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)

Coronary heart disease (CHD) is a major cause of morbidity and mortality worldwide. Elevated low density lipoprotein-cholesterol (LDL-C) and reduced high density lipoprotein-cholesterol (HDL-C) levels are well recognised CHD risk factors, with recent evidence supporting the benefits of intensive LDL-C reduction on CHD risk. Such observations suggest that the most recent National Cholesterol Education Program Adult Treatment Panel III guidelines, with LDL-C targets of 2.6 mmol/L, may result in under-treatment of a significant number of patients and form the basis for the proposed new joint European Societies treatment targets of 2 and 4 mmol/L, respectively, for LDL and total cholesterol. HMG-CoA reductase inhibitors (statins) reduce LDL-C by inhibiting the rate-limiting step in cholesterol biosynthesis and reduced CHD event rates in primary and secondary prevention trials. The magnitude of this effect is not fully accounted for by LDL-C reduction alone and may relate to effects on other lipid parameters such as HDL-C and apolipoproteins B and A-I, as well as additional anti-inflammatory effects. With increasing focus on the benefits of intensive cholesterol reduction new, more efficacious statins are being developed. Rosuvastatin is a potent, hydrophilic enantiomeric statin producing reductions in LDL-C of up to 55%, with about 80% of patients reaching European LDL-C treatment targets at the 10 mg/day dosage. The Heart Protection Study (HPS) demonstrated that LDL-C reduction to levels as low as 1.7 mmol/L was associated with significant clinical benefit in a wide range of high-risk individuals, including patients with type 2 diabetes mellitus, or peripheral and cerebrovascular disease, irrespective of baseline cholesterol levels, with no apparent lower threshold for LDL-C with respect to risk. Various large endpoint trials, including Treating to New Targets (TNT) and Study of Effectiveness of Additional reductions in Cholesterol and Homocysteine (SEARCH) will attempt to further address the issue of optimal LDL-C reduction. At low LDL-C levels, HDL-C becomes an increasingly important risk factor and is the primary lipid abnormality in over half of CHD patients, with the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study set to assess the effect of raising HDL-C on cardiovascular events in patients with low HDL-C and LDL-C levels below 3 mmol/L. A variety of agents are being developed, which affect both LDL-C and HDL-C metabolism, including inhibitors of acyl-coenzyme A-cholesterol acyl transferase, microsomal transfer protein and cholesterol ester transfer protein, as well as specific receptor agonists. Ezetimibe is a selective cholesterol absorption inhibitor, which produces reductions in LDL-C of up to 25 and 60% reduction in chylomicron cholesterol content with a 10 mg/day dosage. A 1 mmol/L reduction in LDL-C results in a 25% reduction in cardiovascular risk, independent of baseline LDL-C levels. Growing evidence supports the concept that lower is better for LDL-C and that increasing HDL-C represents an important therapeutic target. Furthermore, there is growing appreciation of the role of inflammation in atherogenesis. Consequently, increasing numbers of people should receive lipid-regulating therapy with the development of newer agents offering potential mechanisms of optimising lipid profiles and thus risk reduction. In addition, the pleiotropic anti-inflammatory effects of lipid lowering therapy may provide further risk reduction.
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PMID:Medical lipid-regulating therapy: current evidence, ongoing trials and future developments. 1516 26

Recent definitions of the metabolic syndrome from the World Health Organization (WHO) and National Cholesterol Education Program (NCEP) have given us a clearer picture of the prevalence of the metabolic syndrome and the risks it poses for cardiovascular disease and type 2 diabetes. Solid epidemiological and trial evidence support lifestyle changes as the main modifiable risk factors, including abdominal obesity, sedentary lifestyle and a diet rich in saturated fat and low in fiber content, in the treatment of individual components of the metabolic syndrome. Physical activity may prevent the metabolic syndrome as defined by the WHO and NCEP, but the evidence for lifestyle changes using these definitions is still sparse. No trials on the treatment of the metabolic syndrome to prevent diabetes have been published. However, both the Finnish Diabetes Prevention Study and the Diabetes Prevention Program found that moderate lifestyle interventions in persons with impaired glucose tolerance, a condition related to the metabolic syndrome. decreased the incidence of type 2 diabetes by 58%. Some drugs may also prevent diabetes. Further research on lifestyle modifications in the prevention and treatment of the metabolic syndrome, and on how best to promote lifestyle changes, is needed. In the meantime, efforts to curb obesity and overweight, increase physical activity and improve compliance with current dietary recommendations should continue.
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PMID:Epidemiology and treatment of the metabolic syndrome. 1547 8

Early diagnosis of metabolic syndrome is based on detection of insulin resistance, hyperinsulinemia, and clinical presentations of this syndrome. Differences in approaches to diagnosis of metabolic syndrome and its multi component nature hamper comparison of results of different studies and elaboration of generalized guidelines for selection of high risk groups and prevention of cardiovascular diseases and type 2 diabetes. Until present there are no common criteria of the syndrome and this makes difficult standardization of methodology of its investigation. Several organizations (WHO, National Cholesterol Education Program, European Group for the Study of Insulin Resistance) issued documents in which diagnostic approaches to detection of metabolic syndrome and its separate components have been formulated. These approaches as well as comparative analysis of direct and calculated methods of assessment of insulin resistance are presented in this review.
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PMID:[The role of insulin resistance in diagnosis of metabolic syndrome]. 1548 51

A number of patients with type 2 diabetes are GAD antibody positive. A Diabetes Outcome Progression Trial (ADOPT) is a randomized, double-blind clinical trial in recently diagnosed drug-naive patients with type 2 diabetes that allows for the evaluation of GAD positivity in the context of anthropometric and biochemical characteristics. Of the 4,134 subjects enrolled in ADOPT for whom GAD status was obtained, 174 (4.2%) were GAD positive, with the prevalence of GAD antibodies being similar in North America (4.7%) and Europe (3.7%). Although BMI and age were similar, GAD-positive patients had a lower fasting insulin level, compatible with them being more insulin sensitive. The lower fasting insulin concentration was accompanied by a decreased early insulin response to oral glucose. However, when this insulin response was corrected for the degree of insulin sensitivity, GAD-positive and -negative patients had similar beta-cell function. Consistent with the difference in insulin sensitivity, GAD-positive patients had higher HDL cholesterol and lower triglyceride levels. In the GAD-positive individuals, the prevalence of the metabolic syndrome as defined by NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) was also lower (74.1 vs. 83.7%, P = 0.0009). These phenotypic differences may underlie a potential difference in the natural history of hyperglycemia and its clinical outcomes.
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PMID:Phenotypic characteristics of GAD antibody-positive recently diagnosed patients with type 2 diabetes in North America and Europe. 1556 50

Diabetic dyslipidemia requires simultaneous treatment with hypoglycemic agents and lipid-modulating drugs. We recently described glycogen phosphorylase inhibitors that reduce glycogenolysis in cells and lower plasma glucose in ob/ob mice (J. Med. Chem., 41: 2934, 1998). In evaluating the series prototype, CP-320626, in dogs, up to 90% reduction in plasma cholesterol was noted after 2 week treatment. Cholesterol reductions were also noted in ob/ob mice and in rats. In HepG2 cells, CP-320626 acutely and dose-dependently inhibited cholesterolgenesis without affecting fatty acid synthesis. Inhibition occurred together with a dose-dependent increase in the cholesterol precursor, lanosterol, suggesting that cholesterolgenesis inhibition was due to lanosterol 14alpha-demethylase (CYP51) inhibition. In ob/ob mice, acute treatment with CP-320626 resulted in a decrease in hepatic cholesterolgenesis with concomitant lanosterol accumulation, further implicating CYP51 inhibition as the mechanism of cholesterol lowering in these animals. CP-320626 and analogs directly inhibited rhCYP51, and this inhibition was highly correlated with HepG2 cell cholesterolgenesis inhibition (R2 = 0.77). These observations indicate that CP-320626 inhibits cholesterolgenesis via direct inhibition of CYP51, and that this is the mechanism whereby CP-320626 lowers plasma cholesterol in experimental animals. Dual-action glycogenolysis and cholesterolgenesis inhibitors therefore have the potential to favorably affect both the hyperglycemia and the dyslipidemia of type 2 diabetes.
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PMID:Dual-action hypoglycemic and hypocholesterolemic agents that inhibit glycogen phosphorylase and lanosterol demethylase. 1560 16

Three homogenous methods for the automated measurement of high-density lipoprotein-cholesterol (HDL-C) are studied and compared with a precipitation method in diabetic and non-diabetic subjects. All three methods meet the precision criteria of the National Cholesterol Education Programme (NCEP). Triglycerides did not cause significant interference up to 10 mmol/L in the immuno-inhibition method (Wako) and up to 40 mmol/L in the Randox and Roche methods. Haemoglobin, up to a concentration of 5 g/L, had only negligible effect on the performance of all three homogeneous methods. Bilirubin caused an increasing positive bias in all methods above a concentration of 50 micromol/L. In comparison with the precipitation method, the new homogeneous methods agreed for type 1 diabetic patients but showed a positive bias for the control subjects and patients with type 2 diabetes. The bias of HDL-C levels in type 2 diabetes may be sufficient to affect the calculation of cardiovascular risk, and may therefore influence the decision to prescribe lipid-lowering medication.
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PMID:Comparison of three homogeneous methods for measuring high-density lipoprotein cholesterol with a precipitation method in diabetic and non-diabetic subjects. 1564 12

The peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) is a novel transcriptional co-activator that holds an important role in lipid and glucose metabolism. PGC-1alpha is a candidate gene for the metabolic syndrome (MS) as well as type 2 diabetes. Recent studies suggested linkage between the chromosomal region of PGC-1alpha and fasting serum insulin levels, and associates a Gly482Ser polymorphism of the gene with type 2 diabetes and hypertension. In this study, we investigated whether the Gly482Ser variant is associated with the MS per se or other phenotypic traits related to this syndrome. The variant was examined, using PCR-RFLP, in the DanMONICA cohort comprising a population-based sample of 2349 subjects. MS was defined using the National Cholesterol Education Program -- Adult Treatment Panel III (NCEP-ATPIII) criteria. The allelic frequency of the Ser482 allele was 35.8% in the MS group and 35.6% in the non-MS group (P = 0.74). There were no significant differences across the three groups of genotypes with respect to any of the examined variables, including BMI, waist, fasting serum lipids, plasma glucose, serum insulin, HOMA estimates of insulin resistance and insulin secretion, 24-ambulatory blood pressure or left ventricular mass index. In conclusion, the Gly482Ser polymorphism of the PGC-1alpha gene is not associated with the metabolic syndrome, related quantitative traits or cardiac hypertrophy among Danish Caucasian subjects.
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PMID:Studies of the Gly482Ser polymorphism of the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) gene in Danish subjects with the metabolic syndrome. 1564 78

BACKGROUND: In 2001 the National Cholesterol Education Program (NCEP) provided a categorical definition for metabolic syndrome (c-MetS). We studied the extent to which two ethnic groups, Blacks and Whites were affected by c-MetS. The groups were members of the Hypertension Genetic Epidemiology Network (HyperGEN), a part of the Family Blood Pressure Program, supported by the NHLBI. Although the c-MetS definition is of special interest in particular to the clinicians, the quantitative latent traits of the metabolic syndrome (MetS) are also important in order to gain further understanding of its etiology. In this study, quantitative evaluation of the MetS latent traits (q-MetS) was based on the statistical multivariate method factor analysis (FA). RESULTS: The prevalence of the c-MetS was 34% in Blacks and 39% in Whites. c-MetS showed predominance of obesity, hypertension, and dyslipidemia. Three and four factor domains were identified through FA, classified as "Obesity," "Blood pressure," "Lipids," and "Central obesity." They explained approximately 60% of the variance in the 11 original variables. Two factors classified as "Obesity" and "Central Obesity" overlapped when FA was performed without rotation. All four factors in FA with Varimax rotation were consistent between Blacks and Whites, between genders and also after excluding type 2 diabetes (T2D) participants. Fasting insulin (INS) associated mainly with obesity and lipids factors. CONCLUSIONS: MetS in the HyperGEN study has a compound phenotype with separate domains for obesity, blood pressure, and lipids. Obesity and its relationship to lipids and insulin is clearly the dominant factor in MetS. Linkage analysis on factor scores for components of MetS, in familial studies such as HyperGEN, can assist in understanding the genetic pathways for MetS and their interactions with the environment, as a first step in identifying the underlying pathophysiological causes of this syndrome.
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PMID:An evaluation of the metabolic syndrome in the HyperGEN study. 1565 12

The significance of the metabolic syndrome (MetS) resides either in its ability to identify individuals at high risk of future disease and disability or in its ability to identify individuals in need of a specific treatment. We have previously shown that in the general population the ability of the MetS to identify individuals at increased risk of diabetes or cardiovascular disease (CVD) is inferior to the ability of established predicting models for these conditions. Although it may someday become routine to recommend treatment with insulin-sensitising agents for non-diabetic individuals with the MetS, most of whom are insulin resistant, there are no clinical trial data to support such a recommendation at the present time. Currently, the treatment of the MetS is based on treatment of its component parts. In the present paper, we examine the role of the MetS as defined by the National Cholesterol Education Program (NCEP) criteria in predicting all-cause and CVD mortality in patients with prevalent CVD from the San Antonio Heart Study (SAHS). This population contains a high proportion of Mexican Americans, who are at high risk of developing type 2 diabetes. After adjusting for age and gender, the MetS is moderately predictive of all-cause and CVD mortality. After further adjustment for diabetes, however, the effect of the MetS becomes non-significant in this population. Moreover, among non-diabetics with prevalent CVD, the MetS was not associated with either all-cause or CVD mortality. Thus, this study indicates that the effect of the MetS on these endpoints is primarily driven by the inclusion in the NCEP definition of diabetes, itself a well-established, potent CVD risk factor. In fact, the prevalence of diabetes in SAHS patients with CVD and the MetS was 42% compared with only 9% in patients with CVD, but without the MetS. This excess prevalence of diabetes appears to account for the enhanced all-cause and CVD mortality in subjects with the MetS. However, these results will need to be confirmed in other populations.
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PMID:Impact of diabetes/metabolic syndrome in patients with established cardiovascular disease. 1582 90

Using a modified National Cholesterol Education Program (NCEP) definition of the metabolic syndrome (MS) with body mass index instead of waist circumference, we examined the associations of the MS with the risk of developing ST-T abnormalities in 3405 Japanese men aged 35-59 yr who did not have a history of cardiovascular disease or ST-T abnormalities. Of 3405 participants, 3166 men without type 2 diabetes (as diagnosed with the revised criteria of American Diabetes Association) also constituted a non-diabetic cohort. Examinations including electrocardiogram and fasting plasma glucose were repeated annually for 7 subsequent years. The subjects were classified as having ST-T abnormalities or type 2 diabetes when evidence of either of these disorders was found during at least 2 consecutive annual examinations. After adjustment for potential risk factors, the relative risks of ST-T abnormalities were 1.0 (referent), 2.66, 3.07, 4.27, and 8.40 for the presence of 0, 1, 2, 3, and > or =24 components of the MS, respectively (P for trend <0.001). The corresponding results for the risk of type 2 diabetes were 1.0 (referent), 3.49, 7.45, 15.00, and 24.04 (P for trend <0.001). The estimated incident rates for men in the low-WBC count (<7.3 x 10(9) cells/L)/no MS, high-WBC count (> or =7.3 x 10(9) cells/L)/no MS, low-WBC count/yes MS, and high-WBC count/yes MS were 3.4%, 4.6%, 7.4%, and 13.1% for ST-T abnormalities, respectively and were 3.6%, 7.1%, 18.0%, and 27.2% for type 2 diabetes, respectively. The respective multivariate-adjusted relative risks were 1.0 (referent), 1.26, 2.07, and 3.45 for ST-T abnormalities and were 1.0 (referent), 1.75, 5.14, and 6.90 for type 2 diabetes. A modified NCEP MS definition predicts ST-T abnormalities and type 2 diabetes. WBC count adds clinically important information to new-onset ST-T abnormalities and type 2 diabetes.
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PMID:Metabolic syndrome and risk of isolated ST-T abnormalities and type 2 diabetes in Japanese male office workers. 1589 41


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