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)

Usual risk factors for coronary artery disease account for only 25-50% of increased atherosclerotic risk in diabetes mellitus. Other obvious risk factors are hyperglycemia and dyslipidemia. However, hyperglycemia is a very late stage in the sequence of events from insulin resistance to frank diabetes, whereas lipoprotein abnormalities are manifested during the largely asymptomatic diabetic prodrome and contribute substantially to the increased risk of macrovascular disease. The insulin-resistant diabetes course affects virtually all lipids and lipoproteins. Chylomicron and very-low-density lipoprotein (VLDL) remnants accumulate, and triglycerides enrich high-density lipoprotein (HDL) and low-density lipoprotein (LDL), leading to high levels of potentially atherogenic particles and low levels of HDL cholesterol. Hyperglycemia eventually impairs removal of triglyceride-rich lipoproteins, the accumulation of which accentuates hypertriglyceridemia. As triglycerides increase-still within the so-called normal range-abnormalities in HDL and LDL became more apparent. Thus, when triglycerides are >200 mg/dL, LDL particles are small and dense (when they are <90 mg/dL, the particles are of the large, buoyant variety). The atherogenicity of small, dense LDL particles is attributed to their increased susceptibility to oxidation, but in many patients they may be a marker for insulin resistance or the presence of atherogenic VLDL. Hypertriglyceridemia is associated with atherosclerosis because (1) it is a marker for insulin resistance and atherogenic metabolic abnormalities; and (2) the small size of triglyceride-enriched lipoproteins enables them to infiltrate the blood vessel wall where they are oxidized, bind to receptors on macrophages, and ingested, leading to the development of the atherosclerotic lesion. Various studies (primary prevention with gemfibrozil: Helsinki Heart Study; secondary prevention with simvastatin and pravastatin: Scandinavian Simvastatin Survival Study [4S] and Cholesterol and Recurrent Events [CARE], respectively) have demonstrated that lipid-lowering therapy in type 2 diabetes is effective in decreasing the number of cardiac events. Risk reduction was 22% to 50% (statins) and approximately 65% (fibrate) relative to placebo. It was also noted (in 4S and CARE) that the risk of major coronary events in untreated diabetic patients was 1.5-1.7-fold greater than in untreated nondiabetic patients. Although gemfibrozil (fibric acid derivative) is more effective in decreasing triglycerides and increasing HDL cholesterol in diabetic patients than the statins, it does not change and may even increase LDL-cholesterol levels (fenofibrate may be an exception, decreasing LDL cholesterol by 20-25% in some studies). However, gemfibrozil does increase LDL particle size. Nevertheless, the statins are the current lipid-lowering drugs of choice because the change in LDL-cholesterol-to-HDL-cholesterol ratio is better than with gemfibrozil. Moreover, the diabetic patient may be more likely to benefit from statin therapy than the nondiabetic patient. It should be noted that, in theory, nicotinic acid can correct or improve all lipid or lipoprotein abnormalities in patients with type 2 diabetes. Unfortunately, it is relatively contraindicated because it causes insulin resistance and may precipitate or aggravate hyperglycemia (in addition to its other well-known side effects such as flushing, gastric irritation, development of hepatotoxicity, and hyperuricemia). It is unknown at present whether newer formulations such as once-daily Niaspan may be better tolerated in diabetes. In any case, most patients with type 2 diabetes have risk factors for coronary artery disease and qualify for aggressive LDL cholesterol-lowering therapy. At the same time, it is presently unknown whether improved glycemic control decreases coronary artery disease risk in such patients.
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PMID:Diabetic dyslipidemia. 991 65

Recent epidemiological data have reaffirmed that elevated plasma triglyceride and low HDL-cholesterol levels are important risk factors for atherosclerotic vascular disease. The rationale for the clinical use of fibric acid derivatives, which are designed to correct this metabolic nexus, is now on firmer ground. The mechanism of action of fibrates on lipoprotein metabolism has recently been elucidated at the molecular level and involves the activation of peroxisome proliferator-activated receptor-alpha 1 in the liver, with the net effect of improving the plasma transport rates of several lipoproteins. Other potential anti-atherothrombotic effects include the inhibition of coagulation and enhancement of fibrinolysis, as well as the inhibition of inflammatory mediators involved in atherogenesis. These consequences probably underpin the favourable effects of fibrates seen in recent angiographic and clinical trials. Two important clinical trials on the effect of gemfibrozil (Veterans Administration-HDL-Cholesterol Intervention Trial) and bezafibrate (Bezafibrate Infarction Prevention Study) have recently been completed in subjects with elevated triglyceride, low HDL and normal or near-normal LDL-cholesterol levels. The results testify to the efficacy of these agents in decreasing the incidence of cardiovascular events, particularly in patients with multiple risk factors and plasma triglyceride levels of over 2.2 mmol/l. The findings of these trials are compared with the statin-based Air Force/Texas Coronary Atherosclerosis Prevention Study, with a recommendation that future studies in appropriately selected patients should examine the synergistic effect of the fibrate/statin combination. The absolute risk reduction in the incidence of coronary events in the Veterans Administration-HDL-Cholesterol Intervention Trial compares favourably with the statin trials. The therapeutic aspects of the efficacy and safety of fibrates are reviewed. Besides primary mixed hyperlipidaemias, particular indications for the clinical use of fibrates include type 2 diabetes, the metabolic syndrome and renal insufficiency. The St Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention Study has suggested that fibrates may decrease the incidence of coronary events in type 2 diabetes, but this hypothesis will be more extensively tested in the Diabetes Atherosclerosis Intervention Study, Fenofibrate in Event Lowering in Diabetes Study and Lipids in Diabetes Study projects. Although significant new knowledge has accrued over the past few years concerning the fundamental and clinical aspects of fibrates, the success of these agents in clinical practice depends on the availability of methods for assessing cardiovascular risk as well as on treatment guidelines, which as presently designed and recommended may be inaccurate and suboptimal.
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PMID:Fibrates, dyslipoproteinaemia and cardiovascular disease. 1068 50

Several large controlled clinical trials have documented that cholesterol lowering causes a marked reduction in major coronary events in patients with established coronary heart disease. Cholesterol lowering thus joins other proven therapies for risk reduction in secondary prevention. The need to include cholesterol-lowering therapy in secondary prevention has been endorsed as a new practice measure in the Health Plan Employer Data Information Set. This endorsement ensures that managed care will get behind the effort to better control cholesterol in patients with coronary heart disease. The next issue is whether managed care will support cholesterol-lowering therapy in primary-prevention patients. The patients at highest risk for developing coronary heart disease are those with noncoronary forms of atherosclerotic disease, type 2 diabetes, multiple risk factors, and risk factors plus evidence of advanced subclinical atherosclerosis. Such patients can be said to have coronary heart disease risk equivalents. These patients should be good candidates for aggressive cholesterol management. A strong case can be made for managed-care support for this approach. Support for treatment of patients at lower risk may be open to some question, but the current guidelines of the National Cholesterol Education Program provide a strong rationale for cholesterol management for primary prevention in the medical setting.
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PMID:Cholesterol management in the era of managed care. 1069 1

In order to describe the profile and medical management of type 2 diabetes patients in France, a descriptive cross-sectional survey was conducted in 1999 among a national random sample of 311 general practitioners and 51 specialists. A practitioner questionnaire was designed to collect information on a representative sample of 4,119 patients presenting with type 2 diabetes. Data collected included demographic and clinical information and a full description of diabetes management over a 6-month retrospective period. Over 50% of the patients were more than 67 years old; 54% were male. Diabetes had been diagnosed 8.9 years earlier on average, most frequently (73%) during a visit not related to diabetes' symptoms or complications. 42% of patients had a BMI > or =30 kg/m(2), 46% were hypertensive (BP > 140-80 mmHg), 53% had a LDL-Cholesterol over 1.3 g/l. Overall, 33% of patients had at least one diabetic complication. 60% of patients had had at least one HbA1c dosage in the last 6 months. Among them, 31% had a HbA1c level over 8% and 35% between 6. 5% and 8%. 85% of patients were treated with oral anti-diabetic drugs, 9.5% with diet and exercise only and 5% with insulin. Sulfonylureas were the most commonly prescribed anti-diabetic agent, either alone or in combination. This survey confirms that the management of patients with type 2 diabetes is still often inappropriate in France despite recent progress. Improved disease management and monitoring is required in France as in other developed countries.
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PMID:Managing type 2 diabetes in France: the ECODIA survey. 1111 15

Elevated serum triglyceride level is increasingly being recognized as an important indicator of cardiovascular risk. The distribution and correlates of serum triglycerides were examined in a biracial (black-white) community-based sample of 1342 young adults (30% black) aged 20-37 years. Triglyceride levels showed significant race (white>black) and sex (male>female) differences. Black females, despite their relatively increased body fatness, had lowest triglyceride levels. In terms of conjoint trait of dyslipidemia based on the National Cholesterol Education Program cutpoints, 9% of white males displayed high triglyceride (> or =200 mg/dl) in combination with low high-density lipoprotein (HDL)-cholesterol (<35 mg/dl). In comparison, none of the black females fell into this category. Serum triglycerides even at levels between 100 and 150 mg/dl were significantly adversely associated with risk variables of insulin resistance syndrome such as adiposity and visceral fatness measures, HDL-cholesterol, insulin, and systolic blood pressure, especially among whites. Visceral fatness as measured by waist circumference (except black males) and insulin were the major predictors of triglyceride levels. Overall, triglyceride levels above 150 mg/dl were associated with increased risk of hypertension (odds ratio (OR)=1.8, 95% confidence interval (CI)=1.8-3.0), type 2 diabetes (OR=3.1, CI=1.4-6.9), parental history of hypertension (OR=1.3, CI=1.0-1.8) and parental history of type 2 diabetes (OR=1.7, CI=1.2-2.3). Thus, serum triglyceride levels may be valuable in the assessment of cardiovascular risk during young adulthood.
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PMID:Distribution and cardiovascular risk correlates of serum triglycerides in young adults from a biracial community: the Bogalusa Heart Study. 1122 43

Atorvastatin is a potent hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor that decreases low-density lipoprotein (LDL) cholesterol and triglyceride concentrations, but little is known about its effects on LDL subtype distribution in different types of hyperlipoproteinemia. Thus, we evaluated the influence of atorvastatin (10 mg/d, 4 weeks) on lipid concentrations and LDL subtype distribution in patients with hypercholesterolemia (n = 9; LDL cholesterol, 227 +/- 30 mg/dL; triglycerides, 137 +/- 56 mg/dL), patients with type 2 diabetes and dyslipoproteinemia (n = 11; LDL cholesterol, 163 +/- 34 mg/dL; triglycerides, 260 +/- 147 mg/dL), and controls (n = 10; LDL cholesterol, 116 +/- 20 mg/dL; triglycerides, 130 +/- 47 mg/dL). Cholesterol concentration was determined in 7 LDL subfractions isolated by density gradient ultracentrifugation before and during atorvastatin treatment. Atorvastatin decreased LDL cholesterol (-36%, -28%, and -41%, all P <.01) and triglyceride (-4%, NS; -2%, NS; -24%, P <.05) concentrations but had little effect on high-density lipoprotein (HDL) cholesterol (-1%, NS; +10%, P <.05; +6%, NS) in hypercholesterolemic, diabetic, and control subjects, respectively. In all 3 groups, a significant reduction in cholesterol in each LDL subfraction was observed. Large-buoyant (LDL-1, LDL-2) and intermediate-dense (LDL-3, LDL-4) LDL were reduced more than small-dense (LDL-5 through LDL-7) LDL in hypercholesterolemic (-45%, -35%, and -32%, P <.05) and control subjects (-48%, -44%, and -25%, P <.05), but in diabetic patients cholesterol reduction was uniform in all LDL subtypes (-32%, -27%, and -29%, P =.45). Thus, atorvastatin decreases cholesterol concentration in all LDL subfractions in hypercholesterolemic, diabetic, and control subjects. However, the relative reduction of individual LDL subtypes differed between these groups. This finding suggests that the effect of atorvastatin on LDL subtype distribution depends on the type of underlying hyperlipoproteinemia.
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PMID:Effect of atorvastatin on low-density lipoprotein subtypes in patients with different forms of hyperlipoproteinemia and control subjects. 1147 89

Patients with type 2 diabetes mellitus have an elevated risk of morbidity and mortality from cardiovascular disease. This risk is partly attributable to an increased prevalence of classic coronary artery disease risk factors and partly because of hyperglycemia itself and a highly atherogenic lipid profile. The altered composition of lipoproteins and lipids in type 2 diabetic patients, termed diabetic dyslipidemia, is characterized by: (1) elevated levels of triglyceride; (2) normal levels of total and low-density lipoprotein cholesterol (LDL-C); (3) reduced levels of high-density lipoprotein cholesterol (HDL-C); (4) elevated levels of apolipoprotein B; (5) a preponderance of small, dense LDL particles; and (6) increased levels of cholesterol-rich very-low-density lipoprotein. In most cases, diabetic dyslipidemia is preceded by hyperinsulinemia resulting from insulin resistance. Because patients with type 2 diabetes and insulin resistance are at a markedly increased risk of atherosclerosis, and because strict control of glycemia has proved beneficial in reducing microangiopathy but not macroangiopathy, treatment of diabetic dyslipidemia should be aggressive. Target levels have, therefore, been set at <2.6 mmol/L (100 mg/dL) for LDL-C, <2.3 mmol/L [200 mg/dL] for triglycerides, and >1.15 mmol/L (45 mg/dL) for HDL-C. Trial data suggest that these target levels are likely to be achieved with statins, if necessary, in combination with fibrates or nicotinic acid derivatives. Furthermore, in large-scale clinical trials (eg, Scandinavian Simvastatin Survival Study [4S] and the Cholesterol and Recurrent Events [CARE] study), it has been demonstrated that lipid lowering can appreciably reduce cardiovascular events in diabetic patients.
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PMID:Insulin resistance syndrome and type 2 diabetes mellitus. 1159 98

Endothelial dysfunction defined as the impaired ability of vascular endothelium to stimulate vasodilation plays a key role in the development of atherosclerosis and in various pathological conditions which predispose to atherosclerosis, such as hypercholesterolemia, hypertension, type 2 diabetes, hyperhomocyst (e) inemia and chronic renal failure. The major cause of the endothelial dysfunction is decreased bioavailability of nitric oxide (NO), a potent biological vasodilator produced in vascular endothelium from L-arginine by the endothelial NO synthase (eNOS). In vascular diseases, the bioavailability of NO can be impaired by various mechanisms, including decreased NO production by eNOS, and/or enhanced NO breakdown due to increased oxidative stress. The deactivation of eNOS is often associated with elevated plasma levels of its endogenous inhibitor, N(G) N(G)-dimethyl-L-arginine (ADMA). In hypercholesterolemia, a systemic deficit of NO may also increase the levels of low density lipoproteins (LDL) by modulating its synthesis and metabolism by the liver, as suggested by recent in vivo and in vitro studies using organic NO donors. Therapeutic strategies aiming to reduce the risk of vascular diseases by increasing bioavailability of NO continue to be developed. Cholesterol-lowering drugs, statins, have been shown to improve endothelial function in patients with hypercholesterolemia and atherosclerosis. Promising results were also obtained in some, but not all, vascular diseases after treatment with antioxidant vitamins (C and E) and after administration of eNOS substrate, L-arginine, or its cofactor, tetrahydrobiopterin (BH(4)). Novel strategies, which may produce beneficial changes in the vascular endothelium, include the use of natural extracts from plant foods rich in phytochemicals.
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PMID:Nitric oxide therapies in vascular diseases. 1181 65

The third set of guidelines recently issued by the National Cholesterol Education Program (NCEP) differs from the second set issued in 1993 in several ways. The third set introduced a quantitative risk scoring system and identified and/or reclassified certain groups of patients at high or moderate risk for a coronary event. Among these groups are patients with type 2 diabetes, and patients with multiple risk factors other than coronary heart disease or diabetes that cumulatively confer high risk for a coronary event. However, the new guidelines also present physicians with the major challenges of identifying these patients, determining their true risk, and implementing the recommended approaches to treatment in clinical practice settings. Although reducing elevated levels of low-density lipoprotein (LDL) cholesterol remains the primary focus of therapy, the new NCEP guidelines also include strategies to identify and treat patients with low levels of high-density lipoprotein (HDL) cholesterol and/or elevated triglyceride levels. Just as there is "good" cholesterol (HDL) and "bad" cholesterol (LDL), there are also "good" triglycerides, which contain high concentrations of triglyceride remnants and are associated with low risk, and "bad" triglycerides, which contain high concentrations of cholesterol remnants and are associated with increased risk. The mechanisms by which "bad" triglycerides develop explain why elevated triglycerides and low HDL--and patients with the metabolic syndrome--warrant special attention. These mechanisms and others also suggest new targets for therapeutic intervention and the development of new drugs that will correct lipid and lipoprotein abnormalities through a number of different metabolic pathways.
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PMID:Rising to the challenge of the new NCEP ATP III guidelines: exceeding current therapeutic limitations. 1185 98

Cholesterol ester transfer protein (CETP) facilitates reverse cholesterol transport via HDL-C and this activity may be increased in obese subjects. In normal weight subjects the Taq1B variant of the CETP gene is associated with lower CETP activity and higher HDL-C. The aim of this study was to examine the relationship between the Taq1B polymorphism and HDL-C in obese women before and after weight loss. A total of 245 women (41 with type 2 diabetes) were genotyped for the Taq1B variant. Plasma lipids, insulin, glucose and oral glucose tolerance were also measured before and after weight loss. When all subjects were examined together the Taq1B genotype was not associated with HDL-C. However, when non-diabetic subjects were divided by median fasting insulin, a strong linear association was observed between Taq1B genotype and HDL-C in subjects below median for fasting insulin (B1B1 1.19+/-0.07 mmol/l, B1B2 1.35+/-0.06, B2B2 1.71+/-0.09, P<0.000). This association was not observed in subjects with fasting insulin above median or subjects with type 2 diabetes, either before or after weight loss. Therefore, the B2B2 genotype is associated with elevated HDL-C in obese women with low fasting insulin only. Improved insulin sensitivity during weight loss did not change this relationship in women with high fasting insulin or type 2 diabetes.
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PMID:Association between HDL-cholesterol and the Taq1B polymorphism in the cholesterol ester transfer protein gene in obese women. 1199 62


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