Islet Function Improved with Enhanced Oxygen and GHRH Agonist in Bioartificial Pancreas
Transplantation of pancreatic islets has evolved into a treatment option for a subset of patients with type 1 diabetes. However, a number of obstacles prevent widespread application of this process. An international collaborative study with Miller School researchers has uncovered a key strategy that may provide a promising avenue for future approaches to islet transplantation that would open this treatment to a greater number of patients with diabetes.
Among the challenges that limit the use of islet transplantation are a shortage of donor organs, a gradual loss in graft function over time due to poor oxygenation, and a chronic need for immunosuppression. In this study, published in the March 5 online edition of the Proceedings of the National Academy of Sciences, researchers addressed these obstacles with the use of a macrochamber specially engineered for islet transplantation. The device allows for controlled and adequate oxygen and provides immunological protection of donor islets against the patient’s immune system.
The supply of oxygen during the early post-transplant period and in the long term is crucial for islet survival and function. Islets exposed to chronic loss of oxygen experience stress and apoptosis, or cell death. In this study, gas phase oxygen is infused into a compartment that is an integral part of the device and the oxygen diffuses across a thin gas-permeable membrane to the islets. In mouse models, the device was attached just under the skin, providing a minimally invasive implantation procedure and allowing researchers to easily monitor and control oxygen levels.
To address the challenge of generating more robust islets in greater numbers, scientists turned to naturally occurring growth factors. Study co-author Andrew V. Schally, Ph.D., M.D.h.c., D.Sc.h.c., winner of the 1977 Nobel Prize for Physiology or Medicine, Distinguished Medical Research Scientist of the Department of Veterans Affairs, and Distinguished Professor of Pathology at the Miller School, has been a pioneer and international leader in the research of growth hormone-releasing hormone, its agonists and antagonists.
Growth hormone-releasing hormone (GHRH) normally binds to receptors in the pituitary gland, stimulating the release of growth hormone, which induces normal tissue growth. Agonists can increase that expression.
Schally and co-author Norman Block, M.D., professor of pathology, urology, oncology and biomedical engineering and the L. Austin Weeks Family Professor of Urologic Research, engineered artificial GHRH agonist JI-36 for this study.
“We found that the islets treated with JI-36 were able to achieve normal glycemic levels earlier and more consistently than untreated cells,” said Schally. His lab has since synthesized even more potent GHRH agonists than JI-36.
The macroencapsulation of the islets in the chamber device protected the graft from the host’s immune function, preventing rejection of the graft during the delicate early stages of implantation. “The combination of a bioartificial chamber protecting the islets, and use of an agonist to enhance them,” said Block, “appears to be an approach that could make successful islet transplantation a possibility for many more diabetic patients.”