Microsomal triglyceride transfer protein 493-T variant is associated with resistin levels and C-reactive protein

BACKGROUND: The microsomal triglyceride transfer protein (MTP) is a heterodimeric lipid transfer protein that consists of a large unique 97-kDA subunit and protein disulfide isomerase. MTP is involved in the assembly of apoB-containing lipoprotein and enables the secretion of VLDLs by the liver and chylomicrons by the intestine. The MTP gene is highly polymorphic. The less common T variant has been associated with the reduction of plasma LDL-cholesterol levels and with an increased risk in coronary heart disease. We hypothesized that MTP polymorphism could be associated to LDL-cholesterol levels and proinflammatory cytokines, such as resistin. METHODS AND RESULTS: The -493G/T MTP gene polymorphism was investigated in 290 subjects. Subjects carrying the TT genotype had lower level of LDL-cholesterol and higher serum resistin levels than individual carrying one or two copies of the -493G allele. After adjustments for age, BMI, waist circumference, alcohol intake and exercise levels, a significant direct association was evident between hs-CRP and resistin levels and the presence of the TT genotype in a multiple regression model. CONCLUSION: This study supports the notion that the rare MTP-493T/T genotype is associated both with higher levels of inflammatory parameters and with low levels of LDL-cholesterol. Prospective data are needed to investigate if the association between CVD and the MTP-493T/T genotype might be due to the increased sub-clinical proinflammatory state associated with this mutation.     

Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes

OBJECTIVE: The cholesteryl ester transfer protein (CETP) plays a key role in the remodeling of triglyceride (TG)-rich and HDL particles. Sequence variations in the CETP gene may interfere with the effect of lipid-lowering treatment in type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a 30-week randomized double-blind placebo-controlled trial with atorvastatin 10 mg (A10) and 80 mg (A80) in 217 unrelated patients with diabetes. RESULTS: CETP TaqIB and A-629C polymorphisms were tightly concordant (P < 0.001). At baseline, B1B1 carriers had lower plasma HDL cholesterol (0.99 +/- 0.2 vs. 1.11 +/- 0.2 mmol/l, P < 0.05), higher CETP mass (2.62 +/- 0.8 vs. 2.05 +/- 0.4 mg/l, P < 0.001), and slightly increased, though not significant, plasma TGs (2.7 +/- 1.05 vs. 2.47 +/- 0.86, P = 0.34) compared with B2B2 carriers. Atorvastatin treatment significantly reduced CETP mass dose-dependently by 18% (A10) and 29% (A80; both vs. placebo P < 0.001, A10-A80 P < 0.001). CETP mass and activity were strongly correlated (r = 0.854, P < 0.0001). CETP TaqIB polymorphism appeared to modify the effect of atorvastatin on HDL cholesterol elevation (B1B1 7.2%, B1B2 6.1%, B2B2 0.5%; P < 0.05), TG reduction (B1B1 39.7%, B1B2 38.4%, B2B2 18.4%; P = 0.08), and CETP mass reduction (B1B1 32.1%, B1B2 29.6%, B2B2 21.9%; P = 0.27, NS). Similar results were obtained for the A-629C polymorphism. CONCLUSIONS: In conclusion, the B1B1/CC carriers of the CETP polymorphisms have a more atherogenic lipid profile, including low HDL, and they respond better to statin therapy. These results favor the hypothesis that CETP polymorphisms modify the effect of statin treatment and may help to identify patients who will benefit most from statin therapy.     

Changes in triglyceride levels over time and risk of type 2 diabetes in young men

OBJECTIVE—The association between changes in triglyceride concentrations over time and diabetes is unknown. We assessed whether two triglyceride determinations obtained 5 years apart can predict incident type 2 diabetes.RESEARCH DESIGN AND METHODS—Triglyceride levels at baseline (time 1) and 5 years later (time 2), followed by subsequent follow-up of 5.5 years, were measured in 13,953 apparently healthy men (age 26–45 years) with triglycerides <300 mg/dl (<3.39 mmol/l).RESULTS—During 76,742 person-years, 322 cases of diabetes occurred. A multivariate model adjusted for age, BMI, total cholesterol–to–HDL cholesterol ratio, family history of diabetes, fasting glucose, blood pressure, physical activity, and smoking status revealed a continuous independent rise in incident diabetes with increasing time 1 triglyceride levels (P_trend < 0.001). Men in the lowest tertile of time 1 triglyceride levels who progressed to the highest tertile over follow-up (low-high) exhibited a hazard ratio (HR) of 12.62 (95% CI 3.52–31.34) compared with those remaining in the lowest tertile at both time points (reference group: low-low). Whereas men who were at the top triglyceride level tertile throughout follow-up (high-high) had a HR for diabetes of 7.08 (2.52–14.45), those whose triglyceride level decreased to the lowest tertile (high-low) exhibited a HR of 1.97 (0.67–6.13). Alterations in triglyceride levels during follow-up were associated with changes in BMI, physical activity, and eating breakfast habit (P < 0.05), but remained an independent modifier of diabetes risk even after adjustment for such changes.CONCLUSIONS—Two measurements of fasting triglyceride levels obtained 5 years apart can assist in identifying apparently healthy young men at increased risk for diabetes, independent of traditional risk factors and of associated changes in BMI and lifestyle parameters.Elevated triglyceride levels are a common dyslipidemic feature accompanying type 2 diabetes and pre-diabetic states (1). A fasting triglyceride level of ≥150 mg/dl (≥1.70 mmol/l) is one of five accepted criteria for defining individuals at high risk for cardiovascular disease and type 2 diabetes, arguably termed the “metabolic syndrome” (2–4). Some evidence suggests that fasting triglyceride levels can aid in predicting future type 2 diabetes (5,6). However, this was shown mainly when triglyceride levels were combined with additional clinical parameters, such as BMI, blood pressure (7), and other classic risk factors for cardiovascular disease (8,9), or with “high-normal” fasting plasma glucose levels (10).The level of circulating triglycerides is highly influenced by the fed-fasted state, insulin sensitivity, and lifestyle factors such as diet and physical activity (1,11,12). These make triglyceride levels a highly sensitive lifestyle biomarker at a given time point but suggest that a triglyceride determination at a single time point may inaccurately reflect long-term triglyceridemia, particularly if lifestyle modification occurred during follow-up. Whether assessment of triglyceride levels at more than one time point could improve the association between triglyceride levels and diabetes is largely unknown. Recently, we reported in a large cohort of young (aged 26–45 years) men that significant changes between two fasting triglyceride measurements obtained 5 years apart corresponded with alterations in lifestyle parameters (13). Furthermore, such changes modified the risk for heart disease attributed to elevated triglyceride levels (13).Most studies assessing the risk factors for type 2 diabetes have overlooked the parameters specifically relevant for the apparently healthy young adult population. Although the incidence rate of diabetes in this group is relatively low, recent studies suggested a surge in type 2 diabetes in young adults (14). Identifying individuals in this group who have a high risk of developing diabetes is therefore challenging but potentially of significant benefit if preventive measures are used. Here, we used the cohort of young, apparently healthy men (10,13) to assess whether baseline triglyceride measurements as well as lifestyle-associated changes in triglyceride levels over time can predict the risk of diabetes.     

The role of microsomal triglyceride transfer protein in metabolism of apo B-containing lipoprotein

Microsomal triglyceride transfer protein (MTP) plays a central role on secretion of lipoprotein from the liver and the intestine. MTP catalyzes the transfer of triglyceride, cholesteryl ester and phosphatidylcholine between membranes and lipoproteins. In human, defect of MTP activity, result from mutations encoding the MTP large subunit, is the primary cause of abetalipoproteinemia. To investigate the association between hyperlipidemia with obese and MTP, We used Otsuka Long-Evans Tokushima Fatty rat, an animal model of obesity with visceral fat accumulation, hyperlipidemia. In animals, very-low density lipoprotein-triglyceride levels were elevated compared with the control rats. Hepatic mRNA levels of acyl-coenzyme A synthetase, and MTP were also elevated. These results suggest that the enhanced expression of both ACS and MTP genes associated with visceral fat accumulation may be involved in the pathogenesis of hyperlipidemia in obese animal models.     

Interaction between angiotensin-converting enzyme genotype and glycaemic control influences lipoprotein levels in type 2 diabetes mellitus

AIMS: To evaluate the influence of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism on lipid levels in patients with Type 2 diabetes. PATIENTS AND METHODS: 109 patients with Type 2 diabetes were included. The patients were not on any lipid-lowering treatment. The groups with different ACE genotypes had similar ages, sex distributions, body mass indices, systolic blood pressures and indices of glycaemic control. ACE gene I/D polymorphism was determined using polymerase chain reaction. RESULTS: The mean apolipoprotein B (apoB) level was significantly higher in the group of DD homozygotes compared with the subjects with at least one insertion allele (DD: 1.21 +/- 0.25 g/l vs. ID + II: 1.04 +/- 0.27 g/l; P = 0.007). Significant correlations between glycated haemoglobin (HbA1c) and both apoB and cholesterol levels were found (r = 0.27; P < 0.01). For the apoB, this correlation was highly significant in the DD-genotype subgroup (r = 0.54; P < 0.01), and was not significant in the subgroup of patients with genotypes ID or II. In the multivariate analysis, HbA1c and the interaction of genotype DD with HbA1c were significant independent predictors of apoB (r2 = 0.17) and cholesterol levels. CONCLUSION: The present study showed that the interaction between the DD genotype of angiotensin-converting enzyme and chronic hyperglycaemia (expressed by HbA1c level) is related to higher plasma levels of atherogenic lipoproteins, such as apoB and cholesterol, in patients with Type 2 diabetes.     

胃转流术后2型糖尿病与C反应蛋白的关系

目的研究胃转流术(RYGB)后2型糖尿病(T2DM)患者C反应蛋白(CRP)水平变化及与术后体重指数(BMI)下降的关系。方法选择29例进行RYGB手术治疗的T2DM患者。检测术前1周、术后3个月、术后6个月的血清CRP、空腹血糖(FPG)、餐后血糖(PPG)、总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白(LDL-c)、高密度脂蛋白(HDL-c)、糖化血红蛋白(HbA1c)、空腹胰岛素(FINs)及BMI等水平变化,比较并进行各指标之间的相关分析。结果 T2DM组的血糖(FPG、PPG)、血脂(TC、TG、LDL-c)各项水平、FINs、HbA1c、CRP、BMI水平均显著高于对照组(P<0.05)。术后各项指标均得到改善。T2DM组术后3～6个月FFA,HOMA-IR呈进行性下降,均显著低于术前(P<0.05)。CRP与BMI、FINs相关性分析显示,术后6个月时仅FINs与CRP水平差异有显著性(r=0.63,P<0.05)。结论 RYGB术后,T2DM患者血清CRP、BMI、血糖水平均呈下降趋势,但是CRP下降情况与胰岛素水平显著性相关,无BMI无关。RYGB手术可能有助于T2DM患者减少心脑血管的发病风险。     

Anti-oxidized low-density lipoprotein antibody levels are associated with the development of type 2 diabetes mellitus

Background  Anti-oxidized low-density lipoprotein (LDL) antibodies are associated with the oxidative capacity of plasma, but whether they protect or promote diabetes is unknown. We undertook a prospective study to determine the predictive capacity of anti-oxidized LDL antibodies for the onset of type 2 diabetes mellitus (T2DM).
Materials and methods  We selected 391 non-diabetic women aged 18–65 years. The subjects were classified as being normal (oral glucose test tolerance normal, OGTT-N), or having impaired glucose tolerance (IGT), impaired fasting glucose (IFG) or T2DM according to their baseline glucose levels and after an OGTT. The same subjects were studied six years later. The levels of anti-oxidized LDL antibodies were classified as above or below the 50th percentile.
Results  Of the women who were OGTT-N at the start of the study and who had anti-oxidized LDL antibody levels below the 50th percentile, only 65·1% were still OGTT-N after 6 years versus 79·5% of those who had anti-oxidized LDL antibody levels above the 50th percentile ( P  = 0·015). Women who had IGT or IFG at the start of the study whose anti-oxidized LDL antibody levels were below the 50th percentile had a relative risk of 9·79 (95% confidence interval, 1·40–68·45) of developing diabetes ( P  < 0·001). Logistic regression analysis showed that the variables predicting the development of a carbohydrate metabolism disorder in the women after 6 years were body mass index ( P  < 0·001) and the levels of anti-oxidized LDL antibodies ( P  = 0·042).
Conclusions  Levels of anti-oxidized LDL antibodies are independent predictors for the development of T2DM in women.     

Rosiglitazone improves postprandial triglyceride and free fatty acid metabolism in type 2 diabetes

OBJECTIVE: Increased postprandial lipemia is part of diabetic dyslipidemia and is associated with accelerated atherosclerosis. We investigated the effects of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone on postprandial lipemia in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized, 8-week, crossover, placebo-controlled, double-blind trial was performed in which rosiglitazone at 4 mg was administrated twice daily in 19 patients with type 2 diabetes. Standardized 6-h oral fat-loading tests were performed after each treatment period. Postprandial curves were calculated as the total area under the curve (AUC) and the incremental area under the curve (dAUC). RESULTS: Rosiglitazone did not change fasting plasma triglycerides compared with placebo (1.97 +/- 0.22 vs. 1.88 +/- 0.20 mmol/l, respectively) but decreased postprandial triglyceride levels, leading to significantly lower triglyceride dAUC (-37%, P < 0.05), without changing total triglyceride AUC. Significant postprandial triglyceride reductions in the chylomicron fraction (Svedberg flotation rate [Sf] >400) were achieved with rosiglitazone, which resulted in a significant lower triglyceride AUC (-22%) in this fraction. The postprandial triglyceride increase in VLDL1 (Sf 60-400) was also lower after rosiglitazone (-27%), but this did not result in a significant lower triglyceride AUC. In VLDL2 (Sf 20-60), there were no significant differences in triglyceride AUC and triglyceride dAUC between rosiglitazone and placebo. Rosiglitazone decreased free fatty acid (FFA) AUC (-12%) and FFA dAUC (-18%) compared with placebo. CONCLUSIONS: Rosiglitazone improves the metabolism of large triglyceride-rich lipoproteins and decreases postprandial FFA concentrations in type 2 diabetes. This may have clinical implications, as these effects may contribute to cardiovascular risk reduction.     

Plasma phospholipid transfer protein activity and small,dense LDL in type 2 diabetes mellitus

BACKGROUND: Phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) remodel circulating lipoproteins and play a role in the antiatherogenic reverse cholesterol transport pathway. The present study determined whether abnormalities in the LDL subfraction pattern in type 2 diabetic patients were related to changes in lipid transfer proteins. METHODS: Low-density lipoprotein (LDL) subfractions were measured by density gradient ultracentrifugation and plasma PLTP and CETP activities by radiometric assays in 240 diabetic patients and 136 controls. RESULTS: The diabetic patients had lower LDL-I (P < 0.001) and higher LDL-III concentrations than the controls (P < 0.001). Plasma PLTP activity was increased (P < 0.001) whereas no significant differences were seen in CETP activity. In the diabetic patients, small, dense LDL-III correlated with plasma triglyceride (r = 0.18, P < 0.01), HDL (r = -0.14, P < 0.05), PLTP (r = 0.29, P < 0.001) and CETP activity (r = 0.15, P < 0.05). Linear regression analysis showed that plasma PLTP activity, triglyceride and age were the major determinants of LDL-III concentration (r2 = 28%, P < 0.001). The univariate relationship between CETP and LDL-III was no longer significant after adjusting for PLTP activity. CONCLUSIONS: The increase in plasma PLTP activity was independently associated with small, dense LDL concentrations in type 2 diabetes. Hence, elevated PLTP activity might have both antiatherogenic and pro-atherogenic potential in these patients.     

Elevated plasma glucose and lowered triglyceride levels from omega-3 fatty acid supplementation in type II diabetes

We studied the effect of omega-3 fatty acids (omega 3FA) on glucose homeostasis and lipoprotein levels in eight type II (non-insulin-dependent)-diabetic subjects ingesting 8 g/day omega 3FA for 8 wk as marine-lipid concentrate capsules. After omega 3FA supplementation, fasting plasma glucose levels increased 22% (P = .005) and meal-stimulated glucose increased 35% (P = .036). The percentage of glucose elevation correlated with percentage ideal body weight (r = .73, P = .04). No significant changes were seen in fasting or meal-stimulated plasma insulin, glucose disposal, or insulin-to-glucagon ratios. Very-low-density lipoprotein cholesterol and triglyceride (TG) levels showed consistent reductions of 56% (P less than .001) and 42% (P less than .001), respectively, after omega 3FA supplementation. Total cholesterol levels decreased 7% (P less than .05) without alteration in low- or high-density lipoprotein cholesterol. Thus, omega 3FA supplementation at a dose of 8 g/day significantly improves plasma TG levels but increases fasting and meal-stimulated glucose concentrations in the type II diabetic patient not treated with insulin or sulfonylurea agents. Marine-lipid concentrate capsules supplying large amounts of omega 3FAs should be used cautiously in the type II diabetic patient.     

Role of lipases, lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in abnormal high density lipoprotein metabolism in insulin resistance and type 2 diabetes mellitus

Dyslipidaemia, hallmarked by low HDL cholesterol and high plasma triglycerides, is a feature of insulin resistance and type 2 diabetes mellitus. These lipoprotein abnormalities represent major cardiovascular risk factors in these conditions. Among other factors, lipoprotein lipase (LPL), hepatic lipase (HL), lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) play an important role in an abnormal HDL metabolism in insulin resistance and type 2 diabetes mellitus. LPL hydrolyses lipoprotein triglycerides, thus providing lipids for HDL formation. In insulin resistant states, a decreased post-heparin plasma LPL activity contributes to a low HDL cholesterol, whereas an increased activity of HL reduces HDL particle size by hydrolysing its triglycerides and phospholipids. High HL activity coincides with low HDL cholesterol. The esterification of free cholesterol by LCAT increases HDL particle size. Subsequent CETP action results in transfer of cholesteryl esters from HDL towards triglyceride-rich lipoproteins. This cholesteryl ester transfer process results in lower HDL cholesterol and indirectly decreases HDL size. Plasma cholesterol esterification is unaltered or increased, whereas cholesteryl ester transfer is enhanced in type 2 diabetes mellitus, abnormalities which are probably related to the degree of hypertriglyceridaemia. It is plausible that a low LPL activity contributes to premature atherosclerosis as observed in insulin resistance and type 2 diabetes mellitus, but the effects of high HL activity and altered plasma cholesterol esterification on atherosclerosis development are uncertain. Since the cholesteryl ester transfer process between lipoproteins provides a metabolic intermediate between low HDL cholesterol and high plasma triglycerides, hypertriglyceridaemia-associated accelerated transfer of cholesteryl ester out of HDL may be pathogenetically involved in the development of cardiovascular disease in insulin resistance and type 2 diabetes mellitus.     

解偶联蛋白3在2型糖尿病发生发展中的作用

解偶联蛋白3(UCP3)是解偶联蛋白家族成员之一,系线粒体内膜上阴离子转运蛋白,主要通过质子漏的作用降低线粒体膜内外电化学梯度,影响电子呼吸链,从而使ATP和活性氧的产生减少,使能量以热能的形式释放。UCP3主要在骨骼肌中表达,而骨骼肌是机体外周摄取葡萄糖的主要组织,同时骨骼肌胰岛素抵抗是2型糖尿病患者的主要缺陷,故人们推测,解偶联蛋白3可能在2型糖尿病的发生发展中发挥重要作用。深入探索UCP3在2型糖尿病中的作用有助于为2型糖尿病的治疗提供一个新的治疗靶点。     

The effect of L-carnitine on plasma lipoprotein(a) levels in hypercholesterolemic patients with type 2 diabetes mellitus

BACKGROUND: A previous study has demonstrated that L-carnitine reduces plasma lipoprotein(a) (Lp[a]) levels in patients with hypercholesterolemia. OBJECTIVE: To test a tolerable Lp(a)-reducing agent in diabetic patients, we assessed the effect of a dietary supplementation of L-carnitine on plasma lipid levels, particularly Lp(a), of patients with type 2 diabetes mellitus (DM) and hypercholesterolemia. METHODS: In this 6-month, randomized, double-masked, placebo-controlled clinical trial, patients were enrolled, assessed, and followed up at the Diabetic and Metabolic Diseases Center of the Department of Internal Medicine and Therapeutics at the University of Pavia, Pavia, Italy. All study patients had newly diagnosed type 2 DM that was managed through dietary restriction alone throughout the study, as well as hypercholesterolemia. Patients were randomized to 1 of 2 groups. One group received L-carnitine, one 1-g tablet BID. The other group received a corresponding placebo. We assessed body mass index, fasting plasma glucose, postprandial plasma glucose, glycosylated hemoglobin, fasting plasma insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein (apo) A-I, apo B, and Lp(a) at baseline and at 1, 3, and 6 months of treatment. RESULTS: This study included 94 patients. The treatment group included 24 men and 22 women (mean [SD] age, 52 [6] years). The placebo group included 23 men and 25 women (mean [SD] age, 50 [7] years). The baseline characteristics of the groups did not differ significantly. The mean (SD) body weight, height, and body mass index were 78.2 (5.8) kg, 1.70 (0.04) m, and 27.3 (2.5) kg/m(2), respectively, in the L-carnitine group and 77.6 (6.4) kg, 1.71 (0.05) m, and 26.8 (2.2) kg/m(2), respectively, in the placebo group. In the treatment group, Lp(a) was significantly reduced at 3 and 6 months compared with baseline (P < 0.05) and P < 0.01, respectively). We observed a significant improvement after 6 months (P < 0.05) in the Lp(a) value in patients taking L-carnitine compared with those taking placebo. Between-group differences in other variables did not reach a level of significance at months 3 and 6. No drug-related adverse events were reported or observed. CONCLUSION: In this preliminary study, after 3 and 6 months, L-carnitine significantly lowered the plasma Lp(a) level compared with placebo in selected hypercholesterolemic patients with newly diagnosed type 2 DM.     

Divergence in plasmatic and urinary isoprostane levels in type 2 diabetes

BACKGROUND: Oxidative stress is currently suggested as a mechanism underlying diabetes. The present study was designed to evaluate isoprostane levels in plasma and in urine in type 2 diabetic patients, and to compare them to other currently used biomarkers of oxidative stress. METHODS: The work was performed in a control group (n = 10) and in a type 2 diabetic group (n = 10). Besides the traditional biochemical parameters, we evaluated the plasma and urine levels of isoprostanes and malondialdehyde (MDA) as markers of oxidative stress. RESULTS: We found increased plasma and urine MDA in the diabetic patients and almost significantly decreased plasma vitamin E. Urinary isoprostane levels in diabetic patients were increased but they presented a strong tendency to a decrease in plasma isoprostanes. It is therefore suggested that, in the studied diabetic patients, although the production of isoprostanes in the body was increased (as other plasma oxidative stress biomarkers were altered) it did not lead to an increase in plasma isoprostane levels. It could be hypothesised that this results from an increased elimination of this metabolite and therefore an increased excretion in urine. CONCLUSION: Our results showed that the measurement of same oxidative stress biomarker, isoprostane, in two different biologic fluids, plasma and urine, led to divergent results and emphasised the importance to measure a biomarker both in the circulation fluid (plasma) and in the elimination fluid (urine), to have a general idea of what is occurring in the organism.