HYDROXYETHYL STARCH DEFEROXAMINE, A NOVEL IRON CHELATOR, DELAYS DIABETES IN BB RATS

Hydroxyl radicals (.OH) may contribute to beta cell death. Because iron catalyzes .OH production, we examined whether administration of a novel, long-acting iron chelator, hydroxyethyl starch-deferoxamine (HES-DFO) could prevent diabetes in spontaneously diabetic biobreeding (88) rats. In our colony, a peripheral lymphocyte count (PBLC) <4200 mm(3) has an 88% positive predictive value for onset of diabetes mellitus (DM). Rats with PBLC <4200 mm(3) were randomized at 6 weeks of age to receive 50 mg/kg of HES-DFO (a high molecular weight hydroxyethyl starch-conjugated derivative of deferoxamine) or equimolar hydroxyethyl starch (HES) alone given intraperitoneally three times weekly until DM or 120 days of age. Administration of HES significantly decreased the incidence of IDDM to 57% as compared with the incidence of 87% in the lymphopenic unmanipulated BB rats in the colony (p < 0.01). Administration of HES-DFO further significantly decreased the incidence of IDDM to 31% as compared with the lymphopenic unmanipulated rats (p < 0.01). When analyzed by sex, 3 of 17 (18%) HES-DFO-treated males developed DM, versus 10 of 17 (58%) of HES-treated males (p < 0.05, chi square); 8 of 19 (42%) of HES-DFO-treated females developed DM, versus 11 of 20 (55%) HES-treated females (p = NS). There were no differences between the groups in (1) mean time of onset of DM, (2) serum iron levels at study entry and completion, (3) weekly hematocrits, (4) total lymphocyte counts; and (5) weekly weight gains. In HES-DFO-treated male rats that remained normoglycemic, significantly less insulitis was present histologically as compared with the other male rats. No differences were noted among females in the extent of insulitis. These data demonstrate that administration of HES-DFO effectively reduces the incidence of DM in rats selected for an 88% incidence of disease and support a role for .OH in the pathogenesis of DM.