Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study examined the relationships between VO2max, power maintenance and oxygen consumption during intense intermittent work. Female recreational soccer players were assigned to either a low aerobic power group (LOW, n = 6, mean (SD) VO2max = 34.4 (2.4) mL.kg(-1)min(-1) or to a moderate aerobic power group (MOD, n = 7, VO2max = 47.6 (3.8) mL.kg(-1).min(-1)). VO2 was measured while subjects performed 10 6-s all-out sprints (30-s passive recovery) on a Monark cycle ergometer. LOW and MOD subjects generated similar peak 6-s power (p = .58) but MOD had a smaller decrement in power (% DO) over the 10 sprints (LOW vs MOD: 18.0 (7.6) vs 8.8 (3.7) % DO, p = .02). The MOD group also consumed significantly more oxygen than LOW in 9 of the 10 sprint-recovery cycles (p < .05). Significant relationships were seen between VO2max and the aerobic response to the sprint-recovery series (r = .78, p =.002) as well as between VO2max and % DO (r = -.65, p = .02), while a non-significant relationship was seen between the oxygen consumed during the sprint-recovery cycles and % DO (r = -.41, p = .16). Thus, VO2max appears to be related to both an increased aerobic contribution to sprint-recovery bouts and the enhanced ability of the MOD group to resist fatigue during intense intermittent exercise.
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PMID:The relationships between aerobic fitness, power maintenance and oxygen consumption during intense intermittent exercise. 1241 36

In both type 1 and type 2 diabetes, diabetic complications in target organs arise from chronic elevations of glucose. The pathogenic effect of high glucose, possibly in concert with fatty acids, is mediated to a significant extent via increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and subsequent oxidative stress. ROS and RNS directly oxidize and damage DNA, proteins, and lipids. In addition to their ability to directly inflict damage on macromolecules, ROS and RNS indirectly induce damage to tissues by activating a number of cellular stress-sensitive pathways. These pathways include nuclear factor-kappaB, p38 mitogen-activated protein kinase, NH(2)-terminal Jun kinases/stress-activated protein kinases, hexosamines, and others. In addition, there is evidence that in type 2 diabetes, the activation of these same pathways by elevations in glucose and free fatty acid (FFA) levels leads to both insulin resistance and impaired insulin secretion. Therefore, we propose here that the hyperglycemia-induced, and possibly FFA-induced, activation of stress pathways plays a key role in the development of not only the late complications in type 1 and type 2 diabetes, but also the insulin resistance and impaired insulin secretion seen in type 2 diabetes.
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PMID:Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? 1250 86

Accumulating evidence suggests that the pathophysiology of diabetes is analogous to chronic inflammatory states. Circulating levels of inflammatory cytokines such as IL-6 and tumor necrosis factor alpha (TNFalpha) are increased in both type 1 and type 2 diabetes. TNFalpha plays an important role in the pathogenesis of insulin resistance in type 2 diabetes. However, the reason for this increase remains unclear. Levels of the dicarbonyl methylglyoxal (MGO) are elevated in diabetic plasma and MGO-modified bovine serum albumin (MGO-BSA) can trigger cellular uptake of TNF. Therefore we tested the hypothesis that MGO-modified proteins may cause TNFalpha secretion in macrophage-like RAW 264.7 cells. Treatment of cells with MGO-BSA induced TNFalpha release in a dose-dependent manner. MGO-modified ribonuclease A and chicken egg ovalbumin had similar effects. Cotreatment of cells with antioxidant reagent N-acetylcysteine (NAC) inhibited MGO-BSA-induced TNFalpha secretion. MGO-BSA stimulated the simultaneous activation of p44/42 and p38 mitogen-activated protein kinase. PD98059, a selective MEK inhibitor, inhibited MGO-BSA-induced TNFalpha release as well as ERK phosphorylation. Pretreatment of cells with NAC also resulted in inhibition of MGO-BSA-induced ERK phosphorylation. MGO-BSA induced dose-dependent NFkappaB activation as shown by electrophoresis mobility shift assay. The MGO-BSA-induced NFkappaB activation was prevented in the presence of PD98059, NAC, and parthenolide, a selective inhibitor of NFkappaB. Furthermore, the NFkappaB inhibitor parthenolide suppressed MGO-BSA-induced TNFalpha secretion. Confocal microscopy using dichlorofluorescein to demonstrate intracellular reactive oxygen species (ROS) showed that MGO-BSA produced more ROS compared with native BSA. MGO-BSA could also stimulate protein kinase C (PKC) translocation to the cell membrane, considered a key signaling pathway in diabetes. However, there was no evidence that PKC was involved in TNFalpha release based on inhibition by calphostin C and staurosporine. Our findings suggest that the presence of chronically elevated levels of MGO-modified bovine serum albumin may contribute to elevated levels of TNFalpha in diabetes.
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PMID:Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor kappaB and intracellular reactive oxygen species formation. 1250 94

Oxygen free radicals have been implicated in beta-cell dysfunction and apoptosis associated with type 1 and type 2 diabetes mellitus. The roles of free radicals in diabetes have thus far been defined indirectly by monitoring oxidative tissue damage and the effects of antioxidants, free radical scavengers, and overexpression of superoxide dismutase. We employed the superoxide-mediated oxidation of hydroethidine to ethidium to dynamically and directly assess the relative rates of mitochondrial superoxide anion generation in isolated islets in response to glucose stimulation. Superoxide content of isolated islets increased in response to glucose stimulation. We next compared the oxyradical levels in Zucker lean control and Zucker diabetic fatty rat islets by digital imaging microfluorometry. The superoxide content of Zucker diabetic fatty islets was significantly higher than Zucker lean control islets under resting conditions, relatively insensitive to elevated glucose concentrations, and correlated temporally with a decrease in glucose-induced hyperpolarization of the mitochondrial membrane. Importantly, superoxide levels were elevated in islets from young, pre-diabetic Zucker diabetic fatty animals. Overproduction of superoxide was associated with perturbed mitochondrial morphology and may contribute to abnormal glucose signaling found in the Zucker diabetic fatty model of type 2 diabetes mellitus.
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PMID:Visualizing superoxide production in normal and diabetic rat islets of Langerhans. 1251 70

Abdominal obesity and physical inactivity are associated with insulin resistance in humans and contribute to the development of type 2 diabetes. Likewise, sustained increases in the concentration of malonyl coenzyme A (CoA), an inhibitor of fatty-acid oxidation, have been observed in muscle in association with insulin resistance and type 2 diabetes in various rodents. In the present study, we assessed whether these factors are present in a defined population of slightly overweight (body mass index, 26.2 kg/m2), insulin-resistant patients with type 2 diabetes. Thirteen type 2 diabetic men and 17 sex-, age-, and body mass index-matched control subjects were evaluated. Insulin sensitivity was assessed during a two-step euglycemic insulin clamp (infusion of 0.25 and 1.0 mU/kg x min). The rates of glucose administered during the low-dose insulin clamp were 2.0 +/- 0.2 vs. 0.7 +/- 0.2 mg/kg body weight x min (P < 0.001) in the control and diabetic subjects, respectively; rates during the high-dose insulin clamp were 8.3 +/- 0.7 vs. 4.6 +/- 0.4 mg/kg body weight x min (P < 0.001) for controls and diabetic subjects. The diabetic patients had a significantly lower maximal oxygen uptake than control subjects (29.4 +/- 1.0 vs. 33.4 +/- 1.4 ml/kg x min; P = 0.03) and a greater total body fat mass (3.7 kg), mainly due to an increase in truncal fat (16.5 +/- 0.9 vs. 13.1 +/- 0.9 kg; P = 0.02). The plasma concentration of free fatty acid and the rate of fatty acid oxidation during the clamps were both higher in the diabetic subjects than the control subjects (P = 0.002-0.007). In addition, during the high-dose insulin clamp, the increase in cytosolic citrate and malate in muscle, which parallels and regulates malonyl CoA levels, was significantly less in the diabetic patients (P < 0.05 vs. P < 0.001). Despite this, a similar increase in the concentration of malonyl CoA was observed in the two groups, suggesting an abnormality in malonyl CoA regulation in the diabetic subjects. In conclusion, the results confirm that insulin sensitivity is decreased in slightly overweight men with mild type 2 diabetes and that this correlates closely with an increase in truncal fat mass and a decrease in physical fitness. Whether the unexpectedly high levels of malonyl CoA in muscle, together with the diminished suppression of plasma free fatty acid, explains the insulin resistance of the diabetic patients during the clamp remains to be determined.
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PMID:Insulin resistance in type 2 diabetes: association with truncal obesity, impaired fitness, and atypical malonyl coenzyme A regulation. 1251 34

Exercise and improved diet is known to be beneficial in the management of type 2 (non-insulin dependent) diabetes mellitus. In practice, however, it is difficult for patients to implement these changes unaided. We hypothesized that a lifestyle modification programme involving residential visits would result in beneficial effects on glycaemic control and lipid profile. Three hundred and four individuals with type 2 diabetes participated in a lifestyle modification programme, involving three residential visits (2 weeks, 1 week and one 3-day visit) spaced over 31 weeks. The subjects were all referred for treatment following repeated failure to achieve metabolic control in primary care settings. Participants received information and practical guidance regarding exercise training, nutrition, as well as stress management and psychological counselling. Clinical parameters were determined at each visit. After completion of the programme, subjects showed significant improvements in glycaemic control (P<0.0001). Oxygen uptake was significantly improved (P<0.0001) and blood pressure (P<0.0001), body mass index (P<0.0001) and serum cholesterol (P<0.001) was significantly reduced, while HDL cholesterol (P<0.05) was significantly increased. There were no changes in LDL cholesterol values. Subjects also reported increased well-being and reduced stress. In conclusion, a 31-week lifestyle modification programme results in marked improvements in glycaemic control, blood pressure and well-being in subjects with type 2 diabetes. Thus, this type of lifestyle modification programme is a powerful treatment option to reduce risk factors associated with diabetes and diabetic complications, even in patients who have not responded to conventional diabetic therapy.
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PMID:Reduction of risk factors following lifestyle modification programme in subjects with type 2 (non-insulin dependent) diabetes mellitus. 1255 10

Strategies to delay the onset and ameliorate the sequelae of type 2 diabetes are urgently needed in Singapore. Diabetes is accompanied by severe oxidative stress (especially lipid peroxidation) due to increased oxygen free radical production. Oxidative stress in part results from hyperglycaemia, but it may also precede, and accelerate the development of overt type 2 diabetes and then of diabetic complications. Epidemiological evidence indicates low vitamin E intake as a risk factor for development of type 2 diabetes, and small scale human intervention studies have indicated benefit of vitamin E in improving endothelial function, retinal blood flow and renal dysfunction. Animal studies also support its usefulness. The weight of evidence available supports the suggestion that a major double-blind controlled clinical trial of antioxidants in prevention and treatment of type 2 diabetes should be undertaken.
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PMID:Vitamin E and thetreatment and prevention of diabetes: a case for a controlled clinical trial. 1256 28

Chronic exposure to hyperglycemia can lead to cellular dysfunction that may become irreversible over time, a process that is termed glucose toxicity. Our perspective about glucose toxicity as it pertains to the pancreatic beta-cell is that the characteristic decreases in insulin synthesis and secretion are caused by decreased insulin gene expression. The responsible metabolic lesion appears to involve a posttranscriptional defect in pancreas duodenum homeobox-1 (PDX-1) mRNA maturation. PDX-1 is a critically important transcription factor for the insulin promoter, is absent in glucotoxic islets, and, when transfected into glucotoxic beta-cells, improves insulin promoter activity. Because reactive oxygen species are produced via oxidative phosphorylation during anaerobic glycolysis, via the Schiff reaction during glycation, via glucose autoxidation, and via hexosamine metabolism under supraphysiological glucose concentrations, we hypothesize that chronic oxidative stress is an important mechanism for glucose toxicity. Support for this hypothesis is found in the observations that high glucose concentrations increase intraislet peroxide levels, that islets contain very low levels of antioxidant enzyme activities, and that adenoviral overexpression of antioxidant enzymes in vitro in islets, as well as exogenous treatment with antioxidants in vivo in animals, protect the islet from the toxic effects of excessive glucose levels. Clinically, consideration of antioxidants as adjunct therapy in type 2 diabetes is warranted because of the many reports of elevated markers of oxidative stress in patients with this disease, which is characterized by imperfect management of glycemia, consequent chronic hyperglycemia, and relentless deterioration of beta-cell function.
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PMID:Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. 1260 96

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in later life. We have developed a model of uteroplacental insufficiency, a common cause of intrauterine growth retardation, in the rat. Early in life, the animals are insulin resistant and by 6 mo of age they develop diabetes. Glycogen content and insulin-stimulated 2-deoxyglucose uptake were significantly decreased in muscle from IUGR rats. IUGR muscle mitochondria exhibited significantly decreased rates of state 3 oxygen consumption with pyruvate, glutamate, alpha-ketoglutarate, and succinate. Decreased pyruvate oxidation in IUGR mitochondria was associated with decreased ATP production, decreased pyruvate dehydrogenase activity, and increased expression of pyruvate dehydrogenase kinase 4. Such a defect in IUGR mitochondria leads to a chronic reduction in the supply of ATP available from oxidative phosphorylation. Impaired ATP synthesis in muscle compromises energy-dependent GLUT4 recruitment to the cell surface, glucose transport, and glycogen synthesis, which contribute to insulin resistance and hyperglycemia of type 2 diabetes.
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PMID:Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats. 1263 57

Biguanides are a class of drugs widely used as oral antihyperglycemic agents for the treatment of type 2 diabetes mellitus, but they are associated with lactic acidosis, a lethal side effect. We reported previously that biguanides are good substrates of rat organic cation transporter 1 (Oct1; Slc22a1) and, using Oct1(-/-) mice, that mouse Oct1 is responsible for the hepatic uptake of a biguanide, metformin. In the present study, we investigated whether the liver is the key organ for the lactic acidosis. When mice were given metformin, the blood lactate concentration significantly increased in the wild-type mice, whereas only a slight increase was observed in Oct1(-/-) mice. The plasma concentration of metformin exhibited similar time profiles between the wild-type and Oct1(-/-) mice, suggesting that the liver is the key organ responsible for the lactic acidosis. Furthermore, the extent of the increase in blood lactate caused by three different biguanides (metformin, buformin, and phenformin) was compared with the abilities to reduce oxygen consumption in isolated rat hepatocytes. When rats were given each of these biguanides, the lactate concentration increased significantly. This effect was dose-dependent, and the EC(50) values of metformin, buformin, and phenformin were 734, 119, and 4.97 microM, respectively. All of these biguanides reduced the oxygen consumption by isolated rat hepatocytes in a concentration-dependent manner. When the concentration required to reduce the oxygen consumption to 75% of the control value (from 0.40 to 0.29 micromol/min/mg protein) was compared with the EC(50) value obtained in vivo, a clear correlation was observed among the three biguanides, suggesting that oxygen consumption in isolated rat hepatocytes can be used as an index of the incidence of lactic acidosis.
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PMID:Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. 1264 85


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