Epigenetic regulation of HGK/MAP4K4 in T cells of type 2 diabetes patients

Oncotarget. 2016 Mar 8;7(10):10976-89. doi: 10.18632/oncotarget.7686.


Type 2 diabetes (T2D) is a complex and heterogeneous disease. Obesity increases the risk of obese T2D; but in Asia non-obese T2D is prevalent. The cause of non-obese T2D has remained elusive. We studied the potential involvement of HGK/MAP4K4 in T2D using clinical samples from newly diagnosed, drug-naïve patients and healthy controls. HGK levels fell and IL-6 levels increased in T cells from T2D patients. Frequencies of IL-6-producing T cells were correlated with glucose levels after glucose-tolerance tests (but not body mass index and waist circumference) and inversely correlated with HGK expression levels. Moreover, methylation frequencies of the HGK promoter were increased in T2D patients and correlated with glucose levels after glucose-tolerance tests. The correlation was independent of body mass index. Demethylation treatment increased HGK expression levels and reduced IL-6 production in T2D T cells. This report identifies HGK methylation/downregulation in T cells as a potential biomarker for non-obese T2D.

Keywords: HGK downregulation; HGK methylation; IL-6-producing T cells; Immune response; Immunity; Immunology and Microbiology Section; type 2 diabetes.

MeSH terms

  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Epigenesis, Genetic*
  • Female
  • Humans
  • Interleukin-6 / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / immunology
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / immunology
  • Protein-Serine-Threonine Kinases / metabolism*
  • Th17 Cells / immunology
  • Th17 Cells / metabolism*


  • IL6 protein, human
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • MAP4K4 protein, human
  • Protein-Serine-Threonine Kinases