The purpose of this study was to determine whether supplements of plant sterols and/or glucomannan improve lipid profile and cholesterol biosynthesis in mildly hypercholesterolemic type II diabetic and non-diabetic subjects and to compare the response of these two subject groups to the treatments.
A randomized, crossover study consisting of four phases of 21 days, with each phase separated by a 28-day washout.
The Mary Emily Clinical Nutrition Research Unit of McGill University.
Eighteen non-diabetic individuals and 16 type II diabetic individuals aged 38–74 years.
Subjects were supplemented with plant sterols (1.8 g/day), glucomannan (10 g/day), a combination of glucomannan and plant sterols, and a placebo, provided in the form of bars.
Overall plasma cholesterol concentrations were lowered (P<0.05) after combination treatment (4.72±0.20 mmol/l) compared to control (5.47±0.18 mmol/l). Plasma low-density lipoprotein (LDL) cholesterol concentrations were decreased (P<0.05) after glucomannan (3.16±0.14 mmol/l) and combination treatments (2.95±0.16 mmol/l) compared to control (3.60±0.16 mmol/l). The results of lipid profiles did not differ between subject groups. Overall plasma lathosterol concentrations, an index of cholesterol biosynthesis, were lowered (P<0.05) after the combination treatment compared to the plant sterol treatment.
The results suggest that glucomannan and a combination of glucomannan and plant sterols substantially improves plasma LDL cholesterol concentrations.
Forbes Medi-Tech Inc., Vancouver, British Columbia, Canada.
Dyslipidemia occurs frequently in type II diabetic individuals. Some investigators support that altered cholesterol metabolism exists among type II diabetic individuals (Gylling and Miettinen, 1997), which may account for the dislipidemic condition observed in these individuals. As elevated cholesterol concentrations are an independent risk factor of developing cardiovascular disease (CVD), it is important to maintain a lower low-density lipoprotein (LDL) cholesterol concentration (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001).
Plant sterols have been investigated as cholesterol-lowering agents since the early 1950s (Pollack, 1953). The efficacy of sterols has now been unquestionably established through many earlier (Weststrate and Meijer, 1998) and recent studies (Hallikainen et al., 2000; Vanstone et al., 2002; Varady et al., 2004). It has been shown that plant sterols lower LDL cholesterol concentrations by inhibiting cholesterol absorption in the intestine (Ikeda et al., 1988; Nissinen et al., 2002).
A soluble fiber, glucomannan has been acknowledged as being both a cholesterol-lowering (Doi et al., 1979; Arvill and Bodin, 1995; Vuksan et al., 2000; Chen et al., 2003) and hypoglycemic agent (Doi et al., 1990; Huang et al., 1990; Vuksan et al., 2000). It is hypothesized that glucomannan lowers cholesterol concentrations by decreasing the cholesterol biosynthesis rate. Glucomannan swells in the presence of water forming a highly viscous gel, which delays gastric emptying time and reduces the postprandial surge in plasma glucose and insulin concentrations (Doi, 1995; Vuksan et al., 2001). The reduction of postprandial insulin concentration which occurs, suppresses hepatic cholesterol synthesis (Jones et al., 1993) possibly through a reduction in insulin-induced 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity (Lakshmanan et al., 1973). In addition, glucomannan increases fecal weight (Doi et al., 1990) and fecal bile acid excretion (Matsuura, 1986; Chen et al., 2003), and reduces serum bile acid concentration (Matsuura, 1986). The reduction in serum bile acid and increased fecal bile acid excretion are considered to be a part of the cholesterol-lowering mechanism as well.
As plant sterols and glucomannan decrease circulating cholesterol concentrations through distinct mechanisms, it is important to assess whether a combination of plant sterols and glucomannan produces any greater cholesterol-lowering effect compared to the supplementation of plant sterols and glucomannan alone. In addition, considering the altered cholesterol kinetics, which occurs in type II diabetes, it is speculated that the response of diabetic subjects to the supplements may differ from non-diabetic subjects. Thus, the primary objective of the present study was to examine the effects of plant sterols and glucomannan individually and in combination, on plasma lipid concentrations and cholesterol kinetics in type II diabetic and non-diabetic subjects. A secondary objective was to determine whether the response of type II diabetic and non-diabetic groups to the treatments is similar.
Subjects and methods
Eighteen non-diabetic (eight men and 10 women) and 16 type II diabetic (four men and 12 women) volunteers (35–75 year) with mild hypercholesterolemia were recruited through advertisements in local newspapers. All female subjects were postmenopausal. Subjects were asked to provide a medical history and to complete a physical examination before acceptance into the study. Fasting blood and urine samples were collected and screened for biochemical, hematological and urine indices. Subjects with serum LDL cholesterol concentrations between 2.7 and 6.0 mmol/l and triacylglycerol concentrations <4.0 mmol/l were deemed eligible to enter into the study. Diabetic subjects were required to have fasting blood glucose concentrations >7.0 mmol/l and HbA1c concentrations between 6.0 and 9.0% (7.5–13.5 mmol/l plasma glucose equivalent). For non-diabetic subjects, the criterion for fasting blood glucose concentrations was <6.1 mmol/l. Subjects who were receiving hypolipidemic or insulin therapy, or suffered from chronic diseases such as gastrointestinal, renal, pulmonary, hepatic or biliary disease, or had a history of angina, congestive heart failure, or chronic use of laxatives, were excluded from the study. Subjects were permitted to continue their medication of metformin, sulfonylurea, thyroid hormone, antihypertensive agents and postmenopausal estrogens during the course of the study.
Experimental design and protocol
Study subjects were provided with each of four experimental supplements for periods of 21 days using a randomized, crossover, double-blind design. Each treatment phase was followed by a 4-week washout period during which the subjects consumed their habitual diets. Subjects were randomly assigned to each of the following four treatments; 1.8 g/day of plant sterols, 10 g/day of glucomannan, a combination of both, or none as a control with blinding. The optimal dosage of plant sterols has been reported to be 1.8 g/day (Katan et al., 2003), therefore this was the dose administered in the current study. On the other hand, owing to the limited number of studies involving glucomannan, the optimal dose of glucomannan has yet to be established and the range of reported glucomannan dose with significant cholesterol-lowering effect and minor side effects was between 3.6 and 13.0 g/day (Arvill and Bodin, 1995; Vuksan et al., 2000; Chen et al., 2003). Therefore, to avoid underestimating the therapeutic dose level of glucommanan, a relatively large 10 g/day dose was administered, as reported in a previous study showing efficacy of glucomannan (Vuksan et al., 2000). Plant sterols and glucomannan were provided in the form of granola bars (Forbes Medi-tech Inc., Vancouver, BC, Canada). The plant sterols used in the study were derived from tall oil and contained sitosterol (67.3%), sitostanol (10.8%), campesterol (8.2%), campestanol (1.6%) and others (12.1%). The nutritional composition of the granola bars is presented in Table 1. Subjects were instructed to take one bar between meals as a snack, 3 times a day together with 250 ml of any type of beverage. The bars were provided to subjects each week (days 0, 8 and 15) at the Mary Emily Clinical Nutrition Research Unit of McGill University (Montreal, QC, Canada). Compliance was assessed by asking subjects to return uneaten portions of the bars and weighing the amount of returned bars. Palatability of the treatment bars was evaluated on a scale from 0 to 10 at the end (day 21) of each phase by a questionnaire. Physical examinations were performed at the beginning (day 0) and at the end (day 21) of each phase by the study physician to ensure the health status of all participants. The major source of energy in the treatment bars was in the form of carbohydrate; therefore, subjects were instructed to replace their usual carbohydrate sources with the treatment bars while maintaining the rest of their dietary habits stable. Dietary changes during the treatment and washout periods were assessed by a Yes/No questionnaire. In addition more detailed dietary information was collected by study coordinators on day 0 and day 21 of each phase. If there were major dietary changes, dietary counseling was conducted to help subjects maintain their usual dietary habits. Body weight was measured on days 0, 8, 15 and 21. Side effects including the change in the frequency of evacuation and intestinal condition during the study period were monitored by questionnaire at the beginning (day 0) and the end (day 21) of each treatment phase.
Fasting blood samples were obtained at days 0 and 21 of each phase. Plasma and red blood cells were separated by centrifugation for 15 min at 1500 r.p.m. within 30 min of phlebotomy and were stored at −20°C until analysis. Plant sterols, insulin and fructosamine concentrations were measured at the beginning (day 0) and end of each phase (day 21). On the last day of each phase (day 21), after fasting blood sample collection, a 2-h oral glucose tolerance test was conducted before breakfast. An orange flavored glucose tolerance beverage containing 50 g of dextrose (NERL Diagnostics, RI, USA) was provided to each subject, followed by finger prick blood samples that were taken every half hour for 2 h.
All subjects gave informed written consent. Before participating in the study, subjects were given the opportunity to discuss any queries with the primary investigator, the physician and the study coordinator. Ethical approval for the study was obtained from the Institutional Review Board of the Faculty of Medicine at McGill University.
Determination of plasma lipid concentrations
Plasma total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol and triacylglycerol concentrations were determined enzymatically using a Hitachi/991 chemistry analyzer (Roche Diagnostic Inc., Indiana, IN, USA) at the Lachine Hospital (Montreal, QC, Canada) (Siedel et al., 1983; Sugiuchi et al., 1995). Plasma LDL cholesterol concentrations were calculated using the Friedewald equation (Friedewald et al., 1972).
Determination of plasma non-cholesterol sterol concentrations
Plasma plant sterol concentrations were measured in duplicate by gas–liquid chromatography as described elsewhere (Ntanios and Jones, 1998). Briefly, 1.0 ml of plasma was saponified. The non-saponified lipids were extracted with petroleum ether. An internal standard of 5-α-cholestane was used. The lipid extracts were analyzed by a gas–liquid chromatograph equipped with a flame ionization detector (HP 5890 series II; Hewlett Packard, Palo Alto, CA, USA) using a 30-m capillary column with an internal diameter of 0.25 mm (SAC-5; Supelco, Bellefonte, PA, USA). Samples were run isothermally at 285°C. Plant sterol peaks were identified by comparison with authenticated standards (Sigma-Aldrich Canada Ltd, Oakville, ON, Canada).
Determination of plasma insulin, serum fructosamine and blood glucose concentrations
Plasma insulin concentrations were determined in duplicate, using commercially available radioimmunoassay kits (ICN Pharmaceutical, Inc., Costa Mesa, CA, USA) using 125I as a tracer. Radioactivity was determined by gamma counter (LKB Wallac, 1282 compugamma CS, Fisher Scientific, Montreal, QC, Canada) and expressed as count per minute. Plasma insulin concentrations were quantified in reference to a standard curve. Serum fructosamine concentrations were determined by LDS Diagnostic Laboratories (Pointe Claire, QC, Canada). Blood glucose concentrations from finger prick blood samples were measured using a portable glucometer, Glucometer Elite® XL (Bayer Inc., Toronto, ON, Canada). The glucometer was standardized before each assessment.
Baseline characteristics of the participants were compared between subjects with type II diabetes and non-diabetes by using the Student's t-test. To examine the effect of treatments and subject groups on body weight change between baseline (day 0) and end point (day 21), repeated measure analysis of variance with general linear model was used. The independent variables were treatment, subject group, and interaction between treatment and subject group, and the dependent variable was body weight change. When treatment effects were significant, comparisons between individual treatments were analyzed using Scheffé multiple comparisons adjustment. When interaction of treatment and group effects were significant, type II and non-type II groups were analyzed separately. To examine the effect of treatments and group on lipid profiles, plasma non-phytosterols and glycemic controls, repeated measure analysis of variance with general linear model was also used. The difference of body weight between the baseline (day 0) and end point (day 21) was included in the previous model in order to adjust body weight change during each treatment. When treatment or interaction of treatment and group effects were significant, comparisons between individual treatments were analyzed using Scheffé multiple comparisons to identify the significant effects of each treatment. The carry-over effects were examined with a comparison of the baseline values of each treatment by using the same statistical model. The P-value <0.05 was considered statistically significant. The baseline characteristics are presented as means±s.d. while other data are presented as least-squared adjusted means±s.e.m. Data were analyzed using SAS (version 6.12; SAS Institute Inc., Cary, NC, USA).
Characteristics of subjects
Sixteen type II diabetic and 18 non-diabetic individuals participated in the study, with 13 diabetic and 16 non-diabetic subjects completing all treatments. Two subjects (one non-diabetic and one diabetic subject) withdrew their participation after glucomannan supplementation, due to gastric discomfort. Results of three subjects (one non-diabetic and two diabetic subjects) were excluded from the statistical analysis due to poor compliance in supplement intake (<50%), which was evaluated on the weight of the returned bars. The baseline characteristics of subjects are presented in Table 2. Most of the subjects were overweight or obese. Body mass index (BMI), plasma triacylglycerol levels, and all of the diabetic indicators, including glucose, insulin, HbA1c and fructosamine, were higher (P<0.05) in the type II diabetic group compared to the non-diabetic group. Plasma LDL cholesterol concentrations were lower (P<0.01) in diabetic subjects compared with non-diabetic individuals. However, because there is a higher risk of developing CVD in type II diabetes (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001), both of these groups are characterized by mild hypercholesterolemia. Decreased HDL cholesterol (0.92±0.16 mmol/l) and elevated triacylglycerol concentrations (2.69±1.53 mmol/l) were found in the type II diabetic group; therefore, using the National Cholesterol Education Program's Adult Treatment Panel III criteria, individuals with type II diabetes were also characterized by metabolic syndrome (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001). HbA1c (7.02±0.80%) were relatively low in the diabetic group, suggesting that glucose control in type II diabetic subjects was well controlled by medication and diet at the entrance of the study. The oral hypoglycemic agents and other medications administered included metformin (seven subjects), combination of metformin and glyburide (eight subjects), and combination of glyburide and losartan (one subject). None of the participants received insulin therapy or hypolipidemic medication.
Based on the weight of returned bars, consumption of test granola bars was calculated to be 98.8, 99.4, 98.4 and 98.8% in control, plant sterols, glucomannan and combination treatments, respectively. There was no difference between the two groups of subjects or between dietary treatments in the consumption of bars.
Palatability of treatment granola bars
The palatability score of granola bars was 7.16±0.39, 7.63±0.38, 6.36±0.48 and 6.04±0.36 in control, plant sterols, glucomannan and combination treatments, respectively. Plant sterol-containing granola bars showed higher (P<0.05) palatability than glucomannan-containing bars or the bars containing both glucomannan and plant sterols. Type II diabetic subjects showed higher acceptance for the tested granola bars than non-diabetic subjects.
Intestinal changes in response to treatment
Subjects were asked to report intestinal changes at the end of each phase. The number of evacuations increased in 8, 12 and 14 subjects during plant sterols, glucomannan and the combination treatments, respectively. Soft stool was observed in 8, 14 and 12 subjects during plant sterols, glucomannan and the combination treatments, respectively. During the control phase, 12 subjects reported that their stools became harder. Twenty-one subjects reported increased gas production during treatments containing glucomannan. Although majority of the participants (100% for control and plant sterol, 86.7% for glucomannan and 89.7% for combination treatments) reported that the changes in the intestinal habits and stool characteristics were tolerable, owing to the number of gastrointestinal changes reported by subjects it is evident that future studies need daily recordings to define potential side effects associated with glucomannan consumption.
Effects of dietary treatments on body weight
Mean body weight changes from baseline were −0.22±0.32, −0.10±0.18, −0.05±0.18 and −0.70±0.24 kg in control, plant sterols, glucomannan and the combination treatments, respectively. During the combination treatment, type II diabetic subjects decreased (P<0.05) body weight (−1.34±0.24 kg), whereas non-diabetic subjects maintained their body weight (−0.29±0.33 kg). In other treatment periods, no significant changes in body weight were observed as compared to baseline or between the two groups of subjects. Except for the replacement of carbohydrate source with treatment bars, no significant changes in diet and medication were reported during the entire study period.
Effects of dietary treatments on plasma lipids
Plasma lipid concentrations of non-diabetic and type II diabetic groups during the treatment periods are shown in Table 3. No carry-over effects were observed. All results were adjusted for body weight changes during each treatment period. Overall, supplementation of glucomannan combined with plant sterols reduced (P<0.05) plasma total cholesterol concentrations (4.72±0.20 mmol/l) compared to control (5.47±0.18 mmol/l). The overall percentage change of total cholesterol from baseline was also lower (P<0.05) in glucomannan (−11.84±2.32%) and combination (−17.03±3.12%) treatments compared to control (−4.42±1.77%). There was no difference between type II diabetic and non-diabetic subjects in response to the treatments.
After 21 days of supplementation, glucomannan (3.16±0.14 mmol/l) and the combination of glucomannan (2.95±0.16 mmol/l) decreased (P<0.05) LDL cholesterol concentrations compared to control (3.60±0.14 mmol/l) in non-diabetic and type II diabetic subjects. Overall plasma LDL cholesterol concentrations were also lower (P<0.05) after combination treatment compared with plant sterol treatment (3.44±0.14 mmol/l); however, no difference was observed between the glucomannan and combination treatments.
Plasma triacylglycerol concentrations were not affected by dietary treatments. However, the plasma triacylglycerol concentrations were consistently higher (P<0.05) in the diabetic group than in the non-diabetic group during the entire study period.
Plasma HDL cholesterol concentrations did not differ among the treatment periods. There was also no difference in the changes of HDL concentrations between the two subject groups.
Effects of dietary treatments on plasma non-cholesterol sterols
Plasma non-cholesterol sterols in type II diabetic and non-diabetic groups are summarized in Table 4. On day 21, β-sitosterol concentrations were higher (P<0.05) following plant sterol treatment (1.09±0.18 mmol/mol) compared to the glucomannan treatment (0.70±0.09 mmol/mol). β-Sitosterol concentrations and the ratio of β-sitosterol to total cholesterol in the combination treatment were not significantly different from glucomannan or control groups. Plasma β-sitosterol concentrations were not different between type II diabetic and non-diabetic groups after each treatment.
The reductions in plasma lathosterol after 21 days were greater (P<0.05) with the combination treatment (−0.10±0.06 mmol/mol) compared with plant sterol treatment (0.17±0.08 mmol/mol). During the control period, plasma lathosterol concentration changes from baseline (day 0) were greater in individuals with type II diabetes compared to the non-diabetic group.
Effects of dietary treatments on insulin, fructosamine and 2 h oral glucose tolerance test
Plasma fasting insulin concentrations were higher (P<0.05) in the diabetic group (21.0±7.7 pmol/l) compared to the non-diabetic group (39.2±16.1 pmol/l). Serum fructosamine concentrations were also higher (P<0.05) in diabetic subjects (3.95±0.07 umol/g) compared to non-diabetic subjects (3.40±0.03 umol/g). Blood glucose concentrations were consistently higher (P<0.05) in type II diabetic than in non-diabetic subjects during the 50 g 2 h oral glucose test. Dietary treatments did not affect plasma insulin and serum fructosamine concentrations, or the results of the glucose tolerance test.
The main finding of this study is that both a combination of plant sterols and glucomannan significantly lower LDL cholesterol in type II diabetic and non-diabetic mildly hypercholesterolemic individuals. Plant sterols alone reduced LDL cholesterol by 8.5±2.1% compared to baseline LDL cholesterol levels by day 7 (data not shown); however, the reduction in LDL cholesterol concentrations were not significant at weeks 2 and 3. The plateau effect of LDL cholesterol concentrations in weeks 2 and 3 may be related to the food matrix, which plant sterols were supplemented in, and to the free-living design of the study. On the other hand, 10 g/day of glucomannan and a combination treatment reduced plasma LDL cholesterol by 11.2±3.3 and 17.5±3.3%, respectively, in the type II diabetic and non-diabetic individuals. Owing to the large variability in LDL cholesterol concentrations, cholesterol-lowering effect was not statistically different between the glucomannan and combination groups.
The cholesterol lowering by the combination of plant sterols and glucomannan may involve a reduction in both cholesterol absorption and synthesis. Plant sterols have been shown to suppress intestinal cholesterol absorption by reducing dietary and biliary cholesterol incorporation into micelles (Ikeda et al., 1988; Nissinen et al., 2002). However, it has also been shown that the inhibition of the intestinal absorption is partially compensated for by an increase in hepatic cholesterol synthesis rate (Gylling et al., 1999; Jones et al., 2000). Glucomannan, on the other hand, suppresses the postprandial insulin peak by delaying the absorption of nutrients across the small intestine (Doi, 1995), as well as enhancing fecal excretion of neutral sterol and bile acids (Matsuura, 1986; Chen et al., 2003). The reduced postprandial insulin concentrations decrease cholesterol biosynthesis (Jones et al., 1993). As insulin increases HMG-CoA reductase activity (Osborne et al., 2004), the reduction in postprandial insulin decreases HMG-CoA reductase activity and may suppress an increase in cholesterol synthesis induced by plant sterol supplementation. The changes in concentrations of plasma lathosterol, a cholesterol precursor and an index of cholesterol synthesis (Miettinen et al., 1990), may support this proposed cholesterol-lowering action by plant sterols and glucomannan. Plasma lathosterol concentrations (0.17±0.08 mmol/mol) were increased from baseline with plant sterol treatment. Changes in lathosterol concentrations after glucomannan supplementation were not detectable; however, plasma lathosterol was decreased (P<0.05) by −0.10±0.06 mmol/mol after supplementation with the combination treatment compared with plant sterol treatment alone. These changes in plasma lathosterol concentrations may suggest that glucomannan suppresses the compensatory increase of cholesterol synthesis by plant sterol intake. However, because postprandial insulin concentrations were not determined in the current study, it is unclear whether insulin contributed to the reduced cholesterol synthesis during the plant sterol and glucomannan supplementation period.
Contrary to what was expected, no changes in glycemic control were observed by supplementation of glucomannan treatments. Dietary supplementation of glucomannan did not affect fasting insulin and fructosamine concentrations, which are indicators of glycemic control. This finding is in contrast to previous research showing that glucomannan supplementation improves glycemic control in type II diabetic subjects (Doi et al., 1990; Huang et al., 1990; Vuksan et al., 2000) and non-diabetic subjects (Scalfi et al., 1987). The discrepancies between studies may be explained by differences in study design. Although previous studies (Scalfi et al., 1987; Doi et al., 1990; Vuksan et al., 2000) supplemented glucomannan in combination with a controlled diet, in the present study participants were asked to maintain their usual diet in order to determine the effect of glucomannan in the context of a North American lifestyle. Therefore, it is possible that the discrepancy in findings between the present and previous studies may be due to the absence of dietary control. Not only the supplementation of glucomannan but also the improvement in dietary habits may be required to demonstrate an improvement in glycemic control.
One side effect of glucomannan supplementation during this study was an action on intestinal regularity. Particularly, subjects reported that glucomannan supplementation induced increased stool frequency, softened stool condition and increased gas production. Similar intestinal changes have been reported when glucomannan was supplemented at 7.8–13 g/day (Doi et al., 1990; Vuksan et al., 2000). However, no changes in intestinal habits were observed with smaller doses (3.6 g/day) of glucomannan (Arvill and Bodin, 1995). Therefore, reported changes in intestinal habits may only occur with larger doses of glucomannan. Besides changes in intestinal movements, it was reported that the palatability of treatment granola bars with glucomannan was lower compared to plant sterol granola bars, perhaps due to the rheological characteristics of glucomannan. Glucomannan is a soluble fiber that forms a highly viscous gel in aqueous solutions, including saliva. This viscous gel plays an important role in its hypoglycemic and hypocholesterolemic action, but it also creates an undesirable taste and mouth feel. Considering both the possible intestinal side effects and unpalatable texture produced by glucomannan, dosage of glucomannan may play an important role in the acceptance of subjects to comply with the treatment product.
In summary, results of the present study show that glucomannan and a combination of plant sterols and glucomannan mixed in a granola type bar, significantly lower LDL cholesterol concentrations, compared to control and may represent a potential alternative to pharmacological approaches to lower LDL cholesterol concentrations in mildly type II diabetic and non-diabetic hypercholesterolemic individuals.
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We thank Christine Gurekian, Mira Laza and Dr Yanwen Wang for their assistance in conducting the clinical trial, the preparation of the tested bars, and the manuscript preparation.
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Yoshida, M., Vanstone, C., Parsons, W. et al. Effect of plant sterols and glucomannan on lipids in individuals with and without type II diabetes. Eur J Clin Nutr 60, 529–537 (2006) doi:10.1038/sj.ejcn.1602347
- plant sterols
- mild hypercholesterolemia
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