SAT-172 Continuous, Prolonged Treatment with the Oligonucleotide IMT504 in Diabetic NOD Mice Greatly Improves All Parameters of the Diabetic Condition

Abstract

We have shown that the immunomodulatory oligonucleotide IMT504 (IMT) induces a marked recovery of single-dose streptozotocin (STZ)-induced toxic diabetes in rats that correlates with early expression of progenitor cell markers but without altering immune parameters. IMT also improves the diabetic condition in an immunodependent diabetes model induced by multiple low doses of STZ in mice, diminishing glycemia and reducing leukocyte islet infiltration. Besides, a short-term IMT treatment induces an early recovery on glucose homeostasis and insulitis on a spontaneous model of type I diabetes, NOD mice. Here, we evaluated the effects of a continuous chronic IMT treatment in NOD diabetic mice, more similar to what could eventually be used in humans Diabetic female NOD mice (non-fasted glycemia (Gly) levels between 250-350 mg/dl) were sc implanted with constant drug release pumps (Alzet osmotic pumps) with a capacity for 28 days, loaded with IMT (total dose released per day: 20 mg/kg BW) or saline (diabetic control: DC) (day1). Gly and body weight (BW) were determined once a week during the treatment. The weekly food intake was also determined in weeks 1 and 4. On day 21, the intraperitoneal glucose tolerance test (ipGTT) and insulin secretion test (IST) were performed. On day 28, fasted mice were sacrificed, blood samples and pancreases collected for hormonal determinations and histological studies respectively. We observed that 22% of NOD mice showed spontaneous reversion of the diabetic condition whereas IMT treatment ameliorated Gly in 78% of mice (X2: p<0.05). IMT-treated animals quickly attained normal Gly, which was maintained until the end of the experiment [ANOVA, interaction p<0.001; Gly (mg/dl) day 1= DC: 318±10, IMT: 301±12 vs day 7= DC: 330±72, IMT: 174±17; p<0.05 and vs day 28: DC: 540±23, IMT: 151±17; p<0.01]. IMT induced a significant recovery on glucose clearence [GTT: ANOVA: interaction p<0.02, 0 min= DC: 390±62 vs IMT: 141±23, p<0.002; 30 min= DC: 581±56 vs IMT: 239±32, p<0.004; 120 min DC: 422±53 vs IMT: 149±23, p<0.001] as well as on insulin secretion in response to the glucose overload [IST: ANOVA: interaction p<0.02; 0 min= DC: 0.16±0.14 vs IMT: 0.22±0.03, ns; 10 min= DC: 0.15±0.01 vs IMT: 0.33±0.05, p<0.04; 60 min DC: 0.15±0.02 vs IMT: 0.18±0.02, ns]. Body weights did not differ between groups. IMT treatment prevented food intake increase observed in DC group [ANOVA, interaction p<0.001; week 1= DC: 29.8±1.3 vs IMT: 26.0±1.4, ns; week 4= DC: 58.1±3.4 vs IMT: 29.0±1.3, p<0.001]. Besides, beta cell function was improved in IMT-treated animals [HOMA beta cell= DC: 12.3±6.3 vs IMT: 125±48.3, p<0.001]. These results demonstrate the effectiveness of prolonged and constant IMT treatment in promoting a significant improvement in terms of glycemic control and the diabetic condition in this model of type I diabetes. Fundings: CONICET, ANPCYT, UBA, Johnson&Johnson Arg, Fund R Barón, Fund Williams