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Metabolic Mechanisms of Failure of Intraportally Transplanted Pancreatic ß-Cells in Rats

Role of Lipotoxicity and Prevention by Leptin

¹ Gifford Laboratories of the Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, Texas
² Department of Cell Physiology and Metabolism, University Medical Center, Geneva, Switzerland
³ Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas
⁴ Veterans Affair Medical Center, Dallas, Texas

Address correspondence and reprint requests to Roger H. Unger, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8854. E-mail: roger.unger{at}utsouthwestern.edu

Abbreviations: ACC, acetyl CoA carboxylase; FAS, fatty acid synthetase; SCD-1, stearoyl CoA desaturase-1; SREBP-1, sterol regulatory element–binding protein-1; TUNEL, transferase-mediated dUTP nick-end labeling

The objective of this study was to determine whether the late failure of ß-cells in islets transplanted via the portal vein is caused by excess insulin-stimulated lipogenesis and lipotoxicity and, if so, whether the damage can be prevented by reducing lipogenesis surrounding the islets. Based on the premise that high portal vein levels of nutrients and incretins would stimulate hyperinsulinemia, thereby inducing intense lipogenesis in nearby hepatocytes, normal islets were transplanted into livers of syngeneic streptozotocin-induced diabetic recipients. Hydrolysis of the surrounding fat would flood the islet grafts with fatty acids that could damage and destroy the ß-cells. Reducing lipogenesis by leptin or caloric restriction should prevent or reduce the destruction. After a rise after transplantation, insulin levels gradually declined and hyperglycemia increased. Four weeks after transplantation mRNA of the lipogenic transcription factor, sterol regulatory element–binding protein-1c (SREBP-1c) and its lipogenic target enzymes were elevated in livers of these recipients, as was triacylglycerol content. Positive oil red O staining for lipids and immunostaining for SREBP-1 were observed in hepatocytes surrounding islets with damaged ß-cells. Leptin-induced lipopenia prevented and caloric restriction reduced steatosis, hyperglycemia, and apoptotic ß-cell destruction. Excessive SREBP-1c–mediated lipogenesis, induced in hepatocytes by insulin hypersecretion, is followed by ß-cell destruction in the grafts and reappearance of diabetes. Graft failure is prevented by blocking lipogenesis. The results suggest that strict antilipogenic intervention might improve outcomes after human islet transplantation.

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