Abstract
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.
Highlights
One of the major risk factors for type 2 diabetes (T2D) is obesity
Because HGK deletion in T cells leads to the development of T2D in mice [17], we studied whether HGK levels are decreased in peripheral blood T cells of human T2D patients using clinical samples from drugnaïve, impaired-glucose-tolerance (IGT; a pre-diabetic state) and T2D patients, along with samples from healthy controls (Supplementary Table S1 and Supplementary Figure S1)
Our previous publication reported that HGK-deficient IL-6-producing T cells further differentiate into IL-6+ Th17 cells [17], we studied whether the IL-17 cytokine is produced in IL-6+ T cells from human T2D patients
Summary
Not all obese individuals develop diabetes, and not all T2D patients are obese (body mass index (BMI) greater than 30) [1]. The involvement of HGK in macrophage TNF-α signaling and adipocyte insulin resistance has been reported in studies using siRNA knockdown and overexpression systems [12, 13]. The roles of two other MAP4Ks, HPK1 (MAP4K1) and GLK (MAP4K3), in T-cell signaling and T-cell-mediated immune responses have been demonstrated [15, 16]. We studied the in vivo role of HGK in immune responses by generating T-cell-specific HGK conditional knockout (T-HGK cKO) mice; we found that these mice displayed higher serum IL-6 levels and spontaneously developed insulin resistance without large weight gain [17]. We hypothesized that the loss of HGK expression in T cells and the increase of IL-6-producing T cells are associated with human T2D
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