Glucose ingestion induces an increase in intranuclear nuclear factor κB, a fall in cellular inhibitor κB, and an increase in tumor necrosis factor α messenger RNA by mononuclear cells in healthy human subjects
Because hyperglycemia is a major detrimental factor in the prognosis of acute cardiovascular conditions such as acute myocardial infarction (AMI) and stroke, and because an acute glucose challenge in healthy subjects has been shown to induce oxidative stress in mononuclear cells (MNCs), we have now investigated whether glucose induces inflammatory stress at the cellular and molecular level. Glucose ingestion (75 g in 300 mL water) in healthy human subjects resulted in an increase in intranuclear nuclear factor kappaB (NF-kappaB) binding, the reduction of inhibitor kappaB alpha (IkappaBalpha) protein, and an increase in the activity of inhibitor kappaB kinase (IKK) and the expression of IKKalpha and IKKbeta, the enzymes that phosphorylate IkappaBalpha, in MNCs. Glucose intake caused an increase in NF-kappaB binding to NF-kappaB2, NF-kappaB2a, and NF-kappaB3 sequences in the promoter site of tumor necrosis factor alpha (TNF-alpha) gene along with an increase in the expression of TNF-alpha messenger RNA in MNCs. Membranous p47(phox) subunit, an index of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression and activation, also increased after glucose intake. We conclude that glucose intake induces an immediate increase in intranuclear NF-kappaB binding, a fall in IkappaBalpha, an increase in IKKalpha, IKKbeta, IKK activity, and messenger RNA expression of TNF-alpha in MNCs in healthy subjects. These data are consistent with profound acute pro-inflammatory changes in MNCs after glucose intake.
"An increasing body of evidence has shown that acute (or stress) hyperglycemia is an independent predictor of cardiovascular morbidity and mortality [3, 27–29]. Acute or stress hyperglycemia is associated with increased oxidative stress [8, 30–33], inflammation [34–37], and activation of stress-responsive kinase signaling [29, 35]. Infarcts are usually larger in patients with stress or diabetes-related hyperglycemia [4, 5, 29, 38], and animals with acute hyperglycemia sustain markedly larger infarcts following experimental ischemia/reperfusion than do euglycemic controls [7, 8, 10, 11]. "
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This study examined the hypothesis that acute hyperglycemia (HG) blocks ischemic preconditioning (IPC) by inhibiting Akt phosphorylation. Brief HG of approximately 400 mg/dL was induced in C57BL/6 mice via intraperitoneal injection of 20% dextrose (2 g/kg). All mice underwent 40 min LAD occlusion and 60 min reperfusion. The IPC protocol was 2 cycles of 5 min ischemia and 5 min reperfusion prior to index ischemia.
In control mice, infarct size (IF) was 51.7 ± 2.0 (% risk region). Preconditioning reduced IF by 50% to 25.8 ± 3.2 (P < 0.05 versus control). In HG mice, IF was significantly exacerbated to 58.1 ± 2.3. However, the effect of IPC completely disappeared in HG mice. Normalization of blood glucose with insulin 5 min before IPC recovered the cardioprotective effect. Administration of CCPA before index ischemia mimicked IPC effect. The cardioprotective effect of CCPA, not its chronotropic effect, completely disappeared in HG mice. Phosphorylation of cardiac tissue Akt before index ischemia was enhanced by IPC or CCPA but was significantly inhibited by HG in both groups. Normalization of glucose with insulin reversed the inhibition of Akt phosphorylation by HG.
HG abolishes the cardioprotective effect of preconditioning by inhibiting Akt phosphorylation. Normalization of blood glucose with insulin suffices to recover the cardioprotective effect of preconditioning.
Oxidative Medicine and Cellular Longevity 11/2013; 2013(4):329183. DOI:10.1155/2013/329183 · 3.36 Impact Factor
"The concomitant increase in circulating insulin levels is thought to contribute to the early decrease in plasma IL-6 after an oral glucose load  and after meals. Insulin has anti-inflammatory properties  that can attenuate the pro-inflammatory effect of hyperglycemia , . In type 2 diabetic patients, an acute increase in circulating insulin levels during a meal decreases plasma concentrations of IL-6 and other inflammatory cytokines . "
[Show abstract][Hide abstract] ABSTRACT: Plasma interleukin-6 (IL-6) concentrations decrease acutely 1 h after ingestion of a glucose load or mixed meals and this may be mediated by an anti-inflammatory effect of insulin. The aim of the present study was to compare the effect of higher versus lower insulin levels on plasma IL-6 concentrations following oral compared with intravenous glucose administration in overweight/obese subjects.
Fifteen subjects (12 women and 3 men) with BMI >28 kg/m(2) were given an oral glucose load (75g) followed a week later by an intravenous infusion of glucose aimed at matching plasma glucose concentrations during the oral glucose load. A week later, they drank a volume of water equivalent to the volume consumed with the oral glucose load. Plasma glucose, insulin, nonesterified fatty acids, and IL-6 concentrations and blood hematocrit were measured at 30 minute intervals for 2 h following each intervention. Plasma IL-6 decreased (13-20%) significantly (P = 0.009) at 30 min to 90 min following the oral glucose load and did not change significantly following the other two interventions. The incremental area under the curve for plasma IL-6 concentrations following oral intake of glucose was significantly lower compared with concentrations following intravenous glucose (P = 0.005) and water control (P = 0.02). Circulating insulin concentrations were significantly (P<0.001) and 2.8 fold higher following oral compared with intravenous glucose administration.
These data show that plasma IL-6 concentrations did not decrease during isoglycemic, intravenous glucose administration suggesting that the markedly higher circulating insulin levels and/or gut-related factors may mediate the acute decrease in plasma IL-6 after oral glucose intake in overweight/obese subjects.
Australian New Zealand Clinical Trials Registry ACTRN12612000491864.
PLoS ONE 06/2013; 8(6):e66395. DOI:10.1371/journal.pone.0066395 · 3.23 Impact Factor
"A transient release of tissue PPCs induced by glucose control may also reflect regression of pathologic vascular structures in organs hit by diabetic microangiopathy, just as it happens in cancer chemotherapy. Regression of microvascular lesions owing to lower oxidative stress and inflammation achieved by glucose control  may also be responsible for passive mobilization of these cells from tissues to the bloodstream. Alternatively, the transient PPCs increase may be related to the worsening of diabetic microangiopathy that is sometimes induced by rapid glucose control [33, 34]. "
[Show abstract][Hide abstract] ABSTRACT: Chronic diabetic complications result from an imbalance between vascular damage and regeneration. Several circulating lineage-committed progenitor cells have been implicated, but no data are available on pericyte progenitor cells (PPCs). Based on the evidence that PPCs increase in cancer patients after chemotherapy, we explored whether circulating PPC levels are affected by glucose control in type 2 diabetic patients, in relation to the presence of chronic complications. We enumerated peripheral blood PPCs as Syto16+CD45-CD31-CD140b+ events by flow cytometry at baseline and after 3 and 6 months of glucose control by means of add-on basal insulin therapy on top of oral agents in 38 poorly controlled type 2 diabetic patients. We found that, in patients with microangiopathy (n = 23), the level of circulating PPCs increased about 2 fold after 3 months and then returned to baseline at 6 months. In patients without microangiopathy (control group, n = 15), PPCs remained fairly stable during the whole study period. No relationship was found between change in PPCs and macroangiopathy (either peripheral, coronary, or cerebrovascular). We conclude that glucose control transiently mobilizes PPCs diabetic patients with microangiopathy. Increase in PPCs may represent a vasoregenerative event or may be a consequence of ameliorated glucose control on microvascular lesions.
Experimental Diabetes Research 02/2012; 2012(3):274363. DOI:10.1155/2012/274363 · 4.33 Impact Factor
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