How pancreatic islets become so extensively vascularized and innervated

Our group is investigating the molecular events and factors controlling how the pancreatic islet becomes one of the mostly extensively vascularized structures in an organism. We demonstrated that VEGF-A, which is expressed in developing and adult endocrine cells, is a crucial factor in promoting and sustaining intra-islet endothelial cells and hence, the islet vascular network. We also showed that there are crucial interactions and cross-talk between islet endocrine cells and islet endothelial cells that these are critical for normal islet function, mass, and glucose-stimulated insulin secretion. In addition, we demonstrated that islet innervation is dependent on signals that promote islet vascularization and that the islet vascular network provides a scaffold for migration of intra-islet nerve fibers. These studies have also investigated how islet cells proliferate and regenerate.

How islet cells grow, proliferate, and differentiate, and regenerate

Islet cells have limited proliferative or regenerative capacity. Thus, a critical therapeutic need in type 1 and type 2 diabetes is the ability to safely expand and regenerate islets. We have discovered two situations in which islet cells proliferate and expand their mass. As part of our studies on islet vascularization, we discovered that increased expression of VEGF-A created a microenvironment is which β cell loss is followed by a robust islet proliferation and regeneration and that this is dependent on the recruitment of macrophages from the bone marrow. Importantly, this microenvironment promotes both rodent and human β cell proliferation and regeneration. We have also recently demonstrated that interruption of hepatic glucagon signaling generates a factor that stimulates α islet cell proliferation. We are pursing identification of the soluble factors that promote both the α- and β- cell proliferation as potential therapeutic approaches.

How β cells and the islet responds to the increased demands imposed by insulin resistance and obesity

Pancreatic islets respond to the increased demands of insulin resistance by increasing insulin production and secretion; failure of this compensatory response leads to type 2 diabetes. We are working to understand how islet compensatory responses to insulin resistance and have discovered that key islet-enriched transcription factors play a crucial role in the normal response and in type 2 diabetes. Surprisingly, we also discovered that one of the adaptations involves dilation of intra-islet vasculature. Importantly, we have found that the response of the human islet islet is quite different from the rodent islet.

Development of technology to quantify, image, and target islets in the pancreas and after transplantation

Pancreatic islets represent about 1-2% of pancreas and the small islet mass and the location of the pancreatic make it very challenging to assess pancreatic mass in vivo. Our group developed new technologies that have allow visualization of pancreatic mass and processes in vivo in rodents and this has provided insight into normal physiology and diabetes. Mice created in our laboratory have been deposited repositories and are being used by investigators throughout the world.

We are also working with imaging specialists, biomedical engineers, and pediatric endocrinologists to use new MRI modalities to examine the pancreas in individuals with new-onset diabetes.

Study of the human pancreas and islet

The Powers Research Group and other investigators has greatly contributed to discoveries indicating that human and rodent islets have important similarities and differences (morphology, cell composition, gene expression, glucose-stimulated insulin secretion). As the field strives to understand the pathogenesis of human diabetes, it is critical to define and understand these species differences and to develop ways to translate and integrate studies with rodent islets into human islet biology. This has been a major effort for our group both in vitro and in vivo following the transplantation of human islets into immunodeficient mice. Our group has established infrastructure and new approaches that allow the study of the human pancreas and islet. We are part of the NIH-funded Human Islet Research Network (HIRN).