Effect of acute hyperglycaemia and/or hyperinsulinaemia on proinflammatory gene expression, cytokine production and neutrophil function in humans

Abstract

Aims Type 2 diabetes is frequently associated with infectious complications. Swift activation of leucocytes is important for an adequate immune response. We determined the selective effects of hyperglycaemia and hyperinsulinaemia on lipopolysaccharide (LPS)-induced proinflammatory gene expression and cytokine production in leucocytes and on neutrophil functions.Methods Six healthy humans were studied on four occasions for 6 h during: (i) lower insulinaemic euglycaemic clamp, (ii) lower insulinaemic hyperglycaemic clamp, (iii) hyperinsulinaemic euglycaemic clamp, and (iv) hyperinsulinaemic hyperglycaemic clamp. Target levels of plasma glucose were 12.0 mmol/l (hyperglycaemic clamps) or 5.0 mmol/l (euglycaemic clamps). Target plasma insulin levels were 400 pmol/l (hyperinsulinaemic clamps) or 100 pmol/l (lower insulinaemic clamps).Results Hyperglycaemia reduced LPS-induced mRNA expression of nuclear factor of κ light polypeptide gene enhancer in B cells inhibitor alpha ( NFKBIA ), interleukin-1 alpha ( IL1A ) and chemokine (C-C motif) ligand 3 ( CCL3 ), whereas during hyperinsulinaemia enhanced mRNA levels occurred in six out of eight measured inflammation-related genes, irrespective of plasma glucose levels. Combined hyperglycaemia and hyperinsulinaemia led to enhanced IL1A , interleukin-1 beta ( IL1B ) and CCL3 mRNA levels upon LPS stimulation. Neither hyperglycaemia nor hyperinsulinaemia altered cytokine protein production, neutrophil migration, phagocytic capacity or oxidative burst activity.Conclusions These results suggest that short-term hyperglycaemia and hyperinsulinaemia influence the expression of several inflammatory genes in an opposite direction, that the acute effects of hyperinsulinaemia on inflammatory mRNA levels may be stronger than those of hyperglycaemia, and that the effects of insulin, in particular, may be relevant in the concurrent presence of hyperglycaemia.Diabet. Med. 25, 157-164 (2008) Keywords cytokines, hyperglycaemia, hyperinsulinaemia, mRNA, neutrophils Abbreviations C5a, complement 5a; EDTA, ethylenediamine tetraaceticacid; H insu E gluc , hyperinsulinaemic euglycaemic; H insu H gluc , hyperinsulinaemic hyperglycaemic; I κ B α , inhibitor of kappa-B α ; IL, interleukin; L insu E gluc , lower insulinaemic euglycaemic; L insu H gluc , lower insulinaemic hyperglycaemic; LPS, lipopolysaccharide; mRNA, messenger RNA; NF-κ B, nuclear factor kappa B; PAF, platelet-activating factor; PBS, phosphate-buffered saline; RFU, relative fluorescence units; TNF, tumour necrosis factor

Hyperglycemia prevents the suppressive effect of hyperinsulinemia on plasma adiponectin levels in healthy humans

“…The study was approved by the Medical Ethical Committee of the Academic Medical Center in Amsterdam, and all subjects gave written informed consent. The present study was part of a study on effects of insulin and hyperglycemia on different parameters (31,32). The data in the present study, except for the glucose and insulin levels, have not been published previously.…”

Variation in Gene Expression of Inflammatory Cytokines in Leukocyte-Derived Cells of High-Fat-Diet-Induced Insulin-Resistant Rats

“…10,[25][26][27] Furthermore, recent cell studies have revealed that monocyte attachment with the vascular endothelial cells and the dysfunction of phagocytosis in neutrophils under the condition of hyperglycemia and hyperinsulinemia were associated with cytokine production in their cells. [14][15][16][17][18][19] However, it has not been determined whether insulin resistance can induce cytokine gene expression in leukocytes in animal models.…”

“…[14][15][16][17] Cell studies have indicated that the induction of IL-1 and TNF-expression in neutrophils by hyperglycemia and hyperinsulinemia was associated with the dysfunction of phagocytosis in the cells. 18,19) Indeed, it is well known that monocyte/macrophage attachment to vascular endothelial cells and adipose tissues, and the dysfunction of phagocytosis in neutrophils can be found in patients and animals with diabetes. [20][21][22] These results indicate not only that diabetic conditions such as hyperglycemia and hyperinsulinemia lead to disturbance of the monocyte/macrophage and neutrophil functions, but also that cytokine expression in these cells may be concerned with this disturbance.…”

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes

“…From a haemodynamic perspective in the kidney, the influence of hyperglycaemia manifests as a hyperfiltration response characterised by a rise in filtration fraction [2][3][4][5][6], which may cause renal injury through shear-stress effects [7][8][9]. The haemodynamic effects of hyperglycaemia are attributed, in part, to activation of the renin-angiotensin-aldosterone system (RAAS) [6].…”