SAT035 Oligonucleotide IMT504 Markedly Improves Metabolic Sindrome And Type 2 Diabetes In High-Fat Diet Fed Mice

Abstract

Abstract Disclosure: L. Domé: None. J.M. Riaño Gomez: None. M.M. Bonaventura: None. M.O. Fernandez: None. A.D. Montaner: None. V.A. Lux-Lantos: None. M.S. Bianchi: None. We have shown that the immunomodulatory oligonucleotide IMT504 (IMT) improves glucose homeostasis in several animal models of type 1 diabetes by regulating immunomodulatory factors and by improving beta-cell function. Here we evaluated the effects of IMT in a murine model of metabolic syndrome and type 2 diabetes induced by high-fat diet (HFD).Five weeks-old C57BL/6LP male mice were fed either standard diet (SD) or HFD (ResearchDiet, D12492) for 12 weeks. HFD mice showed higher non-fasting glycemia (NF-Gly: p<0.01), and body weight (BW: p<0.01). Thereafter, mice received one daily dose of IMT504 for 12 consecutive days [IMT(mg/kg/day), subcutaneous: 20, 6 or 2, only HFD mice) or saline (SD and HFD). Intraperitoneal glucose tolerance test (ipGTT, day 10), insulin secretion test (IST, day 10) and insulin tolerance test (ITT, day 11) were performed. On day 12, food intake (days 1-12), BW, and non-fasting Gly, were recorded; after 3 hours fasting, Gly were recorded, mice were sacrificed, and blood samples collected. Serum insulin levels were analyzed by ELISA.Food (F) and calories (C) consumed decreased with IMT treatment [F(g): ANOVA, p<0.001; HFD different from IMT6 and IMT20: p<0.05], [C (Kcal): ANOVA, p<0.001; HFD different from SD, IMT6, and IMT20: p<0.05]; BW also decreased [repeated measures ANOVA: interaction, p<0.05; SD: different from all on both days, p<0.01; IMT6: Day1 vs Day12, p<0.01; IMT20: Day1 vs Day12, p<0.002]. NF-Gly did not vary with time in SD and HFD mice (day 12 vs day 1), while it significantly diminished with IMT [NF-Gly (mg/dl): repeated measures ANOVA: interaction, p<0.05; IMT6: Day1 vs Day12, p<0.02; IMT20: Day1 vs Day12, p<0.02]. IMT also induced a significant recovery of glucose clearance [GTT-AUC: ANOVA, p<0.01; HFD different from SD, IMT6, and IMT20: p<0.01], as well as of insulin secretion in response to the glucose overload [IST-AUC: ANOVA: p<0.05; HFD different from SD, IMT6, and IMT20: p<0.05] and peripheral response to insulin [ITT- AUC: ANOVA, p<0.01; HFD different from SD, HFD, IMT6, and IMT20: p<0.01]. In addition, IMT decreased the higher Gly and insulinemia (Ins) present in fasting HFD mice [Gly: ANOVA: p<0.001; HFD different from SD, IMT6, and IMT20: p<0.005], [Ins (ng/mL): ANOVA p<0.05; SD vs HFD: p<0.06; HFD different from IMT6, and IMT20: p<0.05]. These effects were consistent with amelioration of peripheral insulin resistance [HOMA-IR index: ANOVA, p<0.006; HFD different from SD, IMT6, and IMT20: p<0.05], and insulin sensitivity [QUICKI: ANOVA, p<0.02; HFD different from SD and IMT20: p<0.05]. IMT treatment promotes a significant, dose-dependent, improvement in the diabetic condition and food intake in HFD mice. Further research is needed to understand its mechanism of action. Funding: CONICET, ANPCYT, Sidus Arg, F. R Barón, F. Williams. Presentation: Saturday, June 17, 2023