Diabetic peripheral neuropathy is a major complication of diabetes with complex and incompletely understood pathophysiology. We utilised a cafeteria-style diet (Caf) and low dose streptozotocin (STZ) to model varying degrees of hyperglycemia. Adult male Sprague-Dawley rats were divided into four groups: control (chow diet), prediabetic (Caf diet for 21 weeks), diet reversal (13 weeks Caf diet then 8 weeks chow; all n=12) and type 2 diabetic (T2D - Caf+STZ 25mg/kg i.p, n=24). STZ was administered after 5 weeks of diet; one week later, non-fasted blood glucose was 16.09 ± 1.19 [SEM] and 78% of T2D rats had glucose levels ≥10mmol/L. Metabolic phenotyping revealed significantly increased body weight, fat mass, fasting blood HDL cholesterol, plasma insulin and impaired glucose tolerance in both prediabetic and T2D rats compared to controls; fasting glucose and HbA1c were significantly elevated only in T2D. Neuropathy phenotyping included sensory behavioural testing (thermal and mechanical nociceptive sensibility) and electrophysiology (nerve conduction studies and nerve excitability) which were assessed at two timepoints, early (8-11 weeks of diet) and late (17-19 weeks of diet). Nerve excitability abnormalities were present in prediabetes and T2D groups at the early stage (superexcitability p<0.05) while changes in nerve conduction velocity and amplitude emerged later. Mechanical and thermal hypoalgesia was observed in prediabetic and T2D rats only at the late stage. Diet reversal improved body weight, fat mass, HDL, HbA1c, glucose clearance and mechanical nociception response, with no changes in nerve conduction and excitability. Together these data suggest that Caf diet combined with low dose STZ could be utilized to investigate the onset of neuropathological changes in T2D and assessment of subsequent peripheral neuropathy.
M. Hossain: None. M.D. Kendig: None. B.M. Wild: None. M.J. Morris: None. R. Arnold: None.
National Health and Medical Research Council of Australia (1126929, 1091006); Rebecca L. Cooper Foundation (RG160627)