Richard E. Ostlund

The Ratio of Waist-to-Hip Circumference, Plasma Insulin Level, and Glucose Intolerance as Independent Predictors of the HDL2 Cholesterol Level in Older Adults

High plasma levels of HDL2, a subfraction of high-density lipoprotein (HDL) cholesterol, are associated with a reduced risk of coronary heart disease. To investigate the characteristics related to HDL2 cholesterol levels, we measured lipoprotein levels and several metabolic and anthropometric variables in 146 healthy subjects (77 men and 69 women) in the seventh decade of life. The level of HDL2 cholesterol was inversely correlated with the ratio of the waist-to-hip circumference (r = -0.335 for men; r = -0.370 for women; P less than 0.01) and the plasma insulin level (r = -0.400 for men; r = -0.398 for women; P less than 0.001). In a multiple regression model including both sexes, 41 percent of the variance in the HDL2 level was explained by the combined effect of the waist-to-hip ratio (P less than 0.0001), the plasma insulin level (P = 0.0003), and the degree of glucose tolerance indicated by the integrated area under the plasma glucose curve after an oral glucose-tolerance test (P = 0.05). The body-mass index, total percentage of body fat, maximal oxygen uptake, diet, and sex were not significant predictors of the HDL2 level when added to this model, whereas the original variables remained significant predictors. The HDL2 cholesterol level in subjects at the 25th percentile for waist-to-hip ratio was 153 percent of that in subjects at the 75th percentile. We conclude that HDL2 levels are inversely correlated with truncal fat, plasma insulin levels, and the presence of glucose intolerance and are not independently associated with sex or total body fat.

Phytosterols and cholesterol metabolism

Purpose of review Phytosterols are plant sterols structurally similar to cholesterol that act in the intestine to lower cholesterol absorption. Because they have very low systemic absorption and are already present in healthy diets, increasing the intake of phytosterols may be a practical way to reduce coronary heart disease with minimum risk. Recent findings Phytosterols displace cholesterol from intestinal micelles, reducing the pool of absorbable cholesterol, but they are also rapidly taken up by enterocytes and increase expression of the adenosine triphosphate-binding cassette A1 sterol transporter. Phytosterol esters dissolved in food fat reduce LDL-cholesterol by 10% at a maximum effective dose of 2 g/day. However, this work probably understates the true effectiveness of phytosterols because it does not account for those naturally present in baseline diets. Single meal studies show that phytosterols in intact foods are bioactive at doses as low as 150 mg. The potential effectiveness of phytosterols has been improved in several ways. Individuals most likely to respond have been identified as having high cholesterol absorption and low cholesterol biosynthesis. Phytosterols can be emulsified with lecithin and delivered in non-fat or low-fat foods and beverages, and the amount of fat in fat-based preparations can be reduced substantially with the retention of bioactivity. Summary Phytosterols effectively reduce LDL-cholesterol when given as supplements, and the smaller amounts in natural foods also appear to be important. Future work will focus on the better delivery of phytosterols in natural foods and supplements and on further defining the mechanisms of action.

Exercise training decreases plasma cholesteryl ester transfer protein.

To assess the effect of exercise on the plasma concentration of cholesterol ester transfer protein (CETP) and its possible influence in mediating the exercise-associated redistribution of cholesterol among plasma lipoproteins, we measured plasma CETP in 57 healthy normolipidemic men and women before and after 9 to 12 months of exercise training. The training protocol resulted in significant changes in VO2max (mean +/- SD, +5.3 +/- 3.5 mL.kg-1 x min-1), body weight (-2.5 +/- 3.5 kg), plasma triglycerides (-25.7 +/- 36.3 mg/dL), high-density lipoprotein cholesterol (HDL-C) (+2.6 +/- 6.2 mg/dL), and ratios of total cholesterol to HDL-C (-0.30 +/- 0.52) and low-density lipoprotein cholesterol (LDL-C) to HDL-C (-0.18 +/- 0.45) (all P < or = .05) but no change in lipoprotein(a). CETP concentration (in milligrams per liter) fell significantly in response to training in both men (n = 28, 2.47 +/- 0.66 to 2.12 +/- 0.43; % delta = 14.2%; P < .005) and women (n = 29, 2.72 +/- 1.01 to 2.36 +/- 0.76; % delta = 13.2%; P < .047). The CETP change was observed both in subjects who lost weight (n = 28, delta mean weight = -5.0 kg; delta CETP = -0.42 +/- 0.79; % delta = 15.4%; P < .009) and in those who were weight stable (n = 29, delta mean weight = -0.12 kg; delta CETP = -0.29 +/- 0.78; % delta = 10.4%; P < .055).(ABSTRACT TRUNCATED AT 250 WORDS)

Phytosterols, Cholesterol Absorption and Healthy Diets

The purpose of this review is to outline the emerging role of dietary phytosterols in human health. Dietary saturated fat, cholesterol and fiber are currently emphasized in the reduction of low-density lipoprotein cholesterol levels. However, other dietary components such as phytosterols may have equivalent or even larger effects on circulating cholesterol and need further study with respect to the potential for coronary heart disease risk reduction. Phytosterol effects were not considered in classic fat-exchange clinical trials and may account for some of the differences attributed to the food fats studied. Phytosterols reduce cholesterol absorption while being poorly absorbed themselves and the effects can be studied in human subjects in single-meal tests using stable isotopic tracers. Because phytosterols are insoluble and biologically inactive when purified, careful attention needs to be given to ensuring that commercial supplement products are rendered bioavailable by dissolution in fat or by emulsification. Recent work shows that phytosterols in natural food matrices are also bioactive. The retention of phytosterols during food manufacturing and the use of foods with high phytosterol content may constitute an alternative to the use of supplements.

Dose effects of dietary phytosterols on cholesterol metabolism: a controlled feeding study

BACKGROUND Phytosterol supplementation of 2 g/d is recommended by the National Cholesterol Education Program to reduce LDL cholesterol. However, the effects of different intakes of phytosterol on cholesterol metabolism are uncertain. OBJECTIVE We evaluated the effects of 3 phytosterol intakes on whole-body cholesterol metabolism. DESIGN In this placebo-controlled, crossover feeding trial, 18 adults received a phytosterol-deficient diet (50 mg phytosterols/2000 kcal) plus beverages supplemented with 0, 400, or 2000 mg phytosterols/d for 4 wk each, in random order. All meals were prepared in a metabolic kitchen; breakfast and dinner on weekdays were eaten on site. Primary outcomes were fecal cholesterol excretion and intestinal cholesterol absorption measured with stable-isotope tracers and serum lipoprotein concentrations. RESULTS Phytosterol intakes (diet plus supplements) averaged 59, 459, and 2059 mg/d during the 3 diet periods. Relative to the 59-mg diet, the 459- and 2059-mg phytosterol intakes significantly (P < 0.01) increased total fecal cholesterol excretion (36 +/- 6% and 74 +/- 10%, respectively) and biliary cholesterol excretion (38 +/- 7% and 77 +/- 12%, respectively) and reduced percentage intestinal cholesterol absorption (-10 +/- 1% and -25 +/- 3%, respectively). Serum LDL cholesterol declined significantly only with the highest phytosterol dose (-8.9 +/- 2.3%); a trend was observed with the 459-mg/d dose (-5.0 +/- 2.1%; P = 0.077). CONCLUSIONS Dietary phytosterols in moderate and high doses favorably alter whole-body cholesterol metabolism in a dose-dependent manner. A moderate phytosterol intake (459 mg/d) can be obtained in a healthy diet without supplementation. This trial was registered at clinicaltrials.gov as NCT00860054.

Effects of Trace Components of Dietary Fat on Cholesterol Metabolism: Phytosterols, Oxysterols, and Squalene

The effect of dietary fats on serum cholesterol is widely assumed to be due solely to the fatty acids and cholesterol they contain. Phytosterols, sterol oxidation products, and sterol precursors such as squalene, however, are often present in dietary fats. Little is known of the physiology of these substances in natural foods and most published diet studies do not consider them at all. Supplementation of the diet with high-dose phytosterols is now recommended for prevention of heart disease, but both recent and old data strongly suggest that the lower levels of phytosterols naturally present in vegetable fats may also reduce cholesterol absorption and serum cholesterol substantially. Moreover, unmeasured phytosterols may confound otherwise well-controlled diet studies because there is an inverse correlation between phytosterol and saturated fatty acid content of vegetable fats. Sterol oxidation products, many of which are found in foods, are potent regulators of lipoprotein and cholesterol transport pathways in vitro. Squalene is a phytosterol precursor abundant in olive oil that is at least partly absorbed and then quantitatively converted to cholesterol. The effects of dietary triglyceride-derived fatty acids have not been experimentally separated from the effects of trace fat components in most clinical studies. A better understanding of the activity of sterol-related dietary components is needed to reduce variability in diet studies, accurately assess the effects of dietary fatty acids and to maximize the effectiveness of dietary treatment for hypercholesterolemia.

Insulin-stimulated release of d-chiro-inositol–containing inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome

Some actions of insulin are mediated by inositolphosphoglycan (IPG) mediators. Deficient release of a putative D-chiro-inositol-containing (DCI) IPG mediator may contribute to insulin resistance in women with polycystic ovary syndrome (PCOS). Previously, we demonstrated that oral DCI supplementation improved ovulation and metabolic parameters in women with PCOS. However, whether oral DCI mediates an increase in the release of the DCI-IPG mediator and an improvement in insulin sensitivity in women with PCOS is unknown. We conducted a randomized controlled trial of DCI supplementation vs placebo in 11 women with PCOS who were assessed at 2 time points 6 weeks apart. Plasma DCI, DCI-IPG release during oral glucose tolerance test (AUC(DCI-IPG)), and insulin sensitivity (S(i)) by frequently sampled intravenous glucose tolerance test were assessed at baseline and end of study. The study was terminated early because of a sudden unavailability of the study drug. However, in all subjects without regard to treatment assignment, there was a positive correlation between the change in AUC(DCI-IPG)/AUC(insulin) ratio and the change in S(i) during the 6-week period (r = 0.69, P = .02), which remained significant after adjustment for body mass index (P = .022) and after further adjustment for body mass index and treatment allocation (P = .0261). This suggests that, in women with PCOS, increased glucose-stimulated DCI-IPG release is significantly correlated with improved insulin sensitivity. The significant relationship between DCI-IPG release and insulin sensitivity suggests that the DCI-IPG mediator may be a target for therapeutic interventions in PCOS.

Phytosterol glycosides reduce cholesterol absorption in humans.

Dietary phytosterols inhibit intestinal cholesterol absorption and regulate whole body cholesterol excretion and balance. However, they are biochemically heterogeneous and a portion is glycosylated in some foods with unknown effects on biological activity. We tested the hypothesis that phytosterol glycosides reduce cholesterol absorption in humans. Phytosterol glycosides were extracted and purified from soy lecithin in a novel two-step process. Cholesterol absorption was measured in a series of three single-meal tests given at intervals of 2 wk to each of 11 healthy subjects. In a randomized crossover design, participants received approximately 300 mg of added phytosterols in the form of phytosterol glycosides or phytosterol esters, or placebo in a test breakfast also containing 30 mg cholesterol-d7. Cholesterol absorption was estimated by mass spectrometry of plasma cholesterol-d7 enrichment 4-5 days after each test. Compared with the placebo test, phytosterol glycosides reduced cholesterol absorption by 37.6+/-4.8% (P<0.0001) and phytosterol esters 30.6+/-3.9% (P=0.0001). These results suggest that natural phytosterol glycosides purified from lecithin are bioactive in humans and should be included in methods of phytosterol analysis and tables of food phytosterol content.

Greek hyperinsulinemic women, with or without polycystic ovary syndrome, display altered inositols metabolism

UNLABELLED BACKGROUND We have shown that American women with polycystic ovary syndrome (PCOS) have decreased glucose-stimulated release of a putative mediator of insulin action, D-chiro-inositol (DCI)-containing inositolphosphoglycan (DCI-IPG), and increased urinary clearance of DCI (uCl(DCI)), which was associated with hyperinsulinemia. METHODS DCI levels and the release of insulin and DCI-IPG during an oral glucose tolerance test (AUCs) were assessed in 27 Greek PCOS and 10 normal Greek women. RESULTS PCOS women were heavier than controls (BMI = 28.4 versus 23.7 kg/m(2), P = 0.05) with higher waist-to-hip ratios (WHR = 0.78 versus 0.71, P = 0.009) and increased free testosterone (P = 0.048) and AUC(insulin) (P = 0.04). In PCOS women, incremental AUC(DCI-IPG) was significantly decreased by 59% (2158 versus 5276%.min, P = 0.01), even after correction for BMI and WHR. Finally, increased uCl(DCI) (r = 0.35, P = 0.04) and decreased AUC(DCI-IPG) (r = 0.46, P = 0.004) were significantly associated with hyperinsulinemia in all women together, even after correction for BMI and WHR (Ps = 0.02 and 0.007), and regardless of PCOS status. CONCLUSIONS Greek women, with or without PCOS, display increased uCl(DCI) and decreased AUC(DCI-IPG) in association with higher insulin levels but independent of adiposity. Increased clearance of inositols might reduce tissue availability of DCI and decrease the release of DCI-IPG mediator, which could contribute to insulin resistance and compensatory hyperinsulinemia in Greek women, as previously described in American women.

Technical performance of a novel, fully automated electrochemiluminescence immunoassay for the quantitation of β-amyloid (1-42) in human cerebrospinal fluid.

Available assays for quantitation of the Alzheimers disease (AD) biomarker amyloid‐beta 1–42 (Aβ [1–42]) in cerebrospinal fluid demonstrate significant variability and lack of standardization to reference measurement procedures (RMPs). We report analytical performance data for the novel Elecsys β‐amyloid (1–42) assay (Roche Diagnostics).