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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

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Fig. 1
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Data availability

The datasets generated during and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Abbreviations

DKA:

Diabetic ketoacidosis

FABP4:

Fatty acid-binding protein 4

βOHB:

β-Hydroxybutyrate

ROC:

Receiver operating characteristic

SDS:

SD score

STZ:

Streptozotocin

WT:

Wild-type

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Acknowledgements

We would like to thank N. Oz (the Dalia and David Arabov Diabetes Research Center, Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, Tel-Hashomer, Israel) for his technical help with animal experiments. Some of the data were presented as an abstract at the 58th European Society for Pediatric Endocrinology meeting in 2019.

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Funding

A grant from the Israeli Diabetes Association supported this study (to ArT). This work was also supported in part by the Israel Science Foundation to ArT (grant no. 922/17).

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Authors

Contributions

NG, MR, RL and SS researched the data. NG, OP-H and ArT made a substantial contribution to the design of the work and analysis and interpretation of the data. NG made a substantial contribution to collection of data in the human study. NG wrote the first draft and was responsible for all the drafts of this work including the final version. MR and RL performed the animal studies and reviewed the manuscript. MR, RL and SS provided critical comments and approved the final version to be published. SS participated in the analysis of the data EB, IR and RH participated in the laboratory analyses of the human study. EB, IR, RH, AtT and OPH took part in the critical revising of all the drafts including the final version. AtT and OP-H participated in the study design and statistical analysis of the data. ArT was responsible for obtaining all necessary resources for the study and critically revised all drafts of the manuscript, including the final version. NG and ArT are guarantors of this work. All authors approved the final version.

Corresponding authors

Correspondence to Noah Gruber or Amir Tirosh.

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Gruber, N., Rathaus, M., Ron, I. et al. Fatty acid-binding protein 4: a key regulator of ketoacidosis in new-onset type 1 diabetes. Diabetologia (2021). https://doi.org/10.1007/s00125-021-05606-0

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Keywords

  • Adipokine
  • aP2
  • DKA
  • FABP4
  • Fatty acid-binding protein
  • Ketogenesis
  • Type 1 diabetes