(253e) Combinatorial Insulin Secretion Dynamics of Recombinant Hepatic and Intestinal Cells

Insulin dependent diabetes (IDD) is characterized by high blood glucose levels that results from defects in either insulin secretion (Type I) or insulin action (Type II). Cell-based therapies for insulin dependent diabetes (IDD) may provide better regulation of glucose levels than daily insulin injections as they continuously respond to the changing physiological needs by adjusting the insulin secretion. A normal pancreatic β cell secretes insulin in a biphasic manner. The first phase is characterized by a transient stimulation of insulin to rapidly lower the blood glucose levels which is followed by sustaining the lowered blood glucose levels over a long period of time during the second phase. Recombinant hepatic and intestinal cells engineered to express insulin were found to have different insulin secretion dynamics. This work focuses on testing the hypothesis that the combination of these two cells will better mimic the insulin secretion kinetics of a normal β cell than either recombinant cell type alone.

Insulin secretion experiments were conducting with two hepatic cell lines (HepG2 and H4IIE) transduced with one of three adenoviruses expressing insulin along with a stably transfected recombinant intestinal cell line (GLUTag-INS). Insulin secretion was stimulated by exposing the cells either to cocktail of secretagogues (meat hydrolysate and glucose) or glucose only (hepatic cells) or meat hydrolysate only (GLUTag-INS). Samples were taken at various time points to measure the insulin secretion rate. It was found that the recombinant hepatic cells secreted insulin in a more sustained manner where as the recombinant intestinal cell line exhibited rapid insulin secretion kinetics upon stimulation. This work indicates that the combination of these two cells has a potential to better approximate the functioning of a normal β cell. Future studies will focus on conducting similar experiments in a perfusion system to further test the hypothesis by evaluating secretion rates with a better time resolution.