Association of Common Genetic Variants in the MAP4K4 Locus with Prediabetic Traits in Humans

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
PLoS ONE (Impact Factor: 3.23). 10/2012; 7(10):e47647. DOI: 10.1371/journal.pone.0047647
Source: PubMed


Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is expressed in all diabetes-relevant tissues and mediates cytokine-induced insulin resistance. We investigated whether common single nucleotide polymorphisms (SNPs) in the MAP4K4 locus associate with glucose intolerance, insulin resistance, impaired insulin release, or elevated plasma cytokines. The best hit was tested for association with type 2 diabetes. Subjects (N = 1,769) were recruited from the Tübingen Family (TÜF) study for type 2 diabetes and genotyped for tagging SNPs. In a subgroup, cytokines were measured. Association with type 2 diabetes was tested in a prospective case-cohort study (N = 2,971) derived from the EPIC-Potsdam study. Three SNPs (rs6543087, rs17801985, rs1003376) revealed nominal and two SNPs (rs11674694, rs11678405) significant associations with 2-hour glucose levels. SNPs rs6543087 and rs11674694 were also nominally associated with decreased insulin sensitivity. Another two SNPs (rs2236936, rs2236935) showed associations with reduced insulin release, driven by effects in lean subjects only. Three SNPs (rs11674694, rs13003883, rs2236936) revealed nominal associations with IL-6 levels. SNP rs11674694 was significantly associated with type 2 diabetes. In conclusion, common variation in MAP4K4 is associated with insulin resistance and β-cell dysfunction, possibly via this gene's role in inflammatory signalling. This variation's impact on insulin sensitivity may be more important since its effect on insulin release vanishes with increasing BMI.

Download full-text


Available from: Harald Grallert,
27 Reads
  • Source
    • "In this regard, MAP4K4 might prove a worthwhile target. Increased activity of MAP4K4 is associated with TNF-a-dependent disorders in addition to heart failure, like obesity and diabetes (Elbein et al., 2009; Isakson et al., 2009; Sartorius et al., 2012), and many consequences of TNF-a signaling , though importantly, not all, are dependent on MAP4K4 (Bouzakri et al., 2009; Guilherme et al., 2008; Tang et al., 2006; Tesz et al., 2007; Wang et al., 2013). Similarly, in the context of skeletal muscle differentiation , TNF-a is inhibitory, but silencing MAP4K4 only marginally rescued differentiation (Wang et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Heart failure is one of the paramount global causes of morbidity and mortality. Despite this pandemic need, the available clinical counter-measures have not altered substantially in recent decades, most notably in the context of pharmacological interventions. Cell death plays a causal role in heart failure, and its inhibition poses a promising approach that has not been thoroughly explored. In previous approaches to target discovery, clinical failures have reflected a deficiency in mechanistic understanding, and in some instances, failure to systematically translate laboratory findings toward the clinic. Here, we review diverse mouse models of heart failure, with an emphasis on those that identify potential targets for pharmacological inhibition of cell death, and on how their translation into effective therapies might be improved in the future.
    Current Topics in Developmental Biology 06/2014; 109:171-247. DOI:10.1016/B978-0-12-397920-9.00002-0 · 4.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes is characterized by high levels of blood glucose due to either the loss of insulin-producing beta-cells in the pancreas, leading to a deficiency of insulin in type 1 diabetes, or due to increased insulin resistance, leading to reduced insulin sensitivity and productivity in type 2 diabetes. There is an increasing need for new options to treat diabetes, especially type 2 diabetes at its early stages due to the ineffective control of its development in patients. Recently, a novel class of small noncoding RNAs, termed microRNAs (miRNAs), found to play a key role as important transcriptional and posttranscriptional inhibitors of gene expression in fine-tuning the target messenger RNAs (mRNAs). miRNAs are implicated in the pathogenesis of diabetes and have become an intriguing target for therapeutic intervention. This review focuses on the dysregulated miRNAs discovered in various diabetic models and addresses the potential for miRNAs to be therapeutic targets in the treatment of diabetes.
    Pharmacological Research 06/2013; 75. DOI:10.1016/j.phrs.2013.06.005 · 4.41 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Proinflammatory cytokines play important roles in insulin resistance. Here we report that mice with a T-cell-specific conditional knockout of HGK (T-HGK cKO) develop systemic inflammation and insulin resistance. This condition is ameliorated by either IL-6 or IL-17 neutralization. HGK directly phosphorylates TRAF2, leading to its lysosomal degradation and subsequent inhibition of IL-6 production. IL-6-overproducing HGK-deficient T cells accumulate in adipose tissue and further differentiate into IL-6/IL-17 double-positive cells. Moreover, CCL20 neutralization or CCR6 deficiency reduces the Th17 population or insulin resistance in T-HGK cKO mice. In addition, leptin receptor deficiency in T cells inhibits Th17 differentiation and improves the insulin sensitivity in T-HGK cKO mice, which suggests that leptin cooperates with IL-6 to promote Th17 differentiation. Thus, HGK deficiency induces TRAF2/IL-6 upregulation, leading to IL-6/leptin-induced Th17 differentiation in adipose tissue and subsequent insulin resistance. These findings provide insight into the reciprocal regulation between the immune system and the metabolism.
    Nature Communications 08/2014; 5:4602. DOI:10.1038/ncomms5602 · 11.47 Impact Factor
Show more