Purpose: Approximately 50% of islet grafts are destroyed within 72 hours after pancreatic islet transplantation (PITx) due to non-specific inflammatory responses. Previously, we reported that inhibition of NF-ΚB activation shortly after PITx prevents graft loss in mice. A PPAR-Γ agonist exerts anti-inflammatory effect via NF-ΚB inhibition. The effect of Proliferator-activated receptor (PPAR)-Γ agonist on islet graft loss was examined in a canine auto-PITx model.

Methods: Diabetes was induced in beagle dogs by a total pancreatectomy. Islets isolated from the extracted pancreas were auto-transplanted into the liver through the portal vein. To determine the marginal islet number, 500, 1000 or 2000 IEQ/kg islets were transplanted (n=5-7). A PPAR-Γ agonist, pioglitazone (PIO), was given p.o. 1 hour before and twice daily thereafter for 3 days (n=7). Fasting blood glucose level (FBGL) was monitored daily. An intravenous glucose tolerance test (IVGTT) was performed on day 14 after PITx.

Results: Following PITx with 500, 1000 or 2000 IEQ/kg islets, FBGL normalized in 0% (0/6), 42.9% (3/7), 80% (4/5) of islet recipients, respectively. PITx with 1000 IEQ/kg islets was defined as marginal (Control). Treatment with PIO at 5 mg/kg improved the normal glycemic rate to 71.4% (5/7, p=0.32). When PIO was given at 10 mg/kg, FBGL normalized in all PITx animals (7/7, p<0.05) (Fig.1). The calculated BGL-AUC 0-120 after IVGTT in the control, PIO 5 mg/kg and PIO 10 mg/kg groups was 34758±4315, 27778±5509 (p=0.34) and 18949±553 mg*min/dl (p<0.01), respectively.

Conclusion: A PPAR-Γ agonist, PIO prevents early islet graft loss and maintains normoglycemia in canine PITx.

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