The Role of Nitric oxide in IL-1β-mediated Dysfunction of Rodent Islets of Langerhans: Implications for the Function of Intrahepatic Islet Grafts

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Products of inflammation, such as interleukin-1β (IL-1β) and nitric oxide (NO), may impair early function of pancreatic islet grafts. In in vitro studies, freshly isolated rat islets of Langerhans cultured for 24 hr (10 islets/well) in the presence of 20 IU/ml of IL-1β released 57% less insulin (mean ± S.E. of 151±61 μU) on the average than control (385±89 μU) cultures (n=9, P=0.08). Nitrite levels in the medium (indirect measure of NO) after islets were cultured for a 24-hr period were nearly 3-fold greater in IL-1β-exposed islets than control islet cultures (5.8±1.0 μM vs. 2.2±0.3 μM, P=0.03). Production of nitrite by islet cells in the presence of IL-1β was inhibited in cultures also containing 2 mM L-NG-monomethyl-Arginine (L- NMMA) (3.4±0.4 μM, n=9, P=0.09 vs. control). When islets were maintained for 1 hr in 30 mg/dl glucose followed by 300 mg/dl for 1 hr, insulin release (stimulated) increased 6-fold (from 7±2 to 45±11 μU) in control cultures but only 3-fold (from 4±2 to 12±4 μU) in IL-1β-exposed cultures (n=9, P=.01). Addition of 2 mM L-NMMA to islet cultures in the presence of IL-1β (20 IU/ml) (n=9) restored insulin release to normal (from 6±2 to 38±9 μU, P≥0.6), suggesting that NO mediates the inhibitory effect of IL-1β on beta- cell function. In in vivo studies, rats with streptozotocin-induced diabetes (blood glucose >400 mg/dl) received minimal (750 hand-picked islets) intraportal beta cell mass isografts with (n=5) or without (n=9) treatment with 100 mg/7 days of L-NMMA from 3 days before transplantation to 4 days after transplantation (POD -3 to +4). L-NMMA-treated rats became euglycemic (glucose <200 mg/dl) earlier than nontreated rats (mean ± SD of 6.4±2.5 vs. 16.7±4.7 days posttransplant, P=0.001). These findings support the hypothesis that NO is a mediator of beta cell dysfunction after intraportal transplantation of freshly isolated islets of Langerhans.

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