Masumi Ai

Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans

Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle-triglyceride and -cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.

Extended-Release Niacin Alters the Metabolism of Plasma Apolipoprotein (Apo) A-I and ApoB-Containing Lipoproteins

Objectives—Extended-release niacin effectively lowers plasma TG levels and raises plasma high-density lipoprotein (HDL) cholesterol levels, but the mechanisms responsible for these effects are unclear. Methods and Results—We examined the effects of extended-release niacin (2 g/d) and extended-release niacin (2 g/d) plus lovastatin (40 mg/d), relative to placebo, on the kinetics of apolipoprotein (apo) A-I and apoA-II in HDL, apoB-100 in TG-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), and apoB-48 in TRL in 5 men with combined hyperlipidemia. Niacin significantly increased HDL cholesterol and apoA-I concentrations, associated with a significant increase in apoA-I production rate (PR) and no change in fractional catabolic rate (FCR). Plasma TRL apoB-100 levels were significantly lowered by niacin, accompanied by a trend toward an increase in FCR and no change in PR. Niacin treatment significantly increased TRL apoB-48 FCR but had no effect on apoB-48 PR. No effects of niacin on concentrations or kinetic parameters of IDL and LDL apoB-100 and HDL apoA-II were noted. The addition of lovastatin to niacin promoted a lowering in LDL apoB-100 attributable to increased LDL apoB-100 FCR. Conclusion—Niacin treatment was associated with significant increases in HDL apoA-I concentrations and production, as well as enhanced clearance of TRL apoB-100 and apoB-48.

Small Dense LDL Cholesterol and Coronary Heart Disease: Results from the Framingham Offspring Study

OBJECTIVE We sought to establish reference values for a new direct assay for small dense LDL cholesterol (sdLDL-C) and to measure sdLDL-C concentrations in patients with established coronary heart disease (CHD) vs controls. METHODS Direct LDL-C and sdLDL-C were measured in samples from 3188 male and female participants of the Framingham Offspring Study, including 173 men and 74 women with CHD. RESULTS Postmenopausal status and male sex were associated with higher sdLDL-C concentrations (P < 0.0001). Cholesterol-lowering medication use was more frequent (P < 0.0001) in CHD patients than in controls (46.8% vs 11.4% in men; 35.1% vs 8.8% in women). In men, mean LDL-C was lower in CHD than in controls (3.22 vs 3.51 mmol/L, P < 0.0001), whereas mean sdLDL-C concentrations were similar (0.83 vs 0.84 mmol/L, P = 0.609). In women, mean LDL-C was similar in CHD and controls (3.53 vs 3.46 mmol/L, P = 0.543), but mean sdLDL-C was higher (0.83 vs 0.68 mmol/L, P = 0.0015). The mean percentage of LDL-C as sdLDL-C was higher in both men and women with CHD than controls (P < 0.01). Increased LDL-C and sdLDL-C were found in 10.4% and 22.0% of men and in 24.3% and 27.8% of women with CHD, respectively. CONCLUSIONS Despite 4-fold greater cholesterol-lowering therapy use, CHD patients had mean LDL-C concentrations above the LDL-C goal of <2.6 mmol/L (<100 mg/dL). Although women with CHD had higher sdLDL-C concentrations than controls, this difference was not seen in men. These findings may explain some of the high residual risk of future CHD events in CHD patients.

Effects of weight loss, induced by gastric bypass surgery, on HDL remodeling in obese women

Plasma lipoproteins and glucose homeostasis were evaluated after marked weight loss before and over 12 months following Roux-en-Y gastric-bypass (RYGBP) surgery in 19 morbidly obese women. Standard lipids, remnant-lipoprotein cholesterol (RLP-C); HDL-triglyceride (TG); apolipoproteins (apo) A-I, A-II, E, and A-I-containing HDL subpopulations; lecithin-cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) mass and activity; plasma glucose and insulin levels were measured before and at 1, 3, 6, and 12 months after GBP surgery. Baseline concentrations of TG, RLP-C, glucose, and insulin were significantly higher in obese than in normal-weight, age-matched women, whereas HDL cholesterol (HDL-C), apoA-I, apoA-II, alpha-1 and alpha-2 levels were significantly lower. Over 1 year, significant decreases of body mass index, glucose, insulin, TG, RLP-C, HDL-TG, and prebeta-1 levels were observed with significant increases of HDL-C and alpha-1 levels (all P < 0.05). Changes of fat mass were correlated with those of LDL cholesterol (P = 0.018) and LCAT mass (P = 0.011), but not with CETP mass (P = 0.265). Changes of fasting plasma glucose concentrations were inversely correlated with those of CETP mass (P = 0.005) and alpha-1 level (P = 0.004). Changes of fasting plasma insulin concentrations were positively correlated with those of LCAT mass (P = 0.043) and inversely with changes of alpha-1 (P = 0.03) and alpha-2 (P = 0.05) concentrations. These results demonstrate beneficial changes in HDL remodeling following substantial weight loss induced by RYGBP surgery and that these changes are associated with improvement of glucose homeostasis in these patients.

Postprandial lipoprotein metabolism: VLDL vs chylomicrons.

Since Zilversmit first proposed postprandial lipemia as the most common risk of cardiovascular disease, chylomicrons (CM) and CM remnants have been thought to be the major lipoproteins which are increased in the postprandial hyperlipidemia. However, it has been shown over the last two decades that the major increase in the postprandial lipoproteins after food intake occurs in the very low density lipoprotein (VLDL) remnants (apoB-100 particles), not CM or CM remnants (apoB-48 particles). This finding was obtained using the following three analytical methods; isolation of remnant-like lipoprotein particles (RLP) with specific antibodies, separation and detection of lipoprotein subclasses by gel permeation HPLC and determination of apoB-48 in fractionated lipoproteins by a specific ELISA. The amount of the apoB-48 particles in the postprandial RLP is significantly less than the apoB-100 particles, and the particle sizes of apoB-48 and apoB-100 in RLP are very similar when analyzed by HPLC. Moreover, CM or CM remnants having a large amount of TG were not found in the postprandial RLP. Therefore, the major portion of the TG which is increased in the postprandial state is composed of VLDL remnants, which have been recognized as a significant risk for cardiovascular disease.

Adiponectin: An independent risk factor for coronary heart disease in men in the Framingham offspring Study

OBJECTIVE Our aim was to determine whether plasma adiponectin levels were an independent predictor of coronary heart disease (CHD) risk. METHODS AND RESULTS Plasma adiponectin levels were measured in 3188 male and female participants from cycle 6 of the Framingham offspring Study (mean age: 57 years in both men and women; BMI: 28.5 kg/m(2) in men and 27.3 kg/m(2) in women), using a novel fully automated assay. Plasma adiponectin levels (median [25th percentile, 75th percentile]) were significantly higher in female than in male CHD-free subjects (14.8 [10.7,20.5] μg/ml versus 9.0 [7.0,12.2] μg/ml, p<0.001). Participants were followed for a mean of 7.5 years. After adjustment for age, BMI, smoking status, systolic blood pressure, treatment for hypertension, diabetes, use of cholesterol-lowering medication, total cholesterol level, high-density lipoprotein cholesterol level, and C-reactive protein levels, a higher plasma adiponectin level was a significant predictor of lower risk of future CHD events (n=117) in men (HR 0.49, p<0.0022). A similar trend was observed in women, but was no longer significant after multivariate adjustments. CONCLUSIONS Our data indicate that plasma adiponectin levels are an independent predictor of CHD in Caucasian men initially free of CHD.

Relationship between plasma insulin concentration and plasma remnant lipoprotein response to an oral fat load in patients with type 2 diabetes.

OBJECTIVES The goal of this study was to evaluate the relative effects of hyperglycemia and hyperinsulinemia on postprandial remnant lipoprotein (RLP) concentrations in newly diagnosed type 2 diabetics. BACKGROUND Increases in fasting RLP concentration have been described in type 2 diabetics, as well as in insulin-resistant nondiabetics. Given the atherogenicity of RLPs, we have extended these observations by assessing postprandial RLP concentrations and observing that hyperglycemia was necessary for the increase in RLP concentrations. METHODS Patients with type 2 diabetes were subdivided on the basis of their plasma insulin response to oral glucose into hyperinsulinemic (H-DM) and normoinsulinemic (N-DM) groups of 15 patients each. Plasma triglyceride (TG), RLP-TG and RLP cholesterol (RLP-C) concentrations were determined before and 2 and 4 h after an oral fat load in these patients and 10 control (CTL) subjects. RESULTS Plasma TG, RLP-TG and RLP-C concentrations peaked 2 h after the fat load in the CTL group, returning to baseline within 4 h. In contrast, concentrations of these variables increased throughout the 4-h study in both groups of patients with type 2 diabetes. Total integrated plasma RLP-TG and RLP-C responses above baseline after the oral fat load were significantly higher in the H-DM group compared with the CTL (p = 0.019 and 0.009, respectively) or N-DM (p = 0.026 and 0.029, respectively) groups. Post-heparin lipoprotein lipase activities and apo E phenotypes were similar in the H-DM and N-DM groups. CONCLUSIONS Remnant lipoprotein response to an oral fat load is significantly increased in hyperinsulinemic patients with type 2 diabetes. These changes may increase the risk of coronary heart disease in these individuals.

Effects of Maximal Atorvastatin and Rosuvastatin Treatment on Markers of Glucose Homeostasis and Inflammation

Studies have reported an increased risk of developing diabetes in subjects receiving statins versus placebo. Our purpose was to compare the effects of maximum doses of rosuvastatin and atorvastatin on the plasma levels of the insulin, glycated albumin, adiponectin, and C-reactive protein compared to baseline in hyperlipidemic patients. We studied 252 hyperlipidemic men and women who had been randomized to receive atorvastatin 80 mg/day or rosuvastatin 40 mg/day during a 6-week period. Atorvastatin and rosuvastatin were both highly effective in lowering the low-density lipoprotein cholesterol and triglyceride levels, with rosuvastatin more effective than atorvastatin in increasing high-density lipoprotein cholesterol. Atorvastatin and rosuvastatin at the maximum dosage both significantly (p <0.05) increased the median insulin levels by 5.2% and 8.7%, respectively, from baseline. However, only atorvastatin increased the glycated albumin levels from baseline (+0.8% for atorvastatin vs -0.7% for rosuvastatin, p = 0.002). Both atorvastatin and rosuvastatin caused significant (p <0.001) and similar median reductions in the C-reactive protein level of -40% and -26% compared to the baseline values. However, no statistically significant difference was found between the 2 groups in the adiponectin changes from baseline (-1.5% vs -4.9%, p = 0.15). In conclusion, our data have indicated that the maximum dosage of atorvastatin or rosuvastatin therapy significantly lower C-reactive protein levels but also moderately increase insulin levels.

Effects of Maximal Doses of Atorvastatin Versus Rosuvastatin on Small Dense Low-Density Lipoprotein Cholesterol Levels

Maximal doses of atorvastatin and rosuvastatin are highly effective in lowering low-density lipoprotein (LDL) cholesterol and triglyceride levels; however, rosuvastatin has been shown to be significantly more effective than atorvastatin in lowering LDL cholesterol and in increasing high-density lipoprotein (HDL) and its subclasses. Our purpose in this post hoc subanalysis of an open-label study was to compare the effects of daily oral doses of rosuvastatin 40 mg with atorvastatin 80 mg over a 6-week period on direct LDL cholesterol and small dense LDL (sdLDL) cholesterol in 271 hyperlipidemic men and women versus baseline values. Rosuvastatin was significantly (p<0.01) more effective than atorvastatin in decreasing sdLDL cholesterol (-53% vs -46%), direct LDL cholesterol (-52% vs -50%), total cholesterol/HDL cholesterol ratio (-46% vs -39%), and non-HDL cholesterol (-51% vs -48%), The magnitude of these differences was modest, and the 2 statins caused similar decreases in triglyceride levels (-24% and -26%). In conclusion, our data indicate that the 2 statins, given at their maximal doses, significantly and beneficially alter the entire spectrum of lipoprotein particles, but that rosuvastatin is significantly more effective than atorvastatin in lowering direct LDL cholesterol and sdLDL cholesterol.

Plasma glycated albumin level and atherosclerosis: Results from the Kyushu and Okinawa Population Study (KOPS)

BACKGROUND Glycated albumin (GA) is a measure of the mean plasma glucose concentration over approximately 2-3 weeks. This study was done to test the hypothesis that GA can serve as a marker for atherosclerosis, similar to glycosylated hemoglobin A1c (HbA1c). METHODS HbA1c, plasma GA and serum high-sensitivity C-reactive protein (hs-CRP) levels were measured for 1575 residents (age range 26-78 years) of a suburban town in Japan. Carotid artery intima-media thickness (IMT) was measured by ultrasound for each participant. RESULTS GA levels had significantly positive correlation coefficients with HbA1c level, hs-CRP level, and max-IMT (all P<0.001). Receiver operating characteristic curve analysis indicated a GA level of ≥ 15.5% to be optimal for predicting diabetes. A GA level of 15.5% corresponded to an HbA1c level of 5.8%. The hs-CRP and max-IMT values of participants with GA ≥ 15.5% were significantly higher than the values of those with GA <15.5% (median hs-CRP: 2.4 vs. 2.3mg/L, P=0.048; mean max-IMT 0.852 vs. 0.759 mm, P=0.003, respectively). Among obese participants, the hs-CRP and max-IMT values of those with GA ≥ 15.5% (7.5mg/L and 1.014 mm) were significantly higher than the values of those with GA <15.5% (4.7 mg/dL and 0.823 mm) (P=0.024 and P=0.001, respectively). CONCLUSIONS Increased IMT and hs-CRP levels were associated with a high GA level, especially for obese participants, suggesting that GA would be as a useful biomarker for assessing the risk of atherosclerosis.