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

Stegenga ME, van der Crabben SN, Dessing MC, Pater JM, van den Pangaart PS, de Vos AF, Tanck MW, Roos D, Sauerwein HP, van der Poll T - Diabet. Med. (2008)

Bottom Line: Hyperglycaemia reduced LPS-induced mRNA expression of nuclear factor of kappa 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.Neither hyperglycaemia nor hyperinsulinaemia altered cytokine protein production, neutrophil migration, phagocytic capacity or oxidative burst activity.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Infection and Immunity Amsterdam (CINIMA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. m.e.stegenga@amc.uva.nl

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 kappa 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.

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Influence of hyperinsulinaemia and/or hyperglycaemia on neutrophil migration, respiratory burst and phagocytic capacity. Six subjects were studied on four separate occasions: during a lower insulinaemic euglycaemic (LinsuEgluc) clamp (A), a hyperinsulinaemic euglycaemic (HinsuEgluc) clamp (B), a lower insulinaemic hyperglycaemic (LinsuHgluc) clamp (C) and a hyperinsulinaemic hyperglycaemic (HinsuHgluc) clamp (D). Upper panels: neutrophil migration toward platelet-activating factor and complement 5a. Lower left panel: respiratory burst induced by phorbol 12-myristate 13-acetate. Lower right panel: phagocytosis of Escherichia coli. Data are the mean (± sem) values at the end of the clamps relative to the values measured at baseline. *P < 0.05; †P < 0.05 for interaction of hyperglycaemia and hyperinsulinaemia.
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fig02: Influence of hyperinsulinaemia and/or hyperglycaemia on neutrophil migration, respiratory burst and phagocytic capacity. Six subjects were studied on four separate occasions: during a lower insulinaemic euglycaemic (LinsuEgluc) clamp (A), a hyperinsulinaemic euglycaemic (HinsuEgluc) clamp (B), a lower insulinaemic hyperglycaemic (LinsuHgluc) clamp (C) and a hyperinsulinaemic hyperglycaemic (HinsuHgluc) clamp (D). Upper panels: neutrophil migration toward platelet-activating factor and complement 5a. Lower left panel: respiratory burst induced by phorbol 12-myristate 13-acetate. Lower right panel: phagocytosis of Escherichia coli. Data are the mean (± sem) values at the end of the clamps relative to the values measured at baseline. *P < 0.05; †P < 0.05 for interaction of hyperglycaemia and hyperinsulinaemia.

Mentions: We studied three neutrophil functions considered important for adequate innate immune response to invading bacteria: migration, respiratory burst and phagocytosis (Fig. 2). All measurements performed at T = 6 h were expressed as a percentage of the values measured at T = 0 h, and the changes in neutrophil functions as measured at the end of each clamp (T = 6 h) were compared for each individual in the four different clamps. Neither hyperglycaemia nor hyperinsulinaemia per se influenced neutrophil functions. The only effect measured was increased neutrophil migration toward PAF at the end of the HinsuHgluc clamp, when compared with the clamps with hyperglycaemia or hyperinsulinaemia alone. This effect was not seen when C5a was used as chemoattractant.


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

Stegenga ME, van der Crabben SN, Dessing MC, Pater JM, van den Pangaart PS, de Vos AF, Tanck MW, Roos D, Sauerwein HP, van der Poll T - Diabet. Med. (2008)

Influence of hyperinsulinaemia and/or hyperglycaemia on neutrophil migration, respiratory burst and phagocytic capacity. Six subjects were studied on four separate occasions: during a lower insulinaemic euglycaemic (LinsuEgluc) clamp (A), a hyperinsulinaemic euglycaemic (HinsuEgluc) clamp (B), a lower insulinaemic hyperglycaemic (LinsuHgluc) clamp (C) and a hyperinsulinaemic hyperglycaemic (HinsuHgluc) clamp (D). Upper panels: neutrophil migration toward platelet-activating factor and complement 5a. Lower left panel: respiratory burst induced by phorbol 12-myristate 13-acetate. Lower right panel: phagocytosis of Escherichia coli. Data are the mean (± sem) values at the end of the clamps relative to the values measured at baseline. *P < 0.05; †P < 0.05 for interaction of hyperglycaemia and hyperinsulinaemia.
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Related In: Results  -  Collection

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fig02: Influence of hyperinsulinaemia and/or hyperglycaemia on neutrophil migration, respiratory burst and phagocytic capacity. Six subjects were studied on four separate occasions: during a lower insulinaemic euglycaemic (LinsuEgluc) clamp (A), a hyperinsulinaemic euglycaemic (HinsuEgluc) clamp (B), a lower insulinaemic hyperglycaemic (LinsuHgluc) clamp (C) and a hyperinsulinaemic hyperglycaemic (HinsuHgluc) clamp (D). Upper panels: neutrophil migration toward platelet-activating factor and complement 5a. Lower left panel: respiratory burst induced by phorbol 12-myristate 13-acetate. Lower right panel: phagocytosis of Escherichia coli. Data are the mean (± sem) values at the end of the clamps relative to the values measured at baseline. *P < 0.05; †P < 0.05 for interaction of hyperglycaemia and hyperinsulinaemia.
Mentions: We studied three neutrophil functions considered important for adequate innate immune response to invading bacteria: migration, respiratory burst and phagocytosis (Fig. 2). All measurements performed at T = 6 h were expressed as a percentage of the values measured at T = 0 h, and the changes in neutrophil functions as measured at the end of each clamp (T = 6 h) were compared for each individual in the four different clamps. Neither hyperglycaemia nor hyperinsulinaemia per se influenced neutrophil functions. The only effect measured was increased neutrophil migration toward PAF at the end of the HinsuHgluc clamp, when compared with the clamps with hyperglycaemia or hyperinsulinaemia alone. This effect was not seen when C5a was used as chemoattractant.

Bottom Line: Hyperglycaemia reduced LPS-induced mRNA expression of nuclear factor of kappa 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.Neither hyperglycaemia nor hyperinsulinaemia altered cytokine protein production, neutrophil migration, phagocytic capacity or oxidative burst activity.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Infection and Immunity Amsterdam (CINIMA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. m.e.stegenga@amc.uva.nl

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 kappa 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.

Show MeSH
Related in: MedlinePlus