2型糖尿病患者餐后甘油三酯水平与血管并发症关系的研究

目的 研究２型糖尿病患者餐后甘油三酯水平与血管并发症的关系。方法 ４４例２型糖尿病患者以空腹和餐后４小时甘油三酯（ＴＧ和ＴＧ４ｈ）水平分组：空腹及餐后ＴＧ正常组（１９例）、空腹正常餐后增高组（１４例）、空腹增高组（１０例）、分析其血管并发症的发生情况,结果 按上述分组次序,微血管并发症发生率分别为２１．０５％、４２．８５％和７０％,大血管并发症分别为１０．５２％、５７．１４％和８０％。前两组微血管     

Intestinal rather than hepatic microsomal triglyceride transfer protein as a cause of postprandial dyslipidemia in diabetes

Postprandial dyslipidemia may be a major cause of atherosclerosis in diabetes. Microsomal triglyceride transfer protein (MTP) is essential for the synthesis of the chylomicron particle in the intestine and very low-density lipoprotein (VLDL) in the liver. The purpose of the present study was to examine the effect of diabetes on MTP mRNA expression in a rabbit model of diabetes, which develops atherosclerosis. Male New Zealand white rabbits were fed a 0.5% cholesterol diet. Diabetes was induced with alloxan monohydrate. The lymphatic duct was cannulated and lymph collected for isolation of chylomicrons by ultracentrifugation. Apolipoprotein B48 (apo B48) and apo B100 were separated by polyacrylamide gradient gel electrophoresis and quantified by densitometry. MTP mRNA was determined in liver and intestine by RNase protection analysis, and MTP activity was measured. Diabetic animals had significantly increased plasma triglyceride and decreased high-density lipoprotein (HDL) cholesterol (P <.05). They also secreted more lymph chylomicron apo B48 and apo B100 (P <.05) and more lymph chylomicron total and esterified cholesterol/h (P <.05). Lymph chylomicron particles in the diabetic animals contained significantly less lipid/apo B (P <.05). Intestinal MTP activity and mRNA were significantly higher in diabetic compared with control rabbits (0.07 +/- 0.01 v 0.04 +/- 0.015 fluorescent units/microg microsomal protein and 66 +/- 21 v 37 +/- 11 amol MTP mRNA/microg total RNA (P <.005). There was no difference in MTP activity or mRNA expression in the liver. This study suggests that MTP may play an important role in the postprandial dyslipidemia of diabetes.     

Abnormalities in the metabolism of postprandial and fasting triglyceride-rich lipoprotein subfractions in normal and insulin-dependent diabetic subjects: effects of sex

To investigate the effect of sex and diabetes on postprandial lipoprotein metabolism, 15 normal and 12 normolipidemic subjects with insulin-dependent diabetes mellitus (IDDM) were studied. Plasma triglyceride (TG) levels were measured and three TG-rich lipoprotein subfractions (Sf greater than 400, 100 to 400, and 20 to 100) were isolated and their composition analyzed before and every 1.5 hours for a total of 7.5 hours following ingestion of corn oil. Normal women compared with men had lower postprandial plasma TG levels (P less than .05) mostly due to lower TG in Sf 100 to 400. The composition of Sf 100 to 400 and Sf 20 to 100 lipoproteins differed in the two sexes (P less than .01), with normal women having particles poorer in TG in both the fasting and postprandial states. Diabetic men compared with normal men had smaller Sf greater than 400 particles following fat ingestion, as shown by a lower TG protein (PR) ratio (7.6 v 12.8, respectively, P less than .05). The composition of Sf 100 to 400 and 20 to 100 lipoproteins was abnormal in IDDM men due to enrichment in total cholesterol (TC) as shown by higher TC/TG, TC/PR, and TG/phospholipid (PL) ratios in both the fasting (P less than .03 to P less than .003) and the postprandial state (P less than .03 to P less than .0001). A lower PL and TG content was also consistently present. A similar enrichment in TC was observed in diabetic v normal women following fat ingestion in Sf greater than 400 only (P less than .003).(ABSTRACT TRUNCATED AT 250 WORDS)     

The relationship of hyperinsulinaemia to the development of hypertension in type 2 diabetic patients and in non-diabetic subjects

We have carried out a 5 year follow-up study of a group of 41 originally normotensive (BP less than 160/95 mmHg) newly diagnosed Type 2 (non-insulin-dependent) diabetic patients (26 men, 15 women) and 86 non-diabetic subjects (39 men, 47 women) to assess the predictive value of serum insulin levels with regard to the development of hypertension. Hypertension (BP greater than 160/95 mmHg and/or drug treatment) developed in 14% of diabetic patients and 10% of non-diabetic subjects (NS). The baseline postglucose insulin levels tended to be higher in those diabetic and non-diabetic subjects who developed hypertension during the 5 year follow-up than in those who remained normotensive, and in non-diabetic subjects the differences were statistically significant after adjustment for age, sex and body mass index for the baseline 1 hour serum insulin (104 +/- 18 vs. 68 +/- 5 mU/l; P less than 0.05) and area under the insulin curve (138 +/- 34 vs. 85 +/- 8 mU/l.h, P less than 0.05). Both diabetic and non-diabetic subjects who developed hypertension showed elevated total- and VLDL-triglycerides at baseline compared with those subjects who remained normotensive during the follow-up. In conclusion, the results support the hypothesis that hyperinsulinaemia or insulin resistance may play a role in the pathogenesis of hypertension.     

Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes

Aims/hypothesis We assessed the effects of vildagliptin, a novel dipeptidyl peptidase IV inhibitor, on postprandial lipid and lipoprotein metabolism in patients with type 2 diabetes.Subjects, materials and methods This was a single-centre, randomised, double-blind study in drug-naive patients with type 2 diabetes. Patients received vildagliptin (50 mg twice daily, n=15) or placebo (n=16) for 4 weeks. Triglyceride, cholesterol, lipoprotein, glucose, insulin, glucagon and glucagon-like peptide-1 (GLP-1) responses to a fat-rich mixed meal were determined for 8 h postprandially before and after 4 weeks of treatment.Results Relative to placebo, 4 weeks of treatment with vildagliptin decreased the AUC_0–8h for total trigyceride by 22±11% (p=0.037), the incremental AUC_0–8h (IAUC_0–8h) for total triglyceride by 85±47% (p=0.065), the AUC_0–8h for chylomicron triglyceride by 65±19% (p=0.001) and the IAUC_0–8h for chylomicron triglyceride by 91±28% (p=0.002). This was associated with a decrease in chylomicron apolipoprotein B-48 (AUC_0–8h, −1.0±0.5 mg l⁻¹ h, p=0.037) and chylomicron cholesterol (AUC_0–8h, −0.14±0.07 mmol l⁻¹ h, p=0.046). Consistent with previous studies, 4 weeks of treatment with vildagliptin also increased intact GLP-1, suppressed inappropriate glucagon secretion, decreased fasting and postprandial glucose, and decreased HbA_1c from a baseline of 6.7% (change, −0.4±0.1%, p<0.001), all relative to placebo.Conclusions/interpretation Treatment with vildagliptin for 4 weeks improves postprandial plasma triglyceride and apolipoprotein B-48-containing triglyceride-rich lipoprotein particle metabolism after a fat-rich meal. The mechanisms underlying the effects of this dipeptidyl peptidase IV inhibitor on postprandial lipid metabolism remain to be explored.     

微粒体甘油三酯转移蛋白基因多态性与2型糖尿病血脂紊乱的关系

微粒体甘油三酯转移蛋白 (ｍｉｃｒｏｓｏｍａｌｔｒｉｇｌｙｃｅｒｉｄｅｔｒａｎｓ ｆｅｒｐｒｏｔｅｉｎ ,ＭＴＰ)是肝脏、小肠细胞合成和分泌含载脂蛋白Ｂ(ａｐｏＢ)的脂蛋白所必需的脂质转移蛋白 ,具有促进转运甘油三酯、胆固醇酯和磷脂酰胆碱的作用〔1〕。该基因启动子区域内ＭＴＰ 493位点上的单碱基突变能够影响血浆低密度脂蛋白 (ＬＤＬ)的水平〔2〕,因此认为ＭＴＰ启动子区域内的基因多态性与心血管疾病密切相关。本研究旨在了解 2型糖尿病及正常人群中ＭＴＰ基因多态性及此基因与 2型糖尿病脂质代谢的关系。一、对象和方法1.对…     

Atorvastatin reduces postprandial accumulation and cholesteryl ester transfer protein-mediated remodeling of triglyceride-rich lipoprotein subspecies in type IIb hyperlipidemia

The effect of atorvastatin, at 10 mg or 40 mg for 6 wk, on lipid and lipoprotein metabolism during the postprandial phase in subjects (n = 11) displaying type IIB hyperlipidemia was evaluated. The postprandial increment in area under the curve above baseline concentrations in type IIB subjects was significantly decreased by atorvastatin for plasma triglyceride (A10: -42% and A40: -55%, P < 0.01), chylomicrons (CMs) (A10: -24% and A40: -40%, P < 0.03) and VLDL-1 (A10: -54% and A40: -52%, P < 0.02). Before atorvastatin therapy, postprandial cholesteryl ester (CE) transfer from high-density lipoprotein (HDL) to CMs (2.5-fold; P < 0.005), very low-density lipoprotein (VLDL)-1 (1.8-fold; P < 0.005), VLDL-2 (1.4-fold; P < 0.05), and intermediate-density lipoproteins (1.4-fold; P < 0.05) were significantly increased 4 h postprandially. Following statin treatment, the postprandial transfer of CE from HDL to triglyceride-rich lipoproteins (TRLs) at the 4-h time point was significantly reduced at 10 mg/d (-26%; P < 0.05) and at 40 mg/d (-24%; P < 0.05), compared with that before treatment. Such postprandial increase in CE transferred from HDLs to TRLs arose exclusively from accelerated CE transfer from HDLs to CMs (2.5-fold; P < 0.005). In conclusion, atorvastatin attenuates the abnormal intravascular remodeling of postprandial TRL particles via marked reduction in CE transfer in type IIB hyperlipidemia and diminishes the postprandial formation and accumulation of CMs and VLDL-1.     

Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in Type 2 (non-insulin-dependent) diabetic and non-diabetic subjects

Summary The purpose of the present study was to examine 10-year cardiovascular morbidity and mortality in patients with newly-diagnosed Type 2 (non-insulin-dependent) diabetes mellitus and non-diabetic control subjects and to evaluate the effects of general risk factors, plasma insulin, urinary albumin excretion, lipoprotein abnormalities characteristic of Type 2 diabetes and the degree of hyperglycaemia in diabetic patients on cardiovascular mortality. Furthermore, the extent to which the above-mentioned factors could contribute to the excessive cardiovascular mortality observed in diabetic patients was examined. In the years 1979–1981, altogether 133 (70 men, 63 women) newly-diagnosed patients with Type 2 diabetes and 144 (62 men, 82 women) non-diabetic control subjects aged 45–64 years were studied. Both groups were re-examined in the years 1985–1986 and 1991–1992. The impact of different factors on cardiovascular mortality was examined by univariate analyses after adjustment for age and sex and by multiple logistic regression analyses. The age-standardized total and cardiovascular mortality rates were substantially higher in diabetic men (17.8 and 15.0%, total and cardiovascular mortality, respectively p = 0.06 and NS) and women (18.5 and 16.6%, p<0.01 for both) than in non-diabetic control men (5.2 % both total and cardiovascular mortality) and women (4.2 and 2.2 %). Cardiovascular mortality was not related to the treatment modality (diet, oral drugs, insulin) at 5 years from diagnosis. Use of diuretics, beta-blocking agents or their combination at baseline did not make a significant contribution to cardiovascular mortality either. In multiple logistic regression analysis on diabetic patients, age, LDL triglycerides, smoking, blood glucose and ischaemic ECG at baseline had independent associations with cardiovascular mortality. Interestingly, urinary albumin excretion rate measured at 5-year examination also predicted 10-year cardiovascular mortality after adjustment for the effects of major risk factors including lipoprotein abnormalities, but its predictive power reduced to a nonsignificant level when the effect of plasma glucose was taken into account. The relative risk of cardiovascular mortality associated with diabetes was 8.2 after allowing for age alone, but it declined to 3.7 when all contributing factors from the baseline examination (except blood glucose) were taken into account. In conclusion, the present results indicate that LDL triglycerides and/or other changes in lipoprotein composition characteristic of Type 2 diabetes and manifesting as elevated serum triglycerides are atherogenic and they strongly predict increased cardiovascular mortality. Furthermore, it is hypothesized that the consequences of long-term hyperglycaemia could explain a large proportion of the remaining excessive cardiovascular mortality risk among Type 2 diabetic patients.     

Gender-related difference in relationship between insulin resistance and serum leptin level in Japanese type 2 diabetic and non-diabetic subjects

It remains controversial whether or not a correlation exists between serum leptin levels and insulin resistance, and, if such a correlation does exist, whether it is independent of adiposity. To investigate the possible existence of an independent correlation, we have assessed serum leptin levels and insulin resistance in Japanese diabetic and non-diabetic subjects by means of Homeostatic Model Assessment (HOMA-R). Sixty-four Japanese patients with Type 2 diabetes mellitus (DM) (33 men and 31 women) and 53 sex-, age-, and body mass index (BMI)-matched non-diabetic adults (29 men and 24 women) were enrolled. The fasting plasma level of glucose (FPG) and the fasting serum levels of immunoreactive insulin (FIRI) and leptin were determined. Multiple linear regression analysis demonstrated that, in both male diabetic and male non-diabetic subjects, HOMA-R and BMI were independently correlated with serum leptin levels. In females, BMI, but not HOMA-R, was correlated to the serum levels of leptin in both groups. There was no statistically significant difference in the partial regression coefficients between male diabetic and male non-diabetic subjects. These results suggest that the correlation of HOMA-R to the serum levels of leptin in females is dependent on BMI. In males, the relationship between serum leptin levels and the insulin resistance was not affected by the extent of glucose intolerance.     

MTP基因多态性与2型糖尿病血管并发症的关系

目的 探讨微粒体甘油三酯转移蛋白（MTP）基因多态性与2型糖尿病（T2DM）血管并发症的关系。方法 采用PCR—RFLP法和基因测序技术测定MTP-493位点基因型，根据大血管并发症分组进行统计学分析。结果 （1）MTP-493位点存在G—T的单碱基变异。MTP基因型频率和T等位基因频率在T2DM有或无大血管并发症组间差异有统计学意义（χ^2=9．162，P=0．01；χ^2=10．322，P=0．001）。（2）与GG或GT组相比，TT组患者的TG、TC、VLDL—C、LDL-C水平均明显升高（P〈0．05），HDL-C明显降低（P=0．009）或有降低趋势。（3）Logistic多元逐步回归分析显示T等位基因、年龄、糖尿病病程、舒张压、TC是T2DM大血管病变的独立危险因素。HDL-C与T2DM大血管病变发生呈负相关。结论 携带MTP-493TT基因型者易出现致动脉硬化性血脂异常，该基因型的糖尿病患者易出现大血管并发症。     

Levels of adhesion molecules bear a relationship to triglyceride levels in type 2 diabetic subjects with proven silent ischemia

AIM: The aim of the study was to examine the levels of adhesion molecules, high-sensitivity C-reactive protein (hs-CRP) and lipid spectrum of type 2 diabetic subjects with proven silent myocardial ischemia. METHODS: We included in the study 19 patients with ischemia (Group 1) and 16 patients without ischemia (Group 2). We documented silent ischemia by an exercise-myocardial single photon emission computed tomography. We examined the levels of total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, vascular cell adhesion molecule 1, intercellular adhesion molecule 1, E-selectin, HbA1c, microalbuminuria (MAU), hs-CRP and carotid intima-media thickness. RESULTS: The differences among the values of lipids, adhesion molecules, HbA1c, hs-CRP, MAU between the groups were not statistically significant. E-selectin levels positively correlated with triglyceride levels in the group 1 (Spearman correlation, P<0.05). This correlation was not proven in the Group 2. CONCLUSION: Statistically differences between the study groups were not significant. Levels of E-selectin positively correlated with high triglyceride levels in type 2 diabetic subjects with silent ischemia. This correlation documents a disturbance of the reverse cholesterol transport system.     

Intensive insulin therapy reduces small dense low-density lipoprotein particles in patients with type 2 diabetes mellitus: relationship to triglyceride-rich lipoprotein subspecies

It remains unclear whether insulin improves dyslipidemia in patients with type 2 diabetes mellitus. Small dense low-density lipoprotein (sd-LDL) particles are recognized as a powerful risk factor for coronary heart disease and are often elevated in type 2 diabetes mellitus. We examined the effect of intensive insulin therapy on sd-LDL particles and triglyceride (TG)-rich lipoprotein subspecies. Intensive insulin therapy (insulin aspart [NovoRapid, Tokyo, Japan] before each meal and isophane insulin suspension at bedtime) was given to poorly controlled type 2 diabetic patients (n = 46) who were on high doses of sulfonylureas. Fasting serum samples were collected before and 14 days after the commencement of insulin therapy. Low-density lipoprotein size was measured by gradient gel electrophoresis, and the small dense LDL cholesterol (sd-LDL-C) concentration was measured by a new precipitation method. Chylomicrons (Svedberg flotation unit >400), very low-density lipoprotein 1 (VLDL1) (Sf, 60-400), and VLDL2 (Sf, 20-60) were separated by ultracentrifugation. Serum apolipoprotein B-48 and lipoprotein lipase levels were measured by the enzyme immunoassay method. Serum glucose and glycoalbumin levels were substantially decreased by insulin treatment. The LDL size increased (25.8-26.0 nm, P < .05) and the sd-LDL-C level was significantly reduced (44-34 mg/dL, P < .005). Apolipoproteins B-48 and C-III were decreased, whereas lipoprotein lipase was increased. Triglyceride levels in chylomicrons, VLDL1, and VLDL2 all showed a decrease. Changes of sd-LDL-C or LDL size were associated with changes of the TG levels in the major TG-rich lipoprotein subspecies. These results suggest that intensive insulin therapy decreases atherogenic sd-LDL particles by reducing TG in TG-rich lipoproteins. We did not find any specific relationship between VLDL1 and sd-LDL during insulin treatment.     

Effects of short-term low- and high-carbohydrate diets on postprandial metabolism in non-diabetic and diabetic subjects

Background and aimLow-fat high-carbohydrate diets raise plasma triacylglycerol (TG) concentrations. To test whether the nature of the carbohydrate affects metabolic responses, we conducted a randomized cross-over study using a short-term, intensive dietary modification.Methods and resultsEight non-diabetic subjects and four subjects with diet-controlled type 2 diabetes participated. They followed three isoenergetic diets, each for 3 days: high-fat (50% energy from fat), high-starch and high-sugar (each 70% energy from carbohydrate). Normal foods were provided. We measured plasma TG and glucose concentrations, fasting and after a standard test meal, on day 4 following each dietary period. Fasting TG concentrations were greatest following the high-sugar diet (mean ± SEM for all subjects 1900 ± 420 μmol/l) and lowest following high-fat (1010 ± 130 μmol/l) (P = 0.001); high-starch (mean 1500 ± 310) and high-fat did not differ significantly (P = 0.06). There was a greater effect in the diabetic subjects (diet × diabetes status interaction, P = 0.008). Postprandial TG concentrations were similarly affected by prior diet (P < 0.001) with each diet different from the others (P ≤ 0.01). The elevation of fasting TG on the high-sugar versus high-fat diet was strongly related to the average fasting TG concentration (P = 0.01 across both diabetic and non-diabetic subjects). Fasting glucose concentrations were not affected by prior diet but postprandial glucose concentrations were (P = 0.018), with significantly higher values after the high-fat than the high-sugar diet (P = 0.03).ConclusionsThe short-term TG-raising effect of a very low-fat diet is dependent upon the nature of the carbohydrate, with a greater effect of a sugar-rich than a complex-carbohydrate-rich diet.     

The effect of low density lipoprotein composition on the regulation of cellular cholesterol synthesis: a comparison in diabetic and non-diabetic subjects

This study investigates compositional differences in low density lipoprotein (LDL) subfractions and their relationship to cellular cholesterol synthesis. We examined ten normocholesterolaemic (serum cholesterol <6.5 mM) non-diabetic subjects (group 1) and compared them with ten normocholesterolaemic (group 2) and ten hypercholesterolaemic (group 3) (serum cholesterol >6.5 mM) type 2 (non-insulin-dependent) diabetic patients. Serum cholesterol levels for groups 1, 2 and 3 were 5.19±0.27, 5.20±0.27 and 7.51±0.31 mM. LDL₁ (density 1.006–1.028 g/l) and LDL₂ (1.028–1.063 g/l) were isolated by density gradient ultracentrifugation. A significantly greater proportion of cholesterol was carried in LDL₂ than LDL₁ in all groups. There was a significantly lower cholesterol/protein ratio in LDL₁ from the hypercholesterolaemic diabetic patients compared with controls. The LDL esterified/free cholesterol ratio was significantly greater in both LDL₁ and LDL₂ in the hypercholesterolaemic diabetic patients compared with the other two groups. There was a negative correlation between inhibition of cholesterol synthesis and the esterified/free cholesterol ratio of both LDL₁ (r=0.56,P<0.002) and LDL₂ (r=0.63,P<0.001). Cellular cholesterol of 41.0±0.3 g/mg cell protein in the hypercholesterolaemic diabetic patients was also significantly higher compared with values of 30.32±2.0 and 34.1±4.2 g/mg cell protein for the normocholesterolaemic non-diabetic and diabetic groups. In vitro LDL esterification led to a decrease in LDL receptor-mediated binding and resulted in a 40% reduction in the ability of the LDL to suppress cholesterol synthesis. The study demonstrates a relationship between the LDL esterified/free cholesterol ratio, LDL receptor binding and cellular cholesterol and may have implications for the understanding of hypercholesterolaemia in diabetes.     

Determinants of postprandial triglyceride and remnant-like lipoproteins in type 2 diabetes

BACKGROUND: Postprandial changes in remnant-like lipoprotein particles (RLP) contribute to the severity of coronary heart disease in type 2 diabetes. Since the determinants of postprandial response in RLP are not well understood, this study investigated the roles of fasting triglyceride, apolipoprotein (apo) E polymorphism and insulin resistance in a group of overweight/obese Chinese type 2 diabetic subjects. METHODS: Postprandial triglyceride (TG) and RLP-cholesterol (RLP-C) were determined after a mixed meal containing 70-g fat at 2-h intervals for 8 h in 32 normotriglyceridemic (NTG) and 31 hypertriglyceridemic (HTG) subjects. RLP-C was measured using an immunoseparation assay and apo E genotypes using polymerase chain reaction and restriction mapping. Insulin resistance was defined as homeostasis model assessment index (HOMA-IR). RESULTS: The HTG subjects had greater postprandial increase in TG and RLP-C than NTG (p < 0.001), but there were no significant differences in HOMA-IR and apo E allele frequencies. Subjects who were non-E3-carriers had the largest postprandial increment in TG and RLP-C. On stepwise linear regression analysis, log(HOMA-IR) was only an independent determinant of fasting TG but not postprandial TG or RLP-C. The major determinants of fasting and postprandial RLP-C were fasting TG and apo E genotype, accounting for 53 and 6% of the variance of fasting RLP-C (p < 0.01) and 31 and 13% of the variance of postprandial RLP-C respectively (p < 0.01). CONCLUSIONS: Insulin resistance is mainly a determinant of fasting triglyceride in Chinese type 2 diabetic subjects, whereas apo E genotype is a better predictor of both fasting and postprandial concentrations of RLP.     

Effect of the microsomal triglyceride transfer protein -493 G/T polymorphism and type 2 diabetes mellitus on LDL subfractions

Genetic variation in the microsomal triglyceride transfer protein (MTP) affects the secretion pattern and plasma concentration of apolipoprotein (aopB)-containing lipoproteins and a common functional -493 G/T polymorphism has been reported to influence plasma lipids levels. Recent data suggest that carriers of the T allele might be more sensitive to detrimental factors such as features of the insulin resistance syndrome. Since type 2 diabetes is associated with obesity and insulin resistance, the present study investigated the effect of this polymorphism on plasma lipids, apoB and LDL subfractions in 281 Chinese type 2 diabetic subjects and 364 non-diabetic controls. The frequency of the rare T allele was 0.162 and 0.126 in subjects with and without diabetes respectively. There were no differences in the effect of the polymorphism on plasma lipids and apoB in the two groups. However, the TT genotype was associated with a higher concentration of small dense LDL-III than the GT or GG variants in the diabetic subjects (P=0.01) whereas no such effect was observed in the controls. In the diabetic patients, age, plasma triglyceride and the MTP genotype were independent determinants of LDL-III concentrations in linear regression analysis (R(2)=10%, P=0.04) whereas in the controls, only plasma triglyceride and age were important determinants (R(2)=15%, P=0.01). In conclusion, the -493 G/T polymorphism only has a minor effect on LDL subfraction pattern in Chinese and the effect is only apparent in the presence of type 2 diabetes.     

Acute effects of casein on postprandial lipemia and incretin responses in type 2 diabetic subjects

Background and aimsExaggerated and prolonged postprandial lipemia is potentially atherogenic and associated with type 2 diabetes. Limited data exist regarding the influence of dietary protein on postprandial lipemia in type 2 diabetes. We investigated, over 8-h, the acute effects of casein alone or in combination with carbohydrate on postprandial lipid and incretin responses to a fat-rich meal in type 2 diabetes.Methods and resultsEleven type 2 diabetic subjects ingested four test meals in random order: an energy-free soup plus 80 g of fat (control-meal); control-meal plus 45 g carbohydrates (CHO-meal); control-meal plus 45 g of casein (PRO-meal); and PRO-meal plus 45 g carbohydrates (CHO + PRO-meal). Triglyceride and retinyl palmitate responses were measured in plasma and in a chylomicron-rich and chylomicron-poor fraction. We found no significant differences in triglyceride responses to PRO- and CHO + PRO-meal compared to the control-meal. However, the addition of casein to the CHO-meal reduced the raised triglyceride response in the chylomicron-rich fraction. Retinyl palmitate responses did not differ significantly between meals in the chylomicron-rich fraction, whereas the PRO-meal increased retinyl palmitate in the chylomicron-poor fraction. PRO- and PRO + CHO-meal increased insulin and glucagon compared to the control-meal. PRO + CHO-meal increased the glucose-dependent insulinotropic peptide response while no change in glucagon-like peptide-1 responses was detected.ConclusionsThe data presented suggest that casein per se did not modulate the postprandial triglyceride response in type 2 diabetes. When added to carbohydrate, casein suppressed the triglyceride response in the chylomicron-rich fraction, increased insulin and glucagon but did not affect the incretin responses.     

Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice

Although many steatogenic drugs inhibit mitochondrial fatty acid beta-oxidation, limited information is available on possible effects on hepatic lipoprotein secretion. In the endoplasmic reticulum (ER) lumen, microsomal triglyceride transfer protein (MTP) lipidates apolipoprotein B (Apo B), to form triglyceride (TG)-rich very low density lipoprotein (VLDL) particles, which follow vesicular flow to the plasma membrane to be secreted, whereas incompletely lipidated Apo B particles are partly degraded. We studied hepatic MTP activity, the lipoproteins present in the ER lumen, and hepatic lipoprotein secretion 4 hours after administration of a single dose of amineptine (1 mmol/kg), amiodarone (1 mmol/kg), doxycycline (0.25 mmol/kg), tetracycline (0.25 mmol/kg), tianeptine (0.5 mmol/kg), or pirprofen (2 mmol/kg) in mice. These various doses have been shown previously to markedly inhibit fatty acid oxidation after a single dose, and to trigger steatosis either after repeated doses (doxycycline) or a single dose (other compounds) in mice. In the present study, amineptine, amiodarone, pirprofen, tetracycline, and tianeptine, but not doxycycline, inhibited MTP activity in vitro, decreased ex vivo MTP activity in the hepatic homogenate of treated mice, decreased TG in the luminal VLDL fraction of hepatic microsomes of treated mice, and decreased in vivo hepatic lipoprotein secretion (TG and Apo B). In conclusion, several steatogenic drugs inhibit not only mitochondrial beta-oxidation, as previously shown, but also MTP activity, Apo B lipidation into TG-rich VLDL particles, and hepatic lipoprotein secretion. Drugs with these dual effects may be more steatogenic than drugs acting only on beta-oxidation or only MTP.     

An inhibitor of the microsomal triglyceride transfer protein inhibits apoB secretion from HepG2 cells.

The microsomal triglyceride (TG) transfer protein (MTP) is a heterodimeric lipid transfer protein that catalyzes the transport of triglyceride, cholesteryl ester, and phosphatidylcholine between membranes. Previous studies showing that the proximal cause of abetalipoproteinemia is an absence of MTP indicate that MTP function is required for the assembly of the apolipoprotein B (apoB) containing plasma lipoproteins, i.e., very low density lipoproteins and chylomicrons. However, the precise role of MTP in lipoprotein assembly is not known. In this study, the role of MTP in lipoprotein assembly is investigated using an inhibitor of MTP-mediated lipid transport, 2-[1-(3, 3-diphenylpropyl)-4-piperidinyl]-2,3-dihydro-1H-isoindol-1-o ne (BMS-200150). The similarity of the IC50 for inhibition of bovine MTP-mediated TG transfer (0.6 microM) to the Kd for binding of BMS-200150 to bovine MTP (1.3 microM) strongly supports that the inhibition of TG transfer is the result of a direct effect of the compound on MTP. BMS-200150 also inhibits the transfer of phosphatidylcholine, however to a lesser extent (30% at a concentration that almost completely inhibits TG and cholesteryl ester transfer). When BMS-200150 is added to cultured HepG2 cells, a human liver-derived cell line that secretes apoB containing lipoproteins, it inhibits apoB secretion in a concentration dependent manner. These results support the hypothesis that transport of lipid, and in particular, the transport of neutral lipid by MTP, plays a critical role in the assembly of apoB containing lipoproteins.