The P2X7 receptor is an ATP-gated cation channel implicated in pro-inflammatory diseases including diabetic nephropathy. P2X7 is expressed on multiple cell types including pancreatic cells, endothelial cells, and macrophages; glomerular expression increases with the onset of kidney disease (1-3). Mice have five protein coding isoforms; the canonical transcript (P2X7), a full-length variant (P2X7k), and three truncated forms (P2X7Δc). Gene-targeted murine models expressing alternative P2X7 isoforms provide an opportunity to determine their functional importance in vivo. We investigated the role of P2X7 variants in pancreatic injury and diabetes using streptozotocin (STZ) injection (50mg/kg, IP) for five consecutive days following 4-6 hour fasting into mice expressing either all 5 isoforms (control), P2X7Δc only, or P2X7k only. Three weeks after STZ, control mice developed hyperglycaemia (control vehicle = 8.6±1.0 vs. control STZ = 22.8±7.0 mmol/l; P<0.05; mean±s.d.), however P2X7Δc mice were resistant to a rise in blood glucose (P2X7Δc vehicle = 8.5±1.0 vs. P2X7Δc STZ = 14.1±8.6 mmol/l; P=ns; mean±s.d.). P2X7Δc mice had better preservation of islet architecture, β-cell density and insulin staining (p=0.036 vs controls). One explanation for this may be that P2X7Δc mice lack the capacity to assist in the formation of pro-inflammatory membrane pores. P2X7k mice, by contrast, were equally susceptible to STZ induced hyperglycaemia when compared with STZ injected controls at 3 weeks. We extended the protocol to 12-weeks following STZ injections. Resistance to hyperglycaemia was again confirmed in P2X7k mice. In the kidney, CD68+ macrophage accrual was 70% lower in P2X7k mice compared with controls (P<0.01). Following STZ treatment, macrophage accumulation increased (control vehicle = 0.14 ± 0.15 vs. control STZ = 0.87 ± 0.53 cells/glom; p<0.001; mean±s.d.) and type IV collagen deposition increased (control vehicle = 13.9 ± 1.5 vs. control STZ = ; 17.8 ± 2.2 % surface area; p<0.01) in control mice only. In conclusion, our investigations into P2X7Δc and P2X7k mice found abolished and reduced susceptibility to experimental diabetic nephropathy respectively.