The novel inosine analogue, INO-2002, protects against diabetes development in multiple low-dose streptozotocin and non-obese diabetic mouse models of type I diabetes.
Endogenous purines including inosine have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for protection is very high because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic-resistant purine analogue, INO-2002, exerts anti-inflammatory effects in two animal models of type I diabetes. Type I diabetes was induced chemically with streptozotocin or genetically using the non-obese diabetic (NOD) female mouse model. Mice were treated with INO-2002 or inosine as required at 30, 100, or 200 mg/kg per day, while blood glucose and diabetes incidence were monitored. The effect of INO-2002 on the pancreatic cytokine profile was also determined. INO-2002 reduced both the hyperglycaemia and incidence of diabetes in both streptozotocin-induced and spontaneous diabetes in NOD mice. INO-2002 proved to be more effective in protecting against diabetes than the naturally occurring purine, inosine, when administered at the same dose. INO-2002 treatment decreased pancreatic levels of interleukin (IL)-12 and tumour necrosis factor-alpha, while increasing levels of IL-4 and IL-10. INO-2002 also reduced pancreatic levels of the chemokine MIP-1 alpha. The inosine analogue, INO-2002, was protected more effectively than the naturally occurring purine, inosine, against development of diabetes in two separate animal models. INO-2002 exerts protective effects by changing the pancreatic cytokine expression from a destructive Th1 to a protective Th2 profile. The use of analogues of inosine such as INO-2002 should be considered as a potential preventative therapy in individuals susceptible to developing type I diabetes.
School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Lewes Road, Brighton BN2 4GJ, UK. j.g.mabley@brighton.ac.uk
Jon G
JG
Mabley
Pal
P
Pacher
Kanneganti G K
KG
Murthy
William
W
Williams
Garry J
GJ
Southan
Andrew L
AL
Salzman
Csaba
C
Szabo
D015720:5'-Nucleotidase / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000517:prevention & control*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006943:Hyperglycemia / Q000139:chemically induced / Q000517:prevention & control; D007288:Inosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D007291:Inosine Monophosphate / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008820:Mice, Obese; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D010430:Pentosyltransferases / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D016207:Cytokines; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D007291:Inosine Monophosphate; D018664:Interleukin-12; D007288:Inosine; D013311:Streptozocin; D010430:Pentosyltransferases; C067995:nucleoside phosphorylase; D015720:5'-Nucleotidase