Gene-environment interaction in islet serotonin metabolism and impacts on maternal glucose homeostasis

ABSTRACT Gestational diabetes is characterized by chronic maternal hyperglycemia during pregnancy without a prior diagnosis of diabetes. It is a very common obstetric complication affecting ~10-25% pregnant women globally. Because women with gestational diabetes are more likely to have other pregnancy complications, deliver large

for gestational or premature babies, and develop type II diabetes, gestational diabetes poses a serious threat to the health of mother and baby. Although some risk factors have been defined, the underlying mechanisms are complex and the precise etiologies are poorly understood. Recent studies show that pancreatic serotonin

signaling plays a critical role in maternal glucose homeostasis. Increased serotonin synthesis in the pancreatic islet is a critical event that promotes beta cell proliferation and increased insulin secretion that are needed to prevent maternal hyperglycemia during pregnancy. Dietary and genetic factors that reduce islet serotonin

synthesis are causatively linked to gestational diabetes in mice. Our preliminary studies show that low dose exposure to perfluorooctanoic acid (PFOA) is associated with reduced abundance of serotonin and its critical cofactor vitamin B6 in the pancreas from pregnant C57BL/6 mouse. These results are consistent with

epidemiological findings that PFOA exposure in pregnant women is linked to maternal hyperglycemia, insulin resistance, and glucose intolerance. Interestingly, DBA/2J mice exposed to PFOA do not develop gestational diabetes. The C57BL/6 and DBA/2J mice differ in their abilities to metabolize vitamin B6 due to differences in

activities of alkaline phosphatase (ALP). These results suggest that environmental exposure-induced gestational diabetes is modulated by genetic background and higher endogenous vitamin B6 level confers a protection. The overall hypothesis is that PFOA exposure in pregnant mice is causatively linked to gestational

diabetes through mechanisms that perturb serotonin metabolism in maternal pancreatic islets and the effects are modulated by genetic differences in vitamin B6 bioavailability. We propose to investigate beta cell proliferation and serotonin abundance in control and PFOA-exposed pregnant C57BL/6 mice to determine

whether the gestational diabetes is causatively linked to reduced beta cell expansion and reduced insulin secretion. We also wish to investigate whether treatment with an ALP inhibitor in the DBA/2J pregnant mice will reduce vitamin B6 in pancreatic islets and result in loss of protection to gestational diabetes. Finally, to

determine how pregnancy and gestational diabetes influence islet programming, we will perform RNA sequencing and Cleavage Under Targets and Tagmentation followed by sequencing to study changes in the transcriptome and epigenome in response to physiological changes and disease. The proposed research will

provide knowledge on mechanisms underlying gestational diabetes that benefit public health.