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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 proinflammatory mRNA levels. 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). Whole blood obtained at T = 0 and T = 6 h was stimulated for 2 h with lipopolysaccharide. White blood cells were analysed for mRNA levels relative to mRNA levels of the B2M household gene. Data are the mean (± sem) changes in mRNA level ratios at the end of the clamps relative to the change detected at baseline. *P < 0.05; **P < 0.01 and ***P < 0.001; †P < 0.05 for interaction of hyperglycaemia and hyperinsulinaemia.
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fig01: Influence of hyperinsulinaemia and/or hyperglycaemia on proinflammatory mRNA levels. 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). Whole blood obtained at T = 0 and T = 6 h was stimulated for 2 h with lipopolysaccharide. White blood cells were analysed for mRNA levels relative to mRNA levels of the B2M household gene. Data are the mean (± sem) changes in mRNA level ratios at the end of the clamps relative to the change detected at baseline. *P < 0.05; **P < 0.01 and ***P < 0.001; †P < 0.05 for interaction of hyperglycaemia and hyperinsulinaemia.

Mentions: Whole blood that was incubated with control medium yielded very low or undetectable mRNA levels at both T = 0 and 6 h (data not shown). As expected, LPS stimulation of blood leucocytes of all subjects at T = 0 h (Table 2) and 6 h (data not shown) induced strong up-regulation of NFKB1, NFKBIA, IL1A, IL1B, TNF, IL6, IL8 and CCL3 expression. To determine the effect of hyperglycaemia and/or hyperinsulinaemia on leucocyte responsiveness to LPS, we expressed the extent of LPS-induced up-regulation of various genes at T = 6 h as a percentage of the extent of LPS-induced up-regulation at T = 0 h for each individual. Considering that each volunteer was studied in all four clamps, the changes in LPS-induced gene expression as measured at the end of each clamp (T = 6 h) were then compared for each individual (Fig. 1). The extent of proinflammatory gene expression did not change during the LinsuEgluc clamp. Hyperglycaemia and hyperinsulinaemia had distinct effects on LPS-induced proinflammatory gene expression. Hyperglycaemia per se (in the absence of hyperinsulinaemia) in general resulted in attenuated LPS-induced gene expression when compared with the other three clamps; in particular, the expression of NFKB1 (P = 0.09), NFKBIA, IL1A and CCL3 (all P < 0.05) decreased when compared with the LinsuEgluc clamp. In contrast, hyperinsulinaemia enhanced LPS-induced gene expression of several cytokine genes, and its effect on mRNA induction of IL1A, IL1B and CCL3 was especially clear in the concurrent presence of hyperglycaemia. To check for an overall insulin effect, LPS-induced gene expression at the end of the lower insulinaemic clamps was compared with gene expression at the end of both high insulinaemic clamps. Hyperinsulinaemia in either the presence or the absence of hyperglycaemia induced enhanced mRNA levels of all measured genes (Pinsu < 0.05), except for NFKB1 (Pinsu = 0.09) and TNF (Pinsu = 0.16). Thus, hyperinsulinaemia enhanced levels of several inflammation-related genes, and this effect was irrespective of simultaneous glucose levels for NFKBIA, IL1B, IL6 and IL8. We did not find an overall glucose effect on LPS-stimulated whole blood mRNA (Pgluc > 0.05 for all measured genes). Finally, there was a significant interaction between hyperglycaemia and hyperinsulinaemia on post-clamp mRNA levels of IL1A and CCL3 (Pinteraction < 0.05).


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 proinflammatory mRNA levels. 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). Whole blood obtained at T = 0 and T = 6 h was stimulated for 2 h with lipopolysaccharide. White blood cells were analysed for mRNA levels relative to mRNA levels of the B2M household gene. Data are the mean (± sem) changes in mRNA level ratios at the end of the clamps relative to the change detected at baseline. *P < 0.05; **P < 0.01 and ***P < 0.001; †P < 0.05 for interaction of hyperglycaemia and hyperinsulinaemia.
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fig01: Influence of hyperinsulinaemia and/or hyperglycaemia on proinflammatory mRNA levels. 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). Whole blood obtained at T = 0 and T = 6 h was stimulated for 2 h with lipopolysaccharide. White blood cells were analysed for mRNA levels relative to mRNA levels of the B2M household gene. Data are the mean (± sem) changes in mRNA level ratios at the end of the clamps relative to the change detected at baseline. *P < 0.05; **P < 0.01 and ***P < 0.001; †P < 0.05 for interaction of hyperglycaemia and hyperinsulinaemia.
Mentions: Whole blood that was incubated with control medium yielded very low or undetectable mRNA levels at both T = 0 and 6 h (data not shown). As expected, LPS stimulation of blood leucocytes of all subjects at T = 0 h (Table 2) and 6 h (data not shown) induced strong up-regulation of NFKB1, NFKBIA, IL1A, IL1B, TNF, IL6, IL8 and CCL3 expression. To determine the effect of hyperglycaemia and/or hyperinsulinaemia on leucocyte responsiveness to LPS, we expressed the extent of LPS-induced up-regulation of various genes at T = 6 h as a percentage of the extent of LPS-induced up-regulation at T = 0 h for each individual. Considering that each volunteer was studied in all four clamps, the changes in LPS-induced gene expression as measured at the end of each clamp (T = 6 h) were then compared for each individual (Fig. 1). The extent of proinflammatory gene expression did not change during the LinsuEgluc clamp. Hyperglycaemia and hyperinsulinaemia had distinct effects on LPS-induced proinflammatory gene expression. Hyperglycaemia per se (in the absence of hyperinsulinaemia) in general resulted in attenuated LPS-induced gene expression when compared with the other three clamps; in particular, the expression of NFKB1 (P = 0.09), NFKBIA, IL1A and CCL3 (all P < 0.05) decreased when compared with the LinsuEgluc clamp. In contrast, hyperinsulinaemia enhanced LPS-induced gene expression of several cytokine genes, and its effect on mRNA induction of IL1A, IL1B and CCL3 was especially clear in the concurrent presence of hyperglycaemia. To check for an overall insulin effect, LPS-induced gene expression at the end of the lower insulinaemic clamps was compared with gene expression at the end of both high insulinaemic clamps. Hyperinsulinaemia in either the presence or the absence of hyperglycaemia induced enhanced mRNA levels of all measured genes (Pinsu < 0.05), except for NFKB1 (Pinsu = 0.09) and TNF (Pinsu = 0.16). Thus, hyperinsulinaemia enhanced levels of several inflammation-related genes, and this effect was irrespective of simultaneous glucose levels for NFKBIA, IL1B, IL6 and IL8. We did not find an overall glucose effect on LPS-stimulated whole blood mRNA (Pgluc > 0.05 for all measured genes). Finally, there was a significant interaction between hyperglycaemia and hyperinsulinaemia on post-clamp mRNA levels of IL1A and CCL3 (Pinteraction < 0.05).

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