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An enhanced susceptibility to infections is well known to occur in a poorly controlled diabetic state. Since glucose and glutamine are essential for lymphocyte function, we investigated whether their metabolism is changed in lymphocytes obtained from mesenteric lymph nodes of alloxan-induced diabetic rats (40 mg/kg body weight). The activities of hexokinase, phosphofructokinase, glucose-6-phosphate dehydrogenase (G6PDH), citrate synthase and phosphate-dependent glutaminase were determined. Decarboxylation of metabolites [U-14C]-, [1-14C]- and [6-14C]-glucose, [1-14C]- and [2-14C]-pyruvic acid, [U-14C]-palmitic acid and [U-14C]-glutamine was evaluated in incubated lymphocytes isolated from mesenteric lymph nodes. The measurements were carried out in cells following three experimental protocols: (1) lymphocytes freshly obtained from control and alloxan-induced diabetic rats, (2) lymphocytes from insulin-treated (2 U/rat per day) diabetic rats and (3) lymphocytes obtained from control and diabetic rats and cultured in the presence of insulin (1 mU/ml) for 6 h. The activities of hexokinase, G6PDH and citrate synthase were decreased by the diabetic state, whereas that of phosphofructokinase was raised. Decarboxylation of [U-14C]- and [6-14C]-glucose, [1-14C]- and [2-14C]-pyruvate and [U-14C]-glutamine were also decreased in lymphocytes from diabetic rats, whereas [U-14C]-palmitic acid decarboxylation was increased. Insulin administration in vivo or added to the culture medium reversed the changes observed in freshly obtained lymphocytes. Alloxan-induced diabetes did change lymphocyte metabolism and this may be an important mechanism leading to impairment of lymphocyte function.
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The occurrence of DNA fragmentation in lymphocytes obtained from alloxan-induced diabetic rats and diabetic patients was investigated. A high proportion of apoptotic lymphocytes in diabetic states may explain the impaired immune function in poorly controlled diabetic patients. Rat mesenteric lymph node lymphocytes were analysed for DNA fragmentation by using flow cytometry and agarose gel, and for chromatin condensation by Hoescht 33342 staining under different situations. Immediately after being obtained, the proportion of lymphocytes with fragmented DNA was twofold higher in alloxan-induced diabetic rats than in cells from control rats. After 48 h in culture, the occurrence of DNA fragmentation was also higher (81%) in cells from diabetic rats. Hoescht staining and fragmented DNA visualized in agarose gel were also higher in lymphocytes from alloxan-induced diabetic rats than in control cells. To investigate if this phenomenon also occurs in humans, blood lymphocytes from 14 diabetic subjects were examined. Similar results to those of rat lymphocytes were found in cells from diabetic patients immediately after being obtained and after 48 h in culture. The high occurrence of apoptosis in lymphocytes was accompanied by a reduced number of blood-circulating lymphocytes in diabetic patients. The involvement of low insulinaemia for the occurrence of apoptosis in lymphocytes was also examined. Insulin treatment markedly reduced the proportion of lymphocytes with fragmented DNA in alloxan-induced diabetic rats.
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Leptin directly increases the rate of exogenous glucose and fatty acids oxidation in isolated adipocytes. However, the effects of leptin on fatty acid metabolism in white adipose tIssue have not been examined in detail. Here, we report that in adipocytes incubated for 6 h in the presence of leptin (10 ng/ml), the insulin-stimulated de novo fatty acid synthesis was inhibited by 36% (P<0.05), while the exogenous oxidation of acetic and oleic acids was increased by 50% and 76% respectively. Interestingly, leptin did not alter the oxidation of intracellular fatty acids. Leptin-incubated cells presented a 16-fold increase in the incorporation of oleic acid into triglyceride (TG) and a 123% increase in the intracellular TG hydrolysis (as measured by free fatty acids release). Fatty acid-TG cycling was not affected by leptin. By employing fatty acids radiolabeled with (3)H and (14)C, we could determine the concomitant influx of fatty acids (incorporation of fatty acids into TG) and efflux of fatty acids (intracellular fatty acids oxidation and free fatty acids release) in the incubated cells. Leptin increased by 30% the net efflux of fatty acids from adipocytes. We conclude that leptin directly inhibits de novo synthesis of fatty acids and increases the release and oxidation of fatty acids in isolated rat adipocytes. These direct energy-dissipating effects of leptin may play an important role in reducing accumulation of fatty acids into TG of rat adipose cells.
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Leptin is an adipocyte hormone involved in the regulation of energy homeostasis. Generally accepted biological effects of leptin are inhibition of food intake and stimulation of metabolic rate in ob/ob mice, that are defective in the leptin gene. In contrast to these centrally mediated effects of leptin, we are reporting here on leptin effects on glucose incorporation into lipids and glucose decarboxylation in adipocytes isolated from male lean albino rats. Adipocytes previously cultivated (15 h) in the presence of leptin presented a 25% (P < 0.05) reduction of the insulin stimulated incorporation of glucose into lipids. Concurrently, the basal conversion of (U-14C)D-glucose into 14CO2 increased (110%) in the leptin cultivated adipocytes and reached values (1.54 nmol/10(5) cells) similar to the insulin stimulated group (not cultivated with leptin) (1.40 nmol/10(5) cells). In addition, in the presence of insulin, the leptin cultivated adipocytes elicited a 162% (P < 0.05) increase in 14CO2 production that was significantly higher than the increase observed for the not-leptin-cultivated insulin group (92%). We conclude that leptin: 1) directly inhibits the insulin stimulated glucose incorporation into lipids; 2) stimulates glucose decarboxylation, and also potentiates the effect of insulin on glucose decarboxylation in isolated adipocytes. Leptin per se does not alter glucose incorporation into lipids.
Institute of Health Sciences, University of São Judas Tadeu, Taquari, 546-Mooca, 03166-000 São Paulo SP, Brazil
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Institute of Health Sciences, University of São Judas Tadeu, Taquari, 546-Mooca, 03166-000 São Paulo SP, Brazil
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Institute of Health Sciences, University of São Judas Tadeu, Taquari, 546-Mooca, 03166-000 São Paulo SP, Brazil
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Institute of Health Sciences, University of São Judas Tadeu, Taquari, 546-Mooca, 03166-000 São Paulo SP, Brazil
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Institute of Health Sciences, University of São Judas Tadeu, Taquari, 546-Mooca, 03166-000 São Paulo SP, Brazil
Search for other papers by T C Pithon-Curi in
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Several studies have shown impairment of neutrophil function, a disorder that contributes to the high incidence of infections in diabetes. Since glucose and glutamine play a key role in neutrophil function, we investigated their metabolism in neutrophils obtained from the peritoneal cavity of streptozotocin-induced diabetic rats. The activities of hexokinase, glucose-6-phosphate dehydrogenase (G6PDH), phosphofructokinase (PFK), citrate synthase, phosphate-dependent glutaminase, NAD+-linked and NADP+-linked isocitrate dehydrogenase were assayed. Glucose, glutamine, lactate, glutamate and aspartate, and the decarboxylation of [U-14C], [1-14C] and [6-14C]glucose; [U-14C]palmitic acid; and [U-14C]glutamine were measured in 1-h incubated neutrophils. Phagocytosis capacity and hydrogen peroxide (H2O2) production were also determined. All measurements were carried out in neutrophils from control, diabetic and insulin-treated (2–4IU/day) diabetic rats. Phagocytosis and phorbol myristate acetate (PMA)-stimulated H2O2 production were decreased in neutrophils from diabetic rats. The activities of G6PDH and glutaminase were decreased, whereas that of PFK was raised by the diabetic state. The activities of the remaining enzymes were not changed. Diabetes decreased the decarboxylation of [1-14C]glucose and [U-14C]glutamine; however, [6-14C]glucose and [U-14C]palmitic acid decarboxylation was increased. These observations indicate that changes in metabolism may play an important role in the impaired neutrophil function observed in diabetes. The treatment with insulin abolished the changes induced by the diabetic state even with no marked change in glycemia. Therefore, insulin may have a direct effect on neutrophil metabolism and function.
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School of Biomedical Sciences, Department of Physiology and Biophysics, Biomedical Research Group, UCD Institute for Sport and Health, Curtin University, PO Box U1987, Perth, Western Australia 6845, Australia
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Growing evidence indicates that the regulation of intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels is essential for maintaining normal β-cell glucose responsiveness. While long-term exposure to high glucose induces oxidative stress in β cells, conflicting results have been published regarding the impact of ROS on acute glucose exposure and their role in glucose stimulated insulin secretion (GSIS). Although β cells are considered to be particularly vulnerable to oxidative damage, as they express relatively low levels of some peroxide-metabolizing enzymes such as catalase and glutathione (GSH) peroxidase, other less known GSH-based antioxidant systems are expressed in β cells at higher levels. Herein, we discuss the key mechanisms of ROS/RNS production and their physiological function in pancreatic β cells. We also hypothesize that specific interactions between RNS and ROS may be the cause of the vulnerability of pancreatic β cells to oxidative damage. In addition, using a hypothetical metabolic model based on the data available in the literature, we emphasize the importance of amino acid availability for GSH synthesis and for the maintenance of β-cell function and viability during periods of metabolic disturbance before the clinical onset of diabetes.
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