Glucose Ingestion Induces Inflammation; Insulin Is Anti-Inflammatory

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 9 No. 4 • December 2006


Glucose Ingestion Induces Inflammation; Insulin Is Anti-Inflammatory

There is a growing body of evidence that glucose ingestion causes a number of proinflammatory changes in normal as well as in diabetic humans. One of its effects is the production of superoxide radicals by leukocytes and an increase in plasma thiobarbituric acid-reacting substances (TBARS, lipid-peroxidation products). A recent paper1 reports that hyperglycemia is a major predictor of morbidity and mortality in acute heart attack, stroke, and in patients undergoing coronary artery bypass graft surgery. “Mortality in AMI [acute myocardial infarction, heart attack], stroke, and intensive care unit (ICU) patients increases by 100% with significant hyperglycemia and by more than 6 times in patients with hyperglycemia without a prior diagnosis of diabetes.”

The authors1 investigated whether glucose intake activates the key proinflammatory transcription factor, NF-kappaB (nuclear factor-kappa B) and whether this leads to an increase in the transcription of another major proinflammatory signaling molecule, the cytokine TNF-alpha (tumor necrosis factor-alpha). NF-kappaB activation is associated with many types of human cancers.

Eight healthy human subjects participated [5 males and 3 females; 31–39 years old; weight 56.7 to 90.7 kg; mean body mass index (body weight in kilograms divided by height in meters squared) was 25.6 ± 3.1 kg/m2]. The subjects were given 75 g of glucose dissolved in 300 ml of water (whimsically called Glucola) to drink over 5 minutes. Four weeks later, as a comparison, the same subjects were given a drink of 300 ml of water containing saccharine.

Increases in Inflammatory NF-kappaB after Glucose Ingestion

Results showed that plasma glucose concentrations after Glucola increased from 93.5 ± 6.4 to 128.6 ± 21.0, 109.0 ± 20.1, and 94.1 ± 10.1 mg/dL, respectively at 1, 2, and 3 hours (P<0.05). Plasma insulin concentration increased from 9.6 ± 1.9 to 50.4 ± 12.6, 20.6 ± 7.1, and 10.6 ± 4.2 μU/mL, respectively, at 1, 2, and 3 hours (P<0.01). Importantly, the NF-kappaB binding increased by 215.0 ± 36.9%, 206.1 ± 24.3%, and 244.7 ± 65.7% of the basal level at 1, 2, and 3 hours, respectively (P<0.05). There was no significant change in NF-kappaB binding activity after water challenge. The concentration of I-kappaB-alpha protein, which inhibits NF-kappaB migration to the nucleus, where it binds to DNA, was decreased significantly at 1, 2, and 3 hours (P<0.05).

There was a concomitant increase after Glucola in messenger RNA expression of TNF-alpha and of p47phox (a protein that is part of NADPH oxidase, an enzyme involved in inflammation that, for example, increases generation of superoxide radicals).

Anti-Inflammatory Effects of Insulin

Interestingly, insulin has been found to have anti-inflammatory effects,1–3 counteracting the proinflammatory effects of glucose, by suppressing NF-kappaB binding, increasing I-kappaB-alpha protein, and decreasing reactive oxygen species generation. Insulin also suppresses the prothrombotic tissue factor and plasminogen activator inhibitor-1 genes, as well as inhibiting matrix metalloproteinase-9 (MMP-9) and VEGF (vascular endothelial growth factor, responsible for angiogenesis, among other things). It is clear, therefore, that insulin resistance is a recipe for unopposed glucose inflammation.

The authors also note that IKK-beta, which regulates NF-kappaB expression, has been shown to mediate insulin resistance caused by fatty acids and that aspirin, an inhibitor of IKK-beta, prevents the induction of insulin resistance in mice.1

These same authors, in a separate paper,4 report that circulating peripheral blood mononuclear cells in the obese are in a proinflammatory state, as compared to the same cells from normal-weight subjects. They found increases in NF-kappaB binding to DNA and the inhibitor of NF-kappaB-beta (I-kappaB-beta) was significantly lower. There were elevated levels of proinflammatory migration inhibitor factor (MIF), IL-6, TNF-alpha, MMP-9, and C-reactive protein. In endothelial cells, TNF-alpha causes a reduction in the expression of the insulin receptor.4 Thus, the authors propose, the inflammatory mediators may contribute to insulin resistance.

Reference

  1. Aljada et al. Glucose ingestion induces an increase in intranuclear nuclear factor kappaB, a fall in cellular inhibitor kappaB, and an increase in tumor necrosis factor alpha messenger RNA by mononuclear cells in healthy human subjects. Metab Clin Exp 55:1177-85 (2006).
  2. Aljada et al. Insulin inhibits NFkappaB and MCP-1 expression in human aortic endothelial cells. J Clin Endocrinol Metab 86(1):450-3 (2001).
  3. Dandona et al. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 86(7):3257-65 (2001).
  4. Ghanim et al. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 110:1564-71 (2004).

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