Pancreas transplantation (Tx) allows for the study of diabetes by examining the reversal of the disease. Previously, we observed that after pancreas Tx many patients' symptoms reversed before their sugar levels normalized. Preliminary examination of 11 pancreatic Tx patients showed that all had improvement of hypertension (HTN), reduction in cholesterol levels and an increase in the anti-oxidant activity in their serum. While patients who received kidney transplants (N=9) had increased HTN and no change in cholesterol and anti-oxidant activity. Based on these observations we hypothesized that the pancreas has an affect on endothelial cells (ECs) and causes the dilation of small blood vessels throughout the body. In diabetic patients this affect is impaired and causes endothelial dysfunction. To test this theory, we treated ECs with serum from normal, diabetic, or post-pancreatic Tx (pTx) patients. ECs treated with serum from diabetic patients had impaired proliferation (87% and 76% of normal at 24 hrs and 48 hrs, respectively), a more fibroblastic morphology, and an increased sensitivity to high glucose and to treatment with hydrogen peroxide (25% and 48% cell death at 30mM glucose and 100¯o;M H2O2, respectively). In contrast, cells treated with pTx patient serum exhibited normal proliferation (98% and 105% of normal at 24 hrs and 48 hrs, respectively), displayed EC morphology and were resistant to both high glucose and hydrogen peroxide treatments (14% and 21% cell death, respectively). Furthermore, when the number of endothelial progenitor cells (EPCs) was examined, populations treated with diabetic serum had only 2% EPCs, while ECs treated with normal serum had 5% EPCs, and pTx sera had 16% EPCs. Hence, diabetic serum appears to have a deleterious effect on EC biology, while pTx serum ameliorates the effects of diabetes-induced EC dysfunction, promotes EC growth, increases the EPC subpopulation, as well as enhances the cells' ability to resist EC stresses. This data, compiled with our previous clinical observations, strongly indicate that the pancreas affects EC biology in a non-glucose-dependent fashion, and in diabetes this ability is impaired and contributes to diabetes-induced EC dysfunction.

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