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)

Twenty patients (18 men, 2 women) with non-insulin dependent diabetes mellitus (NIDDM) were randomized to receive either gemfibrozil 1200 mg daily or placebo for 3 months in a double-blind study. The effect of gemfibrozil on plasma HDL subfraction distribution was studied with sequential and density gradient ultracentrifugation and in gradient gel electrophoresis. The concentrations of apo A-I, apo A-II, Lp A-I and Lp A-I:A-II particles were measured. Postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities and plasma cholesteryl ester transfer protein (CETP) activities were also determined. Gemfibrozil increased the concentration of HDL cholesterol (P < 0.01), which was due to the rise of HDL3 cholesterol (+16%), while in the placebo group these values remained unchanged. Gemfibrozil increased the concentrations of apo A-I(+12.6%, NS), apo A-II (+28.2%, P < 0.01) and Lp A-I:A-II particles (+21.6%, P < 0.06) but there were no changes in the placebo group. Neither gemfibrozil nor placebo had any effect on the concentration of Lp A-I particles. As determined by density-gradient ultracentrifugation, gemfibrozil increased the concentration of cholesterol in the most dense HDL fractions (mean density 1.193 g/ml, +22%, P < 0.05 and mean density 1.158 g/ml, +19.3%, P < 0.05). In gradient gel electrophoresis, the gemfibrozil-induced elevations of the cholesterol and protein were most pronounced in the HDL3a (8.8-8.2 nm) region. Gemfibrozil increased LPL and HL activities by 14.7% (P < 0.05) and by 18.8% (P < 0.01), respectively, while in the placebo group LPL and HL activities remained unchanged. Plasma CETP activity was also increased during gemfibrozil treatment while in the placebo group it remained unchanged. We conclude that gemfibrozil causes multiple changes in plasma HDL metabolism. The gemfibrozil-induced elevation of HDL3 and dense HDL subpopulations may reflect the concerted action of LPL, HL and CETP on plasma HDL metabolism.
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PMID:Effect of gemfibrozil on high density lipoprotein subspecies in non-insulin dependent diabetes mellitus. Relations to lipolytic enzymes and to the cholesteryl ester transfer protein activity. 825 55

Altered postprandial HDL metabolism is a possible cause of defective reverse cholesterol transport and increased cardiovascular risk in diabetic patients with a normal fasting lipoprotein profile. Ten normolipidemic, normoponderal non-insulin dependent diabetes mellitus (NIDDM) patients and seven controls received a 980 kcal meal containing 78 g lipids with 100 000 IU vitamin A. Chylomicron clearance was not different, but area under the curve (AUC) for retinyl palmitate in chylimicron-free serum (remnant clearance) was greater in patients (P < 0.02). LCAT activity increased postprandially to the same extent in both groups. In control subjects, cholesteryl ester transfer protein (CETP) activity (CETA) also increased by 20% (P < 0.01 at 6 h) in parallel with a 20% decrease in HDL2-CE (r = -0.55, P = 0.009). In NIDDM patients, on the contrary, CETA which was 35% higher in the fasting state (P < 0.005), decreased postprandially yet HDL2-CE remained unchanged. Postprandial HDL3 of controls were enriched with phospholipid (PL) (30.3 +/- 2.6% at 6 h) with respect to fasting (25.6 +/- 2.5%, P < 0.01) and to NIDDM-HDL3 (25.8 +/- 1.7% at 6 h, P < 0.01). These results show that variation in plasma CETA has little impact on HDL2-CE in NIDDH subjects. They support the concept that, in controls, the combined enrichment of HDL3 with PL, increased LCAT and CETA create the conditions for stimulation of cell cholesterol efflux and CE transfer to apo B lipoproteins. In NIDDM, because of the lesser HDL3 enrichment with PL and of the inverse trend of CETA, these conditions fail to occur, depriving the patients of a potentially efficient mechanism of unesterified cholesterol (UC) clearance, despite their strictly normal preprandial profile.
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PMID:Postprandial cholesteryl ester transfer and high density lipoprotein composition in normotriglyceridemic non-insulin-dependent diabetic patients. 864 57

Elevated levels of plasma triglycerides (TG) and reduced concentrations of HDL cholesterol are very common in patients with diabetes, particularly NIDDM. Although regulation of the plasma concentrations of VLDL, the major TG-rich lipoprotein is extremely complex, it is clear from in vivo kinetic studies that increased rates of secretion of VLDL into plasma is almost uniformly present in patients with NIDDM and hypertriglyceridemia. Recent studies at the cellular level indicate that increased fatty acid flux to the liver, also common in NIDDM (and other insulin-resistant states associated with elevated plasma TG levels), will stimulate the assembly and secretion of apoprotein (apo) B-containing lipoproteins by targeting apoB for secretion rather than intracellular degradation. Increased rates of secretion of VLDL into plasma appears to drive the exchange of TG from these lipoproteins for HDL cholesteryl ester. This exchange, which occurs in plasma, is facilitated by cholesteryl ester transfer protein, and generates a TG-enriched HDL that is a substrate for either hepatic lipase or lipoprotein lipase. When the TG in HDL is hydrolyzed, the resultant particle is smaller, and this appears to affect the binding of the major HDL protein, apoA-I. ApoA-I dissociates from the smaller, lipid-poor HDL, and the free apoA-I (molecular weight 28,000) can be filtered by the glomerulus in the kidney and most likely is degraded in renal tubular cells after reabsorption. Thus, increased free fatty acid transport in plasma, a common abnormality in insulin-resistant states, may be the underlying driving force for the two common lipid abnormalities seen in diabetes.
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PMID:Diabetic dyslipidemia: basic mechanisms underlying the common hypertriglyceridemia and low HDL cholesterol levels. 867 85

Apolipoprotein A-IV (apoA-IV) might play an important role in lipoprotein metabolism, including modulation of triglyceride-rich lipoprotein catabolism, reverse cholesterol transport and cholesteryl ester transfer protein (CETP) activity. Increased apoA-IV levels have been reported in plasma from NIDDM patients. The aim of the present study was to look for a possible association between plasma apoA-IV level and prevalence of macrovascular disease in NIDDM. One hundred and thirty-six NIDDM patients were studied (71 men, 65 women). Macrovascular disease was assessed in each patient by a standardized questionnaire, physical examination, resting electrocardiogram (ECG), and laboratory evaluation (ankle/arm blood pressure ratio, continuous wave Doppler velocimetry). Moreover, patients without any history of coronary heart disease and showing a normal resting ECG underwent a bicycle exercise test or a dipyridamole thallium scintigraphy to detect possible silent myocardial ischemia. Among the 136 NIDDM patients, 56 had macrovascular disease. ApoA-IV levels were significantly higher in NIDDM patients with macrovascular disease than in NIDDM patients without macrovascular disease (20.9 +/- 8.6 vs. 13.3 +/- 5.3 mg/dl; P < 0.001). The influence of different factors, such as age, BMI, cigarette smoking, hypertension, total cholesterol, triglycerides, HDL cholesterol, apoA-IV level, apoA-IV phenotype, fasting glycemia, fasting C-peptide, and microalbuminuria, on the prevalence of macrovascular disease was analyzed using a logistic regression model. In the univariate analysis, apoA-IV level (P < 0.00001), age (P = 0.0087), hypertension (P = 0.012), microalbuminuria (P = 0.018), triglycerides (P = 0.02), and fasting C-peptide (P = 0.03) were positively associated with macrovascular disease. In the multivariate analysis, macrovascular disease was positively associated only with apoA-IV (P < 0.0001) and age (P = 0.003) and negatively associated with HDL cholesterol (P = 0.013). These results indicate that increased plasma apoA-IV level is associated with an increased prevalence of macrovascular disease in NIDDM. Moreover, apoA-IV, in NIDDM patients, appears to be a better marker for macrovascular disease than triglycerides.
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PMID:Macrovascular disease is associated with increased plasma apolipoprotein A-IV levels in NIDDM. 897 Oct 92

Although the relationship between the actions of cholesteryl ester transfer protein (CETP) and atherosclerosis is complex, a strong body of evidence suggests that its activity (cholesteryl ester transfer [CET]) is proatherogenic. We have previously shown that CET is increased in IDDM patients receiving conventional subcutaneous insulin treatment and normalized when systemic insulin levels are lowered with intraperitoneal insulin delivery (IP). Since CET has been found by many observers to also be accelerated in NIDDM, we sought to determine whether the same salutary effect could be achieved in insulin-requiring NIDDM men before and 7 months after randomization to an intensive treatment regimen (Rx) of either IP (n = 9) or multiple daily insulin injections (MDI; n = 13). HbA1c improved to the same degree in both groups (MDI group: 9.4 +/- 1.1% pre-Rx vs. 7.2 +/- 0.7% post-Rx [P < 0.001]; IP group: 9.2 +/- 1.3% pre-Rx vs. 7.1 +/- 0.5% post-Rx [P < 0.001]). Compared with pre-Rx levels, plasma triglycerides were not significantly changed by either treatment (MDI group: 136 +/- 80 mg/dl pre-Rx vs. 139 +/- 87 mg/dl post-Rx; IP group: 157 +/- 63 mg/dl pre-Rx vs. 188 +/- 89 mg/dl post-Rx), though an upward trend followed IP. Before randomization, CET estimated with both mass and isotopic assays was greater in the NIDDM subjects than in nondiabetic control subjects (P < 0.001). With improved glycemic control, CE mass transfer declined in both groups, but only reached normal levels in the IP group (MDI group at 2 h: 49.0 +/- 13.7 [mean +/- SD] pg pre-Rx vs. 29.5 +/- 15.3 microg post-Rx [-39.7%, P < 0.01]; IP group at 2 h: 40.8 +/- 23.3 microg pre-Rx vs. 10.9 +/- 6.5 microg post-Rx [-73.2%, P < 0.05]) and remained abnormally increased (P < 0.005) in the subjects receiving MDI. Total lipolytic activity after intensive treatment was unchanged from pretreatment levels, which were similar to those of the reference group. Although directional changes in lipoprotein lipase (LpL) and hepatic triglyceride lipase (HTGL) similar to those found in IDDM after MDI and IP were observed, they were not statistically significant. Thus, while improved glycemic control alone achieved by either MDI or IP reduced the pathological increase in CET in these insulin-treated NIDDM men, normalization was only achieved in those treated with IP. Despite near-normal HbA1c levels, CET remained abnormally increased in NIDDM patients treated rigorously with conventional subcutaneous insulin delivery.
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PMID:Effects of multiple daily insulin injections and intraperitoneal insulin therapy on cholesteryl ester transfer and lipoprotein lipase activities in NIDDM. 903 97

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from HDL to VLDL and LDL. Phospholipid transfer protein (PLTP) transfers phospholipids between lipoproteins, converts HDL3 into larger and smaller particles, and is involved in pre-beta-HDL generation. We examined the effects of 24-h hyperinsulinemia (30 mU x kg(-1) x h(-1)) and 24-h Acipimox (250 mg/4 h) on plasma lipids as well as CETP and PLTP activities (measured with exogenous substrate assays) in eight healthy and eight type 2 diabetic subjects. After 24 h of insulin, plasma free fatty acids (FFAs), HDL cholesterol, and plasma apolipoprotein AI decreased in healthy subjects and type 2 diabetic patients (P < 0.05). Plasma triglycerides did not significantly change in either group. After 24 h of Acipimox, all parameters, including plasma triglycerides, decreased in both groups (P < 0.05). Insulin decreased plasma PLTP activity by 17.6% after 24 h in healthy subjects (P < 0.05) and 10.2% in diabetic patients (P < 0.05 vs. baseline; P < 0.05 vs. healthy subjects). Acipimox lowered PLTP activity by 10.3% in healthy subjects (P < 0.05) and 11.3% in diabetic patients (P < 0.05). When insulin was infused for 3 h after Acipimox, a further decrease was found only in healthy subjects. Plasma CETP activity decreased by 9.5% after 24 h of insulin in healthy subjects (P < 0.05), but not in diabetic patients. Acipimox did not decrease plasma CETP activity in either group. In healthy subjects, the PLTP responses with insulin and Acipimox were larger than the changes in CETP activity (P < 0.05). These findings suggest that there is a metabolic link between the regulation of plasma FFA and PLTP, but not CETP. The PLTP response to insulin is blunted in type 2 diabetes.
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PMID:Plasma phospholipid transfer protein activity is lowered by 24-h insulin and acipimox administration: blunted response to insulin in type 2 diabetic patients. 1042 83

Insulin resistance is a common metabolic abnormality that is associated with an increased risk of both atherosclerosis and type 2 diabetes. The phenotype of insulin resistance includes a dyslipidemia characterized by an elevation of very low-density lipoprotein triglyceride, a reduction in high-density lipoprotein cholesterol, and the presence of small, triglyceride-enriched low-density lipoproteins. The underlying metabolic abnormality driving this dylipidemia is an increased assembly and secretion of very low-density lipoprotein particles, leading to an increased plasma level of triglyceride. Hypertriglyceridemia, in turn, results in a reduction in the high-density lipoprotein level and the generation of small, dense low-density lipoproteins; these events are mediated by cholesteryl ester transfer protein. In addition, hypertension, obesity, and a prothrombotic state are also integral components of the insulin resistance syndrome. In this review, we will provide a pathophysiologic basis, based on studies on humans and in tissue culture, for the dyslipidemia of insulin resistance. We will also review the effects of insulin resistance on the coagulation and fibrinolytic pathways. It is hoped that this review will allow health professionals better to evaluate and treat their patients with insulin resistance, thereby reducing the very much increased risk of atherosclerotic cardiovascular disease carried by these individuals.
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PMID:The insulin resistance syndrome: impact on lipoprotein metabolism and atherothrombosis. 1114 62

Plasma cholesteryl ester transfer protein (CETP) facilitates intravascular lipoprotein remodeling by promoting the heteroexchange of neutral lipids. To determine whether the degree of triglyceridemia may influence the CETP-mediated redistribution of HDL CE between atherogenic plasma lipoprotein particles in type 2 diabetes, we evaluated CE mass transfer from HDL to apoB-containing lipoprotein acceptors in the plasma of type 2 diabetes subjects (n=38). In parallel, we investigated the potential relationship between CE transfer and the appearance of an atherogenic dense LDL profile. The diabetic population was divided into 3 subgroups according to fasting plasma triglyceride (TG) levels: group 1 (G1), TG<100 mg/dL; group 2 (G2), 100<TG<200 mg/dL; and group 3 (G3), TG>200 mg/dL. Type 2 diabetes patients displayed an asymmetrical LDL profile in which the dense LDL subfractions predominated. Plasma levels of dense LDL subfractions were strongly positively correlated with those of plasma triglyceride (TG) (r=0.471; P:=0.0003). The rate of CE mass transfer from HDL to apoB-containing lipoproteins was significantly enhanced in G3 compared with G2 or G1 (46.2+/-8.1, 33.6+/-5.3, and 28.2+/-2.7 microg CE transferred. h(-1). mL(-1) in G3, G2, and G1, respectively; P:<0.0001 G3 versus G1, P:=0.0001 G2 versus G1, and P:=0.02 G2 versus G3). The relative capacities of VLDL and LDL to act as acceptors of CE from HDL were distinct between type 2 diabetes subgroups. LDL particles represented the preferential CE acceptor in G1 and accounted for 74% of total CE transferred from HDL. By contrast, in G2 and G3, TG-rich lipoprotein subfractions accounted for 47% and 72% of total CE transferred from HDL, respectively. Moreover, the relative proportion of CE transferred from HDL to VLDL(1) in type 2 diabetes patients increased progressively with increase in plasma TG levels. The VLDL(1) subfraction accounted for 34%, 43%, and 52% of total CE transferred from HDL to TG-rich lipoproteins in patients from G1, G2, and G3, respectively. Finally, dense LDL acquired an average of 45% of total CE transferred from HDL to LDL in type 2 diabetes patients. In conclusion, CETP contributes significantly to the formation of small dense LDL particles in type 2 diabetes by a preferential CE transfer from HDL to small dense LDL, as well as through an indirect mechanism involving an enhanced CE transfer from HDL to VLDL(1), the specific precursors of small dense LDL particles in plasma.
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PMID:Atherogenic role of elevated CE transfer from HDL to VLDL(1) and dense LDL in type 2 diabetes : impact of the degree of triglyceridemia. 1115 66

A polymorphism in the gene for cholesteryl ester transfer protein (CETP) has been reported to be associated with serum cholesterol levels and risk for atherosclerotic vascular diseases, and to clarify the relationship between the gene polymorphism for CETP and macroangiopathy in diabetes mellitus, a cross-sectional study was performed. The subjects of the study were182 Japanese (age: 59.6+/-8.6 years) with type 2 diabetes and no signs of renal dysfunction, 24 of whom had macroangiopathy, and 158 of whom did not. The genotype of the subjects for the TaqIB polymorphism of CETP in intron one was analyzed by using polymerase chain reaction - restriction fragment length polymorphism. Serum CETP levels were significantly higher in the B1/B1 genotype than in the other genotypes (P<0.05). The serum CETP levels were correlated with the serum LDL cholesterol levels (P<0.01), but not with the HDL cholesterol levels. Macroangiopathy was more frequently observed in subjects with the B1/B1 genotype than in the other genotypes (odds ratio=2.953, 95% confidence interval=1.250-6.977, P=0.0136). Logistic regression analysis revealed that the CETP genotype was independently associated with macroangiopathy. The exact mechanism underlying the association remains unknown, but differences in serum CETP levels may be involved.
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PMID:Cholesteryl ester transfer protein polymorphism associated with macroangiopathy in Japanese patients with type 2 diabetes. 1136 8

Cholesteryl ester transfer protein (CETP) is a key regulating factor of lipid metabolism, and the polymorphism of its gene may therefore be a candidate for modulating the lipid parameters, altering the susceptibility to atherosclerosis in type 2 diabetic subjects. In a group of 443 unrelated Japanese patients with type 2 diabetes, we studied the B1B2 polymorphism at the CETP locus, which is detectable with the restriction enzyme TaqI. Patients were separated into three groups according to genotype and compared based on their clinical characteristics, lipid parameters, and macrovascular complications. The B2 allele was associated in a dose-dependent fashion with higher HDL cholesterol and apolipoprotein AI levels, together with lower CETP concentrations. Furthermore, the prevalence of macrovascular complications, such as coronary heart disease, arteriosclerosis obliterans, and cerebral vascular disease, was significantly higher in subjects with the B1B1 genotype. Multiple logistic regression analysis also showed that the B1 allele of CETP genotype was associated with the incidence of these three complications independently of other risk factors. Thus, in type 2 diabetic patients, the B1B2 polymorphism of CETP gene is likely to be a strong genetic predictor of macrovascular complications.
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PMID:Relationship between TaqIB cholesteryl ester transfer protein gene polymorphism and macrovascular complications in Japanese patients with type 2 diabetes. 1187 95


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