SERUM BIOPTERIN - A NOVEL MARKER FOR IMMUNE ACTIVATION DURING PREDIABETES IN THE BB RAT

Tetrahydrobiopterin (BH4) is a pteridine product which is released by rodent macrophages on activation by cytokines. We have used serial pan creatic biopsy, and measurement of serum biopterin at 30, 60, 90 and 1 20 days in the BB/S rat to relate histological change to macrophage ac tivation during the course of prediabetes. Using immunohistochemistry, and an arbitrary scoring system read blind and standardised against d ay 30, we found that pancreatic MHC class I, MHC class II and infiltra ting macrophage staining were upregulated in the BB/S diabetes-prone r ats (n = 17) at day 60, markedly so at day 90, and less so at day 120. Staining for reside nt pancreatic macrophages remained unchanged thro ughout in diabetes prone, diabetes resistant and Wistar (n = 28) contr ol animals. Serum biopterin fell progressively and identically with ag e in BB diabetes resistant rats (n = 11) and Wistar controls. No chang e in weight gain or biopterin levels was ob served in the biopsied ani mals. Mean serum biopterin levels in diabetes prone rats (of which 13 of 17 became diabetic at median 85 days) were the same as in diabetes resistant and Wistar rats at days 30, 60 and 120, but showed a strikin g and highly significant elevation (p < 0.001) at day 90. Although mac rophages infiltrate the islet early in prediabetes, the timing of thei r activation is unknown. The rise in biopterin we observed is a potent ially important immunological event which occurred late in the progres sion of pre-diabetes. This acute terminal event has not been reported previously, and may modify current concepts concerning the tempo of ce ll destruction during pre-diabetes.