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1.  High levels of tissue plasminogen activator (tPA) antigen precede the development of type 2 diabetes in a longitudinal population study. The Northern Sweden MONICA Study 
Impaired fibrinolysis is found in impaired glucose tolerance and type 2 diabetes, associated with components of the metabolic syndrome. There are no data concerning fibrinolysis in subjects with normal glucose tolerance that convert to diabetes.
We studied the activities of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) and the levels of tPA antigen (a marker of endothelial dysfunction) in 551 subjects with normal glucose tolerance in 1990 in relation to incident diabetes during nine years of follow-up.
Subjects with diabetes at follow-up (n = 15) had significantly lower baseline tPA activity and higher PAI-1 activity and tPA antigen than non-converters. The risk of diabetes increased linearly across quartiles of PAI-activity (p = 0.007) and tPA antigen (p < 0.001) and decreased across quartiles of tPA activity (p = 0.026). The risk of diabetes with low tPA activity or high PAI-1 activity persisted after adjustment for age and sex but diminished to a non-significant level after further adjustments. The odds ratio of diabetes for high tPA antigen was 10.4 (95% confidence interval 2.7–40) adjusted for age and sex. After further adjustment for diastolic blood pressure, waist circumference, insulin, triglycerides, fasting and post load glucose the odds ratio was 6.5 (1.3–33, p = 0.024).
Impaired fibrinolysis and endothelial dysfunction are evident in subjects with normal glucose tolerance who later develop diabetes. High tPA antigen is predictive of future diabetes independent from the metabolic syndrome.
PMCID: PMC328088  PMID: 14690546
2.  Vascular endothelial growth factor (VEGF) fails to improve blood flow and to promote collateralization in a diabetic mouse ischemic hindlimb model 
Angiogenic therapy with vascular endothelial growth factor (VEGF) has been proposed as a treatment paradigm for patients suffering from an insufficiency of collateral vessels. Diabetes is associated with increase in the production of VEGF and therefore additional VEGF may not be beneficial. Accordingly, we sought to determine the efficacy of VEGF therapy to augment collateral formation and tissue perfusion in a diabetic mouse ischemic hindlimb model.
Diabetic and non-diabetic mice were studied in parallel for the efficacy of VEGF administration. Diabetes was induced with streptozotocin. Hindlimb ischemia was produced by severing the left iliac artery. An outlet tube from an osmotic infusion pump with placebo/ 500 micrograms of plasmid-DNA encoding VEGF was fenestrated and tunneled into the left quadriceps muscle.
VEGF induced more rapid and complete restoration of blood flow in normal mice. However, in the setting of diabetes there was no difference between VEGF Vs. placebo in the rate or adequacy of flow restoration. There was a significant increase in smooth muscle actin and Factor-VIII antigen densities in diabetic animals and in animals which received VEGF.
Angiogenic therapy with VEGF in the setting of diabetes does not appear to have the beneficial effects seen in the absence of diabetes.
PMCID: PMC320491  PMID: 14683529
arteries; blood flow; collateral circulation; diabetes
3.  Differential effects of fenofibrate versus atorvastatin on the concentrations of E-selectin and vascular cellular adhesion molecule-1 in patients with type 2 diabetes mellitus and mixed hyperlipoproteinemia: a randomized cross-over trial 
Diabetic dyslipoproteinemia is characterized by hypertriglyceridemia, low HDL-cholesterol and often elevated LDL-cholesterol and is a strong risk factor for atherosclerosis. Adhesion molecule levels are elevated both in hyperlipoproteinemia and diabetes mellitus. It is unclear whether fibrate or statin therapy has more beneficial effects on adhesion molecule concentrations.
Atorvastatin (10 mg/d) was compared to fenofibrate (200 mg/d) each for 6 weeks separated by a 6 week washout period in 11 patients (6 male, 5 female; 61.8 ± 8.2 years; body mass index 29.8 ± 3.1 kg/m2) with type 2 diabetes mellitus (HbA1c 7.3 ± 1.1 %) and mixed hyperlipoproteinemia using a randomized, cross-over design. Fasting blood glucose, HbA1c, lipid parameters, E-selectin, ICAM-1, VCAM-1, and fibrinogen concentrations were determined before and after each drug.
Glucose and HbA1c concentrations remained unchanged during the whole study period. LDL cholesterol was reduced during atorvastatin therapy, triglycerides were lowered more effectively with fenofibrate. Comparison of pre- and postreatment concentrations of E-selectin showed a reduction during atorvastatin (-7 %, p = 0.11) and fenofibrate (-10 %, p < 0.05) therapy. Atorvastatin treatment reduced VCAM-1 levels by 4% (p < 0.05), while VCAM-1 concentrations remained unchanged (+1%, ns) during fenofibate therapy. However, direct comparisons of post-treatment levels during both forms of therapy were not of statistical significance. ICAM-1 levels were not influenced by either form of therapy.
In addition to the different beneficial effects on lipid metabolism, both drugs appear to lower adhesion molecule plasma concentrations in a different manner in patients with type 2 diabetes and mixed hyperlipoproteinemia. Our observations should be confirmed in a larger cohort of such patients.
PMCID: PMC317344  PMID: 14662011
4.  Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study 
Patients with diabetic cardiomyopathy have an impaired myocardial glucose handling and distal distribution of coronary atherosclerosis. Trimetazidine, an anti-ischemic metabolic agent, improves myocardial glucose utilization though inhibition of fatty acid oxidation. Aim of the present study was to evaluate whether the metabolic effect of trimetazidine on left ventricular function in patients with diabetic cardiomyopathy.
32 patients (24 males and 8 females, mean (SE) age = 67 ± 6 years) with type 2 diabetes and ischemic cardiomyopathy were randomized to receive either trimetazidine (20 mg, t.d.s.) or placebo (t.d.s.) for six months in a randomized parallel study. Patients performed an echocardiogram at baseline and after 6 months.
Demographic data were comparable between the two groups. After six month baseline left ventricular end-diastolic diameters increased from 62.4 ± 1.7 to 63 ± 2.1 mm in the placebo group, while decreased from 63.2 ± 2.1 to 58 ± 1.6 mm (p < 0.01 compared to baseline) in the trimetazidine group. Compared to baseline, left ventricular ejection fraction increased by 5.4 ± 0.5% (p < 0.05) in the trimetazidine group while remained unchanged in the placebo group -2.4 ± 1.1% (NS), p < 0.01 between groups. A significant improvement in wall motion score index and in the E/A wave ratio was detected in patients treated with trimetazidine, but not in those receiving placebo.
in diabetic patients with ischemic heart disease trimetazidine added to standard medical therapy has beneficial effect on left ventricular volumes and on left ventricular ejection fraction compared to placebo. This effect may be related to the effect of trimetazidine upon cardiac glucose utilization.
PMCID: PMC305354  PMID: 14641923
5.  The insertion/deletion variation in the α2B-adrenoceptor does not seem to modify the risk for acute myocardial infarction, but may modify the risk for hypertension in sib-pairs from families with type 2 diabetes 
An insertion/deletion polymorphism in the α2B-adrenoceptor (AR) has been associated with the risk for acute myocardial infarction (AMI) and sudden cardiac death. In this study we tested whether this polymorphism is associated with the risk for AMI among members of families with type 2 diabetes.
154 subjects with a history of AMI were matched for age and sex with one of their siblings who did not have a history of AMI. The prevalence of the genotypes of the α2B-AR insertion/deletion polymorphism was compared between the siblings using McNemar's test. We also explored the data to see whether this genetic variation affects the risk for hypertension by using logistic regression models in the two subpopulations of subjects, with and without a history of AMI.
Among all study subjects, 73 (24%) carried the α2B-AR deletion/deletion genotype, 103 (33%) carried the insertion/insertion genotype, and 132 (43%) were heterozygous. The distribution of genotypes of the α2B-AR insertion/deletion variation in the group of subjects with a history of AMI and their phenotype-discordant siblings did not statistically significantly differ from that expected by random distribution (p = 0.52): the deletion/deletion genotype was carried by 34 subjects with AMI (22%), and by 39 subjects without AMI (25%). Neither did we observe any significant difference in deletion allele frequencies of the α2B-AR insertion/deletion polymorphism between patients with a history of AMI (0.44) and their sib-pair controls (0.46, p = 0.65). In an exploratory analysis, the α2B-AR deletion/deletion genotype was associated with increased odds for hypertension compared with subjects carrying any of the other genotypes.
The deletion/deletion genotype of the α2B-AR does not emerge in this study as a risk factor for AMI among members of families with type 2 diabetes; however, it might be involved in the development of hypertension.
PMCID: PMC305364  PMID: 14633283
Receptors; adrenergic; alpha 2; polymorphism; genetics; myocardial infarction; hypertension.
6.  Increased prevalence of left ventricular hypertrophy in hypertensive women with type 2 diabetes mellitus 
Left ventricular hypertrophy (LVH) is a powerful independent risk factor for cardiovascular morbidity and mortality among hypertensive patients. Data regarding relationships between diabetes and LVH are controversial and inconclusive, whereas possible gender differences were not specifically investigated. The goal of this work was to investigate whether gender differences in left heart structure and mass are present in hypertensive patients with type 2 diabetes.
Five hundred fifty hypertensive patients with at least one additional cardiovascular risk factor (314 men and 246 women, age 52 to 81, mean 66 ± 6 years), were enrolled in the present analysis. In 200 (36%) of them – 108 men and 92 women – type 2 diabetes mellitus was found upon enrollment. End-diastolic measurements of interventricular septal thickness (IVS), LV internal diameter, and posterior wall thickness were performed employing two-dimensionally guided M-mode echocardiograms. LVH was diagnosed when LV mass index (LVMI) was >134 g/m2 in men and >110 g/m2 in women.
Mean LVMI was significantly higher among diabetic vs. nondiabetic women (112.5 ± 29 vs. 105.6 ± 24, p = 0.03). In addition, diabetic women presented a significantly higher prevalence of increased IVS thickness, LVMI and left atrial diameter on intra-gender comparisons. The age adjusted relative risk for increased LVMI in diabetics vs. nondiabetics was 1.47 (95% CI: 1.0–2.2) in females and only 0.8 (0.5–1.3) in males.
Type 2 diabetes mellitus was associated with a significantly higher prevalence of LVH and left atrial enlargement in hypertensive women.
PMCID: PMC317343  PMID: 14633284
Diabetes mellitus; Echocardiography; Hypertension; Left ventricular hypertrophy
7.  Usefulness of electronic databases for the detection of unrecognized diabetic patients 
Even mild hyperglycemia is associated with future acute and chronic complications. Nevertheless, many cases of diabetes in the community go unrecognized. The aim of the study was to determine if national electronic patient records could be used to identify patients with diabetes in a health management organization.
The central district databases of Israel's largest health management organization were reviewed for all patients over 20 years old with a documented diagnosis of diabetes mellitus (DM) in the chronic disease register or patient file (identified diabetic patients) or a fasting serum glucose level of >126 mg/100 ml according to the central laboratory records (suspected diabetic patients). The family physicians of the patients with suspected diabetes were asked for a report on their current diabetic status.
The searches yielded 1,694 suspected diabetic patients; replies from the family physicians were received for 1,486. Of these, 575 (38.7%) were confirmed to have diabetes mellitus. Their addition to the identified patient group raised the relative rate of diabetic patients in the district by 3.2%.
Cross-referencing existing databases is an efficient, low-cost method for identifying hyperglycemic patients with unrecognized diabetes who require preventive treatment and follow-up. This model can be used to advantage in other clinical sites in Israel and elsewhere with fully computerized databases.
PMCID: PMC305363  PMID: 14614779
8.  Platelet-neutrophil conjugate formation is increased in diabetic women with cardiovascular disease 
More than seventeen million Americans are afflicted with diabetes and these people have four times the rate of coronary heart disease (CHD) as non-diabetics. Furthermore, diabetic women have a 3.8 fold greater risk for CHD compared to diabetic men. Little is known why diabetic women are at an increased risk for CHD. It is possible that diabetic women with cardiovascular disease (CVD) have a greater inflammatory response resulting in an increased platelet neutrophil conjugate formation than diabetic men with CVD or non-diabetic women with CVD. This study tested the hypothesis that platelet-neutrophil conjugates, which are associated with several cardiovascular diseases, are increased in diabetic women with CVD compared to diabetic men with CVD and non-diabetic women with CVD.
Platelet-neutrophil conjugates were quantified by flow cytometry. The primary method is through direct binding of the neutrophil PSGL-1 receptor with P-selectin expressed on the platelet.
In this study, we found when the blood was stimulated with PAF (platelet activating factor), diabetic women without CVD demonstrated an increase in platelet-neutrophil conjugates compared to diabetic women with CVD and non-diabetic women with CVD (% conjugates: 63.3 ± 5.2 vs 46.8 ± 4.3 vs 48.6 ± 3.4, p < 0.05). The stimulation ratio was significantly increased in diabetic and non-diabetic women with CVD in comparison to diabetic men with CVD (ratio: 3.3 ± 0.4 vs 3.3 ± 0.3 vs 2.1 ± 0.3, p < 0.05).
These results suggest that platelets and neutrophils in diabetic women have a greater potential for activation compared to diabetic men and may contribute to thrombosis/inflammation and the greater severity of coronary heart disease observed in diabetic women as compared to diabetic men.
PMCID: PMC270088  PMID: 14609437
Cardiovascular Disease; Women; Platelet-Neutrophil Conjugates; and Diabetes
9.  Cardiovascular diabetology in the core of a novel interleukins classification: the bad, the good and the aloof 
The impressive correlation between cardiovascular disease and glucose metabolism alterations has raised the likelihood that atherosclerosis and type 2 diabetes may share common antecedents. Inflammation is emerging as a conceivable etiologic mechanism for both. Interleukins are regulatory proteins with ability to accelerate or inhibit inflammatory processes.
Presentation of the hypothesis
A novel interleukins classification is described, based on their role in diabetes and atherosclerosis, hypothesizing that each interleukin (IL) acts on both diseases in the same direction – regardless if harmful, favorable or neutral.
Testing the hypothesis
The 29 known interleukins were clustered into three groups: noxious (the "bad", 8 members), comprising IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-17 and IL-18; protective (the "good", 5 members), comprising IL-4, IL-10, IL-11, IL-12 and IL-13; and "aloof", comprising IL-5, IL-9, IL-14, IL-16 and IL-19 through IL-29 (15 members). Each group presented converging effects on both diseases. IL-3 was reluctant to clustering.
These observations imply that 1) favorable effects of a given IL on either diabetes or atherosclerosis predicts similar effects on the other; 2) equally, harmful IL effects on one disease can be extrapolated to the other; and 3) absence of influence of a given IL on one of these diseases forecasts lack of effects on the other. These facts further support the unifying etiologic theory of both ailments, emphasizing the importance of a cardiovascular diabetologic approach to interleukins for future research. Pharmacologic targeting of these cytokines might provide an effective means to simultaneously control both atherosclerosis and diabetes.
PMCID: PMC212422  PMID: 14525620
Atherosclerosis; Coronary artery disease; Cytokines; Diabetes mellitus; Interleukins
10.  Brachial-ankle pulse wave velocity and symptomatic cerebral infarction in patients with type 2 diabetes: a cross-sectional study 
Recently a new automatic device that measures brachial-ankle pulse wave velocity using an oscillometric method has been developed. However, the practical significance of brachial-ankle pulse wave velocity measurement remains uncertain. The purpose of this study was to examine the association between brachial-ankle pulse wave velocity and symptomatic cerebral infarction in patients with type 2 diabetes.
One thousand sixty six patients with type 2 diabetes were studied cross-sectionally. Measurements of brachial-ankle pulse wave velocity were made using the automatic device. Logistic regression analysis was used to calculate the odds ratio for cerebral infarction.
The presence of symptomatic cerebral infarction was confirmed in 86 patients. In these patients brachial-ankle pulse wave velocity was found to be significantly higher than in patients without cerebral infarction (18.94 ± 4.95 versus 16.46 ± 3.62 m/s, p < 0.01). The association between brachial-ankle pulse wave velocity and cerebral infarction remained significant after adjustment for traditional risk factors. There was an increasing odds ratio for each tertile of brachial-ankle pulse wave velocity, from the second tertile (odds ratio, 2.28; 95% confidence interval, 1.05 to 4.94), to the third (odds ratio, 2.53; 95% confidence interval, 1.09 to 5.86).
Overall, we conclude that an increase in brachial-ankle pulse wave velocity is associated with symptomatic cerebral infarction in patients with type 2 diabetes.
PMCID: PMC194759  PMID: 12969516
11.  Silent myocardial infarction in women with impaired glucose tolerance: The Northern Sweden MONICA study 
Patients with impaired glucose tolerance (IGT) have an increased risk of cardiovascular disease (CVD) that is independent of traditional risk factors. Hence, slightly elevated glucose levels, even in the non-diabetic range, might be associated with increased macrovascular disease.
Within the Northern Sweden MONICA project a population survey was performed in 1986. Electrocardiograms (ECG's) were recorded for half of the survey (n = 790) and oral glucose test was carried out in 78 % of those. The association between subjects with ECG's indicating previously unknown myocardial infarction (ukMI), IGT and conventional risk factors were analyzed by logistic regression for men and women separately, adjusting for age, smoking, hypercholesterolemia and hypertension.
Impaired glucose tolerance was significantly more common among women with ukMI, but not in men, compared to the group with normal ECG. In men, no variable was significantly associated with ukMI although the odds ratio (OR) for hypercholesterolemia was of borderline significance, 3.2 (95% confidence interval (CI) 0.9 to 11). The OR of having ukMI was 4.1 (CI 1.1 to 15) in women with IGT compared to women with normal glucose tolerance after multiple adjustment. The OR for hypertension was of borderline significance; 3.3 (CI 0.97 to 11).
We found that IGT was associated with ECG findings indicating silent myocardial infarction in women in a middle-aged general population in northern Sweden. The results persisted even after adjusting for known risk factors.
PMCID: PMC201007  PMID: 14498994
12.  Coronary artery flow reserve in diabetics with erectile dysfunction using sildenafil 
Diabetics with erectile dysfunction have a high prevalence of microvascular disturbance of the coronary circuit as measured by coronary flow reserve (CFR).
We aimed to evaluate the effects of the phosphodiesterase 5 inhibitor sildenafil on CFR in diabetics with erectile dysfunction.
Diabetics seeking diabetes refinement therapy were screened for vascular or neurogenic erectile dysfunction which was confirmed in 43 patients. No ischemic ECG changes were found in any of the ECG stress tests at the 100 W level. Cardiologic examinations raised suspicion of coronary artery disease in 16 patients; coronary angiography confirmed severe coronary artery lesions in 12, who were excluded from further analysis. CFR measurements were not possible in 10 participants. The 21 diabetics eligible for CFR measurements aged 60 years (50–69) had known diabetes for 11 years (3–30) and a BMI of 27 kg/m2 (24–36). CFR of the left anterior descending artery was assessed at baseline and 1 hour after 50 mg sildenafil, using transthoracic Doppler echocardiography.
Baseline CFR was at the lower level of the normal range (median 245%, range 210 – 490%). After sildenafil administration, CFR decreased insignificantly (ΔCFR -10%, p = 0.3). Patients with a BMI > 25 kg/m2 and left ventricular hypertrophy exhibited the highest reduction of CFR after sildenafil. No decrease of CFR below 200 % was observed. Systemic blood pressure dropped from 130/80 mmHg to 120/72 mmHg (p < 0.002).
Diabetics with erectile dysfunction exhibit a CFR in the lower normal range indicating severe microvascular disturbance. Sildenafil did not alter CFR in those patients. A high prevalence of severe coronary macroangiopathy was identified in asymptomatic diabetic patients screened for contraindications for sildenafil.
PMCID: PMC194431  PMID: 12952551
Coronary flow reserve; Diabetes mellitus; sildenafil.
13.  Metabolic and haemodynamic effects of oral glucose loading in young healthy men carrying the 825T-allele of the G protein β3 subunit 
A C825T polymorphism was recently identified in the gene encoding the β3 subunit of heterotrimeric G-proteins (GNB3). The T-allele is significantly associated with essential hypertension and obesity. In order to further explore a possible pathogenetic link between the T-allele and impaired glucose tolerance we studied metabolic and haemodynamic responses to oral glucose loading in young, healthy subjects with and without the 825T-allele.
Twelve subjects with and 10 without the 825T-allele were investigated at rest and following glucose ingestion (75 g). Blood glucose, serum insulin and haemodynamics were determined prior to and over 2 hours following glucose ingestion. We non-invasively measured stroke volume (SV, by impedance-cardiography), blood pressure (BP), heart rate (HR), and systolic-time-intervals. Cardiac output (CO) was calculated from HR and SV. Total peripheral resistance was calculated from CO and BP. Metabolic and haemodynamic changes were quantified by maximal responses and by calculation of areas under the concentration time profile (AUC). Significances of differences between subjects with and without the T-allele were determined by unpaired two-tailed t-tests. A p < 0.05 was considered statistically significant.
Metabolic and haemodynamic parameters at baseline were very similar between both groups. The presence of the T-allele did not alter the response of any metabolic or haemodynamic parameter to glucose loading.
In conclusion, this study does not support the hypothesis that the C825T polymorphism may serve as a genetic marker of early impaired glucose tolerance.
PMCID: PMC169176  PMID: 12890290
C825T; glucose tolerance; hypertension; diabetes mellitus; polymorphism
14.  Decreased expression of β1- and β2-adrenoceptors in human diabetic atrial appendage 
Using the streptozotocin-induced diabetic rat model, we have recently showed that the expression and function of β1-adrenoreceptor were decreased in the diabetic rat heart. However, the effect of diabetes on expression of β-adrenoreceptors in human cardiac tissue remains undefined. Therefore, the focus of the present study was to investigate the effect of diabetes on mRNA encoding β1- and β2-ARs in human atrial tissues.
Right atrial appendages from five diabetic (mean age 65 ± 4.5; 4 female, 1 male) and five nondiabetic patients (mean age 56.2 ± 2.8; 4 male, 1 female) undergoing coronary artery bypass grafting were collected and assayed using reverse transcriptase-polymerase chain reaction (RT-PCR) for their mRNA content. No patient from these two groups suffered from acute myocardial infarction and/or failure. All diabetic patients received insulin for at least two years and had been diagnosed as diabetics for at least five years.
When compared with levels in nondiabetics, steady state levels of mRNA encoding β1-adrenoreceptor decreased by 69.2 ± 7.6 % in diabetic patients while β2-adrenoreceptor mRNA decreased by 32.2 ± 5.5 % (p < 0.001).
Our findings show a decreased expression of β1- and β2-adrenoreceptors in human diabetic atrial appendage.
PMCID: PMC203305  PMID: 12857355
15.  Plasma interleukin 8 concentrations in obese subjects with impaired glucose tolerance. 
Interleukin 8 (IL-8) is a cytokine with atherogenic properties. In vitro studies revealed that it is produced and secreted by human adipocytes. We recently reported that plasma IL-8 is increased in obese subjects with normal glucose tolerance (NGT). The aim of the present study was to measure plasma IL-8 concentrations in subjects with impaired glucose tolerance (IGT).
A total of 44 subjects with marked overweight or obesity (BMI > 27.8 kg/m2), 27 with NGT and 17 with IGT, were recruited for the present study. Plasma IL-8 levels were measured in fasting state, after an oral glucose tolerance test (OGTT) and after euglycemic hyperinsulinemic clamp.
The studied groups did not differ in fasting IL-8 concentrations. Both OGTT and clamp resulted in a significant increase in plasma IL-8. The change in IL-8 after clamp was similar in both groups. In contrast, after OGTT plasma IL-8 levels (IL-8OGTT) were markedly higher in IGT individuals. In IGT, but not NGT group, IL-8OGTT was positively related to postload glucose and negatively to insulin sensitivity.
Plasma IL-8 concentrations after glucose load are increased in obese IGT subjects in comparison to normoglycemic weight-matched individuals. Increase in plasma IL-8 might be both insulin-mediated (during clamp) and glucose-mediated (during OGTT).
PMCID: PMC162167  PMID: 12793907
interleukin 8; obesity; impaired glucose tolerance
16.  Metabolic syndrome and type 2 diabetes mellitus: focus on peroxisome proliferator activated receptors (PPAR) 
The metabolic syndrome is a highly prevalent clinical entity. The recent Adult Treatment Panel (ATP III) guidelines have called specific attention to the importance of targeting the cardiovascular risk factors of the metabolic syndrome as a method of risk reduction therapy. The main factors characteristic of this syndrome are abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance (with or without glucose intolerance), prothrombotic and proinflammatory states. An insulin resistance following nuclear peroxisome proliferator activated receptors (PPAR) deactivation (mainly obesity-related) is the key phase of metabolic syndrome initiation. Afterwards, there are 2 principal pathways of metabolic syndrome development: 1) with preserved pancreatic beta cells function and insulin hypersecretion which can compensate for insulin resistance. This pathway leads mainly to the macrovascular complications of metabolic syndrome; 2) with massive damage of pancreatic beta cells leading to progressively decrease of insulin secretion and to hyperglycemia (e.g. overt type 2 diabetes). This pathway leads to both microvascular and macrovascular complications. We suggest that a PPAR-based appraisal of metabolic syndrome and type 2 diabetes may improve our understanding of these diseases and set a basis for a comprehensive approach in their treatment.
PMCID: PMC153546  PMID: 12834541
Metabolic syndrome; Diabetes mellitus; Peroxisome proliferator activated receptors (PPAR); Obesity; Insulin resistance
17.  Monocyte matrix metalloproteinase production in Type 2 diabetes and controls – a cross sectional study 
Coronary plaque rupture may result from localised over expression of matrix metalloproteinases (MMPs) within the plaque by infiltrating monocyte – macrophages. As MMP expression can be promoted by the modified lipoproteins, oxidative stress and hyperglycaemia that characterises Type 2 diabetes, we hypothesised that peripheral monocytes in these patients, exposed to these factors in vivo, would demonstrate increased MMP production compared to controls.
We examined peripheral venous monocyte expression of MMP and tissue inhibitor of metalloproteinase-1 (TIMP-1) in 18 controls and 22 subjects with Type 2 diabetes and no previous cardiovascular complications.
No significant difference in MMP-1, 3 or 9 or TIMP-1 production was observed between control and diabetes groups.
Monocyte MMP-1, 3, and 9, and TIMP-1, production are not abnormal in Type 2 diabetes. This data cannot be extrapolated to monocyte – macrophage behaviour in the vessel wall, but it does suggest MMP and TIMP-1 expression prior to monocyte infiltration and transformation are not abnormal in Type 2 diabetes.
PMCID: PMC152657  PMID: 12672267
metalloproteinases; monocytes; Type 2 diabetes; atherosclerosis
18.  Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress. 
Cardiovascular disease accounts for at least 85 percent of deaths for those patients with type 2 diabetes mellitus (T2DM). Additionally, 75 percent of these deaths are due to ischemic heart disease.
Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress.
Testing of the hypothesis
The vulnerable three arms of the eNOS reaction responsible for the generation of eNO is discussed in relation to the hypothesis: (1). The L-arginine substrate. (2). The eNOS enzyme. (3). The BH4 cofactor.
Implications of the hypothesis
If we view T2DM as a vascular disease initially with a later manifestation of hyperglycemia, we may be able to better understand and modify the multiple toxicities associated with insulin resistance, metabolic syndrome, prediabetes, overt T2DM, and accelerated atherosclerosis (atheroscleropathy). The importance of endothelial nitric oxide synthase, endothelial nitric oxide, tetrahydrobiopterin (BH4), L-arginine, and redox stress are discussed in relation to endothelial cell dysfunction and the development and progression of atheroscleropathy and T2DM. In addition to the standard therapies to restore endothelial cell dysfunction and stabilization of vulnerable atherosclerotic plaques, this article will discuss the importance of folic acid (5MTHF) supplementation in this complex devastating disease process.
Atheroscleropathy and hyperglycemia could be early and late manifestations, respectively, in the natural progressive history of T2DM.
PMCID: PMC151667  PMID: 12628022
ADMA; Atherosclerosis; Folic Acid; Oxidative stress; Reactive Oxygen Species (ROS); endothelial Nitric Oxide (eNO); endothelial Nitric Oxide Synthase (eNOS) (NOS-3)
19.  Influence of diabetes mellitus on heart failure risk and outcome 
Our aim is to summarize and discuss the recent literature linking diabetes mellitus with heart failure, and to address the issue of the optimal treatment for diabetic patients with heart failure.
The studies linking diabetes mellitus (DM) with heart failure (HF)
The prevalence of diabetes mellitus in heart failure populations is close to 20% compared with 4 to 6% in control populations. Epidemiological studies have demonstrated an increased risk of heart failure in diabetics; moreover, in diabetic populations, poor glycemic control has been associated with an increased risk of heart failure. Various mechanisms may link diabetes mellitus to heart failure: firstly, associated comorbidities such as hypertension may play a role; secondly, diabetes accelerates the development of coronary atherosclerosis; thirdly, experimental and clinical studies support the existence of a specific diabetic cardiomyopathy related to microangiopathy, metabolic factors or myocardial fibrosis. Subgroup analyses of randomized trials demonstrate that diabetes is also an important prognostic factor in heart failure. In addition, it has been suggested that the deleterious impact of diabetes may be especially marked in patients with ischemic cardiomyopathy.
Treatment of heart failure in diabetic patients
The knowledge of the diabetic status may help to define the optimal therapeutic strategy for heart failure patients. Cornerstone treatments such as ACE inhibitors or beta-blockers appear to be uniformly beneficial in diabetic and non diabetic populations. However, in ischemic cardiomyopathy, the choice of the revascularization technique may differ according to diabetic status. Finally, clinical studies are needed to determine whether improved metabolic control might favorably influence the outcome of diabetic heart failure patients.
PMCID: PMC149427  PMID: 12556246

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