GSBS Dissertations and Theses

ORCID ID

0000-0003-0341-3903

Publication Date

2019-07-17

Document Type

Doctoral Dissertation

Academic Program

Translational Science

Department

Program in Molecular Medicine

First Thesis Advisor

Silvia Corvera, MD

Keywords

Gestational diabetes, adipose tissue, IGFBP5, PAPP-A

Abstract

Pregnancy induces maternal metabolic adaptations including mild glucose intolerance and weight gain in order to support fetal development and lactation. Adipose tissue (AT) function in gestation is featured by reduced insulin sensitivity and fat mass accrual which partly accounts for the weight gain in pregnant women and adaptation of glucose metabolism. A common metabolic pregnancy complication is gestational diabetes mellitus (GDM), a disease characterized by impaired glucose tolerance with onset in gestation. However, the relationship between AT expandability and glucose metabolism in gestation is not well understood. The goal of this thesis was to investigate the adaptations of human AT expansion induced by pregnancy, how these changes are reflected in pregnancies complicated with GDM and characterize a mouse model to study the mechanisms underlying this disease. This dissertation illustrates that pregnancy promotes AT expandability by a signaling mechanism between placental pregnancy-associated plasma protein-A (PAPP-A) and AT- insulin-like growth factor binding protein-5 (IGFBP5). In addition, gravidas with GDM showed impaired AT expansion. Studies investigating the relationship between PAPP-A and glycemic state demonstrated that low levels of PAPP-A in the 1sttrimester are highly associated with the development of GDM. Moreover, PAPP-A knockout mice exhibit reduced insulin sensitivity and impaired AT growth exclusively in gestation. These results expand the knowledge of AT biology in gestation and have the potential to improve maternal care by proposing PAPP-A as an early biomarker and possible therapeutic for GDM. It also introduces a new mouse model to study the etiology of gestational diabetes.

DOI

10.13028/8sqa-6q31

Rights and Permissions

Licensed under a Creative Commons license

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Wednesday, September 09, 2020

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