(affects Type 1 AND Type 2 Diabetics)
Interleukin-1Receptor Antagonist in Type 2 Diabetes Mellitus (NEJM 356:1517-1526, 2007)Background The expression of interleukin-1receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1 in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis. Methods In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemiceuglycemic clamp study. The primary end point was a change in the level of glycated hemoglobin, and secondary end points were changes in beta-cell function, insulin sensitivity, and inflammatory markers. Results At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 percentage point lower than in the placebo group (P=0.03); C-peptide secretion was enhanced (P=0.05), and there were reductions in the ratio of proinsulin to insulin (P=0.005) and in levels of interleukin-6 (P<0.001) and C-reactive protein (P=0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was not observed, and there were no apparent drug-related serious adverse events. Conclusions The blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation. (ClinicalTrials.gov number, NCT00303394 [ClinicalTrials.gov] )
Insulin resistance measured by the euglycaemic insulin clamp predicts subsequent CHD in elderly men. Proinsulin provides a better prediction of CHD than insulin. (Diabetologia 48:1432-0428 (Online)) Aims/hypothesis The association between CHD and insulin sensitivity (Si) measured by the euglycaemic insulin clamp has not been examined previously. Earlier studies found a relationship between CHD and elevated plasma insulin, an analysis that may have been confounded by co-determination of proinsulin, which has evolved as a stronger predictor of CHD. The aim was to determine the longitudinal relationships between Si, intact proinsulin, 3233 split proinsulin, specific insulin and subsequent CHD. Methods This was a population-based cohort study of 815 men in Uppsala, Sweden, aged 70 years at baseline with a follow-up of up to 10 years. Baseline insulin sensitivity was determined by euglycaemic insulin clamp. Fasting proinsulin, 3233 split proinsulin and specific insulin concentrations were analysed using specific two-site immunometric assays. CHD was taken as diagnosed, if stated (in the event of death) on the Cause of Death Registry, or for subjects hospitalised for the first time with CHD, if CHD was recorded in the Hospital-Discharge Registry. The associations were analysed using Cox's proportional hazards, presented as hazard ratios (HRs) with their 95% CIs for a one-SD increase in the predictor. Results In multivariate analysis, Si (HR:0.80, CI:0.650.97) adjusted for serum cholesterol, systolic blood pressure, fasting plasma glucose, BMI and smoking predicted CHD. Intact proinsulin (HR:1.18, CI:1.011.38), adjusted as the model above, predicted CHD, whereas 3233 split proinsulin (HR:1.13, CI:0.951.35) or specific insulin (HR:1.07, CI:0.891.30) did not. Conclusions/interpretation Insulin resistance measured by the euglycaemic insulin clamp predicts subsequent CHD in elderly men. Proinsulin provides a better prediction of CHD than insulin.
Tumor Necrosis Factor-alpha Receptor 1 Is a Major Predictor of Mortality and New-Onset Heart Failure in Patients With Acute Myocardial Infarction(Circulation 111:863-870)Background Tumor necrosis factor alpha (TNF-alpha) activation is an independent prognostic indicator of mortality in patients with heart failure (HF). Despite the recognition that several TNF family cytokines are elevated during myocardial infarction, their role in predicting subsequent prognosis in these setting remains poorly understood. Methods and Results We performed a systematic evaluation of TNF-alpha and its type 1 and 2 soluble receptors, together with interleukin (IL)-6, IL-1 receptor antagonist, and IL-10, in 184 patients (132 men; mean age, 64±12) consecutively admitted for myocardial infarction. We correlated their values to short- and long-term incidence of death and HF (primary outcome). In 10 patients, we also studied the presence of transcardiac gradients for TNF-alpha and its soluble receptors. The control group comprised 45 healthy subjects who were sex and age matched (33 men; mean age, 65±6 years) to the patients. All tested cytokines were increased in patients, and no transcardiac or systemic AV difference was found. After a median follow-up of 406 days (range, 346 to 696 days), 24 patients died and 32 developed HF. Univariate analysis showed that all cytokines were related to outcome, whereas after adjustment for baseline and clinical characteristics, sTNFR-1 remained the only independent predictor of death and HF (hazard ratio, 2.9; 95% CI, 1.9 to 3.8, tertile 1 versus 3), together with left ventricular ejection fraction, Killip class, and creatine kinase-MB at peak. Conclusions sTNFR-1 is a major short- and long-term predictor of mortality and HF in patients with acute myocardial infarction.
Circulating Mononuclear Cells In The Obese Found To Be In Proinflammatory State, Contributing To Diabetes And Heart Disease (Circulation  110:1564-1571) Background In view of the increase in plasma concentrations of proinflammatory mediators tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and C-reactive protein (CRP) in obesity, we investigated whether peripheral blood mononuclear cells (MNC) from obese subjects are in a proinflammatory state. Methods and Results MNC were prepared from fasting blood samples of obese (n=16; body mass index [BMI]=37.7±5.0 kg/m2) and normal-weight control (n=16; BMI=23.8±1.9 kg/m2) subjects. Nuclear factor kB (NF-kB) binding to DNA in nuclear extracts was elevated (P<0.05) and the inhibitor of NFkB-ß (IkB-ß) was significantly lower (P<0.001) in the obese group. Reverse transcriptionpolymerase chain reaction revealed elevated levels of migration inhibitor factor (MIF), IL-6, TNF-a, and matrix metalloproteinase-9 (MMP-9) mRNA expression in the obese subjects (P<0.05). Plasma concentrations of MIF, IL-6, TNF-a, MMP-9, and CRP were also significantly higher. Plasma glucose, insulin, and free fatty acids (FFAs) were measured, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Plasma FFA concentration related significantly to BMI, IL-6, and TNF-a mRNA expression and plasma CRP levels but not to HOMA-IR. On the other hand, the inflammatory mediators were significantly related to BMI and HOMA-IR. Conclusions These data show (1) for the first time that MNC in obesity are in a proinflammatory state with an increase in intranuclear NF-kB binding, a decrease in IkB-ß, and an increase in the transcription of proinflammatory genes regulated by NF-kB; (2) that plasma FFAs are a modulator of inflammation; and (3) that insulin resistance is a function of inflammatory mediators.
Fish intake may influence risk of Atrial Fibrillation (Circulation 110:368-373) Background Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is particularly common in the elderly. Although effects of fish intake, including potential antiarrhythmic effects, may favorably influence risk of AF, relationships between fish intake and AF incidence have not been evaluated. Methods and Results In a prospective, population-based cohort of 4815 adults >=age 65 years, usual dietary intake was assessed at baseline in 1989 and 1990. Consumption of tuna and other broiled or baked fish correlated with plasma phospholipid long-chain n-3 fatty acids, whereas consumption of fried fish or fish sandwiches (fish burgers) did not. AF incidence was prospectively ascertained on the basis of hospital discharge records and annual electrocardiograms. During 12 years follow-up, 980 cases of incident AF were diagnosed. In multivariate analyses, consumption of tuna or other broiled or baked fish was inversely associated with incidence of AF, with 28% lower risk with intake 1 to 4 times per week (HR=0.72, 95% CI=0.58 to 0.91, P=0.005), and 31% lower risk with intake >=5 times per week (HR=0.69, 95% CI=0.52 to 0.91, P=0.008), compared with <1 time per month (P trend=0.004). Results were not materially different after adjustment for preceding myocardial infarction or congestive heart failure. In similar analyses, fried fish/fish sandwich consumption was not associated with lower risk of AF.Conclusions Among elderly adults, consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches, is associated with lower incidence of AF. Fish intake may influence risk of this common cardiac arrhythmia.
Oxidative stress induces insulin resistance by activating the nuclear factor-kB pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase (Diabetologia  47: 794 - 805) Aims/hypothesis Oxidative stress is associated with diabetes, hypertension and atherosclerosis. Insulin resistance is implicated in the development of these disorders. We tested the hypothesis that oxidative stress induces insulin resistance in rats, and endeavoured to identify mechanisms linking the two. Methods Buthionine sulfoximine (BSO), an inhibitor of glutathione synthase, was administered to Sprague-Dawley rats and 3T3-L1 adipocytes. Glucose metabolism and insulin signalling both in vivo and in 3T3-L1 adipocytes were examined. In 3T3-L1 adipocytes, the effects of overexpression of a dominant negative mutant of inhibitory kB (IkB), one role of which is to block oxidative-stress-induced nuclear factor (NF)-kB activation, were investigated. Results In rats given BSO for 2 weeks, the plasma lipid hydroperoxide level doubled, indicating increased oxidative stress. A hyperinsulinaemic-euglycaemic clamp study and a glucose transport assay using isolated muscle and adipocytes revealed insulin resistance in BSO-treated rats. BSO treatment also impaired insulin-induced glucose uptake and GLUT4 translocation in 3T3-L1 adipocytes. In BSO-treated rat muscle, adipose tissue and 3T3-L1 adipocytes, insulin-induced IRS-1 phosphorylation in the low-density microsome (LDM) fraction was specifically decreased, while that in whole cell lysates was not altered, and subsequent translocation of phosphatidylinositol (PI) 3-kinase from the cytosol and the LDM fraction was disrupted. BSO-induced impairments of insulin action and insulin signalling were reversed by overexpressing the dominant negative mutant of IkB, thereby suppressing NF-kB activation. Conclusions/interpretation Oxidative stress induces insulin resistance by impairing IRS-1 phosphorylation and PI 3-kinase activation in the LDM fraction, and NF-kB activation is likely to be involved in this process.
is a positive regulator of tumor necrosis factor -induced
adipose-related protein in 3T3-L1 adipocytes (FEBS Letters  560:153-157) Tumor
necrosis factor (TNF)alpha induced adipose-related
protein (TIARP) is a novel TNF-alpha-stimulated protein
in adipocytes. Besides TNFalpha, interleukin (IL)-6 has
recently been shown to be another adipocytokine
implicated in insulin resistance. Therefore, the impact
of IL-6 on TIARP gene expression in 3T3-L1 adipocytes was
determined by quantitative real-time reverse
transcription-polymerase chain reaction. Interestingly,
TIARP mRNA expression was stimulated up to 3.8-fold by
IL-6 in a dose-dependent fashion with significant
stimulation detectable at effector concentrations as low
as 3 ng/ml and maximal effects seen at 100 ng/ml IL-6.
Induction of TIARP mRNA by IL-6 was time-dependent with
significant upregulation occurring as early as 2 h after
effector addition and maximal effects observed at 4 h. In
parallel, TIARP protein synthesis was upregulated with
maximal effects seen after 8 h of IL-6 treatment.
Furthermore, the Janus kinase 2 inhibitor AG490 decreased
TIARP mRNA expression. The increase of TIARP mRNA could
be reversed by withdrawal of IL-6 for 24 h. Furthermore,
TIARP mRNA induction by IL-6 was also seen in brown
adipocytes but not in muscle and liver cells. Taken
together, these results show that TIARP is acutely
regulated in adipose tissue not only by TNFalphabut also
by IL-6 which has been shown to be another important
cytokine implicated in the pathogenesis of insulin
Beta-blockers enhance natriuretic peptides' effects during exercise (J Am Coll Cardiol  43:353-359) In patients with coronary artery disease, natriuretic peptide levels in plasma are increased during exercise, French physicians now show that treatment with beta-blockers enhances the natriuretic peptide release, thus decreasing cardiac load.Cardiac disease is associated with increased resting levels of atrial and brain natriuretic peptide. Under stress, cardiomyocytes release both atrial and brain natriuretic peptide, which exert vasodilator and diuretic effects, which many be expected to reduce cardiac load. However, this process in patients with coronary artery disease has been poorly characterized.Therefore, Dr. Pierre-Yves Marie and colleagues at UPRES EA in Nancy, measured natriuretic peptide levels at rest and peak exercise in 104 patients with chronic coronary artery disease. They describe their findings in the Journal of the American College of Cardiology for February 4th.The best independent predictors of natriuretic peptide concentrations at rest were aging and the extent of scarred left ventricular area. "No previous study has given evidence of the dramatic influence of the extent of scarred myocardium, as determined by myocardial SPECT," the authors write.Beta blocker treatment did not affect natriuretic peptide concentrations at rest. However, during exercise, the average increase in both atrial and brain natriuretic peptide was more than doubled in the 55 patients treated with beta-blockers, even though their heart rate did not increase as much."This enhanced secretion of potent vasodilating and natriuretic agents might constitute an additional and original mechanism of these drugs for further protecting diseased hearts against stress," Dr. Marie's group concludes.
Stress upregulates arterial matrix metalloproteinase expression and activity via endothelin 1-A receptor activation (Am J Physiol Heart Circ Physiol  285: H2225 - H2232) Degradation of the extracellular matrix proteins by matrix metalloproteinases (MMP) is an important regulatory step in the vascular remodeling process. Recent studies demonstrated that ETA receptors regulate cardiac MMP activity and fibrosis in DOCA-salt hypertension. However, little is known about endothelin (ET)-1 regulation of vascular MMP activity in hypertension. Thus early changes in ET-1-mediated regulation of MMP activity were measured in borderline hypertensive rats that develop impaired vasorelaxation and hypertension with chronic exposure to stress. Experiments were performed after 10 days of exposure to the behavioral stressor, air-jet stress, but before the onset of stress-induced hypertension. Study groups were 1) control (n = 8); 2) air-jet stress for 10 days (n = 8); 3) control plus ETA antagonist ABT-627 (n = 4), and 4) air-jet stress plus ETA antagonist (n = 4). MMP activity in the thoracic aorta was assessed by gelatin zymography. MMP protein and tissue ET-1 levels were evaluated by immunohistochemistry, and ET receptor density was determined by immunoblotting. Exposure to stress caused a twofold increase in plasma ET-1 levels (P < 0.05), and there was increased ET-1 staining at the tissue level. Total MMP activity and expression of MMP-2 and MMP-9 were increased in the stress group. ETA receptor antagonism prevented the increase in MMP expression and activation in the stress group. These results provide evidence that the MMP system is activated before the development of hypertension and ET-1 mediates these early events in vascular remodeling.
Tumor Necrosis Factor-alpha Inhibits Insulins Stimulating Effect on Glucose Uptake and Endothelium-Dependent Vasodilation in Humans (Circulation 108:1815) Background Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-alpha inhibits insulin-stimulated glucose uptake and insulin-stimulated endothelial function in humans. Methods and Results Healthy, lean male volunteers were studied. On each study day, 3 acetylcholine (ACh) or sodium nitroprusside (SNP) dose-response studies were performed by infusion into the brachial artery. Before and during the last 2 dose-response studies, insulin and/or TNF-alpha were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220±44%. This increase was completely inhibited during coinfusion of TNF-alpha (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow. Furthermore, TNF-alpha inhibited the ACh forearm blood flow response (P<0.001), and this inhibition was larger during insulin infusion (P=0.01) but not further increased by NG-monomethyl-L-arginine acetate (P=0.2). Insulin potentiated the SNP response less than the ACh response and the effect of TNF-alpha was smaller (P<0.001); TNF-alpha had no effect on the SNP response without insulin infusion. Thus, TNF-alpha inhibition of the combined response to insulin and ACh was likely mediated through inhibition of NO production. f Conclusion These results support the concept that TNF-alpha could play a role in the development of insulin resistance in humans, both in muscle and in vascular tissue.
IGT and DM2 associate with increased arterial stiffness occurring before the onset of DM2 and explained neither by conventional CV risk factors nor by hyperglycemia nor by hyperinsulinemia (Circulation 107:2089.) Background Type 2 diabetes (DM-2) and impaired glucose metabolism (IGM) are associated with an increased cardiovascular disease risk. In nondiabetic individuals, increased arterial stiffness is an important cause of cardiovascular disease. Associations between DM-2 and IGM and arterial stiffness have not been systematically investigated. Methods and Results In a population-based cohort (n=747; 278 with normal glucose metabolism, 168 with IGM, and 301 with DM-2; mean age, 68.5 years), arterial stiffness was ultrasonically estimated by distensibility and compliance of the carotid, femoral, and brachial arteries and by the carotid elastic modulus. After adjustment for age, sex, and mean arterial pressure, DM-2 was associated with increased carotid, femoral, and brachial stiffness, whereas IGM was associated only with increased femoral and brachial stiffness. Carotid but not femoral or brachial stiffness increased from IGM to DM-2. Standardized ßs (95% CI) for IGM and DM-2, compared with normal glucose metabolism, were -0.06 (-0.23 to 0.10) and -0.37 (-0.51 to -0.23) for carotid distensibility; -0.02 (-0.18 to 0.18) and -0.25 (-0.40 to -0.09) for carotid compliance; -0.05 (-0.23 to 0.13) and 0.25 (0.10 to 0.40) for carotid elastic modulus; -0.70 (-0.89 to -0.51) and -0.67 (-0.83 to -0.52) for femoral distensibility; and -0.62 (-0.80 to -0.44) and -0.79 (-0.94 to -0.63) for femoral compliance. The brachial artery followed a pattern similar to that of the femoral artery. Increases in stiffness indices were explained by decreases in distension, increases in pulse pressure, an increase in carotid intima-media thickness, and, for the femoral artery, a decrease in diameter. Hyperglycemia or hyperinsulinemia explained only 30% of the arterial changes associated with glucose tolerance. Adjustment for conventional cardiovascular risk factors did not affect these findings. Conclusions IGM and DM-2 are associated with increased arterial stiffness. An important part of the increased stiffness occurs before the onset of DM-2 and is explained neither by conventional cardiovascular risk factors nor by hyperglycemia or hyperinsulinemia.
S447X (serine) substitution on lipoprotein lipase (LPL) gene associates frequently with a high-HDL/low-LDL phenotype and infrequently with a low-HDL/high-LDL phenotype (Genetic Epidemiology  24:309-321) S447X, a serine substitution by a stop codon on base 99 of exon 9 of the lipoprotein lipase (LPL) gene, has beneficial effects on blood lipids. Other LPL alleles are associated with lipid levels, but whether one of these variants predominates remains elusive. We performed a systematic survey to identify single-nucleotide polymorphisms (SNPs) in all 10 LPL exons and flanking regions by resequencing the gene in 95 subjects. Of 24 variants, 14 were common (>=3%). We assayed the common SNPs in 186 cases with atherogenic lipid profiles (low HDL, high LDL) and 185 nonatherogenic controls (high HDL, low LDL). Only S447X and exons 6 (base +73) and 10 (base -11) were individually associated with case-control status (P<0.05, adjusted for major nongenetic covariates with known lipid effects). There were no significant SNP×gender interactions. In adjusted multi-SNP and haplotypic analyses, S447X was interpretable as the sole predictor, with a 2-3-fold reduction in the odds of being atherogenic vs. nonatherogenic (adjusted OR, 0.39; 95% CI, 0.21-0.73). S447X and base -11 of exon 10 were statistically interchangeable because they are strongly associated (r=0.92, P<0.0001), but we posit that the LPL association with lipid profile is more likely attributable to the functional S447X rather than the nonfunctional exon 10 SNP. It appears that the S447X variant of LPL may be another rare example (like APOE4, factor V-Leiden, and PPAR-gamma Pro12Ala) of a common variant predisposing to a common disorder
Antileukotriene drugs may be an effective treatment regimen in late-stage atherogenesis (Proc. Natl. Acad. Sci. USA,  10.1073/pnas.242716099) Oxidation products of low-density lipoproteins have been suggested to promote inflammation during atherogenesis, and reticulocyte-type 15-lipoxygenase has been implicated to mediate this oxidation. In addition, the 5-lipoxygenase cascade leads to formation of leukotrienes, which exhibit strong proinflammatory activities in cardiovascular tissues. Here, we studied both lipoxygenase pathways in human atherosclerosis. The 5-lipoxygenase pathway was abundantly expressed in arterial walls of patients afflicted with various lesion stages of atherosclerosis of the aorta and of coronary and carotid arteries. 5-lipoxygenase localized to macrophages, dendritic cells, foam cells, mast cells, and neutrophilic granulocytes, and the number of 5-lipoxygenase expressing cells markedly increased in advanced lesions. By contrast, reticulocyte-type 15-lipoxygenase was expressed at levels that were several orders of magnitude lower than 5-lipoxygenase in both normal and diseased arteries, and its expression could not be related to lesion pathology. Our data support a model of atherogenesis in which 5-lipoxygenase cascade-dependent inflammatory circuits consisting of several leukocyte lineages and arterial wall cells evolve within the blood vessel wall during critical stages of lesion development. They raise the possibility that antileukotriene drugs may be an effective treatment regimen in late-stage disease.
Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study.(Diabetes 2002 Apr;51(4):1131-7) Festa A, D'Agostino R Jr, Tracy RP, Haffner SM; The Insulin Resistance Atherosclerosis Study.Elevated serum levels of acute-phase proteins, indicating chronic subclinical inflammation, have been associated with cardiovascular disease as well as the insulin resistance syndrome. Chronic inflammation may also be a risk factor for developing type 2 diabetes. We studied the concentrations of C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) in 1,047 nondiabetic subjects in relation to incident diabetes within 5 years in the Insulin Resistance Atherosclerosis Study. Subjects with diabetes at follow-up (n = 144) had higher baseline levels of fibrinogen (mean +/- SD; 287.8 +/- 58.8 vs. 275.1 +/- 56.0 mg/dl; P = 0.013) as well as of CRP (median [interquartile range]; 2.40 [1.29, 5.87] vs. 1.67 mg/l [0.75, 3.41]; P = 0.0001) and PAI-1 (24 [15, 37.5] vs. 16 ng/ml [9, 27]; P = 0.0001) than nonconverters. The odds ratio (OR) of converting to diabetes was significantly increased with increasing baseline concentrations of the inflammatory markers. In contrast to PAI-1, the association of CRP and fibrinogen with incident diabetes was significantly attenuated after adjustment for body fat (BMI or waist circumference) or insulin sensitivity (S(I)), as assessed by a frequently sampled intravenous glucose tolerance test. In a logistic regression model that included age, sex, ethnicity, clinical center, smoking, BMI, S(I), physical activity, and family history of diabetes, PAI-1 still remained significantly related to incident type 2 diabetes (OR [95% CI] for 1 SD increase: 1.61 [1.20-2.16]; P = 0.002). Chronic inflammation emerges as a new risk factor for the development of type 2 diabetes; PAI-1 predicts type 2 diabetes independent of insulin resistance and other known risk factors for diabetes.
Nutritionally Induced Obesity Is Attenuated in Transgenic Mice Overexpressing Plasminogen Activator Inhibitor-1 (Arteriosclerosis, Thrombosis, and Vascular Biology 2002) ObjectiveThe objective of this study was to investigate the role of plasminogen activator inhibitor-1 (PAI-1) in adipose tissue development in vivo. Methods and ResultsTransgenic (Tg) mice overexpressing murine PAI-1 under control of the adipocyte promoter aP2 and wild-type (WT) controls were kept on standard food (SFD) or on high-fat diet (HFD) for 15 weeks. The body weight and the weight of the isolated subcuttaneus and gonadal fat deposits of the Tg mice kept on the HFD were significantly lower than those of the WT mice. The number of adipocytes in the adipose tissue was similar for Tg and WT mice on the HFD, but adipocyte hypotrophy and a significantly lower ratio of stroma cells/adipocytes were observed in the Tg mice. A significant negative correlation (P<0.01) was observed between expression of preadipocyte factor-1, which blocks adipocyte differentiation, and adipose tissue weight. Fasting insulin and total cholesterol levels on the HFD were lower in Tg than in WT mice. ConclusionsHigh circulating PAI-1 levels attenuate nutritionally induced obesity. This may be related to modifications in adipose tissue cellularity affecting weight and plasma metabolic parameters.
homocysteine, creatinine, and glucose are predictors of
the severity and extent of
Fasting and postchallenge hyperglycaemia in the early phase of an acute myocardial infarction could be used as early markers of high-risk individuals (Lancet  359: 2140-44)Background Glycometabolic state at hospital admission is an important risk marker for long-term mortality in patients with acute myocardial infarction, whether or not they have known diabetes mellitus. Our aim was to ascertain the prevalence of impaired glucose metabolism in patients without diagnosed diabetes but with myocardial infarction, and to assess whether such abnormalities can be identified in the early course of a myocardial infarction. Methods We did a prospective study, in which we enrolled 181 consecutive patients admitted to the coronary care units of two hospitals in Sweden with acute myocardial infarction, no diagnosis of diabetes, and a blood glucose concentration of less than 11·1 mmol/L. We recorded glucose concentrations during the hospital stay, and did standardised oral glucose tolerance tests with 75 g of glucose at discharge and again 3 months later. Findings The mean age of our cohort was 63·5 years (SD 9) and the mean blood glucose concentration at admission was 6·5 mmol/L (1·4). The mean 2-h postload blood glucose concentration was 9·2 mmol/L (2·9) at hospital discharge, and 9·0 mmol/L (3·0) 3 months later. 58 of 164 (35%, 95% CI 28-43) and 58 of 144 (40%, 32-48) individuals had impaired glucose tolerance at discharge and after 3 months, respectively, and 51 of 164 (31%, 24-38) and 36 of 144 (25%, 18-32) had previously undiagnosed diabetes mellitus. Independent predictors of abnormal glucose tolerance at 3 months were concentrations of HbA1c at admission (p=0·024) and fasting blood glucose concentrations on day 4 (p=0·044). Interpretation Previously undiagnosed diabetes and impaired glucose tolerance are common in patients with an acute myocardial infarction. These abnormalities can be detected early in the postinfarction period. Our results suggest that fasting and postchallenge hyperglycaemia in the early phase of an acute myocardial infarction could be used as early markers of high-risk individuals.
Ang II provokes TNF biosynthesis in the adult mammalian heart through a PKC-dependent pathway. (Circulation  105:2198.)Background Previous studies suggest that angiotensin II (Ang II) upregulates the expression of tumor necrosis factor (TNF) in nonmyocyte cell types; however, the effect of Ang II on TNF expression in the adult mammalian heart is not known. Methods and Results To determine whether Ang II was sufficient to provoke TNF biosynthesis in the adult heart, we examined the effects of Ang II in isolated buffer-perfused Langendorff feline hearts. Ang II (10-7 mol/L) treatment resulted in a time- and dose-dependent increase in myocardial TNF mRNA and protein biosynthesis in the heart as well as in cultured adult cardiac myocytes. The effects of Ang II on myocardial TNF mRNA and protein synthesis were mediated through the angiotensin type 1 receptor (AT1R), insofar as an AT1R antagonist (AT1a) blocked the effects of Ang II, whereas an angiotensin type 2 receptor (AT2R) antagonist (AT2a) had no effect. Stimulation with Ang II led to the activation of nuclear factor-kappaB and activator protein-1 (AP-1), two transcription factors that are important for TNF gene expression. Nuclear factor-kappa-B-alpha activation was accompanied by phosphorylation of Ikappa Balpha on serine 32 as well as degradation of IkappaB-alpha, suggesting that the effects of Ang II were mediated through an IkappaBalpha-dependent pathway. The important role of protein kinase C (PKC) was suggested by studies in which a phorbol ester triggered TNF biosynthesis, and a PKC inhibitor abrogated Ang IIinduced TNF biosynthesis. Conclusions These studies suggest that Ang II provokes TNF biosynthesis in the adult mammalian heart through a PKC-dependent pathway.
Natriuretic Peptide Reduces TNF-Induced Actin
Polymerization and Endothelial Permeability (Circulation Research
90:874) The atrial natriuretic peptide
(ANP) is a cardiovascular hormone possessing
antiinflammatory potential due to its inhibitory action
on the production of inflammatory mediators, such as
tumor necrosis factor-alpha (TNF-alpha). The aim of this
study was to determine whether ANP is able to attenuate
inflammatory effects of TNF-alpha on target cells. Human
umbilical vein endothelial cells (HUVECs) were treated
with TNF-alpha in the presence or absence of ANP. Changes
in permeability, cytoskeletal alterations,
phosphorylation of p38 MAPK and HSP27, and expression of
MKP-1 were determined by macromolecule permeability
assay, fluorescence labeling, RT-PCR, and immunoblotting.
Antisense studies were done by transfecting cells with
MKP-1 antisense oligonucleotides. Activation of HUVECs
with TNF-alpha lead to a significant increase of
macromolecule permeability and formation of stress
fibers. Treatment of cells with ANP (10(-8) to 10(-6)
mol/L) significantly reduced the formation of stress
fibers and elevated permeability. Both TNF-alpha-induced
effects were shown to be mediated via the activation of
p38 using SB203580, a specific inhibitor of p38. ANP
significantly reduced the TNF-alpha-induced activation of
p38 and attenuated the phosphorylation of HSP27, a
central target downstream of p38. ANP showed no effect on
p38 upstream kinases MKK3/6. However, a significant
induction of the MAPK phosphatase MKP-1 mRNA and protein
could be observed in ANP-treated cells. Antisense
experiments proved a causal role for MKP-1 induction in
the ANP-mediated inhibition of p38. These data show the
inhibitory action of ANP on TNF-alpha-induced changes in
endothelial cytoskeleton and macromolecule permeability
involving an MKP-1-induced inactivation of p38 MAPK.
These effects point to an antiinflammatory and
antiatherogenic potential of this cardiovascular hormone.
Insulin resistance in moderate chronic heart failure is related to hyperleptinaemia, but not to norepinephrine or TNF-alpha (International Journal of Cardiology  83:73-81) Objectives: Chronic heart failure (CHF) has emerged as an insulin-resistant state, independently of ischaemic aetiology. The underlying mechanisms of this finding are not known. Catecholamines, tumor necrosis factor alpha (TNF) and leptin, the adipocyte specific hormone, have all been implicated as mediators of impaired insulin sensitivity. The purpose of this study was to examine in patients with CHF and in comparison to healthy controls subjects whether norepinephrine, TNF or leptin relate to insulin sensitivity. Design: 41 patients with CHF (age 60±2 years, NYHA I/II/III/IV 4/12/22/3, peak oxygen consumption 17.6±1.0 ml/kg per min) and 21 healthy controls of similar age and total and regional fat distribution were studied in a cross-sectional study. Insulin sensitivity was assessed by intravenous glucose tolerance testing using the minimal model approach; catecholamines, TNF and soluble TNF receptors 1 and 2 were also measured. Total and regional body fat mass was assessed by dual energy X-ray absorptiometry. Results: Insulin sensitivity was reduced in CHF patients compared to controls by 31% (P<0.01) and fasting insulin was higher in patients than in controls (79.1±9.7 vs. 41.4±6.0 pmol/l, P<0.01). Patients had, compared to healthy controls, elevated serum leptin levels (8.28±0.84 vs. 4.83±0.68 ng/ml), norepinephrine (3.45±0.34 vs. 1.87±0.16 nmol/l, both P<0.01) and soluble TNF-receptors 1 (1280±141 vs. 639±52 pg/ml) and 2 (2605±184 vs. 1758±221 pg/ml, both P<0.01). Leptin levels corrected for total body fat mass were higher in CHF patients than in controls (41.3±3 vs. 24.3±2 pg/ml per 100 g, P<0.001). TNF was not significantly different between the groups. In both groups there was an inverse correlation between insulin sensitivity and serum leptin (r=-0.65, P<0.0001 for pooled subjects); in contrast, no significant relation was found between insulin sensitivity and norepinephrine or TNF. In multivariate regression analysis, leptin emerged as the only significant predictor of insulin sensitivity (standardised COEFFICIENT=-0.59, P<0.001), independent of body fat mass, age and peak V2. Conclusion: In moderate CHF, elevated leptin levels directly and independently predict insulin resistance. Elevated serum leptin levels could play a role in the impaired regulation of energy metabolism in CHF. In contrast to observations in other conditions, TNF and norepinephrine are not related to insulin resistance in moderate CHF.
Increased Serum Levels of Macrophage Migration Inhibitory Factor-Related Protein Is a Sensitive Marker for Acute Coronary Syndrome in Patients With Coronary Artery Disease (ACC 2002) BACKGROUND: In patients with coronary artery disease (CAD), it is important to discriminate acute coronary syndrome (ACS). There is accumulating data that ACS relates to recent activation of inflammation affecting atherosclerotic plaques. Macrophage migration inhibitory factor-related protein (MRP) is a calcium-binding protein (heterodimer), which is expressed in infiltrate macrophages during inflammatory reactions. The purpose of this study was to investigate whether MRP is useful for the diagnosis of ACS. Methods: We studied 92 patients with angiographically proven CAD. They comprised two groups [Group ACS, Braunwald's subclass II or III of unstable angina, and acute myocardial infarction, n=53; Group SA, stable angina, n=39]. We purified MRP from human leukocytes and then prepared rabbit monoclonal antibodies against the MRP. Serum concentrations of MRP were measured using a newly-developed enzyme-linked immunosorbent assay system. In addition, we measured serum concentrations of C-reactive protein (CRP). RESULTS: There were no significant differences in age, gender and coronary risk factors between the two groups. Serum MRP levels were significantly higher in Group ACS than in Group SA [3.25±3.08 (SD) microgram/ml vs. 0.77±0.31 microgram/ml, p < 0.0001]. Serum CRP levels were also significantly higher in Group ACS than in Group SA (3.11±6.14 mg/dl vs. 0.19±0.20 mg/dl, p=0.0039). Sensitivity and specificity of positive serum MRP levels (> 1.2 microgram/ml) for detection of ACS were 84.9% and 89.7%, respectively. On the other hand, sensitivity and specificity of positive serum CRP levels (> 0.5mg/dl) for detection of ACS were 52.8% and 92.3%, respectively. Sensitivity was significantly (p < 0.05) higher in the measurements of MRP than in the measurements of CRP, while specificity was comparable in the two markers. Conclusion: The measurement of serum MRP levels is useful for the discrimination of ACS in patients with CAD.
Patients with chronic heart failure exhibit significant metabolic insulin resistance. (Am J Cardiol  89:696-703) Chronic heart failure (HF) is associated with insulin resistance. Putative mechanisms of insulin resistance are abnormal skeletal muscle blood flow and antagonism of insulin action due to sympathetic nervous system activation. We measured insulin sensitivity, the vasoactive properties of insulin, and the association between insulin resistance and markers of neurohormonal activation in 10 patients with chronic HF and in 9 healthy controls. Noninvasive hemodynamic measurements and an hyperinsulinemic, euglycemic clamp were used. Patients were insulin resistant compared with the controls (p <0.05 for area under insulin dose-response curve). Insulin infusion led to a selective increase in forearm blood flow accompanied by a decrease in mean arterial pressure and superior mesenteric blood flow. Heart rate decreased in patients but not in controls; however, when baseline measurements were controlled for, there was no difference in the overall hemodynamic response to insulin infusion between the study groups. In univariate analysis, age, serum creatinine, fasting insulin, and triglyceride levels correlated inversely with insulin sensitivity (p <0.05 for all). Cardiac output had a significant correlation with insulin sensitivity (p <0.05). On stepwise multiple linear regression analysis, only age and fasting plasma insulin emerged as significant predictors of insulin sensitivity (R2 0.613, P = 0.001). In particular, we found no evidence of a relation between insulin sensitivity and plasma noradrenaline. Patients with chronic HF exhibit significant metabolic insulin resistance. Insulin resistance is not secondary to failure of insulin-mediated vasodilatation or sympathetic nervous system activation and is likely due to abnormalities at the level of the skeletal myocyte
The concentrations of proinsulin-like molecules provide a better way to predict the incidence of CHD than those of insulin (Diabetologia  45:327-336 Aims/hypothesis: Higher concentrations of insulin correlate with several coronary heart disease (CHD) risk factors and have been shown to predict incident CHD in several studies, leading to hypotheses concerning the proatherogenic properties of insulin. However, in cross-sectional studies, relationships of concentrations of the insulin precursor molecules, proinsulin and des 31, 32 proinsulin, relate as strongly, or more strongly, to levels of risk factors and to (prevalent) CHD. Methods: We investigated the relationship between concentrations of insulin, measured with a specific assay, and of proinsulin-like molecules, and risk factors in 1181 non-diabetic men 50-64 years old during Phase II of the Caerphilly Study. We also related concentrations of these molecules to incident CHD during the 10-14 years follow-up. Results: The relationship between concentrations of insulin, of proinsulin and of des 31, 32 proinsulin and BMI (r = 0.36-0.45), triglyceride (r = 0.25-0.31), high density lipoprotein- (HDL-) cholesterol (r = -0.17 to -0.21), systolic (r = 0.05-0.11) and diastolic blood pressure (r = 0.11-0.15) were similarly close, those with risk factors being somewhat and similarly reduced after adjustment for BMI. The correlation between insulin and of proinsulin-like molecules and those plasminogen activator inhibitor-1 (PAI-1) antigen was also similar (r = 0.28-0.29). There was a negative correlation between concentrations of proinsulin-like molecules - but not insulin - and birth weight. Insulin concentrations correlated positively with height (r = 0.12). In logistic regression models, concentrations of proinsulin-like molecules, but not insulin, predicted incident of CHD over a follow-up of 10-14 years (insulin - standardised odds ratio (SOR) 1.30 (95 %-CI) 0.91, 1.85), p = 0.15; des 31, 32 proinsulin - SOR 1.38 (95 %-CI 1.02, 1.85), p = 0.034; sum of proinsulin-like molecules - SOR 1.54 (95 %-CI 1.07, 2.20), p = 0.019 after adjusting for age and BMI. The predictive ability of these molecules was reduced by around one third after adjustment for standard risk factors and concentrations of tryglyceride and HDL-cholesterol, and by about half after further adjustment for PAI-1 concentrations. Conclusion/ interpretation: We conclude that concentrations of proinsulin-like molecules provide a better way to predict the incidence of CHD than those of insulin. However, the lack of biological evidence for a causative relationship suggests an association through a common antecedent, and this antecedent is not likely to be intrauterine growth retardation. [Diabetologia (2002) 45: 327-336]
Chronic vitamin C deficiency does not influence the initiation or progression of atherosclerotic plaques but severely compromises collagen deposition and induces a type of plaque morphology that is potentially vulnerable to rupture (Circulation. ;105:1485.) Background Oxidative stress is thought to play an important role in atherogenesis, suggesting that antioxidants could prevent coronary artery disease. However, the efficacy of vitamin C in reducing atherosclerosis is debatable in humans and has not been tested rigorously in animals. Methods and Results Gulo-/-Apoe-/- mice were used to test a hypothesis that chronic vitamin C deficiency enhances the initiation and development of atherosclerosis. These mice are dependent on dietary vitamin C because of the lack of L-gulonolactone-gamma-oxidase and are prone to develop atherosclerosis because of lacking apolipoprotein E. Beginning at 6 weeks of age, the Gulo-/-Apoe-/- mice were fed regular chow or Western-type diets containing high fat and supplemented with either 0.033 g or 3.3 g/L of vitamin C in their drinking water. This regimen produced mice with chronically low vitamin C (average 1.5 µg/mL in plasma) or high vitamin C (average 10 to 30 µg/mL in plasma). Morphometric analysis showed that within each sex, age, and diet group, the sizes of the atherosclerotic plaques were not different between low vitamin C mice and high vitamin C mice. However, advanced plaques in the low vitamin C mice had significantly reduced amounts of Sirius redstaining collagen (36.4±2.2% versus 54.8±2.3%, P<0.0001), larger necrotic cores within the plaques, and reduced fibroproliferation and neovascularization in the aortic adventitia. Conclusions Chronic vitamin C deficiency does not influence the initiation or progression of atherosclerotic plaques but severely compromises collagen deposition and induces a type of plaque morphology that is potentially vulnerable to rupture.
In CHD, vWF and tPAag -but not thrombomodulin - are independent markers of atherosclerosis. (Thrombosis Research  105(1):25-31) von Willebrand factor (vWF), thrombomodulin and tissue plasminogen activator antigen (tPAag) are regarded as markers of endothelial activation and/or damage. Elevated levels have been associated with atherosclerotic disease states. The aim of the present study was to compare the levels of vWF, thrombomodulin and tPAag in patients with coronary heart disease (CHD) and matched healthy individuals to see if they discriminated significantly between the study groups also after adjustment for established CHD risk factors. Patients (n=193) in various stages of CHD and matched controls (n=193) were included. To evaluate possible influence of acute phase reaction, reinvestigation was performed after 6 months. We observed elevated levels of vWF (P<.001) and tPAag (P<.001) but not thrombomodulin (P=.082) in CHD patients when compared to controls, still statistically significant after 6 months and also after adjustment for established risk factors. Our results indicate that vWF and tPAag but not thrombomodulin in the present population are independent markers of atherosclerosis.
ablation results in a lean mouse with aberrant adipocyte
lipolysis, enhanced leptin production [per adipocyte
mass], a resistance to diet-induced obesity, as well as a
tendency toward insulin resistance (Proc. Natl. Acad. Sci. USA  98:
6494-6499) Perilipin coats the lipid droplets
of adipocytes and is thought to have a role in regulating
triacylglycerol hydrolysis. To study the role of
perilipin in vivo, we have created a perilipin knockout
mouse. Perilipin null (peri(-/-)) and wild-type
(peri(+/+)) mice consume equal amounts of food, but the
adipose tissue mass in the null animals is reduced to
approximately 30% of that in wild-type animals. Isolated
adipocytes of perilipin null mice exhibit elevated basal
lipolysis because of the loss of the protective function
of perilipin. They also exhibit dramatically attenuated
stimulated lipolytic activity, indicating that perilipin
is required for maximal lipolytic activity. Plasma leptin
concentrations in null animals were greater than expected
for the reduced adipose mass. The peri(-/-) animals have
a greater lean body mass and increased metabolic rate but
they also show an increased tendency to develop glucose
intolerance and peripheral insulin resistance. When fed a
high-fat diet, the perilipin null animals are resistant
to diet-induced obesity but not to glucose intolerance.
The data reveal a major role for perilipin in adipose
lipid metabolism and suggest perilipin as a potential
target for attacking problems associated with obesity.
Triglycerides >200 mg/dl (But Not Triglyceride Reduction) Strongly Associate with Stroke Risk in BIP (Circulation  104:2892)Background Despite unclear associations between blood lipids, including fractionated cholesterol and triglycerides, and stroke, recent evidence demonstrates that lipid-modifying agents decrease the risk of stroke in patients with coronary heart disease (CHD). Methods and Results Patients with documented CHD who were screened for but not included in the Bezafibrate Infarction Prevention study and had no history of stroke or transient ischemic attack (TIA) (n=11 177) were followed up. At baseline, medical histories were obtained and blood lipids assessed at a central study laboratory. During a 6- to 8-year follow-up period, 941 patients were identified as having nonhemorrhagic cerebrovascular disease, of whom 487 had verified ischemic stroke (per clinical findings and brain CT) or TIA. Patients experiencing an ischemic stroke/TIA had higher mean levels of triglycerides, lower levels of HDL cholesterol, and lower percentages of cholesterol contained in the HDL cholesterol moiety (%HDL; P<0.01 for all). In a logistic regression model, the adjusted ORs for developing an ischemic stroke/TIA were 1.27 (95% CI 1.01 to 1.60) associated with triglycerides >200 mg/dL and 0.87 (95% CI 0.78 to 0.97) associated with a 5% decrease in %HDL. The increased risk associated with high triglycerides was found across subgroups of age, sex, patient characteristics, and cholesterol fractions. Conclusions High triglycerides constitute an independent risk factor for ischemic stroke/TIA across subgroups of age, sex, patient characteristics, and cholesterol fractions, whereas high %HDL was an independent protective factor among patients with CHD. These findings support the role of blood lipids, including triglycerides, as important modifiable stroke risk factors.
Elevated plasma CRP levels significantly predict the risk of future ischemic stroke and TIA in the elderly and independently of other cardiovascular risk factors. (Stroke.  32:2575) Background The role of C-reactive protein (CRP) as a novel plasma marker of atherothrombotic disease is currently under investigation. Previous studies have mostly related CRP to coronary heart disease, were often restricted to a case-control design, and failed to include pertinent risk factors to evaluate the joint and net effect of CRP on the outcome. We related plasma CRP levels to incidence of first ischemic stroke or transient ischemic attack (TIA) in the Framingham Study original cohort. Methods There were 591 men and 871 women free of stroke/TIA during their 1980 to 1982 clinic examinations, when their mean age was 69.7 years. CRP levels were measured by using an enzyme immunoassay on previously frozen serum samples. Analyses were based on sex-specific CRP quartiles. Risk ratios (RRs) were derived, and series of trend analyses were performed. Results During 12 to 14 years of follow-up, 196 ischemic strokes and TIAs occurred. Independent of age, men in the highest CRP quartile had 2 times the risk of ischemic stroke/TIA (RR=2.0, P=0.027), and women had almost 3 times the risk (RR=2.7, P=0.0003) compared with those in the lowest quartile. Assessment of the trend in risk across quartiles showed unadjusted risk increase for men (RR=1.347, P=0.0025) and women (RR=1.441, P=0.0001). After adjustment for smoking, total/HDL cholesterol, systolic blood pressure, and diabetes, the increase in risk across CRP quartiles remained statistically significant for both men (P=0.0365) and women (P=0.0084). Conclusions Independent of other cardiovascular risk factors, elevated plasma CRP levels significantly predict the risk of future ischemic stroke and TIA in the elderly.
Augmentation of the synthesis of plasminogen activator inhibitor type-1 by precursors of insulin. A potential risk factor for vascular disease. (Circulation  89:321-330) BACKGROUND: Both vascular disease and elevated concentrations in plasma of plasminogen activator inhibitor type-1 (PAI-1) are prominent in patients with non-insulin-dependent diabetes mellitus (NIDDM). We and others have hypothesized that the increased PAI-1 may contribute to acceleration of atherosclerosis in this condition and in other states characterized by insulin resistance as well. Surprisingly, however, elevations of PAI-1 decrease when type II diabetic patients are treated with exogenous insulin, as do circulating concentrations of the precursor of insulin, proinsulin, in plasma. Accordingly, the increased PAI-1 in patients with NIDDM may reflect effects of precursors of insulin rather than or in addition to those of insulin itself. To assess this possibility directly, this study was performed to identify potential direct effects of proinsulin and proinsulin split products on synthesis of PAI-1 in liver cells, thought to be the major source of circulating PAI-1 in vivo. METHODS AND RESULTS: Hep G2 cells (highly differentiated human hepatoma cells) were exposed to human proinsulin, des(31,32)proinsulin and des(64,65)proinsulin (split products of proinsulin), or C-peptide. Accumulation of PAI-1 in conditioned media increased in a time- and concentration-dependent fashion in response to the two des-intermediates [3.3-fold with des(31,32)proinsulin and 4.5-fold with des(64,65)proinsulin]. C-peptide elicited no increase. Stimulation was transduced at least in part by the insulin receptor as shown by inhibition of stimulation by insulin receptor antibodies, mediated at the level of PAI-1 gene expression as shown by the 2.2- to 2.9-fold increases in steady-state concentrations of PAI-1 mRNA, and indicative of newly synthesized protein as shown by results in metabolic labeling experiments. CONCLUSIONS: Our results are consistent with the hypothesis that precursors of insulin (proinsulin and proinsulin split products), known to be present in relatively high concentrations in plasma in patients with NIDDM and conditions characterized by insulin resistance, may directly stimulate PAI-1 synthesis, thereby attenuating fibrinolysis and accelerating atherogenesis.
Prolonged hyperlipidemia - independent of insulin - may contribute to increased fat metabolism and storage as a result of FAT/CD36, PPAR-2, leptin, UCP-2, UCP-3, and TNF-alpha induction. Diabetes  49:319324
JAMA publishes *VA VOODOO* study - utilizing such inane concepts as *utility index* of blindness and *quality adjusted life years* as well as innumerable assumptions predicting *days of blindness* - to suggest that yearly visual screens in type 2 patients are not cost-effective....(JAMA 283:889-896)
In multivariate Cox models, the age-adjusted hazard ratio for insulin resistance factor during the 22-year Helsinki Policemen Study follow-up was 1.28 (95% CI 1.10 to 1.50) with regard to CHD risk and 1.64 (95% CI 1.29 to 2.08) with regard to stroke risk. Lipid factor predicted the risk of CHD but not that of stroke, and lifestyle factor predicted a reduced CHD risk. Factor analysis including only 6 risk factor variables proposed to be central components of insulin resistance syndrome (body mass index, subscapular skinfold, AUC insulin, AUC glucose, mean blood pressure, and triglycerides) produced only a single insulin resistance factor that predicted the risk of CHD and stroke independently of other risk factors....(Arteriosclerosis,Thrombosis and Vascular Biology20:538)
Platelet-derived thrombogenesis in stable coronary patients associates weakly with blood glucose (R2 = 0.19, p < 0.008), and apo-B (R2 = 0.18, p = 0.002) at a threshold glucose value of 88.2 mg/dl (JACC35:300-307)
In normal glucose tolerant offspring of type 2 diabetics, PAI-1 activity was correlated with plasma PAI-1 antigen level (r = 0.40, P = 0.02), fibrinogen (r = 0.45, P = 0.01), and HDL cholesterol (r = 0.36, P = 0.04). However, tPA antigen level, fasting and postload plasma glucose and insulin, total cholesterol, triglycerides, WHR, and BMI did NOT correlate with PAI-1 activity
Physiologic elevation in the local plasma insulin concentration increases coronary blood flow in the absence of any increase in myocardial oxygen demand or consumption. These observations are consistent with insulin-mediated elaboration of vasoactive and/or paracrine factors within the coronary circulation.
Diabetic subjects have significantly (P<0.001) more increased Dicarboxylic Acid (DA) excretion in urine than corresponding healthy subjects. The yields of DA's in each group decreased in the order adipic>suberic>sebacic acid. Being stable and easily detectable compounds, DA's may be considered potential markers of oxidative attack on PUFA in diabetes
HDL (HDL2) from poorly-controlled diabetics is abnormal and does not inhibit LDL-oxidation or Apo-A1 fragmentation or HDL2-associated platelet-activating factor acetylhydrolase activity as well as non-diabetic HDL(HDL2) in vitro
Should we recognize another class of diabetes called "Prandial Diabetes" with different risk factors? (The new fasting ADA criteria seem to be less predictive than the WHO criteria for the burden of cardiovascular disease associated with abnormal glucose in the elderly.)
Results suggest a dose-response relation of glucose intolerance at baseline with CHD incidence, CHD mortality, and total mortality, independent of other risk factors, in this cohort of middle-aged and older Japanese-American men.Diabetes Care 22:12621265, 1999
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