CONICET | Buscador de Institutos y Recursos Humanos

[P2-373] Oligonucleotide IMT504 Improves Hyperglycemia, Polyphagia, Polydipsia, and Islet Morphology in Streptozotocin-Induced Diabetes in Rats.MS Bianchi, A Hernando-Insua, JM Rodriguez, F Elias, C Mirabelli, N Lago, J Zorzopulos, NA Chasseing, C Libertun, A Montaner, V Lux-Lantos, Lab Neuroendocrinology, Inst de Biología y Med Experimental, Buenos Aires, Argentina; Immunotech SA, Buenos Aires, Argentina; Gemma Biotech, Buenos Aires, Argentina; Dept Fisiología, Univ de Buenos Aires, Buenos Aires, ArgentinaIMT504, the prototype of the PyNTTTTGT class of immunomodulatory oligonucleotides (ODN), stimulates Mesenchymal Stem Cells (MSC) expansion both in vitro and in vivo (1). We evaluated the effect of IMT504 administration on blood glucose, solid and liquid food-intake, and pancreatic islet morphology in streptozotocin (STZ)-induced diabetes in rats. Male Sprague Dawley rats (200-250 g BW) were injected with STZ i.p. (60 mg/kg, diluted in citrate buffer) or citrate buffer as control (C). Animals with blood glucose levels 200 mg/dl (range: 200-500 md/dl) 3 days after STZ were considered diabetic and injected subcutaneously with daily doses of ODN IMT504 (4 mg/dose) for 5 days, 2 days of rest, and another 5 days (10 doses in all, STZ-ODN) or saline as control (STZ). Food and water intakes were recorded and glycemia was measured from tail blood with a glucometer every four days for a total of 30 days. Thereafter, glucose tolerance tests (GTT) were performed to study islet beta cell function (2g/kg BW glucose was injected ip and glucose determined in blood samples at 0, 30, 60, and 120 min). Two days later animals were sacrificed, blood samples and pancreata were collected for hormonal determinations and histological studies respectively.Treatment with ODN effectively lowered blood glucose in 33% of STZ-ODN-treated rats (STZ-ODN+=4/12) [Day 15: Blood glucose (mg/dl): C=122 3 (n=11), STZ=477 31 (n=8), STZ-ODN+=125 17 (n=4), p<0.01] while in the non-responsive animals glucose levels were similar to STZ (STZ-ODN-=441 14 mg/dl, n=8). STZ-induced food-intake increase was normalized by ODN treatment in all tested animals (5/5), whether they normalized glycemia or not, while STZ-induced water-intake increase was significantly lowered by ODN treatment in all tested animals too (5/5), though not attaining control levels. Compared to controls, GTTs were moderately impaired in STZ-ODN+ animals showing increased blood glucose levels at 30 min post-glucose injection and normalizing thereafter. Histomorphological analysis of pancreatic sections showed severe lesions in islets from STZ animals, while an improvement was observed in islets from STZ-ODN+ animals, supporting our findings.These preliminary data show that ODN IMT504 can attenuate various characteristics of the diabetic condition in STZ-treated rats and suggest the feasibility of such therapeutic approach for treatment of diabetes. The molecular mechanisms involved in this recovery should be further characterized.(1) Hernando IA, et al., Stem Cells 2007; 25:1047Supported by CONICET, UBA, ANPCYT.