Fatty acid-binding protein 4: a key regulator of ketoacidosis in new-onset type 1 diabetes

Abstract

Aims/hypothesis: Fatty acid-binding protein 4 (FABP4) is an adipokine with a key regulatory role in glucose and lipid metabolism. We prospectively evaluated the role of FABP4 in the pathophysiology of diabetic ketoacidosis (DKA) in new-onset type 1 diabetes. Methods: Clinical and laboratory data were prospectively collected from consecutive children presenting with new-onset type 1 diabetes. In addition to blood chemistry and gases, insulin, C-peptide, serum FABP4 and NEFA were collected upon presentation and 48 h after initiation of insulin treatment. In a mouse model of type 1 diabetes, glucose, insulin, β-hydroxybutyrate and weight were compared between FABP4 knockout (Fabp4−/−) and wild-type (WT) mice. Results: Included were 33 children (mean age 9.3 ± 3.5 years, 52% male), of whom 14 (42%) presented with DKA. FABP4 levels were higher in the DKA group compared with the non-DKA group (median [IQR] 10.1 [7.9–14.2] ng/ml vs 6.3 [3.9–7] ng/ml, respectively; p = 0.005). The FABP4 level was positively correlated with HbA1c at presentation and inversely correlated with venous blood pH and bicarbonate levels (p < 0.05 for all). Following initiation of insulin therapy, a marked reduction in FABP4 was observed in all children. An FABP4 level of 7.22 ng/ml had a sensitivity of 86% and a specificity of 78% for the diagnosis of DKA, with an area under the receiver operating characteristic curve of 0.78 (95% CI 0.6, 0.95; p = 0.008). In a streptozotocin-induced diabetes mouse model, Fabp4−/− mice exhibited marked hypoinsulinaemia and hyperglycaemia similar to WT mice but displayed no significant increase in β-hydroxybutyrate and were protected from ketoacidosis. Conclusions/interpretation: FABP4 is suggested to be a necessary regulator of ketogenesis in insulin-deficient states. Graphical abstract: [Figure not available: see fulltext.]