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Distal symmetrical sensory neuropathy in diabetes involves the dying back of axons, and the pathology equates with axonal dystrophy generated under conditions of aberrant Ca 2+ signalling. Previous work has described abnormalities in Ca 2+ homoeostasis in sensory and dorsal horn neurons acutely isolated from diabetic rodents. We extended this work by testing the hypothesis that sensory neurons exposed to long-term Type 1 diabetes in vivo would exhibit abnormal axonal Ca 2+ homoeostasis and focused on the role of SERCA (sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase). DRG (dorsal root ganglia) sensory neurons from age-matched normal and 3–5-month-old STZ (streptozotocin)-diabetic rats (an experimental model of Type 1 diabetes) were cultured. At 1–2 days in vitro an array of parameters were measured to investigate Ca 2+ homoeostasis including (i) axonal levels of intracellular Ca 2+ , (ii) Ca 2+ uptake by the ER (endoplasmic reticulum), (iii) assessment of Ca 2+ signalling following a long-term thapsigargin-induced blockade of SERCA and (iv) determination of expression of ER mass and stress markers using immunocytochemistry and Western blotting. KCl- and caffeine-induced Ca 2+ transients in axons were 2-fold lower in cultures of diabetic neurons compared with normal neurons indicative of reduced ER calcium loading. The rate of uptake of Ca 2+ into the ER was reduced by 2-fold ( P <0.05) in diabetic neurons, while markers for ER mass and ER stress were unchanged. Abnormalities in Ca 2+ homoeostasis in diabetic neurons could be mimicked via long-term inhibition of SERCA in normal neurons. In summary, axons of neurons from diabetic rats exhibited aberrant Ca 2+ homoeostasis possibly triggered by suboptimal SERCA activity that could contribute to the distal axonopathy observed in diabetes.