Skip to main content

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



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.


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.


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.


FABP4 is suggested to be a necessary regulator of ketogenesis in insulin-deficient states.

Graphical abstract

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

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.



Diabetic ketoacidosis


Fatty acid-binding protein 4




Receiver operating characteristic


SD score






  1. 1.

    Furuhashi M, Hotamisligil GS (2008) Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 7(6):489–503.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Hotamisligil GS, Bernlohr DA (2015) Metabolic functions of FABPs - mechanisms and therapeutic implications. Nat Rev Endocrinol 11:592–605.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Ertunc ME, Sikkeland J, Fenaroli F et al (2015) Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity. J Lipid Res 56(2):423–434.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Mita T, Furuhashi M, Hiramitsu S et al (2015) FABP4 is secreted from adipocytes by adenyl cyclase-PKA- and guanylyl cyclase-PKG-dependent lipolytic mechanisms. Obesity (Silver Spring) 23(2):359–367.

    CAS  Article  Google Scholar 

  5. 5.

    Syamsunarno MRAA, Iso T, Hanaoka H et al (2013) A critical role of fatty acid binding protein 4 and 5 (FABP4/5) in the systemic response to fasting. PLoS One 8(11):e79386.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM (1996) Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274(5291):1377–1379.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Cao H, Sekiya M, Ertunc ME et al (2013) Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab 17(5):768–778.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Kralisch S, Fasshauer M (2013) Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease? Diabetologia 56(1):10–21.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Liu H, Guo M, Jiang F-L (2018) Serum concentrations of fatty acid-binding protein 4 in Chinese children with type 1 diabetes mellitus. J Diabetes Complicat 32(5):488–491.

    Article  Google Scholar 

  10. 10.

    Furuhashi M (2019) Fatty acid-binding protein 4 in cardiovascular and metabolic diseases. J Atheroscler Thromb 26(3):216–232.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Wotherspoon AC, Young IS, McCance DR et al (2016) Serum fatty acid binding protein 4 (FABP4) predicts pre-eclampsia in women with type 1 diabetes. Diabetes Care 39(10):1827–1829.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Patterson CC, Dahlquist GG, Gyürüs E, Green A, Soltész G (2009) Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet 373(9680):2027–2033.

    Article  PubMed  Google Scholar 

  13. 13.

    Dabelea D, Mayer-Davis EJ, Saydah S et al (2014) Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA 311(17):1778.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Große J, Hornstein H, Manuwald U, Kugler J, Glauche I, Rothe U (2018) Incidence of diabetic ketoacidosis of new-onset type 1 diabetes in children and adolescents in different countries correlates with human development index (HDI): an updated systematic review, Meta-analysis, and Meta-regression. Horm Metab Res 50(03):209–222.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Usher-Smith JA, Thompson M, Ercole A, Walter FM (2012) Variation between countries in the frequency of diabetic ketoacidosis at first presentation of type 1 diabetes in children: a systematic review. Diabetologia 55(11):2878–2894.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Scibilia J, Finegold D, Dorman J, Becker D, Drash A (1986) Why do children with diabetes die? Acta Endocrinol Suppl (Copenh) 279:326–333

    CAS  Article  Google Scholar 

  17. 17.

    Secrest AM, Becker DJ, Kelsey SF, Laporte RE, Orchard TJ (2010) Cause-specific mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes. Diabetes 59(12):3216–3222.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Wolfsdorf J, Glaser N, Sperling MA (2006) Diabetic ketoacidosis in infants, children, and adolescents: a consensus statement from the American Diabetes Association. Diabetes Care 29(5):1150–1159.

    Article  PubMed  Google Scholar 

  19. 19.

    Goldstein A, Haelyon U, Krolik E, Sack J (2001) Comparison of body weight and height of Israeli schoolchildren with the Tanner and Centers for Disease Control and Prevention growth charts. Pediatrics 108(6):E108.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Wu KK, Huan Y (2008) Streptozotocin-Induced Diabetic Models in Mice and Rats. In: Current Protocols in Pharmacology. John Wiley & Sons, Inc., Hoboken, NJ, USA, p Unit 5.47

  21. 21.

    Xu A, Wang Y, Xu JY et al (2006) Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin Chem 52(3):405–413.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Aeberli I, Beljean N, Lehmann R, l’Allemand D, Spinas GA, Zimmermann MB (2008) The increase of fatty acid-binding protein aP2 in overweight and obese children: interactions with dietary fat and impact on measures of subclinical inflammation. Int J Obes 32(10):1513–1520.

    CAS  Article  Google Scholar 

  23. 23.

    Tirosh A, Calay ES, Tuncman G et al (2019) The short-chain fatty acid propionate increases glucagon and FABP4 production, impairing insulin action in mice and humans. Sci Transl Med 11(489):eaav0120.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Coe NR, Simpson MA, Bernlohr DA (1999) Targeted disruption of the adipocyte lipid-binding protein (aP2 protein) gene impairs fat cell lipolysis and increases cellular fatty acid levels. J Lipid Res 40(5):967–972.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Scheja L, Makowski L, Uysal KT et al (1999) Altered insulin secretion associated with reduced lipolytic efficiency in aP2−/− mice. Diabetes 48(10):1987–1994.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Grabacka M, Pierzchalska M, Dean M, Reiss K (2016) Regulation of ketone body metabolism and the role of PPARα. Int J Mol Sci 17(12):2093–2116.

    Article  PubMed Central  Google Scholar 

  27. 27.

    Furuhashi M, Fucho R, Görgün CZ, Tuncman G, Cao H, Hotamisligil GS (2008) Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice. J Clin Invest 118(7):2640–2650.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Laffel L (1999) Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 15(6):412–426.<412::aid-dmrr72>;2-8

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Gruber N, Reichman B, Lerner-Geva L, Pinhas-Hamiel O (2015) Increased risk of severe diabetic ketoacidosis among Jewish ultra-orthodox children. Acta Diabetol 52(2):365–371.

    Article  PubMed  Google Scholar 

  30. 30.

    Vicinanza A, Messaaoui A, Tenoutasse S, Dorchy H (2019) Diabetic ketoacidosis in children newly diagnosed with type 1 diabetes mellitus: role of demographic, clinical, and biochemical features along with genetic and immunological markers as risk factors. A 20-year experience in a tertiary Belgian center. Pediatr Diabetes 20(5):pedi.12864.

    Article  Google Scholar 

  31. 31.

    Kelsey MM, Zeitler PS (2016) Insulin resistance of puberty. Curr Diab Rep 16(7):64.

    CAS  Article  PubMed  Google Scholar 

Download references


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.


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).

Author information




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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information


(PDF 47 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation


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