Project Summary/Abstract
In collaboration with a non-human primate (NHP) consortium with over a decade of experience studying the
developmental origins of health and disease in response to maternal overnutrition, this proposal will evaluate
the effect that intrauterine exposure to metformin and overnutrition has on the development of pancreatic beta
cells and islet mitochondrial health in fetal Rhesus macaques. In the United States, 31% of women of
childbearing age are classified as overweight or obese. As global rates of obesity rise, the influence of
developmental exposure to maternal overnutrition and the drugs prescribed to treat maternal metabolic
disease on offspring metabolic outcomes is of critical interest. Metformin is typically prescribed for the
treatment of Type 2 Diabetes; however, use of metformin has been expanded over the past decade to
treatment for gestational diabetes, polycystic ovarian syndrome, and preeclampsia. Data suggests that
metformin crosses the placental barrier and equilibrates in fetal circulation, raising concerns for unintended
fetal harm. While the target of metformin is unknown, a proposed mechanism of metformin is activation of 5’
adenosine monophosphate kinase (AMPK), a nutrient sensing kinase that is central to regulation of pathways
associated with cellular growth, proliferation, metabolism, and epigenetic regulation. Metformin has also been
shown to inhibit complex I of the mitochondrial electron transport chain, reducing the production of ATP, which
is important for glucose-stimulated insulin secretion from beta cells. The goal of the studies outlined in this
proposal is to elucidate the influence that maternal consumption of a western style diet and metformin has on
beta-cell mass, identity, and function at the fetal stage of development in a highly relevant NHP model.
Additionally, this proposal includes studies investigating the individual and combined effects of maternal
overnutrition and metformin on islet mitochondrial morphology and function in offspring. To accomplish these
goals, I will use high resolution microscopy, real time metabolic analyses, and single nucleus RNA sequencing
to identify programmed mechanisms that may correlate to increased propensity for beta cell failure later in the
offspring’s life.
