The metabolic syndrome sensitizes leukocytes for glucose-induced immune gene expression

Abstract

Definitions of the metabolic syndrome (MetS) include obesity, dyslipidemia, elevated levels of fasting blood glucose, and blood pressure as criteria, but it is also known that the MetS is associated with chronic, subclinical inflammation. Hyperglycemia (fasting and postprandial) may be important in exacerbating this proinflammatory state. We aimed to assess the impact of oral glucose challenge and in vitro glucose-stimulation on gene expression and secretion of inflammatory parameters in peripheral blood leukocytes and to investigate whether presence of the MetS could "prime" leukocytes to up-regulate proinflammatory markers in response to glucose. Using quantitative real-time PCR, we could show that the expression of intercellular adhesion molecule 1 (ICAM-1), tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) significantly increased in peripheral blood leukocytes from "MetS" subjects (n=39) compared to "no MetS" subjects (n=35) 2 h after an oral glucose tolerance test (ICAM-1 +52%, TNF-alpha +107%, and IL-6 +38%) and also in vitro after 72 h cultivation in high-glucose medium (ICAM-1 +74%, TNF-alpha +71%, and IL-6 +44%). Using ELISA and Luminex technique, we further observed a trend towards increased immune mediator concentrations in the corresponding cell culture supernatants from MetS patients (ICAM-1 +21%, TNF-alpha +31%, and IL-6 +175%). Thus, the MetS may support peripheral inflammation by sensitizing leukocytes to up-regulate proinflammatory markers in response to glucose, which in turn increases the risk for type-2 diabetes mellitus and cardiovascular disease.

Downregulation of genes involved in NFκB activation in peripheral blood mononuclear cells after weight loss is associated with the improvement of insulin sensitivity in individuals with the metabolic syndrome: the GENOBIN study

“…Glucose and insulin metabolism has been implicated in NFκB activation [36][37][38][39]. No correlation was found between IKBKB mRNA expression and S I changes, but the downregulation of genes associated with S I improvement was in general highly correlated with the change in IKBKB.…”

Anti-inflammatory effect of lifestyle changes in the Finnish Diabetes Prevention Study

“…According to our current understanding of the role of IL-6, although it exerts beneficial effects locally (i.e. in muscle), elevated expression of the gene encoding IL-6 in adipose tissue and leucocytes is a hallmark of obesity, the metabolic syndrome, type 2 diabetes and cardiovascular disease risk [10,21,[37][38][39][40].…”

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

“…Likewise, high glucose levels increase mitochondrial and respiratory activity and give rise to enhanced release of superoxide anions (El Osta et al, 2008). This oxidative stress induces the expression of pro-inflammatory cytokines, such as IL-6 and TNF-α, through signaling cascades involving JNK, MAP-kinases, and transcription factors, such as NFκB and AP-1 (Kempf et al, 2007). The cell response varies depending on the tissue affected and may include ectopic fat storage, mitochondrial dysfunction and endoplasmic reticulum stress, but the inflammatory response is usually self-limiting.…”