Barton Wicksteed, MD

Research Interests

My research interests are based upon the control of glucose homeostasis by hormones secreted from the islets of Langerhans. I am interested in both the islet ß-cells, which secrete insulin to promote insulin uptake and storage and the islet α-cells, which secrete glucagon to counter-regulate the effects of insulin.

Cyclic AMP signaling in the islet ß-cell

Cyclic AMP is an important signaling molecule in the ß-cell. It has wide ranging effects in the ß-cell that protect ß-cell mass through effects upon ß-cell survival and proliferation and enhance ß-cell function by stimulating insulin secretion, proinsulin translation and preproinsulin mRNA levels. Due to these effects upon the ß-cell there is considerable interest in exploiting cAMP to protect ß-cell mass and improve ß-cell function in diabetes. However the signaling pathways by which cAMP acts in the ß-cell are poorly understood. cAMP signals are transduced mainly via two pathways in the ß-cells, the cAMP dependent protein kinase (PKA) and the guanine nucleotide exchange factor activated by cAMP (EPAC). Our focus is upon PKA with one project determining the role of PKA activity in maintaining beta cell mass and function in vivo while another project is studying the targeting of PKA to specific locations in the cell. This localization of PKA is achieved through binding of PKA to A-kinase anchoring proteins (AKAPs) that are structural molecules that bind, not only PKA, but also many molecules that are components of the cAMP signaling system. We believe that by studying these localized PKA complexes we will be able to understand the mechanisms by which cAMP can influence ß-cell mass and function.

Islet ß-cells showing localization of the PKA-RIIa subunit (red stain) within the cells to a region close to the nucleus (blue stain)

Nutrient sensing in the islet a-cell

Glucose is essential for brain function and so low circulating glucose (hypoglycemia) is particularly dangerous. Normally glucagon acts in counter-regulation to insulin to prevent glucose levels from falling too low. However in type I diabetes glucagon secretion from the islet a-cells is impaired. Conversely, in type 2 diabetes elevated glucagon secretion may contribute to the elevated circulating glucose levels (hyperglycemia). We are currently developing systems to study the islet a-cell and understand the mechanisms by which glucagon secretion is controlled in response to circulating glucose levels.