AMT, an Inducible Nitric Oxide Synthase Inhibitor, Enhances Islet Engraftment

Abstract We co-transplanted silica gel-entrapping 4H-1,3-Thiazin-2-amine,5,6-dihydro-6-methyl monohydrochloride (AMT) with islets to evaluate the effects of AMT on early graft dysfunction in a syngeneic mouse model. The mean diameter of AMT-embedding silica gel particles was 595 ± 275 nm. The cumulative release of AMT was 29% at 1 hour and 45% at 72 hours. Sixteen streptozotocin-induced diabetic mice were separated into 3 groups. Group A received 50 islets ( n = 4). Group B received 50 islets and blank silica gel ( n = 6). Group C received 50 islets plus silica-gel containing 6.4 μg AMT ( n = 6). Mice in group C required significantly less time for temporary posttransplantation hyperglycemia than those in groups A and B (A, 39 ± 7 vs B, 40 ± 5 vs C, 24 ± 2 days; P < .05). The insulin contents of grafts retrieved at 13 weeks were 1.17 ± 0.11 ( n = 4), 1.01 ± 0.16 ( n = 6), and 1.68 ± 0.30 μg ( n = 6) for mice in groups A, B, and C, respectively. Pancreatic remnant insulin did not differ significantly between the 3 groups (A, 0.32 ± 0.04 [ n = 4] vs B, 0.29 ± 0.06 [ n = 6] vs C, 0.40 ± 0.05 μg [ n = 6]; P > .05). In vitro study revealed that 4 and 20 nmol/L of sol-gel-embedded AMT protected 87% and 96% RIN-m5F cells from 1 ng/mL interleukin-1β–mediated destruction, respectively. Silica-gel-entrapped AMT protects islet graft from a nonspecific inflammatory destruction, which is partly mediated via interleukin-1β.