Effect of pioglitazone on atherogenic outcomes in type 2 diabetic patients: a comparison of responders and non-responders

The aim of this study was to evaluate the anti-atherogenic efficacy of pioglitazone, a thiazolidinedione derivative, on the change in atherogenic outcomes by comparing responder and non-responder groups in type 2 diabetic patients. Twenty-three patients with poor diabetic control were treated with 15 mg of pioglitazone for 12 months. The levels of fasting plasma glucose (FPG), HbA1c, triglycerides (TG), total cholesterol (T-Cho), low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C) were measured monthly, and those of remnant-like particle-cholesterol (RLP-C) and lipoprotein (a) [Lp (a)] were measured every 3 months. In Month 6, the patients were divided into two groups according to the decrease in HbA1c level: the responder group showed a decrease of > or =1%; the non-responder group, a decrease of <1%. In the responder group, the levels of FPG and HbA1c decreased significantly after Month 3. The values of the body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR) index, LDL-C, and RLP-C were significantly higher in the responder group than in the non-responder group. Although the levels of T-Cho and HDL-C were unchanged in both groups, those of TG and RLP-C were drastically reduced in the responder group. Interestingly, the relative change in Lp (a) was significantly decreased in both groups. These results strongly suggest that pioglitazone is beneficial for type 2 diabetic patients with high levels of BMI, HOMA-IR, LDL-C, and RLP-C, as it helps to prevent the progression of atherosclerosis, including coronary heart diseases.     

Postprandial elevation of remnant lipoprotein leads to endothelial dysfunction.

Recent studies have demonstrated that elevated levels of cholesterol in the form of remnant-like particles (RLP-C) induce deterioration of endothelial function during the fasting state, but it is not known whether postprandial RLP-C elevation has the same effect. The objective of this study was to assess the effect of postprandial RLP-C elevation on endothelial function in 24 fasting normolipidemic subjects. Flow-mediated dilatation (FMD) during reactive hyperemia in the brachial artery was investigated. Serum lipids and lipoproteins during fasting and 4h after regular fat-loading were measured. Subjects were divided into 2 groups: the high responders (postprandial RLP-C level >7.5mg/dl, n=8) and the normal responders (postprandial RLP-C level < or =7.5mg/dl, n=16). Significant increases in the level of both triglycerides and RLP-C were observed in the high responders. Basal FMD in the high responders (4.3+/-3.0%) was significantly lower than that in the normal responders (8.3+/-2.4%) (p<0.01), but FMD after the fat-loading in both groups did not change significantly. The change in RLP-C levels during the fat-loading test correlated significantly with basal FMD (r=-0.588, p<0.01). Multiple regression analysis showed a significant correlation between basal FMD and the change in RLP-C levels (r=-0.488, p<0.02). The results of this study suggest that postprandial RLP-C elevation could be associated with atherosclerotic progression even in normolipidemic subjects.     

Cilostazol,a potent phosphodiesterase type III inhibitor,selectively increases antiatherogenic high-density lipoprotein subclass LpA-I and improves postprandial lipemia in patients with type 2 diabetes mellitus

Low levels of high-density lipoproteins cholesterol (HDL-C) as well as impaired postprandial lipemia are known to be associated with the increased risk for coronary artery disease (CAD) in patients with type 2 diabetes mellitus (type 2 DM). HDL are heterogeneous in size and apolipoprotein composition. Recent evidence indicates that among the 2 major HDL subclasses, those without apolipoprotein A-II (LpA-I) are more antiatherogenic compared with those with apoA-II (LpA-I:A-II). Cilostazol, a novel selective phosphodiesterase type III inhibitor, has been shown to inhibit platelet activation and is also a potent vasodilator. Additionally, cilostazol has been shown to modulate lipoprotein profiles by raising HDL-C and lowering plasma triglyceride (TG) levels. The present study investigated the effect of cilostazol on HDL composition (LpA-I and LpA-I:A-II levels) and postprandial lipemia in patients with type 2 DM. Seventeen patients were given cilostazol 200 mg twice daily for 12 weeks. At weeks 0 and 12, fat tolerance tests (30 g/m(2)) were performed to assess postprandial lipemia. Plasma TG and remnant-like lipoprotein particles cholesterol (RLP-C) were significantly decreased by 17% and 26%, respectively (P <.05), and HDL-C was significantly increased by 14% (P <.01). LpA-I was significantly increased by 23% (P <.01) from the mean value of 45 mg/dL to 55 mg/dL. In contrast, LpA-I:A-II remained unchanged, resulting in significantly increased %LpA-I (apoA-I on LpA-I/total apoA-I x 100) from 35% to 40% (P <.01). Areas under the curve for TG and RLP-C after the fat meal were both nonsignificantly decreased by 17%. Patients with higher plasma TG levels had a greater benefit from the treatment with cilostazol as revealed by fasting TG levels and fat tolerance tests. HDL-C responses to cilostazol were independent of baseline plasma TG levels or percentage changes in TG, indicating that the underlying mechanisms for raising HDL and reducing TG levels are distinct. In conclusion, cilostazol selectively increased LpA-I, thus favorably altering HDL towards a more antiatherogenic composition. This finding, together with the improved postprandial lipemia, indicates that cilostazol has a potent antiatherogenic function by modulating HDL and remnant metabolism in patients with type 2 DM.     

Effect of a mixed meal on plasma lipids,insulin resistance and systemic inflammation in non-obese Indian adults with normal glucose tolerance and treatment naïve type-2 diabetes

Aim

Asian Indians are believed to have a lower capacity to clear a glucose load even during normoglycemia. High post meal glucose levels have been linked to postprandial dyslipidemia and generation of proinflammatory cytokines. Since humans spend most of their time in the postprandial state, the present study aims to evaluate the relationship of insulin resistance (IR) in the basal state with dyslipidemia and systemic inflammation (hs-CRP, IL-6 and TNF-a), in the fasting state, 2 h and 4 h after a mixed meal, in Indian adults with normal glucose tolerance, and new onset type-2 diabetes.

Methods

Forty-eight people with type 2 diabetes and 32 individuals with normoglycemia, 30–70 years age, not on medications, underwent blood sampling after overnight (12 h) fast and 2 and 4 h after a mixed meal (carbohydrates, proteins and fat content 79.1%, 7.7% and 13.2%, respectively).

Results

Triglyceride (TG), TG/HDL-C (high density lipoprotein), HDL-C/LDL-C (low density lipoprotein) ratios, IR parameters, and inflammatory markers were significantly higher among patients with diabetes. There was a fall in total cholesterol (TC), HDL-C and LDL-C at 2 and 4 h after the meal in both groups. Compared with fasting, 4-h postprandial TC, TG and HDL-C were significantly better positively correlated with IR in normal individuals. Postprandial hs-CRP was not significantly different to fasting in both groups. Postprandial IL-6 and TNF-α were significantly lower in both groups.

Conclusion

Consumption of a carbohydrate rich meal is associated with a rise in TG and fall in TC, HDL-C, LDL-C, IL-6 and TNF-α among normal individuals and people with type 2 diabetes.     

Postprandial remnant-like lipoproteins in hypertriglyceridemia.

It has been proposed that remnants of chylomicrons and very-low-density lipoproteins (VLDL) are atherogenic. We have used an immunochemical method to isolate remnant-like particles (RLP) and measured them in terms of their cholesterol and triglycerides (TG). RLP consist of apoB-48-containing triglyceride-rich lipoproteins and remnant-like VLDL containing apoB-100. The study aim was to look for information from postprandial RLP data that could not be known from other markers of triglyceride-rich lipoproteins and fasting TG and RLP data alone. A total of 41 subjects were studied. Eight subjects had hypertriglyceridemia (HTG) and low high-density lipoprotein (HDL), 14 had combined hyperlipidemia (CH), 5 had the apo E2/2 genotype receiving gemfibrozil, 10 were normolipidemic (NL) controls, and 4 had hypercholesterolemia. As a whole group, there was correlation among 1) fasting TG, RLP cholesterol (RLP-C), and RLP-TG but not VLDL apo B100, VLDL apo B48 and their respective postprandial responses measured as incremental area under the curve (IAUC), 2) fasting TG and postprandial IAUC of RLP-C and RLP-TG, 3) RLP-C IAUC, RLP-TG IAUC, and TG IAUC, retinyl palmitate (RP) IAUC, and VLDL apo B48 IAUC but not VLDL apo B100 IAUC. The HTG/low HDL-C and CH groups had higher IAUC for RLP-C, RLP-TG, TG, and RP than the NL group. Fasting and postprandial RLP were triglyceride enriched in the HTG/low HDL-C group and to a lesser extent in the CH group. The HTG/low HDL-C and CH groups had a delay in their RLP-C but not RLP-TG peaks suggesting a delay in hepatic clearance of RLP and/or a protracted period of lipolysis and/or processing of RLP. The fasting and postprandial RLP-C/RLP-TG and RLP-C/TG ratios were elevated in the apo E2/2 group in spite of gemfibrozil therapy. The increment in postprandial RLP was, however, not exaggerated. Our data indicate that 1) postprandial RLP lipemia is enhanced in HTG subjects when compared with NL subjects, 2) postprandial RLP lipemia is proportional to fasting RLP and TG levels and mirrors, to a large extent, increases in postprandial TG, RP, and VLDL apo B48 but not VLDL apo B100, 3) there are compositional differences in fasting and postprandial RLP in the three forms of HTG studied, RLP being triglyceride enriched in the HTG/low HDL-C group and to a lesser extent in the CH group, and cholesterol-enriched in the apo E2/2 group, and 4) apo E2/2 subjects had high fasting and postprandial RLP-C concentrations in spite of being on treatment with gemfibrozil and having normal fasting and postprandial TG concentrations.     

The close relationship between postprandial remnant metabolism and insulin resistance

The aim of this study was to investigate the relationship between postprandial remnant-like particle (RLP) metabolism and insulin resistance (IR). The study group consisted of 52 randomly selected subjects. To evaluate postprandial hyperlipidemia, serum lipid and lipoprotein concentrations during fasting and 4h after the fat-loading test were measured in each subject. IR was assessed using the index of homeostasis model assessment (HOMA-R). The subjects were divided into two groups according to the value of HOMA-R: an IR group (n=17) with a HOMA-R value >/=1.73, and a normal (NR) group (n=35) with a HOMA-R value <1.73. Both fasting and postprandial RLP-cholesterol (RLP-C) concentrations were higher in the IR group than in the NR group (6.2+/-2.6 versus 4.1+/-1.7mg/dl fasting value, and 9.7+/-4.0 versus 5.8+/-2.9mg/dl postprandial value). The changes in RLP-C concentration during the fat-loading test were twice as high in the IR group compared with the NR group (3.5+/-2.4 versus 1.6+/-1.6mg/dl, P=0.0022). The HOMA-R correlated significantly with both fasting and postprandial triglyceride (r=0.41 and 0.43, respectively) and RLP-C (r=0.36 and 0.50, respectively) in all subjects. Multiple regression analysis indicate that postprandial RLP-C concentration was an independent predictor of HOMA-R regardless of age, BMI, and other lipid profiles. Thus, postprandial RLP metabolism is closely related to IR. Atherosclerotic proliferation in IR syndrome may be caused by the accumulation of postprandial remnant lipoproteins after the daily fat intake.     

空腹甘油三酯正常的2型糖尿病患者餐后血脂的动态变化

目的探讨空腹甘油三酯正常的2型糖尿病患者脂肪餐后血脂水平的动态变化。方法通过脂肪餐负荷试验对25例空腹甘油三酯正常的2型糖尿病患者和20例健康对照者进行餐后血脂代谢的研究。分别于餐前、餐后2、4、6和8h用酶法测定总胆固醇和甘油三酯,一步法测定高低密度脂蛋白,葡萄糖氧化酶法测定血糖,化学发光免疫分析法测定免疫反应胰岛素,计算曲线下甘油三酯面积和增加面积。结果两组餐后甘油三酯平均值都有所升高,峰值在餐后4h。但糖尿病组餐后8h甘油三酯仍明显高于空腹水平(P<0.05),而对照组在餐后8h甘油三酯已恢复接近空腹水平(P>0.05)。两组的高密度脂蛋白在餐后4h都有一个轻微的低谷出现,但无组间差异(P>0.05)。总胆固醇和低密度脂蛋白在餐后无明显变化。两组曲线下甘油三酯面积和增加面积与餐后4h血清甘油三酯水平的相关性最显著(P<0.05)。结论2型糖尿病患者餐后脂代谢异常发生在空腹血脂异常之前。有必要联合检测空腹与餐后4h的甘油三酯水平来全面反映甘油三酯代谢是否存在异常。     

Effect of fibrates on postprandial remnant-like particles in patients with combined hyperlipidemia

We have investigated the effect of standard doses of two fibrates, gemfibrozil and fenofibrate, on fasting and postprandial remnant-like particles (RLP) in subjects with combined hyperlipidemia. Forty-eight subjects participated; of these, 14 underwent a Vitamin A-fat loading test before and after 6 months of treatment with gemfibrozil (n = 8) and fenofibrate (n = 6). Blood was drawn every 2h for 12h after the test meal. The postprandial response was calculated as the area under the curve (AUC). There was no difference in fasting levels and pre-treatment AUC for triglycerides (TG), RLP cholesterol (RLP-C), RLP triglycerides (RLP-TG) and retinyl palmitate (RetP) between the two treatment groups. There was also no difference in the treatment effect on all parameters between the two treatment groups. Combining the two treatment groups, treatment resulted in a significant reduction in fasting levels and AUC of all four parameters. Assigning the difference observed between pre-treatment AUC of the combined study group and AUC of a normolipidemic (NL) control group as 100%, fibrate treatment resulted in decreases in AUC for TG, RLP-C, RLP-TG and RetP of 68, 69, 69 and 94%, respectively. These results indicate that fibrates are effective agents in reducing the postprandial increase in remnant lipoprotein particles.     

A hypertriglyceridemic state increases high sensitivity C-reactive protein of Japanese men with normal glucose tolerance

Both fasting and postprandial hypertriglyceridemia have been identified as risk markers for cardiovascular disease. High-sensitivity C-reactive protein (hs-CRP), known to independently predict future cardiovascular disease, has also been reported to be a direct participant in the progression of atherosclerosis. We evaluated whether or not fasting and/or postprandial hypertriglyceridemia influence hs-CRP of men with normal glucose tolerance. According to the triglyceride (TG) level, measured before and 1 and 2 h after a meal tolerance test, subjects were classified into a normotriglyceridemic (NTG) group (n = 86), a postprandial hypertriglyceridemia (PHTG) group (n = 50), or a fasting hypertriglyceridemia (FHTG) group (n = 53). Hs-CRP and HOMA-R were significantly higher in the FHTG group than in the other groups (P < 0.01). The PHTG group had higher hs-CRP than the NTG group (P < 0.05). No significant differences in age, BMI, LDL cholesterol, or carotid intima-media thickness were found in comparison of the three groups. Multivariate linear regression analysis showed that the area under the TG curve (AUC-TG), HbA1c, and BMI were independently correlated with hs-CRP (P < 0.001, P = 0.016, P = 0.032, respectively). Our data suggests that a hypertriglyceridemic state is associated with hs-CRP irrespective of BMI, LDL-C, and HDL-C, indicating that hs-CRP might represent chronic inflammation induced by hypertriglyceridemia in Japanese men with normal glucose tolerance.     

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.     

Effects of pioglitazone vs glibenclamide on postprandial increases in glucose and triglyceride levels and on oxidative stress in Japanese patients with type 2 diabetes

To investigate the relationship between insulin resistance, postprandial hyperglycemia, postprandial hyperlipidemia, and oxidative stress in type 2 diabetes, changes in postprandial glucose, triglyceride, and nitrotyrosine levels vs baseline after diet loading were examined in type 2 diabetic patients given pioglitazone (PG) or glibenclamide (GB). Twenty-four outpatients with type 2 diabetes treated with oral PG for 6 mo (BMI, 26.3±0.9; HbA1c, 8.2±0.2%) and 10 type 2 diabetic patients treated with GB (BMI, 27.4±1.6; HbA1c, 8.1±0.2%) at our institutions were compared. These patients were given meal tolerance tests (MTT; each consisting of energy 400 kcal, protein 8.7 g, fat 22.4 g, carbohydrate 41 g) before and 6 mo after administration of either agent. PG produced a significant decrease in FPG, HbA1c, HOMA-R, and TG levels in the subjects compared to baseline. In contrast, GB significantly decreased FPG and HbA1c levels, while not affecting HOMA-R and TG values. While PG produced a significant increase in LPL, HDL-cholesterol, and adiponectin levels, GB did not affect these values. At MTT 6 mo after PG administration, insulin levels before and 4 h after MTT, free fatty acid (FFA) levels 1, 2, and 4 h after MTT, glucose, TG, and RLP-TG levels before and 1, 2, 4, and 6 h after MTT were significantly decreased compared to baseline. At MTT6 mo after GB administration, while a significant decrease in fasting and 2 h, postprandial glucose values compared to baseline MTT levels was observed, fasting and postprandial TG and RLP-TG levels remained unchanged compared to baseline. After 6 mo of PG and GB administration, serum nitrotyrosine levels before and after MTT were significantly decreased compared to baseline in both groups, while the decrease in nitrotyrosine levels before and after MTT was more marked in the subjects given PG. Our study results suggest that PG suppresses increases in postprandial glucose and TG levels, and improves insulin resistance; and, in addition, that PG may have a favorable impact on oxidative stress in type 2 diabetic patients.     

代谢综合征患者餐后血脂与颈动脉内膜中层厚度关系的探讨

目的探讨代谢综合征(MS)患者餐后血脂代谢情况及其与颈动脉内中膜厚度(IMT)的相关性。方法选择40名健康人为对照组,60例MS患者为MS组。MS组以空腹甘油三酯为标准(≥1.7mmol/L)分为两个亚组:空腹甘油三酯正常组(MS1)与空腹高甘油三酯组(MS2)。禁食12h后,分别接受高脂肪饮食,于空腹、餐后2、4、6h测定血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)。使用彩超仪检测各组颈动脉IMT。结果餐后血清TG水平显著升高,浓度峰值是4h,TC、LDL-C、HDL-C无明显改变(P>0.05)。MS1组、MS2组餐后TG峰值浓度明显高于对照组(P<0.05)。MS组颈动脉IMT明显增厚,MS1、MS2颈动脉IMT与对照组相比,差异有统计学意义(P<0.05),但MS1与MS2之间差异无统计学意义(P>0.05)。直线相关分析示,年龄、体重指数、腰臀围比、TG0h、TG4h和收缩压均与颈动脉IMT呈显著正相关(r1=0.1513,r2=0.2111,r3=0.2312,r4=0.3441,r5=0.3765,r6=0.1839,P<0.05),且颈动脉IMT与TG4h的相关系数最大。结论MS患者脂肪餐后TG水平异常升高是其血脂代谢异常的重要内容之一,且餐后脂代谢异常常发生在空腹血脂异常之前,易引起动脉粥样硬化,故应常规检测MS患者的餐后血脂和颈动脉IMT。     

Association between LDL particle size and postprandial increase of remnant-like particles in Japanese type 2 diabetic patients

Small, dense LDL, as well as chylomicron- and VLDL-remnant lipoproteins, are known to be important risk factors for coronary heart disease in patients with type 2 diabetes mellitus. The aim of this study was to clarify the relationship between LDL particle size and postprandial remnant lipoprotein levels in Japanese type 2 diabetic patients. Forty-six patients with type 2 diabetes mellitus were divided into tertiles according to LDL particle size. The peak LDL particle diameter was <26.30 nm in tertile 1, 26.30-26.85 nm in tertile 2, and >26.85 nm in tertile 3. After a test meal, tertile 1 had a significantly greater increment of triglycerides (TG), remnant-like particle (RLP)-TG, and RLP-cholesterol (RLP-C) than tertiles 2 and 3. There was a negative correlation between LDL particle size and the postprandial increases of TG, RLP-TG, and RLP-C. These results indicate that smaller sized LDL particles may be a marker of fasting state for an exaggerated postprandial increase of remnant lipoproteins as well as an increase of TG-rich lipoproteins.     

Bezafibrate reduces blood glucose in type 2 diabetes mellitus

The clinical efficacy of bezafibrate was examined with special reference to glucose metabolism in patients with type 2 diabetes mellitus (DM2). In protocol 1, 342 patients with DM2 and hyperlipidemias were randomly divided into 2 groups, 16-week bezafibrate treatment (n = 174) and no bezafibrate treatment (n = 168). In protocol 2, 20 DM2 patients were randomly divided into 2 groups, 8-week bezafibrate treatment (n = 10) and no bezafibrate treatment (n = 10), and a meal tolerance test (MTT) was performed. In protocol 1, bezafibrate treatment significantly reduced the fasting levels of triglyceride (TG) by 50% +/- 1.6%, total cholesterol (TC) by 12% +/- 1.1%, plasma glucose (PG) from 151.3 +/- 3.5 to 128.6 +/- 3.4 mg/dL, and hemoglobin A1c (HbA1c) from 7.2% +/- 0.1% to 6.9% +/- 0.1%, and significantly increased high-density lipoprotein cholesterol (HDL-C) by 20% +/- 0.8%. In protocol 2, fasting TG, PG, and insulin levels were significantly reduced by bezafibrate treatment. Moreover, in the MTT, postprandial increments of TG were significantly blunted after bezafibrate treatment, whereas postprandial PG and insulin levels were not significantly changed. Leptin levels were significantly decreased, while tumor necrosis factor alpha (TNF-alpha) levels were not changed. In conclusion, both hyperglycemia and hyperlipidemia can be improved by bezafibrate treatment in DM2.     

Influence of aging and menopause on postprandial lipoprotein responses in healthy adult women

AIM: To analyze the influence of menopause and age on postprandial lipoprotein responses in healthy adult women. METHOD: Twenty-seven healthy young and middle-aged pre- and postmenopausal female volunteers aged 21-53 y were enrolled. They ingested OFTT cream(Jomo, Takasaki, Japan). Fasting and postprandial blood samples were obtained for up to 6 h, and serum concentrations of lipoproteins were analyzed. RESULTS: In the postprandial phase, serum triglycerides(TG), remnant-like particle(RLP)-TG(RLP-TG), RLP-cholesterol(RLP-C), and TG-rich lipoprotein-TG(TRL-TG)concentrations in all groups peaked after 2 h. After 4 h, the TG, RLP-C, RLP-TG and TRL-TG concentrations in the young women returned to the fasting concentrations. However, at 6 h, these parameters in the pre- and postmenopausal women had barely returned to the fasting concentrations. CONCLUSION: The present results suggest that:(1)the magnitude of postprandial TG concentrations is dependent on age, but not on menopause;(2)clearance of remnant lipoproteins is delayed with age in pre- and postmenopausal women compared to young women, and(3)menopause is associated with an increase of RLP-C, but may not influence LDL particle size.     

Serum CRP levels are equally elevated in newly diagnosed type 2 diabetes and impaired glucose tolerance and related to adiponectin levels and insulin sensitivity

AIMS: To measure the serum highly sensitive C-reactive protein (hs-CRP) and adiponectin levels, assess insulin sensitivity index (SI) and acute insulin response (AIR) in normal control (NC) subjects, patients with impaired glucose tolerance (IGT) and newly diagnosed type 2 diabetes mellitus (DM), and further explore the possible correlation between hs-CRP and SI, AIR and adiponectin in IGT and newly diagnosed type 2 DM groups. METHODS: Age and sex matched 28 normal subjects, 31 patients with IGT, and 31 patients with newly diagnosed type 2 DM were included in the study. SI and AIR were assessed by the reduced sample number of Bergman's minimal model method with intravenous glucose tolerance test in subjects of each group. RESULTS: Compared with NC group, serum hs-CRP was significantly increased in IGT and type 2 DM groups (p < 0.001), although there was no significant difference between the latter groups. Hs-CRP was negatively correlated with high density lipoprotein cholesterol (HDL-C), SI and adiponectin levels (p < 0.05 to p < 0.001), and positively correlated with systolic blood pressure (SBP), fasting plasma glucose (FPG), BMI, waist-to-hip ratio (WHR), postprandial 2h plasma glucose (2hPG), fasting serum insulin (FINS) and postprandial serum insulin (PSI) in IGT and newly diagnosed type 2 DM groups (p < 0.05 to p < 0.001). In general multivariate regression, only adiponectin was the significantly independent determinant for serum hs-CRP (regression coefficient -1.380; 95% CI -2.062 to 0.698, p < 0.001); meanwhile, TG, SI, hs-CRP, FINS, 2hPG and WHR were significantly independent determinants for serum adiponectin concentration (p < 0.05 to p < 0.001). CONCLUSIONS: Elevated serum hs-CRP may play a role in the development of insulin resistance syndrome and type 2 diabetes. This elevation is accompanied by the opposite changes of adiponectin.     

High dose of simvastatin normalizes postprandial remnant-like particle response in patients with heterozygous familial hypercholesterolemia

Familial hypercholesterolemia (FH) and disturbances in postprandial lipoprotein metabolism are both associated with premature atherosclerosis. The effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors on plasma cholesterol levels in patients with FH is well established; however, it is not known whether postprandial lipoproteins are also influenced. In this case-controlled intervention study, we investigated the effects of high-dose simvastatin on postprandial lipoproteins. We used a new method to analyze remnant lipoproteins based on the immunoseparation principle (remnant-like particle cholesterol [RLP-C] assay) and the well-established measurement of retinyl ester (RE) analysis in plasma and in the Svedberg flotation unit (Sf)<1000 fraction. Seven heterozygous FH patients and 7 control subjects matched for sex, age, body mass index, triglycerides, and apolipoprotein E genotype were enrolled in the study. An oral vitamin A (RE) fat-loading test was performed at baseline in both groups and after 3 months of high-dose simvastatin (80 mg/d) treatment in the FH patients. Before treatment, FH patients had significantly higher fasting and postprandial concentrations of lipoprotein remnants (plasma RLP-C 42+/-19 mg/dL and area under the RLP-C curve 415+/-82 mg. L(-1). h(-1), respectively) than did control subjects (7+/-3 mg/dL and 101+/-35 mg. L( -1). h(-1), respectively; P<0.05), suggesting a delayed clearance of chylomicron remnant particles in the FH patients. Treatment with simvastatin significantly reduced fasting and postprandial remnant lipoprotein cholesterol concentrations (13+/-3 mg/dL and 136+/-53 mg. L(-1). h(-1), respectively; P<0.05 for both). Postprandial RE in the Sf<1000 fraction, not total RE in plasma, was also significantly higher in FH patients than in control subjects (24+/-10 versus 6.3+/-5.9 mg. L( -1). h(-1), P<0.05), but treatment with simvastatin did not result in improvement of the postprandial RE response, either in the Sf<1000 fraction or in plasma. It is concluded that heterozygous FH patients have increased fasting and postprandial remnant lipoprotein concentrations. Treatment with simvastatin significantly reduced the fasting and postprandial RLP-C concentrations but did not result in improved postprandial RE response.     

Isolation of remnant particles by immunoseparation: a new approach for investigation of postprandial lipoprotein metabolism in normolipidemic subjects.

Abnormal postprandial lipoproteins are associated with an increased risk for cardiovascular disease. Postprandial remnant lipoproteins were usually analyzed indirectly using retinyl esters (RE) as a chylomicron core label during an oral fat loading test. Apo B-100 containing VLDL remnants in addition to apo B-48 containing chylomicron remnants can also be directly quantified using the RLP-Cholesterol Immunoseparation Assay. This recently available method uses monoclonal antibodies to apo A-I and apo B-100 to remove non-remnant lipoproteins and quantifies cholesterol in the remaining apo E-rich remnant fraction. In the present study we compared the analysis of retinyl ester with the immuno-based RLP-Cholesterol (RLP-C) analysis in measuring postprandial remnant lipoproteins in healthy normolipidemic subjects. Sixteen healthy normolipidemic subjects were selected for this study. Postprandial plasma retinyl esters peaked at 5.0+/-1.2 h, whereas plasma RLP-C showed a peak significantly earlier (P<0.001) at 3.5+/-0.6 h. In comparison, postprandial plasma TG and FFA peaked at 3.3+/-1.1 h (P<0.005 compared to retinyl esters). In conclusion, levels of RLP-C changed, during the postprandial phase, in parallel with plasma TG and FFA concentrations and peaked significantly earlier than retinyl esters. Postprandial measurements of RLP-C can be considered as a fast alternative method for the more laborious retinyl-ester analysis in clinical studies.     

那格列奈与阿卡波糖对2型糖尿病患者餐后血清游离脂肪酸水平的影响

目的比较那格列奈和阿卡波糖对新诊断2刑糖尿病患者餐后血清游离脂肪酸（FFA）和甘油三酯（TG）的影响。方法16例新诊断2型糖尿病患者随机分为两组,进行为期9周的自身交叉对照研究。前4周两组分别给于阿卡波糖（50mg,日三次）和那格列奈（120mg,日三次）,而后停药清洗药物1周。后4周两组交换药物。在第1周和第6周的第1天,所有患者进行标准餐试验,同时服用阿卡波糖50mg或那格列奈120mg,测定0、30、60、120min的血糖、胰岛素、FFA及TG。在第4周和第9周末,测定空腹血糖、胰岛素、FFA、TG。结果单剂景那格列奈和阿卡波糖降低标准餐后血糖的效果相似。与阿卡波糖相比,那格列奈可显著增加2型糖尿病患者标准餐后30min胰岛素分泌水平,降低餐后120min血清FFA水平,但对餐后血清TG水平兀明显影响。那格列奈或阿卡波糖治疗4周前后,空腹FFA和TG水平无显著改变。结论那格列奈在降低餐后血清FFA方而优于阿号波糖,这可能与其部分恢复早时相胰岛素分泌有关。     

Acute effect of orlistat on post-prandial lipaemia and free fatty acids in overweight patients with Type 2 diabetes mellitus.

AIMS: Post-prandial lipaemia is prolonged and exaggerated in patients with Type 2 diabetes mellitus, with an accumulation of atherogenic triglyceride-rich lipoprotein remnants. We postulate that orlistat, a gastrointestinal lipase inhibitor, may cause changes in post-prandial lipoprotein metabolism by reducing dietary triglyceride absorption. METHODS: The acute effect of a single dose of 120 mg orlistat on post-prandial glucose, lipids, remnant lipoproteins and free fatty acids (FFA) was evaluated in a randomized, double-blind, placebo-controlled cross-over study of 63 overweight patients with Type 2 diabetes mellitus (body mass index 30.4 +/- 3.8 kg/m2). Either a single dose of orlistat or placebo was given before a standard mixed meal containing 70 g of fat and plasma triglyceride (TG), remnant-like particles cholesterol (RLP-C) and FFA were sampled at 2-h intervals for 8 h. RLP-C was measured by an immunoseparation assay and FFA by an enzymatic colorimetric method. RESULTS: The concentrations of plasma TG (P < 0.0001), RLP-C (P = 0.003), and FFA (P < 0.0001) were significantly lower at 2 h after orlistat compared with placebo. Both plasma RLP-C (P = 0.04) and FFA (P < 0.0001) remained lower after orlistat than placebo at 4 h. The incremental area under the curve (iAUC) above baseline fasting level for both TG and RLP-C was significantly more reduced after orlistat than placebo (iAUC-TG 5.8 (3.7-8.2) mmol/l x h-1 vs. 5.7 (4.1-10.9), respectively, P = 0.04; iAUC-RLP-C: 0.53 (0.23-1.04) mmol/l x h-1 vs. 0.56 (0.35-1.40), respectively, P = 0.02). The test meal was well tolerated by all subjects, with only three subjects reporting faecal urgency after orlistat. CONCLUSIONS: Orlistat has a beneficial effect on post-prandial lipaemia in overweight Type 2 diabetic patients and lowers plasma TG, RLP-C and FFA in the early post-prandial period.