To elucidate the role of neutrophils in the early inflammatory response to mycobacterial infection, expression of chemokines interleukin (IL)-8 and macrophage inflammatory protein-1alpha (MIP-1alpha) was examined in human blood neutrophils in response to the lipopolysaccharide (LPS) of Escherichia coli, which induces acute inflammation, or to Mycobacterium tuberculosis or purified protein derivative (PPD), which induce chronic mycobacterial inflammation. Neutrophils stimulated with LPS, M. tuberculosis, or PPD expressed both IL-8 and MIP-1alpha. Expression of IL-8 and MIP-1alpha was lower after stimulation with M. tuberculosis or PPD than after stimulation with LPS, but the kinetics of expression did not differ significantly. In contrast, both M. tuberculosis and PPD with tumor necrosis factor-alpha induced neutrophils to undergo rapid cell death, which might remove neutrophils and activate macrophages at sites of mycobacterial inflammation. The findings suggest that neutrophils play important roles in the host defense against mycobacterial infection.

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We previously demonstrated that impaired glucose-induced insulin secretion (IS) and ATP elevation in islets of Goto-Kakizaki (GK) rats, a nonobese model of diabetes, were significantly restored by 30–60-min suppression of endogenous reactive oxygen species (ROS) overproduction. In this study, we investigated the effect of a longer (12 h) suppression of ROS on metabolism-secretion coupling in β-cells by exposure to tempol, a superoxide (O2−) dismutase mimic, plus ebselen, a glutathione peroxidase mimic (TE treatment). In GK islets, both H2O2 and O2− were sufficiently reduced and glucose-induced IS and ATP elevation were improved by TE treatment. Glucose oxidation, an indicator of Krebs cycle velocity, also was improved by TE treatment at high glucose, whereas glucokinase activity, which determines glycolytic velocity, was not affected. Lactate production was markedly increased in GK islets, and TE treatment reduced lactate production and protein expression of lactate dehydrogenase and hypoxia-inducible factor 1α (HIF1α). These results indicate that the Warburg-like effect, which is characteristic of aerobic metabolism in cancer cells by which lactate is overproduced with reduced linking to mitochondria metabolism, plays an important role in impaired metabolism-secretion coupling in diabetic β-cells and suggest that ROS reduction can improve mitochondrial metabolism by suppressing lactate overproduction through the inhibition of HIF1α stabilization.

Aims/Introduction: Chronic hyperlipidemia impairs pancreatic b-cell function, referred to as lipotoxicity. We have reported an important role of endogenous reactive oxygen species (ROS) overproduction by activation of Src, a non-receptor tyrosine kinase, in impaired glucose-induced insulin secretion (GIIS) from diabetic rat islets. In the present study, we investigated the role of ROS production by Src signaling in palmitate-induced dysfunction of b-cells. Materials and Methods: After rat insulinoma INS-1D cells were exposed to 0.6 mmol/L palmitate for 24 h (palmitate exposure); GIIS, ROS production and nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity were examined with or without exposure to10 lmol/L 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), a Src inhibitior, for 30 or 60 min. Results: Exposure to PP2 recovered impaired GIIS and decreased ROS overproduction as a result of palmitate exposure. Palmitate exposure increased activity of NOX and protein levels of NOX2, a pathological ROS source in b-cells. Palmitate exposure increased the protein level of p47 phox , a regulatory protein of NOX2, in membrane fraction compared with control, which was reduced by PP2. Transfection of small interfering ribonucleic acid of p47 phox suppressed the augmented p47 phox protein level in membrane fraction, decreased augmented ROS production and increased impaired GΙIS by palmitate exposure. In addition, exposure to PP2 ameliorated impaired GIIS and decreased ROS production in isolated islets of KK-A y mice, an obese diabetic model with hyperlipidemia. Conclusions: Activation of NOX through Src signaling plays an important role in ROS overproduction and impaired GΙIS caused by chronic exposure to palmitate, suggesting a lipotoxic mechanism of b-cell dysfunction of obese mice.

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Procyanidins, the main ingredient of apple polyphenols, are known to possess antioxidative and anti-inflammatory effects associated closely with the pathophysiology of insulin resistance and type 2 diabetes. We investigated the effects of orally administered apple procyanidins (APCs) on glucose metabolism using diabetic ob/ob mice. We found no difference in body weight or body composition between mice treated with APCs and untreated mice. A 4 week oral administration of APCs containing water [0.5% (w/v)] ameliorated glucose tolerance, insulin resistance, and hepatic gluconeogenesis in ob/ob mice. APCs also suppressed the increase in the level of the pancreatic β-cell. Insulin-stimulated Akt phosphorylation was significantly enhanced; pro-inflammatory cytokine expression levels were significantly decreased, and c-Jun N-terminal kinase phosphorylation was downregulated in the liver of those mice treated with APCs. In conclusion, APCs ameliorate insulin resistance by improving hepatic insulin signaling through suppression of hepatic inflammation in ob/ob mice, which may be a mechanism with possible beneficial health effects of APCs in disturbed glucose metabolism.