Enhanced Insulin Production From Porcine Islets: More Insulin, Less Islets.

Clinical pancreatic islet xenotransplantation will most probably rely on genetically modified pigs as donors. Several lines of transgenic pigs carrying one and more often, multiple modifications already exist. The vast majority of these modifications aim to mitigate the host immune response by suppressing major xeno-antigens, or expressing immunomodulatory molecules that act locally at the graft site. While these modifications are essential and have proven beneficial in preclinical trials, ensuring good intrinsic islet secretory function is equally important to achieve normoglycemia in recipients. Neonatal and even adult porcine islets are known for their low secretory response to physiological stimulation, a shortcoming that is often overcome by implanting extremely large numbers of such islets to compensate for insulin requirement incompatibilities between donor pigs and rodent, non-human primate or human recipients. Recent studies have revealed the existence of secretory amplifying pathways in porcine beta-cells previously identified in murine and human cells. Building upon these findings, a new line of transgenic pigs where these pathways are activated specifically in beta-cells has been created. Compared to their wild-type counterparts, islets from these transgenic pigs have proven to be better insulin secretors in their native pancreas environment, in vitro after isolation and most importantly in vivo after transplantation to diabetic mice.