As a graduate student in evolutionary biology, Dr. Philip DiIorio studied the genetics of fish adaptation Sonoran guppies. During his post-doctoral work in the Department of Endocrinology at New England Medical Center in Boston and subsequently in the Diabetes Division here at UMass Medical School he developed his interests in the genetic mechanisms underlying pancreas development and insulin signaling in zebrafish.

 

The Research: Insulin Expression and Signaling During Pre-pancreatic Embryogenesis

 

Epidemiological and experimental evidence strongly suggest that reduced fetal growth predisposes humans and animals (including zebrafish) to develop metabolic disorders later in life – metabolic disorders that can lead to obesity, cardiovascular disease and insulin resistance (type 2 diabetes). In humans, low birth weight is associated with reduced fetal levels of Insulin-like Growth Factor (IGF) signaling components and insulin. Research has almost exclusively focused on IGF’s role in embryonic growth, but evolutionary and experimental evidence suggests an important role for insulin in this process.

 

Insulin and its receptors are expressed during very early embryonic development in zebrafish and many mammals, including humans. This expression occurs as early as one cell, prior to the formation of organs, including the pancreas and its insulin-producing ß cells.

Where does this early expression of insulin come from? What is its role this early in the development of an embryo? Insulin may in fact have a role in its own development by influencing the activities of pathways involved in gut development. By studying zebrafish, Dr. DiIorio hopes to identify the cells expressing pre-pancreatic insulin and the cells receiving the signal. According to Dr, DiIorio, “Zebrafish embryos are perfect for mechanistic studies of insulin signaling in early development. One mother lays about 200 eggs, they grow rapidly (the development of organs occurs within five days), and are amenable to DNA and mRNA overexpression, and pharmacological manipulation.”

 

He is using over-expression, dominant negative, and antisense morpholino approaches to modulate expression of insulin signaling pathway genes and to assess the effects on cell proliferation, cell survival and the development of organs. Hopefully the data will allow him to develop methods for conducting a cell-based, small molecule screen for compounds that modulate insulin signaling. Dr. DiIorio’s ground-breaking genetic analysis of insulin’s role in early embryogenesis may lay the foundation to identify potential therapeutics for metabolic diseases such as diabetes.