Effect of oligonucleotide IMT504 in a type I diabetes model induced by multiple low doses of streptozotocin in mice

BIANCHI MS; CALVO V; CHASSEING NA; LIBERTUN C; MONTANER A; LUX LANTOS,V

Boston, MA

Encuentro; The Endocrine Society's 93nd Annual Meeting; 2011

The Endocrine Society

IMT504, the prototype of the PyNTTTTGT class of oligonucleotides, stimulates mesenchymal stem cells both in vitro and in vivo (1). We have shown that the oligonucleotide IMT504 induces a marked recovery of single-dose streptozotocin (STZ)-induced toxic diabetes in male rats that correlates with early expression of progenitor cell markers (2). Here, we evaluated the effect of IMT504 on a type I diabetes model induced by multiple low doses of STZ in mice. Male Balb/C mice (6-8 week-old) were injected with STZ ip (40mg/kg, diluted in citrate buffer) daily for 5 consecutive days or with citrate buffer as control (C). Normal glycemia (Gly) in the fed condition was 149 13 mg/dl.  250 mg/dl were considered diabetics and?dAnimals which developed Gly levels  injected daily with IMT504 doses (20mg/kg/day, sc) for 10 days (STZ-IMT) or saline as control (STZ) (day 1). Another 5 doses of IMT504 starting on days 21 and 36 were then administrated. A group of C mice were injected with the same IMT doses (C-IMT).Body weight was recorded and Gly was measured for a total of 66 days. At the end of the experiment, glucose tolerance tests (GTT) were performed (2g/kg BW glucose was injected ip, and glucose determined in tail blood samples). Four days later fasted animals were sacrificed, blood samples and pancreases collected for hormonal determinations and histological studies respectively. We observed that 20% of STZ mice (2/10) showed spontaneous reversion of the diabetic condition whereas IMT treatment induced a marked blood glucose decrease in 88% of STZ-IMT-treated mice (7/8) [day 66= Gly (mg/dl): C: 130 9 (n=6) vs STZ-IMT: 278 46, p<0.01, STZ-IMT vs STZ: 557 20, p<0.01]. GTTs showed a partial recovery in the STZ-IMT responsiveness [ANOVA: p<0.001, 0 min= C: 117 11, STZ-IMT: 164 9, STZ: 309 53, STZ vs C and STZ-IMT: p<0.02; 30 min= C: 292 51, STZ-IMT: 342 33, STZ: 488 36, C vs STZ: p<0.02; 120 min C: 133 15, STZ-IMT: 352 28, STZ: 472 52, C vs STZ and vs STZ-IMT: p<0.02]. Regarding body weight, IMT promoted a transient decrease in STZ mice. Besides IMT improved beta cell function in diabetic animals [HOMA beta cell= C: 66 29, STZ-IMT: 46 8, STZ: 13 5, ANOVA: p<0.01, STZ vs C and vs STZ-IMT: p<0.03]. Histomorphological analysis of pancreatic sections showed severe decreases in islets number from STZ mice, while a recovery was observed in islets from STZ-IMT animals, supporting our findings. IMT504 improves the diabetic condition in this model of type I diabetes. References: (1) Hernando IA et al., Stem Cells 2007; 25:1047. (2) Bianchi MS et al., Diabetologia 2010; 53:1184 Sources of Support: CONICET (PIP 363 2010); ANPCyT (BID PICT 2006 N 00200); ANPCyT (BID PICT 2007 N  01050; Universidad de Buenos Aires (ME 038); Johnson & Johnson Argentina.