Remnant-like Particle Research Articles

Is There a Relation Between Triglyceride Concentrations in Very Low Density Lipoprotein and the Index of Insulin Resistance in Nondiabetic Subjects?

Serum very low density lipoprotein (VLDL) levels increase during the early stages of insulin resistance; therefore, determination of VLDL levels would be useful for evaluating the progression of metabolic syndrome and diabetes mellitus. The aim of this study was to clarify the clinical utility of triglyceride in VLDL (VLDL-TG) level, determined using a homogeneous assay kit (Shino-test Corporation, Tokyo, Japan), as an index of insulin resistance. We enrolled 74 subjects in this study (diabetic subjects, n = 42; nondiabetic subjects, n = 32). The levels of VLDL-TG, remnant-like lipoprotein particle cholesterol, preheparin lipoprotein lipase mass, and other biochemical markers were determined. VLDL-TG levels were significantly higher in the diabetic group (1.04 ± 0.84 mmol/l vs. 0.64 ± 0.42 mmol/l, P < 0.01) than in the nondiabetic group. In the nondiabetic group, VLDL-TG was significantly correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), the index for insulin resistance (r = 0.513, P = 0.003). VLDL-TG levels, but not TG levels, were higher in the highest quartile (HOMA-IR) of the nondiabetic group. VLDL-TG level was a useful early marker for insulin resistance, especially in nondiabetic subjects. The homogeneous VLDL-TG assay is a simple, low-cost method for determining insulin resistance.

Lipid and non-lipid cardiovascular risk factors in postmenopausal type 2 diabetic women with and without coronary heart disease

Coronary heart disease (CHD) is the leading cause of death in diabetic women. In addition to hyperglycemia, other factors may contribute to the excessive cardiovascular risk. In this study we evaluated common and emerging risk factors in a selected group of postmenopausal type 2 diabetic women with (n = 36) and without CHD (n = 59), not taking lipid-lowering medications. Clinical and lifestyle data were collected, and metabolic and lipid profile, as well as fasting plasma levels of total homocysteine (tHcy), folate, vitamin B12, C-reactive protein (hsCRP), interleukin 6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1) were measured in all participants. Age, menopause and diabetes duration, family history for cardiovascular disease, prevalence of hypertension and current insulin use were greater in diabetic women with than without CHD (P < 0.05 for all comparisons). CHD women also showed higher levels of triglycerides, small dense LDL (sdLDL), remnant-like particle cholesterol, tHcy, and VCAM-1, and a lower creatinine clearance (P < 0.05 all). Conversely, the two groups were comparable for BMI, waist circumference, smoking habit, fasting plasma glucose, HbA1c, total cholesterol, low-density lipoprotein cholesterol (LDL-C), HDL cholesterol, folate, vitamin B12, hsCRP and IL-6 levels. At multivariate analysis, lower creatinine clearance (OR = 0.932, P = 0.017) and higher sdLDL serum concentration (OR = 1.224, P = 0.037) were the strongest risk factors associated with CHD in this population, whereas no significant association was noted with LDL-C. Our data suggest that beyond LDL-C, a lower creatinine clearance and more subtle alterations of LDL particles, together with a constellation of several well known and emerging cardiovascular risk factors, are stronger contributors to the high CHD risk of diabetic women.

Elevated Small Dense Low-Density Lipoprotein Cholesterol as a Predictor for Future Cardiovascular Events in Patients with Stable Coronary Artery Disease

The aim of the present study was to investigate how small dense low-density lipoprotein cholesterol (sdLDL-C) compared with LDL-C affect the long-term prognosis in patients with stable coronary artery disease (CAD). sdLDL-C measured by heparin magnesium precipitation and LDL particle size measured by non-denatured gradient-gel electrophoresis were compared in 190 consecutive CAD patients who underwent coronary arteriography between 2003 and 2004 who did or did not develop cardiovascular events during a seven-year follow-up period. Cardiovascular events were death caused by cardiovascular diseases(CVDs), onset of acute coronary syndrome, need for coronary and peripheral arterial revascularization, hospitalization for heart failure, surgical procedure for any CVDs, and/or hospitalization for stroke. First-time cardiovascular events were observed in 72 patients. Those who experienced cardiovascular events were older and had higher prevalence rates of hypertension and diabetes; significantly higher Gensini coronary atherosclerotic scores; significantly higher levels of sdLDL-C, sdLDL-C/LDL-C, and LDL-C/high-density lipoprotein cholesterol (HDL-C) ratios; and greater glycated hemoglobin(Hb)A1c and brain natriuretic peptide (BNP) levels. They also had significantly smaller LDL particle sizes, HDL-C, apolipoprotein A-1, and estimated glomerular filtration rate (GFR) compared with patients without cardiovascular events. Conversely, LDL-C, non-HDL-C, apolipoprotein B, remnantlike particle cholesterol, and high-sensitivity C-reactive protein (hs-CRP) levels were similar between the two groups. A Kaplan-Meyer event-free survival curve demonstrated that patients with sdLDL-C≥35 mg/dL (median level) had significantly poorer prognosis compared with those with lower sdLDL-C levels, while patients with LDL-C ≥100 mg/dL had a non-significantly lower survival rate. These results confirm that sdLDL-C is a very promising biomarker to predict future cardiovascular events in the secondary prevention of stable CAD.

Short-Term Effect of Pitavastatin Treatment on Glucose and Lipid Metabolism and Oxidative Stress in Fasting and Postprandial State Using a Test Meal in Japanese Men

Introduction. The objective of this study was to clarify how pitavastatin affects glucose and lipid metabolism, renal function, and oxidative stress. Methods. Ten Japanese men (average age of 33.9 years) were orally administered 2 mg of pitavastatin for 4 weeks. Postprandial glucose, lipoprotein metabolism, and oxidative stress markers were evaluated at 0 and 4 weeks of pitavastatin treatment (2 mg once daily) with a test meal consisting of total calories: 460 kcal, carbohydrates: 56.5 g (226 kcal), protein: 18 g (72 kcal), lipids: 18 g (162 kcal), and NaCl: 1.6 g. Metabolic parameters were measured at 0, 60, and 120 minutes after test meal ingestion. Results. After administration of pitavastatin, serum total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, arachidonic acid, insulin, and adjusted urinary excretion of uric acid decreased, whereas creatinine clearance (C Cr) and uric acid clearance (C UA) increased. And postprandial versus fasting urine 8-hydroxydeoxyguanosine remained unchanged, while postprandial versus fasting isoprostane decreased after pitavastatin treatment. Next, we compared postprandial glucose and lipid metabolism after test meal ingestion before and after pitavastatin administration. Incremental areas under the curve significantly decreased for triglycerides (P < 0.05) and remnant-like particle cholesterol (P < 0.01), while those for apolipoprotein E (apoE), glucose, insulin, and high-sensitivity C-reactive protein remained unchanged. Conclusion. Pitavastatin improves postprandial oxidative stress along with hyperlipidemia.

Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: The EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial

Omega-3 fatty acids in free fatty acid form have enhanced bioavailability, and plasma levels are less influenced by food than for ethyl ester forms. The aim was to evaluate the safety and lipid-altering efficacy in subjects with severe hypertriglyceridemia of an investigational pharmaceutical omega-3 free fatty acid (OM3-FFA) containing eicosapentaenoic acid and docosahexaenoic acid. This was a multinational, double-blind, randomized, out-patient study. Men and women with triglycerides (TGs) ≥ 500 mg/dL, but <2000 mg/dL, took control (olive oil [OO] 4 g/d; n = 99), OM3-FFA 2 g/d (plus OO 2 g/d; n = 100), OM3-FFA 3 g/d (plus OO 1 g/d; n = 101), or OM3-FFA 4 g/d (n = 99) capsules for 12 weeks in combination with the National Cholesterol Education Program Therapeutic Lifestyle Changes diet. Fasting serum TGs changed from baseline by -25.9% (P < .01 vs OO), -25.5% (P < .01 vs OO), and -30.9% (P < .001 vs OO) with 2, 3, and 4 g/d OM3-FFA, respectively, compared with -4.3% with OO. Non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol-to-HDL-C ratio, very low-density lipoprotein cholesterol, remnant-like particle cholesterol, apolipoprotein CIII, lipoprotein-associated phospholipase A2, and arachidonic acid were significantly lowered (P < .05 at each OM3-FFA dosage vs OO); and plasma eicosapentaenoic acid and docosahexaenoic acid were significantly elevated (P < .001 at each OM3-FFA dosage vs OO). With OM3-FFA 2 and 4 g/d (but not 3 g/d), low-density lipoprotein cholesterol was significantly increased compared with OO (P < .05 vs OO). High-sensitivity C-reactive protein responses with OM3-FFA did not differ significantly from the OO response at any dosage. Fewer subjects reported any adverse event with OO vs OM3-FFA, but frequencies across dosage groups were similar. Discontinuation due to adverse event, primarily gastrointestinal, ranged from 5% to 7% across OM3-FFA dosage groups vs 0% for OO. OM3-FFA achieved the primary end point for TG lowering and secondary end point of non-HDL-C lowering at 2, 3, and 4 g/d in persons with severe hypertriglyceridemia. This trial was registered at www.clinicaltrials.gov as NCT01242527.

Association of triglyceride-rich lipoproteins-related markers and low-density lipoprotein heterogeneity with cardiovascular risk: Effectiveness of polyacrylamide-gel electrophoresis as a method of determining low-density lipoprotein particle size

BackgroundDespite well-controlled low-density lipoprotein cholesterol (LDL-C), hypertriglyceridemia is an independent predictor of coronary events. We investigated the risk of atherosclerotic cardiovascular disease through examining the relation between triglyceride (TG) metabolism and LDL-heterogeneity as assessed by polyacrylamide-gel electrophoresis (PAGE). Methods and resultsEstimated LDL-particle size [relative LDL migration (LDL-Rm value)] measured by PAGE with the LipoPhor system (Joko, Tokyo, Japan) was evaluated in 645 consecutive patients with one additional risk factor for atherosclerotic cardiovascular disease.Multivariate regression analysis after adjustments for traditional risk factors revealed an elevated triglyceride-rich lipoproteins (TRLs)-related markers [TG, remnant-like particle cholesterol (RLP-C), very LDL (VLDL) fraction, apolipoprotein (apo) C-II, and apo C-III] level to be an independent predictor of smaller-size LDL-particle size, both in the overall population, and in a subset of patients with serum LDL-C <100mg/dL. Even among the patients with LDL-C levels <100mg/dL, the serum levels of atherogenic lipid markers in those with a LDL-Rm value ≥0.40, suggesting the presence of large amounts of small-dense LDL and upper limit (mean+2 standard deviation) in this population, were significantly higher than in those with a LDL-Rm value <0.40. Moreover, the serum levels of TRLs-related markers showed high accurate area under the receiver-operating characteristic curve (TG, 0.896; RLP-C, 0.875; VLDL fraction, 0.803; apo C-II, 0.778; and apo C-III, 0.804, respectively) in terms of evaluation of the indicators of LDL-Rm value ≥0.40. ConclusionTo further reduce the risk of atherosclerotic cardiovascular disease, it may be of particular importance to pay attention not only to the quantitative change in the serum LDL-C, but also TG-metabolism associated with LDL-heterogeneity. Combined evaluation of TRLs-related markers and LDL-Rm value may be useful for assessing the risk of atherosclerotic cardiovascular disease.

Association Between Urinary Albumin Excretion and Low-density Lipoprotein Heterogeneity Following Treatment of Type 2 Diabetes Patients with the Dipeptidyl Peptidase-4 Inhibitor, Vildagliptin: A Pilot Study

Few data exist as to whether dipeptidyl peptidase (DPP)-4 inhibitors affect cardio-renal interaction, which is a strong independent prognostic factor for cardiovascular disease (CVD), in diabetic patients. We evaluated the effects of a DPP-4 inhibitor on atherogenic low-density lipoprotein (LDL) heterogeneity and albuminuria in diabetics as an indicator of the severity of diabetic nephropathy. Type 2 diabetes patients (n=47) inadequately controlled with diabetes therapy were treated with vildagliptin 50mg bid for 8weeks. LDL heterogeneity was evaluated on the basis of the patients' small dense (sd) LDL levels and sd-LDL proportion (sd-LDL/LDL cholesterol [LDL-C]). The level of albuminuria was evaluated on the basis of the urinary albumin-to-creatinine ratio (UACR). After 8weeks of treatment, there was no significant change in serum LDL-C level, but the serum sd-LDL level had decreased significantly by 8.8%, and the UACR had also decreased significantly by 44.6%. Triglyceride (TG)-metabolism-related markers (TG, remnant-like particle cholesterol, apolipoprotein [apo] B, apoC-2, and apoC-3) had decreased significantly. The Δ (absolute change from baseline) sd-LDL values correlated positively with ΔTG-metabolism-related markers, but not with the Δ hemoglobin (Hb) A1c or Δ fasting blood sugar (ΔFBS). Furthermore, multivariate regression analysis revealed that Δsd-LDL proportion, but not ΔHbA1c or ΔFBS, was an independent predictor of ΔUACR (β=0.292, p=0.0016). Although this was a single-arm study, treatment of type 2 diabetes with vildagliptin might prevent the progression of CVD complicating diabetes by improving LDL heterogeneity, and it might improve renal function by decreasing albuminuria. A randomized controlled trial is warranted.

Highly purified eicosapentaenoic acid may increase the low-density lipoprotein particle size by improving triglyceride metabolism in patients with hypertriglyceridemia

Background: We hypothesized that highly purified Eicosapentaenoic Acid (EPA) might increase the Low-Density Lipoprotein (LDL)-particles size, thereby leading to prevention of coronary artery disease. The purpose of this prospective randomized trial was to evaluate the effect of EPA in increasing the LDL-particle size, as one of the possible mechanisms by which intake of EPA may prevent coronary events. Methods: One hundred fifty hypertriglyceridemic patients who gave consent for participation in this trial were randomized with a simple sealed envelope method to EPA treatment: the EPA group (n=75) or non-EPA treatment: the control group (n=75). Subjects in the EPA group were administered a 900-mg capsule containing EPA ethyl ester of >98% purity twice a day (total daily dose, 1,800 mg). Results: In the EPA group, while the serum levels of LDL-cholesterol and high-density lipoprotein cholesterol remained changed, significant increase of LDL-particle size, as judged based on the LDL-relative mobility value measured by lipoprotein polyacrylamide-gel electrophoresis, and significant decrease of the serum levels of Triglyceride-Rich Lipoproteins (TRLs)-related markers (triglyceride, very LDL fraction, remnant-like particle cholesterol, apolipoprotein C2, and apolipoprotein C3) were noted. No such changes were observed in the control group. In multi-logistic regression analysis after adjustments for the coronary risk factors, elevation of the serum EPA-related markers (serum level of EPA at 6 months, the EPA/ arachidonic acid (AA) ratio at 6 months, absolute change from the baseline of (Δ) EPA level, and Δ EPA/AA ratio), and treatment with statins and EPA were identified as independent variables of increase in LDL-particle size. Moreover, negative correlations were found between the Δ TRLs-related markers and Δ LDL-particle size, suggesting that improvement of the triglyceride-metabolism was associated with an increase of LDL-particle size. Conclusions: This study demonstrated that EPA administration increased the LDL-particle size by improving the triglyceride-metabolism. Furthermore, the serum EPA level and EPA/AA ratio after administration of EPA might be useful markers of increased LDL-particle size.

Skew of Plasma Low- and High-Density Lipoprotein Distributions to Less Dense Subfractions in Normotriglyceridemic Chronic Kidney Disease Patients on Maintenance Hemodialysis Treatment

Background: Plasma levels of small, dense low-density lipoprotein (LDL) were reported to increase in chronic kidney disease (CKD) patients on hemodialysis (HD), but most of these patients were hypertriglyceridemic. Plasma levels of small, dense LDL are known to increase in hypertriglyceridemic subjects. Therefore, to investigate the direct effect of CKD on the distribution of LDL subfractions, we investigated the distribution of LDL subfractions in normotriglyceridemic CKD patients on HD. Methods: The levels of plasma lipoprotein subfractions and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), which markedly influence the distributions of plasma LDL and high-density lipoprotein (HDL) subfractions, were compared between 40 HD patients and 40 normolipidemic controls. Plasma lipoproteins were subfractionated into seven subfractions by ultracentrifugation. Results: Plasma levels of cholesterol (C) in remnant-like particle, which is equivalent to the triglyceride (TG)-rich lipoprotein remnant, were twice as high in HD patients as those in controls with matched TG levels. Plasma levels of C and TG in VLDL and IDL (intermediate density lipoprotein) were slightly higher in HD patients than in controls. The C/TG ratio of VLDL was significantly higher in HD patients than in controls. In comparison with the corresponding values in controls, the C and TG levels in low-density LDL and HDL₂ in HD patients were high, whereas those in medium-density LDL, high-density LDL, and HDL₃ were low. Plasma LCAT activity and CETP mass were lower in HD patients than in controls. Conclusion: Distribution of LDL and HDL skewed toward less dense fractions in normotriglyceridemic CKD patients on HD. A decrease in reverse C transport likely played an important role in these changes in the patients.

臨床 コレステロール値正常患者での冠動脈病変予測因子としてRLP-Cが有用である

臨床 コレステロール値正常患者での冠動脈病変予測因子としてRLP-Cが有用である

High Level of Plasma Remnant-like Particle Cholesterol May Predispose to Development of Hypertension in Normotensive Subjects

Remnant-like lipoprotein particle cholesterol (RLP-C) is a highly atherogenic factor. RLP-C induces endothelial dysfunction and is associated with hyperinsulinemia. This study was designed to determine whether high plasma RLP-C levels predispose to the development of hypertension in subjects with normal blood pressure (BP). A total of 1,485 subjects aged >40 years in a Japanese Cohort of the Seven Countries Study received health examinations. We examined BP, anthropometric parameters, and blood chemistries, including fasting RLP-C levels. RLP-C levels were measured by an immune-separation method. We excluded from the analysis 676 subjects who had hypertension (BP ≥ 140/90mm Hg), or were on antihypertensive medication, and/or were on antihyperlipidemic medication at baseline. Ten years later, 681 subjects were re-examined. Of 681 normotensive subjects at baseline, 303 subjects had developed hypertension 10 years later. Baseline RLP-C level was significantly higher (P < 0.01) in the subjects who developed hypertension than in those who remained normotensive (3.7±1.9 vs. 3.3±1.6mg/dl). Multivariable logistic regression analysis demonstrated that baseline RLP-C was a significant factor for incident hypertension after adjustments for homeostasis model assessment index and other hypertension-related factors (odds ratio = 1.05, 95% CI = 1.00-1.10; P = 0.04). A high level of plasma RLP-C in normotensive subjects may predispose to the development of hypertension in a population of community-dwelling Japanese.

Effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance

AimTo evaluate the effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance. MethodsSeventy-six patients with diabetes and glucose intolerance were enrolled in this study. At baseline and 12 weeks after treatment with ezetimibe 10mg/day, we measured the levels of lipid and glucose parameters. ResultsEzetimibe reduced the mean levels of low-density lipoprotein cholesterol (LDL-C) (−20%, P<0.001), remnant-like particle cholesterol (−22%, P<0.001), small dense-LDL (−19%, P<0.001), apolipoprotein B-48 (−2%, P<0.01), malondialdehyde modified-LDL (−15%, P<0.001), and serum immunoreactive insulin (IRI) (−4%, P<0.01). In the insulin resistance subgroup, ezetimibe reduced the abdominal circumference (−1%, P<0.05) and mean levels of fasting plasma glucose (−7%, P<0.05), IRI (−36%, P<0.01), s-CPR (−27%, P<0.01), HOMA-IR (−39%, P<0.01) and HbA1c tended to decrease (−2%, P=0.06). ConclusionsEzetimibe reduced atherogenic lipoproteins in patients with diabetes and glucose intolerance; besides, it improved glucose metabolism in patients with insulin resistance.

Simultaneous Ingestion of Fructose and Fat Exacerbates Postprandial Exogenous Lipidemia in Young Healthy Japanese Women

To investigate the acute effects of the simultaneous ingestion of fructose and fat on postprandial lipoprotein metabolism in healthy young women. Nine young healthy Japanese women with a normal weight (body mass index: 18.5≤-< 25 kg/m(2)), a normal ovarian cycle and an apolipoprotein E 3/3 phenotype were enrolled as participants and studied on four occasions. At each session, the subjects ingested one of four beverages containing either glucose or fructose (0.5 g/kg body weight each) with or without OFTT cream (1 g/kg, 0.35 g/ kg as fat) in a randomized crossover design. Blood samples were collected at baseline and at 0.5, 1, 2, 4 and 6 hours after ingestion. The ingestion of fructose combined with fat led to significantly higher rises in the serum triglyceride (TG), remnant-like particle (RLP)-TG, remnant lipoprotein-cholesterol (RemL-C) and apolipoprotein B-48 (apoB48) concentrations with delayed peaks compared with that observed following ingestion of the other three types of beverages. The incremental area under the curve (ΔAUC)-TG and ΔAUC-apoB48 were larger than those observed for the ingestion of fat only. The serum RLP-TG and apoB48 concentrations returned to the fasting levels (0 hours) at the end of the test (6 hours) following the ingestion of fat only; however, these concentrations did not return to the fasting levels following the intake of fructose combined with fat. These findings suggest a delay in the clearance of intestinal TG-rich lipoproteins, namely chylomicron and its remnant, following the ingestion of fructose combined with fat. The simultaneous ingestion of fructose and fat markedly enhances postprandial exogenous lipidemia in young healthy Japanese women.

Relationships between the Visceral Fat Area on CT and Coronary Risk Factor Markers

The visceral fat area (VFA) was measured, and the relationships between the VFA and the body mass index (BMI), waist circumference, blood pressure, and indices of lipid and sugar metabolism were evaluated. The subjects included 607 consecutive patients who underwent VFA examinations using computed tomography (CT) scans. In addition to the routine examination parameters, the levels of adiponectin and homeostasis model assessment as an index of insulin resistance (HOMA-IR) were measured in all subjects, and the levels of malondialdehyde-modified low-density lipoprotein (MDA-LDL), remnant-like particles (RLP), lipoprotein (a) (Lp(a)), apolipoprotein (Apo) AI, ApoB and ApoE were measured in 270 subjects. In both men and women, the VFA showed significant positive correlations with the age, BMI, waist circumference, subcutaneous fat area, visceral fat area/subcutaneous fat area (v/s) ratio, systolic blood pressure, diastolic blood pressure, the fasting blood sugar (FBS), the hemoglobin A1c (HbA1c), high-density lipoprotein cholesterol (HDLC), triglyceride (TG), uric acid, HOMA-IR and ApoB and the ApoB/LDLC ratio and significant negative correlations with the levels of HDLC and adiponectin. The levels of the total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), non-HDLC, MDA-LDL and Lp(a) and the ApoB/ApoAI ratio were not correlated with the VFA in either men or women. The RLP exhibited a significant positive correlation with the VFA in women. The VFA exhibited high positive correlations with the waist circumference, blood pressure and TG level and a negative correlation with the HDLC level, regardless of gender, supporting the validity of the present diagnostic method for evaluating metabolic syndrome (MS). Although the LDLC level is not included in the diagnostic criteria for MS, the positive correlations between the VFA and the ApoB level and ApoB/LDLC ratio observed in both men and women indicate qualitative abnormalities of lipoproteins, such as an increase in the amount of small dense LDL. Measuring the levels of apolipoproteins in addition to lipoproteins during health screening is therefore useful for evaluating of atherogenicity.

Effects of icosapent ethyl on lipid and inflammatory parameters in patients with diabetes mellitus-2, residual elevated triglycerides (200–500 mg/dL), and on statin therapy at LDL-C goal: the ANCHOR study

BackgroundIcosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. ANCHOR was a 12-week, phase 3 study that evaluated the efficacy and safety of IPE in patients (N = 702) with residual high fasting TG levels (≥200 and <500 mg/dL) despite having optimized low-density lipoprotein cholesterol (LDL-C) levels (≥40 and <100 mg/dL) on statin therapy. Among patients randomized to IPE (4 g/day or 2 g/day) or placebo, 514 (73%) had diabetes mellitus.MethodsA post hoc subgroup analysis of the ANCHOR study was conducted to assess the effects of IPE on median placebo-adjusted percent change from baseline in efficacy end point parameters in 3 subgroups: total (all subjects with diabetes—overall median baseline glycosylated hemoglobin A1c [A1c] = 6.8%), better-controlled diabetes (below median baseline A1c), and less-controlled diabetes (above median baseline A1c).ResultsBaseline efficacy parameters were similar among all groups except high-sensitivity C-reactive protein (hsCRP), which was higher in the total and less-controlled diabetes groups. Compared with placebo, IPE 4 g/day significantly reduced TG, non-high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol (VLDL-C), lipoprotein-associated phospholipase A2, apolipoprotein B (Apo B), total cholesterol, high-density lipoprotein cholesterol, VLDL-TG, oxidized LDL, and remnant-like particle cholesterol in all 3 diabetes groups, LDL-C in the total diabetes group, and hsCRP in the total and less-controlled diabetes groups. Decreases in hsCRP and Apo B were much greater in patients with less-controlled diabetes. There were no significant increases in fasting plasma glucose, A1c, insulin, or homeostasis model assessment-estimated insulin resistance in any group.ConclusionIPE 4 g/day significantly improved lipid and lipid-related parameters without worsening glycemic control in patients with diabetes and mixed dyslipidemia, with possibly greater effects among those with less-controlled diabetes.Trial registrationClinicaltrials.gov Identifier NCT01047501

Impact of Serum Retinol-Binding Protein 4 Levels on Regulation of Remnant-Like Particles Triglyceride in Type 2 Diabetes Mellitus

Background. Although retinol-binding protein 4 (RBP4) associates with insulin resistance and remnant-like particles triglyceride (RLP-TG) elevated in the insulin resistant state, few data exist regarding the relationship between RBP4 and RLP-TG. Subjects and Methods. The study included 92 Japanese type 2 diabetic mellitus (T2DM) male patients (age 60.5 ± 13.6 years, body mass index (BMI) 24.7 ± 4.1 kg/m2, waist circumference (WC) 88.4 ± 10.7 cm, and HbA1c (NGSP) 7.2 ± 1.9%). Patients on medications affecting insulin sensitivity, including fibrates, biguanides, and thiazolidinedione, were excluded. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by computed tomography. Results. RBP4 levels showed a significant positive correlation with RLP-TG (r = 0.2544 and P = 0.0056), TG (r = 0.1852 and P = 0.041), RLP-TG/TG (r = 0.23765 and P = 0.0241), and age (r = −0.2082 and P = 0.0219), although there was no significant correlation with VFA, SFA, adiponectin levels, or homeostasis model of assessment insulin resistance (HOMA-R). Multiple regression analysis revealed that RBP4 was an independent determinant of RLP-TG (P = 0.0193) but was not a determinant of TG. Conclusions. RBP4 correlates positively with serum RLP-TG independent of fat accumulation in T2DM. RBP4 may regulate remnant metabolism independent of glycemic control in T2DM.

Eicosapentaenoic Acid Improves Glycemic Control in Elderly Bedridden Patients with Type 2 Diabetes

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are ω3-polyunsaturated fatty acids mainly contained in the blue-backed fish oil, and are effective in decreasing the lipids disorder and the cardiovascular incidence among diabetic patients. Moreover, it has been suggested that EPA and DHA may improve the insulin resistance and glucose metabolism. However, the clinical effects of EPA and DHA on glucose metabolism remain unclear. We aimed to clarify the effects of EPA/DHA treatment on glycemic control in type 2 diabetes mellitus. This study was a multicenter prospective randomized controlled trial involving 30 elderly type 2 diabetic patients on a liquid diet. Their exercises were almost zero and the content of their meals was strictly managed and understood well. Therefore, the difference by the individual's life was a minimum. The subjects were divided into two groups: those receiving EPA/DHA-rich liquid diet [EPA/DHA (+)] or liquid diet lacking EPA/DHA [EPA/DHA (-)]. Changes in factors related to glucose and lipid metabolism were assessed after the three-month study. Serum concentrations of EPA rose in EPA/DHA (+), although the levels of DHA and fasting C-peptide remained unchanged in EPA/DHA (+). In addition, there was a significant decline in the fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), fasting remnant-like particles and apolipoprotein (apo) B in EPA/DHA (+), compared with the values in EPA/DHA (-). EPA/DHA-rich diet might improve glucose metabolism in elderly type 2 diabetic patients on a liquid diet. This phenomenon may be due to the improved insulin resistance mediated by the rise in serum EPA concentrations.

Acute Effects of Postprandial Aerobic Exercise on Glucose and Lipoprotein Metabolism in Healthy Young Women

To investigate the acute effects of postprandial exercise on glucose and lipoprotein metabolism after the intake of glucose with or without fat cream in healthy but sedentary young women. Healthy young Japanese women with a sedentary lifestyle, normal weight (18.5≤BMI<25), normal ovarian cycle, and apolipoprotein (apo) E3/3 were enrolled as participants. They ingested 1 g/kg body weight of glucose only or glucose supplemented with 1 g/kg oral fat tolerance test (OFTT) cream 4 (0.35 g/kg as fat) with or without postprandial walking exercise on a motorized treadmill (ca. 50%V(·)o(2)max for 30 min) 20 min after intake of the beverage. Each subject performed 4 trials in a randomized, cross-over design. Venous blood was drawn before (0 h), and 20 min, 1, 2, 4, and 6 h after ingestion. Postprandial exercise alleviated the sharp rise of serum glucose and insulin, and transiently mitigated the decrease of free fatty acids (FFA) after ingestion of the glucose-only beverage. Although no fat was contained in the glucose beverage, transient apoB48 secretion was observed without the rise of serum triglyceride (TG) and remnant-like particle (RLP)-TG, suggesting that apoB48-containing lipoprotein particles with little TG were released by the exercise. Serum apoB48 concentrations at 6 h had decreased to levels lower than the baseline (0 h, after 12-h overnight fast) with or without exercise, suggesting that the 12-h overnight fast may not have been a 'true' fast. Similarly, postprandial exercise suppressed the sharp rise of serum glucose and insulin, and transiently mitigated the decrease of FFA after the ingestion of glucose with OFTT cream. Postprandial exercise stimulated the transient secretion of apoB48-containing TG-rich lipoproteins (TRL) with a rapid rise of serum apoB48, TG, and RLP-TG; however, the subsequent course of lipemia was not significantly changed. Serum apoB48 and RLP-TG values did not return to the baseline even after 6 h, suggesting that postprandial lipoprotein metabolism was not finished at the end of the experiment. Postprandial aerobic exercise alleviated the glycemic peak at 1 h associated with insulin 'sparing'. The effect of exercise on fat metabolism was transient, enhancing the secretion of intestinal TRL at an early phase, but no further significant effects were observed. Postprandial exercise transiently stimulated the secretion of apoB48 after glucose intake without a fat load.

Effect of L-thyroxine replacement on apolipoprotein B-48 in overt and subclinical hypothyroid patients

Apolipoprotein B-48 (ApoB-48) is a constituent of chylomicrons and chylomicron remnants, and is thought to be one of the risk factors for atherosclerosis. We evaluated the effect of L-thyroxine (L-T(4)) replacement on serum ApoB-48 levels in patients with primary hypothyroidism. Eighteen patients with overt hypothyroidism (OH) and 18 patients with subclinical hypothyroidism (SH) participated in the study. The lipid profiles, including ApoB-48, were measured in patients with hypothyroidism before and 3 months after L-T(4) replacement. After L-T(4) replacement, the serum concentrations of all lipoproteins, exclusive of lipoprotein(a) (Lp(a)), were significantly decreased in patients with OH. In patents with SH, the serum levels of total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), remnant-like particle cholesterol (RLP-C), apolipoprotein B (ApoB), and ApoB-48 decreased significantly after L-T(4) replacement. The serum levels of triglycerides (TG), HDL-C, low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA-1), and Lp(a) did not change significantly. In all 36 patients, the reduction in the ApoB-48 levels correlated significantly with the reduction in TSH levels (r = 0.39, P<0.05). This study showed clearly that L-T(4) replacement might reduce serum levels of ApoB-48 in both OH and SH patients. Such altered serum levels of ApoB-48 in patients with OH and SH may be related to the disturbed metabolism of chylomicron remnants in patients with hypothyroidism.

Association between Remnant-Like Particle Cholesterol and Gamma-Glutamyltransferase in Dyslipidemic Patients

Objective: To investigate the correlation between gamma-glutamyltransferase (GGT) and remnant-like particle cholesterol (RLP-C) in dyslipidemic patients. Subjects and Methods: General cardiometabolic variables, plus serum GGT and RLP-C levels, were measured in 118 dyslipidemic patients (59 males, mean age 58 ± 13 years). Correlation analyses of GGT with other variables, including RLP-C, were performed. Results: The median levels (interquartile ranges) of RLP-C and GGT were 0.21 mmol/l (0.14–0.35) and 26 IU/l (17–39), respectively. A stepwise multiple regression analysis revealed an independent, significant and positive correlation between GGT and RLP-C (β = 0.351, p < 0.001), followed by male gender and BMI. Conclusion: There was a significant positive association between GGT and RLP-C, thereby indicating that the association between GGT and cardiovascular disease may be partly due to the interaction with RLP-C in dyslipidemic patients. Further research is therefore warranted to confirm the observed relationship.