Targeting Uncoupling Protein-2 Improves Islet Graft Function

Abstract

Preserving and enhancing the primary function of transplanted islets is not only crucial for improving the outcome of the islet transplantation, but is also important for reducing the islet mass required to achieve insulin independence. Uncoupling protein 2 (UCP2) is a member of the uncoupling protein family, which is localized to the inner mitochondrial membrane and negatively regulates insulin secretion in the pancreatic β-cells. In this study, we assessed the importance of UCP2 in improving islet graft primary function by using UCP2 gene-knockout (UCP2-KO) mice in a syngeneic islet transplantation model. Islets were isolated from UCP2-KO or wild-type (WT) C57BL/6J mice. The effects of deficiency of UCP2 on islet transplantation and islet function were determined. Two hundred islets from UCP2-KO, but not from WT, donors were capable of completely restoring normoglycemia in 1 week in all syngeneic diabetic recipients. Islets harvested from UCP2-KO mice secreted onefold more insulin in GSIS assay than that from WT mice, and maintained normal GSIS after 72-h exposure to high glucose challenge. In addition, UCP2-KO islets expressed twohold higher Bcl-2 mRNA than that from WT islets, and were resistant to high glucose and proinflammatory cytokine induced death. Our study explored a potential mechanism that may explain the benefit of UCP2-KO islets in islet transplantation. Targeting UCP2 may provide a novel strategy to improve primary function of transplanted islets and reduce the number of islets required in transplantation.Key words: Uncoupling protein 2 (UCP2); Diabetes; Islets transplant; Primary function INTRODUCTIONTransplanted islets are particularly vulnerable in the immediate posttransplantation period (7). Recent study indicated recipient hyperglycemia rendered islet grafts Diabetes mellitus is now fast emerging as one of the biggest health catastrophes in modern society. It was essusceptible to dysfunction and failure. An increased incidence of primary nonfunction was observed when a timated that approximately 160 million people worldwide suffered from diabetes in 2000, and this number marginal number of islets were transplanted into severely diabetic mice, in comparison with moderately diwas projected to increase to 221 million in 2010 and to 366 million in 2030 (25). abetic mice (12). Hyperglycemia increased oxidative stress and deteriorated β-cell function in transplanted isRecent progress in the pancreas' enzymatic digestion process along with novel immunosuppression strategies lets. Islet graft response to transplantation injury includes upregulation of protective as well as apoptotic has led to successful clinical trials of islet transplantation in humans (18). However, successful islet transplangenes (17). Therefore, preserving and enhancing the primary function of transplanted islets are not only crucial tation depends on the infusion of higher mean islet mass (>10,000 IE/kg) prepared from 2-4 donor pancreases to for improving the outcome of the islet transplantation, but also important for reduc...

A systematic review of medicinal plants and compounds for restoring pancreatic β-cell mass and function in the management of diabetes mellitus

“…Oral administration of P. ginseng berry extract and its major constituent, ginsenoside Re, demonstrated a hypoglycemic effect in obese diabetic C57BL/6J ob/ob mice, and that ginsenoside Re plays a crucial role as an anti-hyperglycemic agent (Attele et al, 2002). High glucose and fatty acid levels upregulate uncoupling protein-2 (UCP2) expression, which is relatively high in diabetic models (Reilly and Thompson, 2000;Zhang et al, 2011). Furthermore, superoxide stimulates UCP2 activity (Krauss et al, 2003).…”

Mizoribine as Sole Immunosuppressive Agent in Islet Xenotransplantation Models: A Candidate Immunosuppressant Causing no Adverse Effects on Islets

“…However, results from long-term follow-up have shown that most recipients revert to some level of insulin use, although islet transplantation can relieve glucose instability and problems with hypoglycemia by improving endogenous insulin secretion (28,31). Further progress in improving long-term results for islet transplantation will thus require immunosuppressive protocols (40,41). Sirolimus and tacrolimus were used in the Edmonton protocol, but have various adverse effects, including islet toxicity and suppression of both islet revascularization and islet regeneration (1,3,19,21,23).…”