Objective: Type 1 diabetes mellitus (T1DM) leads to increased serum levels of the soluble leptin receptor (sOB-R) by an as yet unknown cellular mechanism. The aim of our study was to investigate potential metabolic factors that may be associated with the induction of the sOB-R release from its membrane receptor. Materials and methods: Twenty-five children (aged between 1.5 and 17.0 years) were studied at the onset of T1DM. Blood samples were collected before (nZ25), during the first 18 h (meanGS.D. 11.1G 4.3 h, nZ16) and 92 h (47.5G22.5 h; nZ14) after beginning insulin therapy. Serum sOB-R and leptin levels were determined by in-house immunoassays. Results: The sOBR-level and the molar sOB-R/leptin ratio were significantly higher before than after starting insulin treatment (P!0.05). In contrast, leptin levels were significantly lower (P!0.05) before insulin therapy. The correlation between sOB-R and blood glucose (rZ0.49; P!0.05), as well as sOB-R with parameters of ketoacidosis, such as pH (rZK0.72), base excess (rZK0.70), and bicarbonate (rZK0.69) (P!0.0001) at diagnosis of T1DM remained significant during the first 18 h of insulin treatment. Multiple regression analysis revealed that base excess predicted 41.0% (P!0.001), age 16.4% (P!0.05), and height SDS 13.9% (P!0.01) of the sOB-R variance. Conclusions: Metabolic decompensation in children with new onset T1DM is associated with dramatic changes of the leptin axis; serum levels of sOB-R are elevated and of leptin are reduced. The molar excess of sOB-R over leptin (median 11.3) in this condition may contribute to leptin insensitivity. Upregulation of the soluble leptin receptor appears to be a basic mechanism to compensate for intracellular substrate deficiency and energy-deprivation state.European Journal of Endocrinology 155 609-614