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Circulation. 2002;106:2067-2072
Published online before print September 30, 2002, doi: 10.1161/01.CIR.0000034509.14906.AE
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(Circulation. 2002;106:2067.)
© 2002 American Heart Association, Inc.


Clinical Investigation and Reports

Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans

Role of Oxidative Stress

Katherine Esposito, MD; Francesco Nappo, MD, PhD; Raffaele Marfella, MD, PhD; Giovanni Giugliano, MD; Francesco Giugliano; Myriam Ciotola; Lisa Quagliaro, BS; Antonio Ceriello, MD; Dario Giugliano, MD, PhD

From the Department of Geriatric and Metabolic Diseases (K.E., F.N., R.M., G.G., F.G., M.C., D.G.) and Cardiovascular Research Centre (R.M., D.G.), Second University of Naples; and Chair of Internal Medicine (A.C., L.Q.), University of Udine, Italy.

Correspondence to Dario Giugliano, MD, Dept of Geriatrics and Metabolic Diseases, Policlinico della Seconda Università di Napoli, Piazza Miraglia, 80138 Napoli, Italy. E-mail dario.giugliano{at}unina2.it


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Background— Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-{alpha} (TNF-{alpha}) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-{alpha}, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione.

Methods and Results— Plasma glucose levels were acutely raised in 20 control and 15 IGT subjects and maintained at 15 mmol/L for 5 hours while endogenous insulin secretion was blocked with octreotide. In control subjects, plasma IL-6, TNF-{alpha}, and IL-18 levels rose (P<0.01) within 2 hours of the clamp and returned to basal values at 3 hours. In another study, the same subjects received 3 consecutive pulses of intravenous glucose (0.33 g/kg) separated by a 2-hour interval. Plasma cytokine levels obtained at 3, 4, and 5 hours were higher (P<0.05) than the corresponding values obtained during the clamp. The IGT subjects had fasting plasma IL-6 and TNF-{alpha} levels higher (P<0.05) than those of control subjects. The increase in plasma cytokine levels during the clamping lasted longer (4 hours versus 2 hours, P<0.01) in the IGT subjects than in the control subjects, and the cytokine peaks of IGT subjects after the first glucose pulse were higher (P<0.05) than those of control subjects. On another occasion, 10 control and 8 IGT subjects received the same glucose pulses as above during an infusion of glutathione; plasma cytokine levels did not show any significant change from baseline after the 3 glucose pulses.

Conclusions— Hyperglycemia acutely increases circulating cytokine concentrations by an oxidative mechanism, and this effect is more pronounced in subjects with IGT. This suggests a causal role for hyperglycemia in the immune activation of diabetes.


Key Words: hyperglycemia • tumor necrosis factor • interleukins • glutathione


*    Introduction
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Type 2 diabetes mellitus is associated with an increased risk of premature atherosclerosis: Coronary artery disease, cerebrovascular disease, or peripheral vascular disease is the cause of death in 75% to 80% of adult diabetic subjects.1 Although the conviction that hyperglycemia plays a role in the pathogenesis of cardiovascular complications in diabetic patients has waxed and waned in recent years, both prospective studies on the relationship between plasma glucose and cardiovascular events and clinical trials of intensive glucose control have found a link between high glucose levels and cardiovascular diseases, without any apparent threshold.2

It has been postulated that type 2 diabetes mellitus may represent a disease of the innate immune system responsible for an ongoing cytokine-mediated acute phase response.3 Consistent with this hypothesis, a prospective study found that two circulating markers of systemic inflammation, C-reactive protein and interleukin-6 (IL-6), were determinant of risk for development of type 2 diabetes mellitus in apparently healthy middle-aged women.4 Moreover, several studies have demonstrated elevated levels of IL-6 and tumor necrosis factor-{alpha} (TNF-{alpha}) among individuals both with features of the insulin resistance syndrome and with clinically overt type 2 diabetes mellitus.58

The aim of the present study was to test whether circulating levels of cytokines are regulated by glucose levels in humans. The study protocol was designed to measure serum TNF-{alpha}, IL-6 and interleukin-18 (IL-18) concentrations during acute hyperglycemia in subjects with normal or impaired glucose tolerance (IGT); a role for IL-18 in plaque destabilization has recently been suggested,9 and stress hyperglycemia is an important risk factor for post–myocardial infarction mortality in subjects with or without diabetes.10 Because oscillatory hyperglycemia may be more toxic for endothelial cells than continuous hyperglycemia,11,12 we also assessed the cytokine behavior in response to consecutive glucose pulses. Finally, we tested the effect of the antioxidant glutathione on cytokine responses to acute hyperglycemia; there is evidence that the release of TNF-{alpha} induced by high glucose in vitro may be mediated by reactive oxygen species13 and that oxidative stress might be implicated in promoting a low-grade systemic inflammation in patients with type 2 diabetes mellitus.6


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Study Population
The control subjects were recruited from the medical and paramedical staff of the Department of Geriatrics and Metabolic Diseases at the Second University of Naples. Subjects with IGT were selected from the type 2 diabetic patients’ first-degree relatives who presented a 2-hour plasma glucose value between 7.7 and 11 mmol/L after a standard 75-g oral glucose tolerance test. The clinical and metabolic characteristics of all subjects are shown in the Table. The control subjects had normal glucose tolerance (2-hour plasma glucose value below 7.7 mmol/L) and no evidence of hypertension, hyperlipidemia, or any systemic conditions; the IGT subjects had no evidence of any cardiovascular complications. All subjects were on weight-maintaining diets with 250 g of carbohydrate per day, had no recent change in body weight or intercurrent illness, and were taking no medications. Particular care was taken to exclude subjects with infections or inflammatory diseases, as confirmed with measurement of C-reactive protein level of <5 mg/L. None of the subjects were engaged in physical activity for >3 hours per week or smoked. The ethics committee of our institution approved the protocol of the study. All subjects gave informed consent before being tested.


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Clinical and Metabolic Characteristics of the Study Population

Study Protocol
After a 12-hour overnight fast, subjects were placed in a supine comfortable position with a room temperature between 20° and 24°C. Intravenous lines were inserted into a large antecubital vein of one arm for infusions and into a dorsal vein of the contralateral arm for blood sampling. Patency was preserved by a slow saline infusion (0.9% NaCl). The study began after the subjects had rested for 30 minutes. The subjects underwent the tests in random order and separated by at least a 3-day interval.

Study 1
All subjects participated in the glucose clamp study. After withdrawal of baseline blood samples, plasma glucose concentrations were acutely raised with a bolus injection of 0.33 g/kg glucose followed by a varying 30% glucose infusion to achieve steady-state plasma glucose concentrations of about 15 mmol/L for 240 minutes. This test was performed with the aid of an artificial pancreas (Biostator, Life Science), which allowed exogenous glucose to be infused in order to match the prefixed plasma glucose value on the basis of continuous blood glucose monitoring. Octreotide (25 µg IV bolus followed by a 0.5 µg/min infusion, Longastatina; Italfarmaco) was infused to block the release of endogenous insulin. The octreotide infusion was started 5 minutes before the priming glucose pulse and was interrupted at the end of the clamp. To prevent hypokalemia, 0.26 mmol/L KCl was added to the glucose infusion.

To exclude any direct effect of octreotide on cytokine levels, 5 control and 5 IGT subjects received an additional infusion of octreotide alone at the dose administered earlier, in the absence of the hyperglycemic clamp.

Study 2
All subjects participated in the glucose pulse study. In this study, three consecutive bolus of intravenous glucose (0.33 g/kg) were injected in a large antecubital vein separated by a 2-hour interval. After the first glucose pulse, plasma glucose levels had returned to baseline before the administration of the subsequent glucose pulse. Even in this study, and as described earlier, an octreotide infusion was started 5 minutes before the first glucose pulse and was interrupted 60 minutes after the third glucose pulse, ie, 5 hours later.

Study 3
Ten (5 male, 5 female) control and 8 (4 male, 4 female) IGT subjects participated in the glutathione study. This study consisted of the consecutive glucose pulses as described in study 2 plus glutathione infusion (600 mg as an intravenous bolus followed by a 5-mg/min infusion). Both octreotide and glutathione infusions were started 5 minutes before the first glucose pulse and lasted 5 hours.

Analyses
Samples for analysis of plasma glucose were collected in tubes containing a trace of sodium fluoride, and samples for analysis of insulin were collected in tubes containing a mixture (0.1 mL/mL blood) of EDTA-aprotinin (Trasylol) solution (500 U/mL Trasylol [Bayer], 1.2 g/L disodium EDTA). Plasma glucose was determined according to the glucose oxidase method with an autoanalyzer (Beckman Instruments). Labile and stable forms of glycated hemoglobin A1 (HbA1) were determined in duplicate as previously described.14 Plasma insulin levels were determined with radioimmunoassay.15 Serum samples for cytokines levels were stored at -80°C until assay. Serum concentrations of TNF-{alpha}, IL-6, and IL-18 were determined in duplicate with commercially available kits (R&D Systems). Dilution curves of serum samples were parallel those of standard. Intra-assay and interassay coefficients of variation were 3.8% and 5.8%, respectively, for TNF-{alpha}; 3.9% and 5.9%, respectively, for IL-6; and 3.5% and 6.1%, respectively, for IL-18.

Statistical Analysis
Results are given as mean±SD. One-way ANOVA was used to compare baseline data, followed by Scheffé’s test for pairwise comparisons. Multiple comparison tests were made with ANOVA, followed by post hoc analysis (Student-Newman-Keuls test) to locate the significant difference indicated with ANOVA. A value of P<0.05 was considered statistically significant.


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Hyperglycemic Clamp
Control Subjects
During the clamp (Figure 1), plasma glucose stabilized at 15 mmol/L with oscillations not exceeding 5% of the prefixed value. Labile HbA1 levels increased from the value of 0.15±0.03% to 1.1±0.1% (P<0.01) at 5 hours; stable HbA1 levels did not show any significant change during the clamp. Insulin secretion in response to glucose was completely suppressed during octreotide infusion: Circulating insulin levels remained below 70 pmol/L during the study. Plasma IL-6 levels rose from a basal value of 2.0±0.7 pg/mL to a peak of 3.1±0.9 pg/mL at 1 hour (P<0.01) and returned to basal level at 3 hours (Figure 2). Fasting plasma TNF-{alpha} levels were 3.3±1.2 pg/mL; they peaked at 1 hour (4.9±1.4 pg/mL, P<0.01), and returned to baseline at 3 hours. Plasma IL-18 levels rose from a basal value of 116±28 pg/mL to a peak of 140±31 pg/mL at 2 hours (P<0.01) and returned to basal levels at 3 hours (110±26 pg/mL).



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Figure 1. Plasma glucose concentrations attained during hyperglycemic clamps and after consecutive glucose pulses.



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Figure 2. Circulating cytokine levels during hyperglycemic clamps in 20 control subjects ({image}) and in 12 IGT subjects ({image}).

IGT Subjects
Plasma glucose, insulin, and labile HbA1 levels during the clamp were not significantly different from values obtained in control subjects. Fasting plasma IL-6 and TNF-{alpha} levels were higher than those in control subjects (Table). The increase in plasma cytokine levels during the clamping lasted longer than in control subjects (4 hours versus 2 hours, respectively, P<0.01) and returned to basal levels at 5 hours (Figure 2).

The infusion of octreotide alone in 5 control and 5 IGT subjects did not cause any significant variations in the plasma concentration of IL-6, TNF-{alpha}, and IL-18 levels (data not shown).

Glucose Pulses
Control Subjects
The fasting concentrations of plasma glucose and insulin were not significantly different from the corresponding values obtained in the clamp study. Plasma glucose peaked between 3 and 5 minutes after each pulse and returned to basal values before the subsequent glucose injection (Figure 1). Both first-phase (0 to 10 minutes) and second-phase (10 to 60 minutes) insulin secretion were completely suppressed by octreotide. The increase in labile HbA1 level during the study (1.1±0.2%) was not different from that obtained in the clamp study (0.98±0.17%). The fasting concentrations of IL-6 (1.9±0.7 pg/mL), TNF-{alpha} (3.3±1.2 pg/mL), and IL-18 (112±28 pg/mL) were not significantly different from those obtained during the clamping. Plasma IL-6 levels peaked at 1 hour after the first glucose pulse and returned to baseline at 2 hours (Figure 3). Values obtained at 3, 4, and 5 hours were significantly (P<0.05) higher than the corresponding values observed during the clamping. A similar trend of response was also observed for TNF-{alpha} and IL-18: For both, the greatest peak occurred 60 minutes after the third glucose pulse, which was significantly greater than the baseline value (P<0.01) and the corresponding 5-hour value obtained in the clamp study (P<0.02).



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Figure 3. Circulating cytokine levels after consecutive glucose pulses in 20 control subjects ({image}) and in 12 IGT subjects ({image}).

IGT Subjects
Plasma glucose peaks, insulin, and labile HbA1 levels after glucose injections were not significantly different from values obtained in control subjects. Fasting cytokine levels were not significantly different from those obtained during the clamping. However, cytokine peaks after the glucose pulses were higher (P<0.05) than the corresponding values obtained in control subjects and did not return to baseline by 2 hours (Figure 3).

Glutathione Study
The clinical and metabolic characteristics of the 10 control subjects participating in this study were not significantly different from the other 10. In particular, their age was 34.5±3.9 years and body mass index was 24.3±1.2 kg/m2, and there was no difference in the basal levels of plasma glucose (5.2±0.5 mmol/L), insulin (64±16 pmol/L), IL-6 (1.8±0.8 pg/mL), TNF-{alpha} (3.4±1.2 pg/mL), and IL-18 (115±25 pg/mL). During glutathione infusion, the 3 consecutive glucose pulses produced plasma glucose levels not significantly different from those observed without glutathione; plasma insulin levels were fully suppressed by octreotide. On the other hand, plasma IL-6, TNF-{alpha}, and IL-18 concentrations did not shown any significant change from baseline after the three consecutive glucose pulses (Figure 4).



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Figure 4. Circulating cytokine levels after consecutive glucose pulses with an infusion of glutathione in 10 control subjects ({image}) and in 8 IGT subjects ({image}).

Similarly, there was no significant change from baseline in plasma cytokine concentrations during glutathione infusion in 8 IGT subjects receiving the 3 glucose pulses (Figure 4).


*    Discussion
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*Discussion
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The novel findings of the present study were that (1) acute hyperglycemia in control and in IGT subjects induces an increase in plasma IL-6, TNF-{alpha}, and IL-18 concentrations; (2) the effect of sustained hyperglycemia is reproduced by transient oscillations in plasma glucose and is amplified by the IGT status; and (3) the antioxidant glutathione completely prevents the rise in plasma cytokines induced by hyperglycemia. These results indicate that hyperglycemic spikes affect cytokine concentrations more than continuous hyperglycemia, at least in the short term, and suggest that an oxidative mechanism mediates the effect of hyperglycemia.

To our knowledge, this is the first demonstration that acute hyperglycemia affects the concentration of plasma cytokines in humans. In vitro studies using supraphysiological glucose concentration (>22 mmol/L) have reported an increase in TNF-{alpha} and IL-6 secretion from healthy human mononuclear cells.16 Furthermore, increased synthesis of TNF-{alpha} has been reported both in primary cultures of rat uterine cells cultured in vitro with increasing concentrations of glucose17 and in placental tissue explants from women with gestational diabetes incubated with high glucose (25 mmol/L).18 There is also evidence that IL-6 production by human monocytes isolated from healthy volunteers is enhanced during 24-hour incubation in high-glucose medium.19

Previous studies have demonstrated increased circulating levels of TNF-{alpha} and IL-6 in diabetic patients,3,58 with a significant correlation of IL-6 levels with HbA1c,7 progression of diabetic nephropathy,8 and amelioration of glycemic control after treatment.6 In a more general sense, an augmented acute-phase response may be a mechanism that explains many of the clinical and biochemical features of type 2 diabetes and its complications. For example, TNF-{alpha} can impair insulin receptor signaling in adipose tissue and skeletal muscle, thereby decreasing insulin-stimulated glucose uptake and promoting insulin resistance associated with obesity and type 2 diabetes.20 Administration of human recombinant IL-6 in humans has been shown to induce hyperglycemia and compensatory hyperinsulinemia,21 two biological markers of insulin resistance. Moreover, subjects homozygous for the C allele of the IL-6 gene present lower levels of plasma IL-6 and an increased insulin sensitivity index than do carriers of the G allele.22 Lastly, elevated levels of IL-6 predict the development of type 2 diabetes in healthy women.4

The TNF-{alpha} and IL-6 found in plasma are likely produced by various tissues, including activated leukocytes, adipocytes, and endothelial cells. Because the increased circulating cytokine levels found in diabetes seem to originate from noncirculating cells,5 and given the prompt increase of plasma cytokine levels after acute hyperglycemia in the present study, likely candidates for its production may be adipocytes and endothelial cells. Further support for this hypothesis comes from the evidence that adipocytes secrete {approx}25% of in vivo systemic IL-6 concentration23 and that high glucose increases the secretion of IL-1 from cultured human aortic endothelial cells.24

We could not find any study that assessed the circulating levels of IL-18 in diabetes or the effect of high glucose on IL-18–producing cells in vitro. IL-18 is a pleiotropic cytokine acting in both acquired and innate immunity and might be involved in atherosclerosis.25 Beside acting as a proinflammatory cytokine by inducing the expression of adhesion molecules, IL-18 is also able to stimulate the production of granulocyte-macrophage colony–stimulating factor, TNF-{alpha}, and inducible nitric oxide synthase by mononuclear and mesenchymal cells.25 In human atheroma in situ, IL-18 signaling evokes effectors involved in atherogenesis, such as IL-6, intracellular adhesion molecule-1, and matrix metalloproteinases 1, 9, and 1326; moreover, the recent demonstration of significantly higher levels of IL-18 mRNA in symptomatic plaques than in asymptomatic plaques suggests a major role in atherosclerotic plaque destabilization leading to acute ischemic syndrome.9 Following this line of thought, it might be speculated that the detrimental effect of stress hyperglycemia in acute coronary syndromes10 might also be due to the effect of acute hyperglycemia to increase circulating IL-18 levels.

Epidemiological studies published in recent years suggest that postprandial blood glucose might be an independent risk factor of cardiovascular disease and that postprandial hyperglycemia in diabetic subjects is a more powerful marker of cardiovascular disease risk than is fasting hyperglycemia.27 In this context, hyperglycemic spikes might be seen as surrogate markers of oscillations of plasma glucose levels after meals. We have shown that cytokine levels are affected more by oscillatory than continuous hyperglycemia and that the IGT status amplifies the phenomenon. The molecular mechanisms triggered by intermittent hyperglycemia are not known. However, some metabolic variations induced by sustained hyperglycemia might change or feed back regulatory cell controls, partially counteracting the glucose effects. Intermittent exposure to hyperglycemia might reduce such adaptation, causing more pronounced toxicity. Consistent with this, in human umbilical vein endothelial cells in culture, apoptosis is enhanced in response to intermittent, rather than continuous high glucose concentrations.28 The different pattern of cytokine secretion after hyperglycemic spikes might have clinical significance because prospective epidemiological studies have found increased vascular risk in association with increased levels of cytokines such as IL-6 and TNF-{alpha}.2931

Another finding of the present study was that glutathione, a powerful antioxidant, completely prevented cytokine increase induced by oscillatory hyperglycemia in healthy humans. Hyperglycemia-induced oxidative stress, 32 along with soluble advanced glycation end products and products of lipid peroxidation, possibly serves as a key activator of upstream kinases, leading to induction of inflammatory gene expression.33 In cultured monocytic cells incubated with high glucose (15 mmol/L for 18 hours) a dramatic increase in the release of TNF-{alpha} has been reported to be mediated by reactive oxygen species via activation of transcription factors nuclear factor-{kappa}B (NF-{kappa}B) and activating protein-1.13 Interestingly enough, I{kappa}B kinase ß repression (leading to increased NF-kB deactivation) protects against the development of insulin resistance during high-fat feeding and in ob/ob mice.34

The present study introduces an additional aspect of how hyperglycemia might contribute to early stages of atherogenesis and also favor cardiovascular death in myocardial infarction patients10: Acute hyperglycemia increases circulating cytokine concentrations, which have been implicated in insulin resistance (TNF-{alpha}, IL-6), plaque destabilization (IL-18), and future cardiovascular events (IL-6). Although the relevance of these acute changes in plasma cytokines to the chronic vascular complications of diabetes is, at present, speculative, an increased oxidative stress seems a likely mechanism linking acute hyperglycemia to cardiovascular diabetic complications via an increased cytokine secretion.

Received June 17, 2002; revision received August 2, 2002; accepted August 5, 2002.


*    References
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up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
up arrowDiscussion
*References
 
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21. Tsigos C, Papanicolau DA, Kyrou I, et al. Dose-dependent effects of recombinant human interleukin-6 on glucose regulation. J Clin Endocrinol Metab. 1997; 82: 4167–4170.[Abstract/Free Full Text]

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J. Clin. Endocrinol. Metab.Home page
J. P. Crandall, H. Shamoon, H. W. Cohen, M. Reid, S. Gajavelli, G. Trandafirescu, V. Tabatabaie, and N. Barzilai
Post-Challenge Hyperglycemia in Older Adults Is Associated with Increased Cardiovascular Risk Profile
J. Clin. Endocrinol. Metab., May 1, 2009; 94(5): 1595 - 1601.
[Abstract] [Full Text] [PDF]


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StrokeHome page
Y. Doi, T. Ninomiya, J. Hata, K. Yonemoto, H. Arima, M. Kubo, Y. Tanizaki, M. Iwase, M. Iida, and Y. Kiyohara
Proposed Criteria for Metabolic Syndrome in Japanese Based on Prospective Evidence: The Hisayama Study
Stroke, April 1, 2009; 40(4): 1187 - 1194.
[Abstract] [Full Text] [PDF]


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Diabetes CareHome page
M. Troseid, I. Seljeflot, E. M. Hjerkinn, and H. Arnesen
Interleukin-18 Is a Strong Predictor of Cardiovascular Events in Elderly Men With the Metabolic Syndrome: Synergistic effect of inflammation and hyperglycemia
Diabetes Care, March 1, 2009; 32(3): 486 - 492.
[Abstract] [Full Text] [PDF]


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J Am Coll CardiolHome page
P. Dandona, A. Chaudhuri, H. Ghanim, and P. Mohanty
Insulin as an anti-inflammatory and antiatherogenic modulator.
J. Am. Coll. Cardiol., February 3, 2009; 53(5 Suppl): S14 - S20.
[Abstract] [Full Text] [PDF]


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Clin. Chem.Home page
J. Shen and J. M. Ordovas
Impact of Genetic and Environmental Factors on hsCRP Concentrations and Response to Therapeutic Agents
Clin. Chem., February 1, 2009; 55(2): 256 - 264.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
A. B. M. Reddy, K. V. Ramana, S. Srivastava, A. Bhatnagar, and S. K. Srivastava
Aldose Reductase Regulates High Glucose-Induced Ectodomain Shedding of Tumor Necrosis Factor (TNF)-{alpha} via Protein Kinase C-{delta} and TNF-{alpha} Converting Enzyme in Vascular Smooth Muscle Cells
Endocrinology, January 1, 2009; 150(1): 63 - 74.
[Abstract] [Full Text] [PDF]


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Diabetes and Vascular Disease ResearchHome page
A. Ceriello
Cardiovascular effects of acute hyperglycaemia: pathophysiological underpinnings
Diabetes and Vascular Disease Research, November 1, 2008; 5(4): 260 - 268.
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Am J EpidemiolHome page
C. Chao and J. H. Page
Type 2 Diabetes Mellitus and Risk of Non-Hodgkin Lymphoma: A Systematic Review and Meta-Analysis
Am. J. Epidemiol., September 1, 2008; 168(5): 471 - 480.
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Am. J. Clin. Nutr.Home page
F. W. te Braake, H. Schierbeek, K. de Groof, A. Vermes, M. Longini, G. Buonocore, and J. B van Goudoever
Glutathione synthesis rates after amino acid administration directly after birth in preterm infants
Am. J. Clinical Nutrition, August 1, 2008; 88(2): 333 - 339.
[Abstract] [Full Text] [PDF]


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J. Am. Coll. Nutr.Home page
M. R. Rizzo, A. M. Abbatecola, M. Barbieri, M. T. Vietri, M. Cioffi, R. Grella, A. Molinari, R. Forsey, J. Powell, and G. Paolisso
Evidence for Anti-Inflammatory Effects of Combined Administration of Vitamin E and C in Older Persons with Impaired Fasting Glucose: Impact on Insulin Action
J. Am. Coll. Nutr., August 1, 2008; 27(4): 505 - 511.
[Abstract] [Full Text] [PDF]


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Ann. Thorac. Surg.Home page
T. Albacker, G. Carvalho, T. Schricker, and K. Lachapelle
High-Dose Insulin Therapy Attenuates Systemic Inflammatory Response in Coronary Artery Bypass Grafting Patients
Ann. Thorac. Surg., July 1, 2008; 86(1): 20 - 27.
[Abstract] [Full Text] [PDF]


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Diabetes CareHome page
S. Dotson, R. Freeman, H. J. Failing, and G. K. Adler
Hypoglycemia Increases Serum Interleukin-6 Levels in Healthy Men and Women
Diabetes Care, June 1, 2008; 31(6): 1222 - 1223.
[Abstract] [Full Text] [PDF]


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Am. J. Clin. Nutr.Home page
P. Kallio, M. Kolehmainen, D. E Laaksonen, L. Pulkkinen, M. Atalay, H. Mykkanen, M. Uusitupa, K. Poutanen, and L. Niskanen
Inflammation markers are modulated by responses to diets differing in postprandial insulin responses in individuals with the metabolic syndrome
Am. J. Clinical Nutrition, May 1, 2008; 87(5): 1497 - 1503.
[Abstract] [Full Text] [PDF]


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CirculationHome page
L. H. Opie
Metabolic Management of Acute Myocardial Infarction Comes to the Fore and Extends Beyond Control of Hyperglycemia
Circulation, April 29, 2008; 117(17): 2172 - 2177.
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Eur Heart JHome page
U. N. Das
Risk of type 2 diabetes mellitus in those with hypertension
Eur. Heart J., April 1, 2008; 29(7): 952 - 953.
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J. Nutr.Home page
A. C. Nilsson, E. M. Ostman, J. J. Holst, and I. M. E. Bjorck
Including Indigestible Carbohydrates in the Evening Meal of Healthy Subjects Improves Glucose Tolerance, Lowers Inflammatory Markers, and Increases Satiety after a Subsequent Standardized Breakfast
J. Nutr., April 1, 2008; 138(4): 732 - 739.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Gastrointest. Liver Physiol.Home page
R. Xiao, Y. Su, R. C. M. Simmen, and F. A. Simmen
Dietary soy protein inhibits DNA damage and cell survival of colon epithelial cells through attenuated expression of fatty acid synthase
Am J Physiol Gastrointest Liver Physiol, April 1, 2008; 294(4): G868 - G876.
[Abstract] [Full Text] [PDF]


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CirculationHome page
P. Deedwania, M. Kosiborod, E. Barrett, A. Ceriello, W. Isley, T. Mazzone, and P. Raskin
Hyperglycemia and Acute Coronary Syndrome: A Scientific Statement From the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism
Circulation, March 25, 2008; 117(12): 1610 - 1619.
[Abstract] [Full Text] [PDF]


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Am. J. Clin. Nutr.Home page
A. C Nilsson, E. M Ostman, Y. Granfeldt, and I. M. Bjorck
Effect of cereal test breakfasts differing in glycemic index and content of indigestible carbohydrates on daylong glucose tolerance in healthy subjects
Am. J. Clinical Nutrition, March 1, 2008; 87(3): 645 - 654.
[Abstract] [Full Text] [PDF]


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Nutr Clin PractHome page
B. Collier, L. A. Dossett, A. K. May, and J. J. Diaz
Glucose Control and the Inflammatory Response
Nutr Clin Pract, February 1, 2008; 23(1): 3 - 15.
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Am. J. Clin. Nutr.Home page
D. Giugliano, A. Ceriello, and K. Esposito
Glucose metabolism and hyperglycemia
Am. J. Clinical Nutrition, January 1, 2008; 87(1): 217S - 222S.
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Diabetes CareHome page
A. Chaudhuri, M. Miller, R. Nesto, N. Rosenberg, and P. Dandona
Targeting Glucose in Acute Myocardial Infarction: Has glucose, insulin, and potassium infusion missed the target?
Diabetes Care, December 1, 2007; 30(12): 3026 - 3028.
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DiabetesHome page
L. Qi, N. Rifai, and F. B. Hu
Interleukin-6 Receptor Gene Variations, Plasma Interleukin-6 Levels, and Type 2 Diabetes in U.S. Women
Diabetes, December 1, 2007; 56(12): 3075 - 3081.
[Abstract] [Full Text] [PDF]


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Eur J EndocrinolHome page
J. Evans, M. Collins, C. Jennings, L. van der Merwe, I. Soderstrom, T. Olsson, N. S Levitt, E. V Lambert, and J. H Goedecke
The association of interleukin-18 genotype and serum levels with metabolic risk factors for cardiovascular disease
Eur. J. Endocrinol., November 1, 2007; 157(5): 633 - 640.
[Abstract] [Full Text] [PDF]


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JRSMHome page
K. Asadollahi, N. Beeching, and G. Gill
Hyperglycaemia and mortality
J R Soc Med, November 1, 2007; 100(11): 503 - 507.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
C. Patel, H. Ghanim, S. Ravishankar, C. L. Sia, P. Viswanathan, P. Mohanty, and P. Dandona
Prolonged Reactive Oxygen Species Generation and Nuclear Factor-{kappa}B Activation after a High-Fat, High-Carbohydrate Meal in the Obese
J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4476 - 4479.
[Abstract] [Full Text] [PDF]


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Diabetes CareHome page
E. Brignardello, C. Runzo, M. Aragno, M. G. Catalano, M. Cassader, P. C. Perin, and G. Boccuzzi
Dehydroepiandrosterone Administration Counteracts Oxidative Imbalance and Advanced Glycation End Product Formation in Type 2 Diabetic Patients
Diabetes Care, November 1, 2007; 30(11): 2922 - 2927.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
T. Mita, H. Watada, T. Shimizu, Y. Tamura, F. Sato, T. Watanabe, J. B. Choi, T. Hirose, Y. Tanaka, and R. Kawamori
Nateglinide Reduces Carotid Intima-Media Thickening in Type 2 Diabetic Patients Under Good Glycemic Control
Arterioscler Thromb Vasc Biol, November 1, 2007; 27(11): 2456 - 2462.
[Abstract] [Full Text] [PDF]


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Eur J EndocrinolHome page
J. M Bruun, B. Stallknecht, J. W Helge, and B. Richelsen
Interleukin-18 in plasma and adipose tissue: effects of obesity, insulin resistance, and weight loss
Eur. J. Endocrinol., October 1, 2007; 157(4): 465 - 471.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
K. V. Ramana, R. Tammali, A. B. M. Reddy, A. Bhatnagar, and S. K. Srivastava
Aldose Reductase-Regulated Tumor Necrosis Factor-{alpha} Production Is Essential for High Glucose-Induced Vascular Smooth Muscle Cell Growth
Endocrinology, September 1, 2007; 148(9): 4371 - 4384.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
A. Zirlik, S. M. Abdullah, N. Gerdes, L. MacFarlane, U. Schonbeck, A. Khera, D. K. McGuire, G. L. Vega, S. Grundy, P. Libby, et al.
Interleukin-18, the Metabolic Syndrome, and Subclinical Atherosclerosis: Results From the Dallas Heart Study
Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 2043 - 2049.
[Abstract] [Full Text] [PDF]


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ThoraxHome page
R. Varraso, T. T Fung, F. B Hu, W. Willett, and C. A Camargo
Prospective study of dietary patterns and chronic obstructive pulmonary disease among US men
Thorax, September 1, 2007; 62(9): 786 - 791.
[Abstract] [Full Text] [PDF]


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J. Am. Soc. Nephrol.Home page
D.-T. Lin-Tan, J.-L. Lin, L.-H. Wang, L.-M. Wang, L.-M. Huang, L. Liu, J.-Y. Huang, and Y.-L. Huang
Fasting Glucose Levels in Predicting 1-Year All-Cause Mortality in Patients Who Do Not Have Diabetes and Are on Maintenance Hemodialysis
J. Am. Soc. Nephrol., August 1, 2007; 18(8): 2385 - 2391.
[Abstract] [Full Text] [PDF]


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Diabetes CareHome page
J. L. Kitzmiller, L. Dang-Kilduff, and M. M. Taslimi
Gestational Diabetes After Delivery: Short-term management and long-term risks
Diabetes Care, July 1, 2007; 30(Supplement_2): S225 - S235.
[Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
E. P. Zorrilla, M. Sanchez-Alavez, S. Sugama, M. Brennan, R. Fernandez, T. Bartfai, and B. Conti
Interleukin-18 controls energy homeostasis by suppressing appetite and feed efficiency
PNAS, June 26, 2007; 104(26): 11097 - 11102.
[Abstract] [Full Text] [PDF]


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Diabetes CareHome page
A. G. Niehoff, T. W. van Haeften, N. C. Onland-Moret, C. C. Elbers, C. Wijmenga, and Y. T. van der Schouw
C-Reactive Protein Is Independently Associated With Glucose but Not With Insulin Resistance in Healthy Men
Diabetes Care, June 1, 2007; 30(6): 1627 - 1629.
[Full Text] [PDF]


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Diabetes CareHome page
H. Ghanim, P. Mohanty, R. Pathak, A. Chaudhuri, C. L. Sia, and P. Dandona
Orange Juice or Fructose Intake Does Not Induce Oxidative and Inflammatory Response
Diabetes Care, June 1, 2007; 30(6): 1406 - 1411.
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J. Appl. Physiol.Home page
E. H. Baker, N. Clark, A. L. Brennan, D. A. Fisher, K. M. Gyi, M. E. Hodson, B. J. Philips, D. L. Baines, and D. M. Wood
Hyperglycemia and cystic fibrosis alter respiratory fluid glucose concentrations estimated by breath condensate analysis
J Appl Physiol, May 1, 2007; 102(5): 1969 - 1975.
[Abstract] [Full Text] [PDF]


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Diabetes CareHome page
N. Katakami, H. Kaneto, M. Matsuhisa, K. Yoshiuchi, K. Kato, K. Yamamoto, Y. Umayahara, K. Kosugi, M. Hori, and Y. Yamasaki
Serum Interleukin-18 Levels Are Increased and Closely Associated With Various Soluble Adhesion Molecule Levels in Type 1 Diabetic Patients
Diabetes Care, January 1, 2007; 30(1): 159 - 161.
[Full Text] [PDF]


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EndocrinologyHome page
M. Aragno, R. Mastrocola, C. Medana, M. G. Catalano, I. Vercellinatto, O. Danni, and G. Boccuzzi
Oxidative Stress-Dependent Impairment of Cardiac-Specific Transcription Factors in Experimental Diabetes
Endocrinology, December 1, 2006; 147(12): 5967 - 5974.
[Abstract] [Full Text] [PDF]


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J. Nutr.Home page
J. A. Nettleton, L. J. Harnack, C. G. Scrafford, P. J. Mink, L. M. Barraj, and D. R. Jacobs Jr.
Dietary Flavonoids and Flavonoid-Rich Foods Are Not Associated with Risk of Type 2 Diabetes in Postmenopausal Women
J. Nutr., December 1, 2006; 136(12): 3039 - 3045.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
R. Gyurko, C. C. Siqueira, N. Caldon, L. Gao, A. Kantarci, and T. E. Van Dyke
Chronic Hyperglycemia Predisposes to Exaggerated Inflammatory Response and Leukocyte Dysfunction in Akita Mice
J. Immunol., November 15, 2006; 177(10): 7250 - 7256.
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Eur Heart JHome page
M. Ishihara, I. Inoue, T. Kawagoe, Y. Shimatani, S. Kurisu, T. Hata, Y. Nakama, Y. Kijima, and E. Kagawa
Is admission hyperglycaemia in non-diabetic patients with acute myocardial infarction a surrogate for previously undiagnosed abnormal glucose tolerance?
Eur. Heart J., October 2, 2006; 27(20): 2413 - 2419.
[Abstract] [Full Text] [PDF]


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Am. J. Clin. Nutr.Home page
S. Devaraj, B. C Autret, and I. Jialal
Reduced-calorie orange juice beverage with plant sterols lowers C-reactive protein concentrations and improves the lipid profile in human volunteers.
Am. J. Clinical Nutrition, October 1, 2006; 84(4): 756 - 761.
[Abstract] [Full Text] [PDF]


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Diabetes and Vascular Disease ResearchHome page
P. N Bavenholm and S. Efendic
Postprandial hyperglycaemia and vascular damage - the benefits of acarbose
Diabetes and Vascular Disease Research, September 1, 2006; 3(2): 72 - 79.
[Abstract] [PDF]


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SEMIN CARDIOTHORAC VASC ANESTHHome page
J. W. A. Smit and J. A. Romijn
Acute insulin resistance in myocardial ischemia: causes and consequences.
Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2006; 10(3): 215 - 219.
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SEMIN CARDIOTHORAC VASC ANESTHHome page
H. B. Van Wezel
Glucose-insulin-potassium techniques in cardiac surgery: historical overview and future perspectives.
Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2006; 10(3): 224 - 227.
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J Am Coll CardiolHome page
D. Giugliano, A. Ceriello, and K. Esposito
The Effects of Diet on Inflammation: Emphasis on the Metabolic Syndrome
J. Am. Coll. Cardiol., August 15, 2006; 48(4): 677 - 685.
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Am. J. Clin. Nutr.Home page
K. Esposito and D. Giugliano
Whole-grain intake cools down inflammation
Am. J. Clinical Nutrition, June 1, 2006; 83(6): 1440 - 1441.
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J. Clin. Endocrinol. Metab.Home page
B. Okopien, R. Krysiak, and Z. S. Herman
Effects of Short-Term Fenofibrate Treatment on Circulating Markers of Inflammation and Hemostasis in Patients with Impaired Glucose Tolerance
J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1770 - 1778.
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DiabetesHome page
J. M. Starkey, S. J. Haidacher, W. S. LeJeune, X. Zhang, B. C. Tieu, S. Choudhary, A. R. Brasier, L. A. Denner, and R. G. Tilton
Diabetes-Induced Activation of Canonical and Noncanonical Nuclear Factor-{kappa}B Pathways in Renal Cortex.
Diabetes, May 1, 2006; 55(5): 1252 - 1259.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
J. de Jager, J. M. Dekker, A. Kooy, P. J. Kostense, G. Nijpels, R. J. Heine, L. M. Bouter, and C. D.A. Stehouwer
Endothelial Dysfunction and Low-Grade Inflammation Explain Much of the Excess Cardiovascular Mortality in Individuals With Type 2 Diabetes: The Hoorn Study
Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 1086 - 1093.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
P. R. Galassetti, K. Iwanaga, A. M. Pontello, F. P. Zaldivar, R. L. Flores, and J. K. Larson
Effect of prior hyperglycemia on IL-6 responses to exercise in children with type 1 diabetes
Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E833 - E839.
[Abstract] [Full Text] [PDF]


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CirculationHome page
J.-a Kim, M. Montagnani, K. K. Koh, and M. J. Quon
Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction: Molecular and Pathophysiological Mechanisms
Circulation, April 18, 2006; 113(15): 1888 - 1904.
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Am. J. Clin. Nutr.Home page
S. E Kasim-Karakas, A. Tsodikov, U. Singh, and I. Jialal
Responses of inflammatory markers to a low-fat, high-carbohydrate diet: effects of energy intake.
Am. J. Clinical Nutrition, April 1, 2006; 83(4): 774 - 779.
[Abstract] [Full Text] [PDF]


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DiabetesHome page
S. Srivastava, K. V. Ramana, R. Tammali, S. K. Srivastava, and A. Bhatnagar
Contribution of aldose reductase to diabetic hyperproliferation of vascular smooth muscle cells.
Diabetes, April 1, 2006; 55(4): 901 - 910.
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J. Am. Soc. Nephrol.Home page
A. Arimura, M. Li, V. Batuman, W.F. Clark, A.K. Stewart, G.A. Rock, M. Sternbach, D.M. Sutton, B.J. Barrett, A.P. Heidenheim, et al.
Cast Nephropathy in Myeloma--Does PACAP38, a New Member of the Vasoactive Intestinal Peptide Family, Open a Therapeutic Window?: Potential Protective Action of Pituitary Adenylate Cyclase-Activiating Polypeptide (PACAP38) on In Vitro and In Vivo Models of Myeloma Kidney Injury. Blood 107: 661-668, 2006
J. Am. Soc. Nephrol., April 1, 2006; 17(4): 911 - 919.
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QJMHome page
J.R. Timmer, J.P. Ottervanger, H.J.G. Bilo, J.H.E. Dambrink, K. Miedema, J.C.A. Hoorntje, and F. Zijlstra
Prognostic value of admission glucose and glycosylated haemoglobin levels in acute coronary syndromes
QJM, April 1, 2006; 99(4): 237 - 243.
[Abstract] [Full Text] [PDF]


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J Am Coll CardiolHome page
F. Santilli, G. Davi, A. Consoli, F. Cipollone, A. Mezzetti, A. Falco, T. Taraborelli, E. Devangelio, G. Ciabattoni, S. Basili, et al.
Thromboxane-Dependent CD40 Ligand Release in Type 2 Diabetes Mellitus
J. Am. Coll. Cardiol., January 17, 2006; 47(2): 391 - 397.
[Abstract] [Full Text] [PDF]


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Eur Heart JHome page
K. Esposito and D. Giugliano
Diet and inflammation: a link to metabolic and cardiovascular diseases
Eur. Heart J., January 1, 2006; 27(1): 15 - 20.
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Diabetes CareHome page
A. Nakamura, K. Shikata, M. Hiramatsu, T. Nakatou, T. Kitamura, J. Wada, T. Itoshima, and H. Makino
Serum Interleukin-18 Levels Are Associated With Nephropathy and Atherosclerosis in Japanese Patients With Type 2 Diabetes
Diabetes Care, December 1, 2005; 28(12): 2890 - 2895.
[Abstract] [Full Text] [PDF]


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DiabetesHome page
J. Yang, C. E. Robert, B. R. Burkhardt, R. A. Young, J. Wu, Z. Gao, and B. A. Wolf
Mechanisms of Glucose-Induced Secretion of Pancreatic-Derived Factor (PANDER or FAM3B) in Pancreatic {beta}-Cells
Diabetes, November 1, 2005; 54(11): 3217 - 3228.
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J. Am. Coll. Nutr.Home page
Y. Song, J. E. Manson, J. E. Buring, H. D. Sesso, and S. Liu
Associations of Dietary Flavonoids with Risk of Type 2 Diabetes, and Markers of Insulin Resistance and Systemic Inflammation in Women: A Prospective Study and Cross-Sectional Analysis
J. Am. Coll. Nutr., October 1, 2005; 24(5): 376 - 384.
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Diabetes CareHome page
N. W. Cheung, B. Napier, C. Zaccaria, and J. P. Fletcher
Hyperglycemia Is Associated With Adverse Outcomes in Patients Receiving Total Parenteral Nutrition
Diabetes Care, October 1, 2005; 28(10): 2367 - 2371.
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Br J AnaesthHome page
L. Visser, C. J. Zuurbier, F. J. Hoek, B. C. Opmeer, E. de Jonge, B. A. J. M. de Mol, and H. B. van Wezel
Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: effects on inflammatory response during coronary artery surgery
Br. J. Anaesth., October 1, 2005; 95(4): 448 - 457.
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Am. J. Clin. Nutr.Home page
A. T Merchant, G. C Curhan, E. B Rimm, W. C Willett, and W. W Fawzi
Intake of n-6 and n-3 fatty acids and fish and risk of community-acquired pneumonia in US men
Am. J. Clinical Nutrition, September 1, 2005; 82(3): 668 - 674.
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Diabetes CareHome page
Y. Kataoka, S. Yasuda, I. Morii, Y. Otsuka, A. Kawamura, and S. Miyazaki
Quantitative Coronary Angiographic Studies of Patients With Angina Pectoris and Impaired Glucose Tolerance
Diabetes Care, September 1, 2005; 28(9): 2217 - 2222.
[Abstract] [Full Text] [PDF]


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ThoraxHome page
B J Philips, J Redman, A Brennan, D Wood, R Holliman, D Baines, and E H Baker
Glucose in bronchial aspirates increases the risk of respiratory MRSA in intubated patients
Thorax, September 1, 2005; 60(9): 761 - 764.
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J. Clin. Endocrinol. Metab.Home page
C. S. Mantzoros, T. Li, J. E. Manson, J. B. Meigs, and F. B. Hu
Circulating Adiponectin Levels Are Associated with Better Glycemic Control, More Favorable Lipid Profile, and Reduced Inflammation in Women with Type 2 Diabetes
J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4542 - 4548.
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J. Clin. Endocrinol. Metab.Home page
B. Capaldo, M. Galderisi, A. A. Turco, A. D'Errico, S. Turco, A. A. Rivellese, G. de Simone, O. de Divitiis, and G. Riccardi
Acute Hyperglycemia Does Not Affect the Reactivity of Coronary Microcirculation in Humans
J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 3871 - 3876.
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Diabetes CareHome page
I. Shai, M. B. Schulze, J. E. Manson, K. M. Rexrode, M. J. Stampfer, C. Mantzoros, and F. B. Hu
A Prospective Study of Soluble Tumor Necrosis Factor-{alpha} Receptor II (sTNF-RII) and Risk of Coronary Heart Disease Among Women With Type 2 Diabetes
Diabetes Care, June 1, 2005; 28(6): 1376 - 1382.
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J. Hung, B. M. McQuillan, C. M. L. Chapman, P. L. Thompson, and J. P. Beilby
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V. W. Wong, M. McLean, S. C. Boyages, and N. W. Cheung
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K. Esposito, D. Giugliano, F. Nappo, R. Marfella, and for the Campanian Postprandial Hyperglycemia Study
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M. B. Schulze, E. B. Rimm, I. Shai, N. Rifai, and F. B. Hu
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Arterioscler. Thromb. Vasc. Bio.Home page
A. Ceriello and E. Motz
Is Oxidative Stress the Pathogenic Mechanism Underlying Insulin Resistance, Diabetes, and Cardiovascular Disease? The Common Soil Hypothesis Revisited
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Am. J. Physiol. Endocrinol. Metab.Home page
R. Krogh-Madsen, K. Moller, F. Dela, G. Kronborg, S. Jauffred, and B. K. Pedersen
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