucose intolerance due to reduced pancreatic islet serotonin synthesis and reduced β-cell proliferation, which can be rescued with an HTR2B agonist. Additionally, my work highlights that genetic differences in vitamin B6 metabolism significantly modulates risk for GDM. In mice, strain-specific differences in vitamin B6 metabolism are causatively linked to differences in susceptibility to gestational diabetes, e.g., C57BL6/J mice are more susceptible and DBA/2J mice resistant due to genetic differences in vitamin B6 metabolism. Overall, my findings show that maternal status of vitamin B6 during pregnancy significantly influences risk for GDM and suggest that pregnant women should be screened for vitamin B6 deficiency to determine if they are at risk at developing GDM. The findings in this dissertation will advance the field of maternal medicine and provide a better understanding of GDM etiology.