We are studying the human islet and pancreas using in vitro and in vivo methods and infrastructure our group has established. We are part of the NIH-funded Human Islet Research Network (HIRN). Rodent islets have important similarities and differences (morphology, cell composition, gene expression, glucose-stimulated insulin secretion).
We are investigating how both α and β cells change in type 1 (T1D) and type 2 (T2D) diabetes. We have found that several functional and molecular features of normal β cells are maintained in the remaining T1D β cells; however, α cells have impaired glucagon secretion and an altered gene expression profile. To elucidate the mechanism of α cell dysfunction, we using a pseudoislet model system.
We identified a human β cell-specific highly enriched biomarker, Ectonucleoside Triphosphate Diphosphohydrolase-3 (NTPDase3) that is expressed in adult human β cells. We have shown that an NTPDase3 antibody can be used for in vivo live β cell sorting and imaging, for purification of live human β cells, and for in vivo imaging of transplanted human β cells. We are collaborating with several groups to use this marker to better understand human islet biology.
Our group is investigating how the pancreatic islet becomes so extensively vascularized and innervated. 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 are critical for normal islet function, mass, and glucose-stimulated insulin secretion. We also 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.
Human islet cells have limited proliferative or regenerative capacity - we are studying factors that promote both the α- and β- cell function and proliferation. We have discovered two situations in which islet cells proliferate and expand: 1) 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, 2) we found that interruption of hepatic glucagon signaling generates stimulates α islet cell proliferation.
Pancreatic islets represent only about 1-2% of pancreas. The small islet mass and the location of the pancreatic islets make it very challenging to assess pancreatic mass in vivo. Our group developed new technologies that allow visualization of pancreatic mass and processes in vivo in rodents. This has provided insight into normal physiology and diabetes. Mice created in our laboratory have been deposited in 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. We discovered that the entire pancreas is smaller at the onset of type 1 diabetes.
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 (T2D). 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 T2D. Importantly, we have found that the response of the human islet is quite different from the rodent islet.