Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist.

Abstract

Islet transplantation is a feasible therapeutic alternative for metabolically labile patients with type 1 diabetes. The primary therapeutic target is stable glycemic control and prevention of complications associated with diabetes by reconstitution of endogenous insulin secretion. However, critical shortage of donor organs, gradual loss in graft function over time, and chronic need for immunosuppression limit the indication for islet transplantation to a small group of patients. Here we present a promising approach to address these limitations by utilization of a macrochamber specially engineered for islet transplantation. The s.c. implantable device allows for controlled and adequate oxygen supply and provides immunological protection of donor islets against the host immune system. The minimally invasive implantable chamber normalized blood glucose in streptozotocin-induced diabetic rodents for up to 3 mo. Sufficient graft function depended on oxygen supply. Pretreatment with the growth hormone-releasing hormone (GHRH) agonist, JI-36, significantly enhanced graft function by improving glucose tolerance and increasing β-cell insulin reserve in rats thereby allowing for a reduction of the islet mass required for metabolic control. As a result of hypervascularization of the tissue surrounding the device, no relevant delay in insulin response to glucose changes has been observed. Consequently, this system opens up a fundamental strategy for therapy of diabetes and may provide a promising avenue for future approaches to xenotransplantation.

• Authors: Barbara Ludwig, Avi Rotem, Janine Schmid, Gordon C Weir, Clark K Colton, Mathias D Brendel, Tova Neufeld, Norman L Block, Karina Yavriyants, Anja Steffen, Stefan Ludwig, Triantafyllos Chavakis, Andreas Reichel, Dimitri Azarov, Baruch Zimermann, Shiri Maimon, Mariya Balyura, Tania Rozenshtein, Noa Shabtay, Pnina Vardi, Konstantin Bloch, Paul de Vos, Andrew V Schally, Stefan R Bornstein, Uriel Barkai
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 13 Pg. 5022-7 (Mar 27 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22393012 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Growth Hormone-Releasing Hormone
• Oxygen

Topics

• Animals
• Diabetes Mellitus, Experimental (metabolism, pathology, physiopathology, therapy)
• Growth Hormone-Releasing Hormone (agonists, metabolism)
• Islets of Langerhans (drug effects, metabolism, pathology, physiopathology)
• Islets of Langerhans Transplantation
• Materials Testing
• Oxygen (metabolism)
• Pancreas, Artificial
• Quality Control
• Rats