Reduction in Primary Nonfunction of Syngeneic Islet Transplants with Nordihydroguaiaretic Acid, a Lipoxygenase Inhibitor

Abstract

To study the effectiveness of a lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), in the reduction of primary nonfunction, an insufficient number of syngeneic islets were transplanted underneath the renal capsule with NDGA administered daily for 4 weeks. After transplantation of the 150 islets, the decrement of blood glucose levels was significantly faster in the mice that had received NDGA than in the mice that had received no drug at all or dimethyl sulfoxide (DMSO) (p < 0.005, p < 0.05). The mean duration of temporary posttransplant hyperglycemia was 22.3 ± 3.2 (n = 10), 35.9 ± 2.3 (n = 14), and 33.7 ± 4.1 (n = 6) days for the respective groups. The diabetic mice that received 300 islets had their blood glucose levels decrease faster than those that received 150 islets (19.7 ± 1.6 vs. 35.9 ± 2.3 days, n = 14, p < 0.0001). There was no significant difference in the blood glucose reducing effect between the mice that received 150 islets with NDGA and the mice that received 300 islets [22.3 ± 3.2 (n = 10) vs. 19.7 ± 1.6 (n = 14) days, p > 0.05]. The insulin content of the graft from the mice treated with 150 islets and NDGA (3.02 ± 0.24 μg, n = 4) was higher than that from the mice that received 150 islets but no treatment (1.10 ± 0.26 μg, n = 15, p < 0.005) or that had been treated with DMSO (1.21 ± 0.30 μg, n = 4, p < 0.05). The insulin content of the pancreas remnant had no significant differences among the three groups. The net glucose-stimulated insulin secretion was 0.82 ± 0.14 vs. 0.20 ± 0.10 μIU/islet × 60 min (n = 8, p < 0.005) and 0.59 ± 0.08 vs. 0.04 ± 0.02 μIU/islet × 60 min (n = 8, p < 0.0001) for islets cultured without NDGA vs. with NDGA at 1 and 2 weeks, respectively. However, the insulin content of the cultured islets was similar between the two groups for up to 2 weeks of incubation (at 1 week: 0.71 ± 0.01 vs. 0.67 ± 0.04 ng/islet, n = 8, p > 0.05; at 2 weeks: 0.71 ± 0.02 vs. 0.80 ± 0.07 ng/islet, n = 8, p > 0.05). Serum leukotriene B4 (LTB4) concentrations before and between the fifth and seventh days after transplantation were determined. For diabetic mice that received 150 islets, serum LTB4 levels were 25,835 ± 3,335 and 27,631 ± 3,136 pg/ml (n = 4, p > 0.05). For diabetic mice that received 150 islets and NDGA, the corresponding figures were 22,401 ± 2,706 pg/ml and 27,530 ± 2,190 pg/ml (n = 8, p > 0.05). The graft histology revealed viable islet cells and networks of close vascular structures around the islets and did not reveal microscopic differences among the samples of all four groups. In conclusion, our data revealed that daily administration of NDGA for 4 weeks enhanced isoislet engraftment and preserved three times more mass of the islet beta cells in the isografts. This result indicates that NDGA reduces primary nonfunction of islet syngeneic grafts in diabetic mice.