Kinkel Lab

Developmental Biology of the Pancreas

Our lab investigates how an embryo makes a pancreas. We study the signaling molecules that are required for generating the endocrine (hormone-secreting) pancreas from the early, undifferentiated endoderm. One of our goals is to understand the network of molecular interactions required for endocrine pancreas specification and differentiation. We are focused on the beta-cell, which secretes insulin in order to maintain blood glucose homeostasis. Beta-cell dysfunction or loss results in diabetes, which affects nearly 8% of the U.S. population. We believe that in vivo studies of beta-cell development will yield insights relevant for therapeutic treatments of diabetes. Important questions include how is the size of the pancreas determined during embryonic development? How is beta-cell mass expanded and then maintained throughout life? Do new beta-cells arise strictly from pre-existing beta-cells? Is there a resident stem cell capable of repopulating the islet following injury? Ultimately, we would like to learn from the embryo how beta-cells are specified, expanded, and renewed. Study of pancreas development is relevant not only for advancing our basic understanding of this organ, but also for potentially improving treatments for human diabetics. 
 

We use the zebrafish as a model because it offers several advantages as a genetic and cell biological system:  

  • Embryos are fertilized externally. This allows us to easily observe development from the one cell stage. Ease of access allows cellular manipulations such as transplanting cells between embryos, and microinjection of reagents including mRNAs, DNAs, and antisense morpholinos.
     
  • Embryos are transparent. In combination with fluorescent transgenes, the transparency allows us to image gene expression in live embryos, in real time. 
  • Development is rapid. The embryo completes gastrulation by 10 hours post fertilization. Pancreas-specific gene expression begins a few hours later, and the first pancreatic islet is formed by the end of the first day of development. 
Live, 2 day old, larval zebrafish expressing green fluorescent protein in the pancreatic beta-cells.

Live, 2 day old, larval zebrafish expressing green fluorescent protein in the pancreatic beta-cells.

 

Beta-cell Function Studies

 
Our lab studies the role of the beta-cell in maintaining blood glucose homeostasis. One of our goals is to understand how specific developmental defects can result in failure of the beta-cell to properly regulate blood glucose levels. We have developed tools that allow us to measure blood glucose and circulating insulin in adult zebrafish. We have also developed several zebrafish lines that express transgenes for human insulin mutations. In humans, these mutations cause beta-cell apoptosis, and the resulting loss of cell mass leads to hyperglycemia. Unlike mammals, zebrafish are able to regenerate their beta-cells and to maintain blood glucose homeostasis despite expressing mutant insulin. This model allows us to investigate the mechanisms that permit beta-cell regeneration in the zebrafish.

Contact Information for Kinkel Lab:
 
Mary Kinkel, PhD
Associate Scientist
Sanford Children's Health Research Center
2301 E 60th St N
Sioux Falls, SD 57104

email: Mary.Kinkel@SanfordHealth.org
phone: 605-312-6421