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

Atherosclerotic risk is increased in diabetes partly because of increased plasma levels of the oxidized low-density lipoprotein and homocysteine, 2 independent and important cardiovascular disease (CVD) risk factors. Paraoxonase (PON) is a multifunctional antioxidant enzyme component of high-density lipoprotein (HDL), which can protect against low-density lipoprotein (LDL) oxidation. It also exhibits homocysteine thiolactonase (HCTL) activity that detoxifies homocysteine thiolactone, which can damage proteins by homocysteinylation of the lysine residues, thus leading to atherosclerosis. We conducted a cross-sectional study to correlate PON-1, HCTL activities, and the lag time of LDL oxidation in 15 healthy control subjects and in 55 subjects with type 2 diabetes mellitus with different degrees of CVD. Compared with healthy controls and diabetic subjects without evidence of overt CVD, we not only found 47% (P < .005) decrease in PON-1 activity, but also for the first time, 30% (P = .019) decrease in HCTL activity in subjects with a prior coronary artery bypass surgery. There was corresponding decreased effectiveness of HDLs from diabetic groups (with and without CVD) in protecting against LDL oxidation. Moreover, the PON-1 activity was significantly inversely correlated to the extent of intracoronary lesions determined at catheterization (ie, a high Gensini score). These decreases in PON-1 and HCTL activity were not due to any bias in preferential distribution of low-activity QQ homozygotes in the diabetic groups compared with the control group because QQ allele was equally distributed in all the experimental groups, whereas RR allele tended to increase in the diabetic subjects with coronary artery bypass surgery compared with the other groups. Therefore, clinical intervention to restore the impaired antiatherogenic activities of HDL should be considered an important goal in the treatment of persons with diabetes.
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PMID:Inverse correlation of serum paraoxonase and homocysteine thiolactonase activities and antioxidant capacity of high-density lipoprotein with the severity of cardiovascular disease in persons with type 2 diabetes mellitus. 1691 39

Partially inconsistent data exist on mutual relations between nontraditional atherosclerotic risk factors, including the magnitude of insulin resistance (IR), as well as on their relevance for atherogenesis in the metabolic syndrome. Subjects exhibiting combined impaired fasting glucose and impaired glucose tolerance (IFG/IGT) are exposed to an exceptionally high risk for atherogenesis and development of type 2 diabetes mellitus. Because of islet Beta-cell dysfunction, the usefulness of commonly used indices of IR is limited in IFG/IGT. Our aim was to assess the relationship between extent of angiographic coronary artery disease (CAD) and nontraditional atherosclerotic risk factors (including IR by a clamp-based golden standard method) in IFG/IGT. Fifty-three subjects (32 men, 21 women; mean age, 55 +/- 11 years) with stable angina, preserved left ventricular systolic function, and IFG/IGT were divided into 3 groups: group A (no coronary stenoses >50%, n = 22), group B (1-vessel CAD, n = 15), and group C (2/3-vessel CAD, n = 16). Insulin sensitivity was quantified by a hyperinsulinemic euglycemic clamp technique and expressed as M. M value, plasma homocysteine (Hcy) level, and asymmetric dimethyl-L-arginine (ADMA)/L-arginine ratio were independent determinants of CAD extent as shown by forward stepwise discriminant function analysis. Compared with group A (M = 32.7 +/- 9.3 micromol/kg fat-free mass [FFM] per minute; Hcy, 8.1 +/- 1.4 micromol/L), lower M and higher Hcy levels were found in group B (M = 16.9 +/- 8.2 micromol/kg FFM per minute, P < .001; Hcy, 11.2 +/- 2.9 micromol/L, P = .003) and C (M = 16.4 +/- 7.8 micromol/kg FFM per minute, P < .001; Hcy, 12.8 +/- 3.9 micromol/L, P < .001). The ADMA/L-arginine ratio was increased in group C (0.0078 +/- 0.0011) compared with group A (0.0063 +/- 0.0013, P = .03) and B (0.0058 +/- 0.0012, P = .01). Multivariate correlates (P < .05) of plasma Hcy concentrations were M (beta = -.34 +/- .12, P = .008), creatinine clearance (beta = -.23 +/- .10, P = .03) and fasting insulin (beta = .25 +/- .12, P = .04). This indicates an additive contribution of IR, plasma Hcy, and elevated ADMA/L-arginine ratio to the extent of angiographic CAD in combined IFG/IGT.
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PMID:Nontraditional atherosclerotic risk factors and extent of coronary atherosclerosis in patients with combined impaired fasting glucose and impaired glucose tolerance. 1716 Dec 29

This study aims to investigate the relationship between the circulating level of homocysteine and body adiposity in Japanese patients with type 2 diabetes mellitus. We measured the body mass index (BMI), waist and hip circumferences, visceral and subcutaneous adiposities, visceral/subcutaneous (V/S) adiposity ratio, and insulin resistance as assessed by the Homeostasis Model Assessment (HOMA) index in patients with hyperhomocysteinemia. The study group consisted of 17 Japanese patients with type 2 diabetes and hyperhomocysteinemia (age: 62+/-10 years, mean+/-S.D.), and the control group consisted of 24 age-matched type 2 diabetes patients with normohomocysteinemia (60+/-11 years). The visceral adiposity, HOMA index, and V/S ratio were significantly higher in the hyperhomocysteinemia group than in the normohomocysteinemia group (P<0.05). In contrast, the BMI, hip circumference, and subcutaneous adiposity were similar between the two groups (P>0.1). Furthermore, multiple regression analysis showed that hyperhomocysteinemia was closely related to insulin resistance and visceral adiposity. Our results indicate that the presence of hyperhomocysteinemia in our population of Japanese patients with type 2 diabetes-associated insulin resistance was associated with increased visceral but not subcutaneous adiposity.
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PMID:Hyperhomocysteinemia is associated with visceral adiposity in Japanese patients with type 2 diabetes mellitus. 1729 21

Because of their wide range of actions on glucose homeostasis, lipid metabolism and vascular inflammation, peroxisome proliferator-activated receptors (PPARs) are promising targets for the development of new drugs for the treatment of metabolic disorders such as diabetes, dyslipidemia and atherosclerosis. In clinical practice, PPARalpha agonists, such as the already available fibrates, improve dyslipidemia, while PPARgamma agonists, such as thiazolidinediones, improve insulin resistance and diabetes. The complementary action of simultaneous activation of each PPAR in patients suffering from metabolic syndrome and type 2 diabetes has led to new pharmacological strategies focused on the development of agonists targeting more than one receptor such as the dual PPARalpha/gamma agonists. However, despite the proven benefits of targeting PPARs, safety concerns have recently led to late stage development failures of various PPAR agonists including novel specific PPARgamma agonists and dual PPARalpha/gamma agonists. These safety concerns include potential carcinogenicity in rodents, signs of myopathy and rhabdomyolysis, increase in plasma creatinine and homocysteine, weight gain, fluid retention, peripheral edema and potential increased risk of cardiac failure. Although the discontinued compounds shared common side effects, the reason for discontinuation was always compound specific and the toxicological or adverse effects which have motivated the discontinuation could be either due to the activation of PPARgamma, PPARalpha or both (class effect) or due to a PPAR unrelated effect. Thus, the risk evaluation of each adverse effect should be viewed on a case by case basis considering both the PPAR profile of the drug, its absorption/distribution profile, the nature of the side effect and the putative PPAR-related mechanism of action. This review mainly focuses on the preclinical and clinical adverse events of PPAR agonists that could be of concern when considering the development of new PPAR agonists. The selective modulation of PPAR activities is a promising approach to develop new drugs with preserved efficacy but diminished adverse effects.
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PMID:Safety issues and prospects for future generations of PPAR modulators. 1742 30

The aim of this study was to investigate the influence of homocysteine (hcy) levels on endothelial function by the method of brachial artery ultrasonography and their relation with microvascular complications in type 2 diabetes mellitus (T2DM) patients without macrovascular disease. Fifty-nine T2DM patients with a mean age of 53.4+/-8.6 years and diabetes duration of 8.1+/-6.2 years and 16 healthy controls with a mean age of 47+/-14.5 years were included in the study. Endothelialdependent and endothelium-independent flow-mediated dilatation (FMD) were evaluated via brachial artery ultrasonography. Fasting plasma glucose (FPG), glycosylated haemoglobin (A1c), lipid profile, hcy, B12 and folic acid levels were measured. Diabetic patients and control group individuals were compared with regard to the laboratory values and brachial artery vascular reactivity. Factors influencing endothelium-dependent FMD were investigated with linear regression analysis. Age, gender, body mass index, lipid profiles and hcy levels were similar in both groups (p>0.05). Endothelium-dependent FMD percentages were significantly lower in diabetics than in the control group (7.7+/-5.9 vs. 11.7+/-7.1%, p<0.05). Endothelial-independent FMD percentage was similar for both groups (p>0.05). The upper limit of the reference hcy value was found to be 12.6 micromol/l in the control group. In the diabetic group, hcy levels were high in 33 patients and normal in 26 patients. No difference was detected between the patients with high hcy levels and those with a normal level with regard to endothelium-dependent and endothelium-independent FMD values (p>0.05). Mean hcy levels were 16+/-1.7 and 13.3+/-4.3 micromol/l in T2DM patients with microvascular complication and those with no microvascular complication, respectively (p<0.05). Regression analysis revealed that the main factors influencing the endothelial-dependent FMD were FPG, total cholesterol (TC), triglycerides (TG) and high-density lipoprotein (HDL-C) levels (p<0.05, p=0.05, p=0.05, p=0.02, respectively). Hcy, folic acid and B12 values did not influence endothelium-dependent FMD (p>0.05). Diabetes duration and A1c levels were close to being significant although they did not reach statistical significance (p=0.07 and p=0.08 respectively). Hcy levels have no effect on endothelium-dependent and endothelium-independent FMD in T2DM patients without macrovascular complications. The influence of classical atherogenic factors (such as FPG, TC, TG and HDL-C levels) on endothelium functions, detected with endothelium-dependent FMD, is greater.
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PMID:The influence of homocysteine levels on endothelial function and their relation with microvascular complications in T2DM patients without macrovascular disease. 1753 Apr 70

This study aimed to investigate whether endothelial cells are damaged and to evaluate fibrinolytic system function in patients with type 2 diabetes. For this proposal, plasma levels of von Willebrand factor (an endothelial marker of injury), homocysteine (an inductor of endothelial injury), D-dimer (a marker of coagulation cascade activation) and plasminogen activator inhibitor-1 (a fibrinolysis marker) were measured in individuals with both type 2 diabetes and high blood pressure, with type 2 diabetes, with high blood pressure and in healthy control individuals. No significant differences among groups were observed for von Willebrand factor and homocysteine plasma levels. The type 2 diabetes and high blood pressure group presented a significant difference to the other groups for D-dimer and also presented high values for plasminogen activator inhibitor-1. The high blood pressure group and type 2 diabetes group presented separately higher values of plasminogen activator inhibitor-1 compared with the control group. High levels of D-dimer and plasminogen activator inhibitor-1 in patients with type 2 diabetes and high blood pressure with normoalbuminuria therefore indicate a state of hypercoagulability and hypofibrinolysis, despite no evident microvascular injury supported by normal levels of von Willebrand factor and homocysteine.
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PMID:Type 2 diabetes: assessment of endothelial lesion and fibrinolytic system markers. 1758 12

The purpose of the study was to evaluate the effects of hyperhomocysteinemia (HHC) on vascular-thrombocyte and coagulation hemostasis and the development of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (DM2). DM 2 patients with or without CAD were examined; high incidence of HHC (40.3%) was revealed. The level of homocysteine was significantly higher in DM2 patients with CAD vs. non-CAD subjects. Among patients with DM2 and CAD the level of the amino acid was elevated in 77.1% of cases with a history of myocardial infarction. In patients with DM2, CAD, and HHC, vascular-thrombocyte hemostasis factors were found to be hyperactive, while anticoagulatory ones were suppressed. These changes in the hemostatic system in HHC increase the probability of thrombus formation and CAD progress.
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PMID:[Hyperhomocysteinemia in coronary artery disease and hemostasis disorders in patients with type 2 diabetes mellitus]. 1766

Serum gamma-glutamyl transferase (gamma-GT), a marker of oxidative stress, predicts morbidity and mortality from cardiovascular disease. Plasma total homocysteine (tHcy), a pro-oxidant and also an independent risk factor for cardiovascular disease, correlates with gamma-GT among some populations. It is not known whether tHcy correlates with gamma-GT among type 2 diabetic patients in whom oxidative stress is increased and implicated for the development of diabetic complications. In the present study, we analyzed the association between gamma-GT, tHcy and related vitamins cross-sectionally among patients with type 2 diabetes without overt nephropathy (age range 17-76 years; n = 110). In a univariate regression analysis model, gamma-GT (logarithm) was positively associated with tHcy (beta = 0.288, P = 0.002) but not with folate or vitamin B(12). The association between tHcy and gamma-GT (logarithm) remained significant in a multivariate analysis model including age, lifestyle factors, folate, vitamin B(12), creatinine, HbA(1c) and medical history (beta = 0.219, P = 0.027). These results suggest that tHcy generates oxidative stress among type 2 diabetic patients and may partly explain the reported association between gamma-GT and cardiovascular disease.
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PMID:Serum gamma-glutamyl transferase is associated with plasma total homocysteine in Japanese patients with type 2 diabetes. 1788 50

Elevated total plasma homocysteine (tHcy) level and aortic stiffness are associated with high mortality in type 2 diabetic patients. We tested the hypothesis that tHcy correlates with aortic stiffness and insulin resistance in type 2 diabetic patients. The study consisted of 40 Japanese patients with type 2 diabetes mellitus and high tHcy levels (mean age +/- SD, 57 +/- 7 years) and a control group of 45 age-matched patients with normal tHcy levels (mean age +/- SD, 57 +/- 6 years). Brachial-ankle pulse wave velocity (BaPWV) was measured by an automatic oscillometric method. Brachial-ankle pulse wave velocity was used as an index of atherosclerosis. Body mass index values (P < .05), waist circumferences (P < .05), and the waist-to-hip ratios (P < .05) were larger in the high-tHcy group than in the normal-tHcy group. The BaPWV was higher in the high-tHcy group than in the normal-tHcy group (P < .0001). Fasting plasma glucose (P < .005) and insulin concentrations (P < .0001), and the homeostasis model assessment (HOMA) index (P < .0001) were higher in the high-tHcy group than in the normal-tHcy group. Multiple regression analysis showed that tHcy levels were independently predicted by BaPWV and the HOMA index. In conclusion, our results indicate that the elevated level of tHcy in Japanese patients with type 2 diabetes mellitus is characterized by increased aortic stiffness and insulin resistance, and that the BaPWV and the HOMA index are independent predictors of tHcy.
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PMID:Correlations between homocysteine levels and atherosclerosis in Japanese type 2 diabetic patients. 1788 50

Genome-wide association studies have identified a region on chromosome 9p that is associated with coronary artery disease (CAD). The region is also associated with type 2 diabetes (T2D), a risk factor for CAD, although different SNPs were reported to be associated to each disease in separate studies. We have undertaken a case-control study in 4251 CAD cases and 4443 controls in four European populations using previously reported ('literature') and tagging SNPs. We replicated the literature SNPs (P = 8x10(-13); OR = 1.29; 95% CI: 1.20-1.38) and showed that the strong consistent association detected by these SNPs is a consequence of a 'yin-yang' haplotype pattern spanning 53 kb. There was no evidence of additional CAD susceptibility alleles over the major risk haplotype. CAD patients without myocardial infarction (MI) showed a trend towards stronger association than MI patients. The CAD susceptibility conferred by this locus did not differ by sex, age, smoking, obesity, hypertension or diabetes. A simultaneous test of CAD and diabetes susceptibility with CAD and T2D-associated SNPs indicated that these associations were independent of each other. Moreover, this region was not associated with differences in plasma levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, fibrinogen, albumin, uric acid, bilirubin or homocysteine, although the CAD-high-risk allele was paradoxically associated with lower triglyceride levels. A large antisense non-coding RNA gene (ANRIL) collocates with the high-risk haplotype, is expressed in tissues and cell types that are affected by atherosclerosis and is a prime candidate gene for the chromosome 9p CAD locus.
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PMID:Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. 1804 6


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