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Diabetes Publish Ahead of Print published online ahead of print June 11, 2007
DOI: 10.2337/db07-0460
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Original Research

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

Young Lee1, Mariella Ravazzola2, Byung-Hyun Park1, Yuriy K. Bashmakov3, Lelio Orci2, and Roger H. Unger1,,4

1Gifford Laboratories of the Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8854
2Department of Cell Physiology and Metabolism, University Medical Center, 1 rue Michel Servet, 1211-Geneva 4, Switzerland
3Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390
4Veterans Affair Medical Center, Dallas, TX 75216

Correspondence: roger.unger{at}utsouthwestern.edu

OBJECTIVES:To determine if 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.

RESEARCH DESIGN AND METHODS: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-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.

RESULTS:After a post-transplantation rise, insulin levels gradually declined and hyperglycemia increased. Four weeks post-transplantation mRNA of the lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c), and its lipogenic target enzymes was elevated in livers of these recipients, as was triacylglycerol (TG) 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.

CONCLUSIONS: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 anti-lipogenic intervention might improve outcomes following human islet transplantation.


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