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.
References
[1]
Muoio DM, Newgard CB (2008) Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 9: 193–205.
[2]
Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, et al. (1992) Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet 340: 925–929.
[3]
Perry JR, Frayling TM (2008) New gene variants alter type 2 diabetes risk predominantly through reduced beta-cell function. Curr Opin Clin Nutr Metab Care 11: 371–377.
[4]
Staiger H, Machicao F, Fritsche A, Haring HU (2009) Pathomechanisms of type 2 diabetes genes. Endocr Rev 30: 557–585.
[5]
Haupt A, Guthoff M, Schafer SA, Kirchhoff K, Machicao F, et al. (2009) The inhibitory effect of recent type 2 diabetes risk loci on insulin secretion is modulated by insulin sensitivity. J Clin Endocrinol Metab 94: 1775–1780.
[6]
Jin W, Patti ME (2009) Genetic determinants and molecular pathways in the pathogenesis of Type 2 diabetes. Clin Sci (Lond) 116: 99–111.
[7]
Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, et al. (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11: 191–198.
[8]
Kintscher U, Hartge M, Hess K, Foryst-Ludwig A, Clemenz M, et al. (2008) T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler Thromb Vasc Biol 28: 1304–1310.
[9]
Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, et al. (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15: 914–920.
[10]
Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72: 219–246.
[11]
Kroder G, Bossenmaier B, Kellerer M, Capp E, Stoyanov B, et al. (1996) Tumor necrosis factor-alpha- and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on insulin signaling. J Clin Invest 97: 1471–1477.
[12]
Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444: 860–867.
[13]
Yao Z, Zhou G, Wang XS, Brown A, Diener K, et al. (1999) A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway. J Biol Chem 274: 2118–2125.
[14]
Tesz GJ, Guilherme A, Guntur KV, Hubbard AC, Tang X, et al. (2007) Tumor necrosis factor alpha (TNFalpha) stimulates Map4k4 expression through TNFalpha receptor 1 signaling to c-Jun and activating transcription factor 2. J Biol Chem 282: 19302–19312.
[15]
Tang X, Guilherme A, Chakladar A, Powelka AM, Konda S, et al. (2006) An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARgamma, adipogenesis, and insulin-responsive hexose transport. Proc Natl Acad Sci U S A 103: 2087–2092.
[16]
Bouzakri K, Zierath JR (2007) MAP4K4 gene silencing in human skeletal muscle prevents tumor necrosis factor-alpha-induced insulin resistance. J Biol Chem 282: 7783–7789.
[17]
Stefan N, Machicao F, Staiger H, Machann J, Schick F, et al. (2005) Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat. Diabetologia 48: 2282–2291.
[18]
Boeing H, Wahrendorf J, Becker N (1999) EPIC-Germany–A source for studies into diet and risk of chronic diseases. European Investigation into Cancer and Nutrition. Ann Nutr Metab 43: 195–204.
[19]
Stefan N, Fritsche A, Weikert C, Boeing H, Joost HG, et al. (2008) Plasma fetuin-A levels and the risk of type 2 diabetes. Diabetes 57: 2762–2767.
[20]
Baecke JA, Burema J, Frijters JE (1982) A short questionnaire for the measurement of habitual physical activity in epidemiological studies. Am J Clin Nutr 36: 936–942.
[21]
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, et al. (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28: 412–419.
[22]
Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22: 1462–1470.
[23]
Herzberg-Schafer SA, Staiger H, Heni M, Ketterer C, Guthoff M, et al. (2010) Evaluation of fasting state？/oral glucose tolerance test-derived measures of insulin release for the detection of genetically impaired beta-cell function. PLoS One 5: e14194.
[24]
American Diabetes Association (2011) Diagnosis and classification of diabetes mellitus. Diabetes Care 34 Suppl 1S62–S69.
[25]
Aouadi M, Tesz GJ, Nicoloro SM, Wang M, Chouinard M, et al. (2009) Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature 458: 1180–1184.
[26]
Bouzakri K, Ribaux P, Halban PA (2009) Silencing mitogen-activated protein 4 kinase 4 (MAP4K4) protects beta cells from tumor necrosis factor-alpha-induced decrease of IRS-2 and inhibition of glucose-stimulated insulin secretion. J Biol Chem 284: 27892–27898.
[27]
Bouzakri K, Plomgaard P, Berney T, Donath MY, Pedersen BK, et al. (2011) Bimodal Effect on Pancreatic {beta}-Cells of Secretory Products From Normal or Insulin-Resistant Human Skeletal Muscle. Diabetes 60: 1111–1121.
