The Metabolic Syndrome Maria Luz Fernandez, PhD

June 2007(II): S30 S34 The Metabolic Syndrome Maria Luz Fernandez, PhD The metabolic syndrome is a cluster of symptoms associated with insulin resistance and known to precede the onset of type 2 diabetes. Overweight and obesity contribute significantly to the development of the metabolic syndrome. In fact, weight loss has a huge impact in decreasing the symptoms associated with the metabolic syndrome. Several studies have demonstrated that just by losing 7% to 10% of initial body weight is sufficient to have improvement in waist circumference, dyslipidemias (elevated triglycerides and low high-density-lipoprotein cholesterol), trunk fat, and plasma glucose. This paper underlines the importance of weight loss and type of diet in reversing the symptoms of the metabolic syndrome. Key words: carbohydrate restriction, metabolic syndrome, overweight, waist circumference, weight loss 2007 International Life Sciences Institute doi: 10.1301/nr.2007.jun.S30 S34 INTRODUCTION Despite the continuing effort to educate the public that excessive weight increases the risk of chronic disease, the prevalence of overweight and obesity continues to increase. 1 Overweight has historically been defined as a body mass index (BMI) of 25 to 29.9 kg/m 2 and obesity as a BMI equal to or greater than 30 kg/m 2. 1 Research has shown that overweight/obese individuals have a higher risk of developing insulin resistance, the metabolic syndrome, diabetes, hypertension, and coronary heart disease (CHD). 1,2 More recently, waist circumference has been used as a more reliable criteria than BMI to predict risk for CHD, 3,4 and it is also one of the parameters for classification of the metabolic syndrome. 5 The metabolic syndrome has been defined as the Dr. Fernandez is with the Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA. Please address all correspondence to: Dr. Maria Luz Fernandez, Department of Nutritional Sciences, 3624 Horsebarn Road Ext., University of Connecticut, Storrs, CT 06269; Phone: 860-486-5547; Fax: 860-486-3674; E-mail: maria-luz.fernandez@uconn.edu. cluster of symptoms that are present just before the onset of type 2 diabetes (associated with adult overweight). 6 The Adult Treatment Panel III has determined that individuals are classified with metabolic syndrome if they present three or more of the parameters shown in Table 1. 7 Also, high levels of C-reactive protein have been correlated with the metabolic syndrome. 7 The metabolic syndrome is also considered a marker for obesity and dyslipidemia. In the United States, the obesity epidemic has reached alarming proportions. The first census, which covered the obesity epidemic in 1960 1962, estimated obesity prevalence at around 13.4%. In the year 2000, it was estimated that 64.5% of the adults in United States were overweight or obese. Currently, approximately 16 million people in the United States have type 2 diabetes mellitus. In addition, CHD is the leading cause of death for men and women. 8 Because type 2 diabetes and cardiovascular disease can progress silently, the identification of risk factors relative to these diseases that can be utilized and interpreted by the general public is of vital importance. In addition, it is clearly established that both type 2 diabetes and CHD can be greatly improved by weight reduction. 9 Several types of interventions have been used to decrease the symptoms of the metabolic syndrome. One of the most effective interventions appears to be carbohydrate restriction. CARBOHYDRATE RESTRICTION As described above, waist circumference seems to play an important role in the development of the metabolic syndrome. While abdominal obesity is determined by the accumulation of both subcutaneous adipose tissue and visceral adipose tissue, some studies described that visceral adipose tissue (VAT) appears to play a major role in the metabolic syndrome. 10 The portal theory suggests that insulin resistance and many of its related features could arise from VAT delivering free fatty acids at a high rate to the liver via the portal vein into which VAT directly drains. This in turn would increase hepatic glucose production, reduce hepatic insulin clearance, and finally lead to insulin resistance, hyperinsulinemia, hyperglycemia, and non-alcoholic fatty liver disease. 11 S30 Nutrition Reviews, Vol. 65, No. 6

STUDY WITH OVERWEIGHT/OBESE PREMENOPAUSAL WOMEN Carbohydrate-restricted diets seem to improve all of the biomarkers associated with the metabolic syndrome. 12 Recent studies by Volek et al. 13 showed that a short-term, isoenergetic, very-low-carbohydrate diet significantly decreased fasting and postprandial triglycerides, increased high-density lipoprotein cholesterol (HDL-C) and decreased the total cholesterol/hdl-c ratio. The large increase in HDL-C could be related to increased production of this lipoprotein by hepatocytes and the intestinal mucosa and/or increased lipoprotein lipase (LPL) activity, which results in disassociation of surface components that are acquired by HDL. Studies conducted in mice fed a high-fat diet observed a very strong correlation between increases in post-heparin LPL activity and HDL-C. 14 In humans, moderate- to high-fat diets (46% 65% of total energy) significantly increased post-heparin plasma LPL activity and skeletal muscle LPL activity. 15 In another study, the effects of a high-monounsaturated fat diet (low in carbohydrate) and a high-carbohydrate diet were tested on the resistance of low-density lipoprotein (LDL) to oxidation in type 2 diabetic patients in an intervention that followed a randomized crossover design. 16 When the acceptability of the two diets was compared at the end of 6 weeks, the high-fat diet was preferred by the patients. Although no significant effects on plasma cholesterol, triglycerides, HDL-C, parameters of LDL oxidation, body weight, or glycemic control were observed between the two dietary periods, significant reductions were observed in both very-low-density lipoprotein cholesterol (VLDL-C) and triglycerides during the high-fat period. The investigators concluded that a high-fat diet rich in monounsaturated fat is a good alternative for patients with type 2 diabetes due to its palatability and high acceptance, in addition to the observed beneficial effects on plasma lipid profiles. 18 We have conducted two studies in which improvement of cardiovascular risk factors and those of the metabolic syndrome were evident. These two weight loss studies involving men and premenopausal women will be described in detail below. When the intervention was initiated, these individuals were either overweight or obese and presented with dyslipidemias or symptoms associated with insulin resistance or the metabolic syndrome. The purpose of this study was to evaluate whether the weight loss induced by dietary modification including caloric restriction and modifications in macronutrient composition plus increased physical activity would produce favorable metabolic changes regarding risk for CVD and metabolic syndrome in young women. Eighty women (age 29.9 5.1 years) who were classified as being overweight or obese (BMI 26 27 kg/m 2 ) were recruited. 6,17 Although their levels of total cholesterol, HDL-C, and triglycerides were within normal recommendations, the levels of LDL cholesterol (LDL-C) were higher than 100 mg/dl. In addition, a great number of these subjects had small, dense LDL particles, which are associated with increased risk for CHD. 18 The presence of small, dense LDL (B phenotype) has been correlated with high levels of triglycerides and abdominal fat and low levels of HDL-C. 19 Eleven women were identified with the metabolic syndrome according to the classification presented in Table 1, while 25 of these women were classified with insulin resistance. Women followed a 10-week intervention that consisted of a low-calorie diet adapted to individual needs and level of activity. 20,21 The diet had the following energy distribution: 30% protein, 30% fat, and 40% carbohydrate. Participants increased their level of activity by increasing the number of steps taken per day, which were assessed at baseline by the use of a pedometer. Subjects were asked to increase 1500 steps each week until they completed an additional 4500 steps compared with their baseline. Women also took a supplement of either carnitine (3 g/d) or a placebo (cellulose) in a randomized, double-blind design. All subjects received 90% of their food. They were responsible for buying cooking oil and milk (nonfat). Meat, fruits, vegetables, bread, pasta, and snacks were provided by the investigators. At the end of the study, participants experienced significant changes in body weight, abdominal fat, waist circumference, 22 cholesterol, triglycerides, and LDL-C, as well as in the size of the LDL particles 23 and in plasma insulin concentrations. 22 Carnitine had no effect on any of the measured parameters, so data for the 70 subjects who completed the study were pooled. Results are presented between baseline and post-treatment (10 weeks) in Tables 2 and 3. As seen in Table 2, women decreased their BMI, waist circumference, body weight, total fat, and abdominal fat following the intervention (P 0.001). 22 Similarly, there were significant decreases in total cholesterol, LDL-C, and triglycerides, and increases in the size of Nutrition Reviews, Vol. 65, No. 6 S31

LDL particles. Also, a significant percentage of subjects changed from pattern B to pattern A after 10 weeks (Table 3). 23 In summary, all of the changes were beneficial. However, the values for HDL-C did not change after the participants lost weight, nor there were significant changes in blood pressure. Another key variable that was affected by the intervention was plasma insulin, which clearly indicates that weight loss was associated with the regulation of insulin levels (Table 2). This decrease in insulin is central in this study, because is indicative that insulin resistance, a condition associated with the onset of diabetes, decreases as body weight returns to normal. The most significant result from this study is that out of the 25 women who were insulin resistant, 17 became insulin sensitive (with a very significant reduction in risk for diabetes). Of the 11 women who were classified with metabolic syndrome, 10 of them were no longer classified as having the metabolic syndrome after they reduced their plasma triglycerides and their waist circumference. 22 The results of this study, an intervention that only required the consumption of a lower-carbohydrate diet and increasing the number of steps walked per day, had very important implications for health, because the biomarkers for chronic disease and the metabolic syndrome had a tendency to be eliminated. Future studies addressing whether weight maintenance results in healthy lipid profiles and in maintaining subjects away from the metabolic syndrome classification are necessary to provide adequate information to the general public. other traditionally measured markers of CHD and the metabolic syndrome. Using a parallel-arm, double-blind, placebo-controlled design, 30 overweight and obese men (BMI 25 35 kg/m 2 ) were randomly assigned to supplement a carbohydrate-restricted diet with soluble fiber (Konjac-mannan, 3 g/d) (n 15) or placebo (n 15). Plasma lipids, anthropometrics, body composition, blood pressure, and nutrient intake were evaluated at baseline, 6 weeks, and 12 weeks. Compliance was excellent, as assessed by 7-day weighed dietary records and ketonuria. 22 Following recruitment, all subjects attended a group meeting at which registered dietitians provided instructions on how to follow a carbohydrate-restricted diet similar to those employed in our previous studies. 14,23 Subjects were instructed to determine ketonuria at the same time nightly using reagent strips to assess compliance. Since there were no significant differences between fiber and placebo, data from all subjects were pooled to evaluate the effect of the intervention on anthropometrics and plasma lipids. There was a significant decrease in body weight (P 0.01), percent body fat (P 0.01), systolic blood pressure (P 0.01), waist circumference, and plasma glucose (P 0.01) following the intervention (Table 4). Most significantly, after 12 weeks, HDL-C was higher and triglycerides were lower (P 0.0001), while LDL-C had decreased by 14.1% (Table 4). As expected, because of the reductions in plasma triglycerides, consumption of the carbohydrate-restricted diet resulted in significant reductions in apolipoprotein C-I ( 13.8%), apolipoprotein C-III ( 21.2%), and apolipoprotein E ( 12.5%). Lecithin cholesterol acyltransferase (LCAT) activity was significantly increased from 18.3 6.8 to 28.3 16.6 nmol/mg/h after 12 weeks (P 0.01), while cholesterol ester transfer protein activity did not differ between baseline and week 12 (P 0.05). 24 STUDY WITH OBESE/OVERWEIGHT MEN The objective of this study was to determine the effect of adding soluble fiber to a carbohydrate-restricted diet with a distribution of energy of 60% fat, 30% protein, and 10% carbohydrate on plasma LDL-C and S32 Nutrition Reviews, Vol. 65, No. 6

The carbohydrate-restricted diet had a huge impact on the number of VLDL, LDL, and HDL particles. The total number of VLDL particles was reduced by 19.0% as a result of a reduction in large ( 47.7%), medium ( 40.2%), and small ( 4.3%) VLDL (P 0.001) 25 between baseline and 12 weeks. LDL particle size increased (P 0.001), while particle number decreased (P 0.05) from baseline to week 12. The increase in particle size was due to a 35% increase in large LDL particles (P 0.001) and a 25% reduction in very small LDL particles (P 0.001). Medium and small LDL were also reduced by 27% and 30%, respectively (P 0.01) (Figure 1). Consumption of a carbohydrate-restricted diet for 12 weeks also caused an increase in HDL particle size (P 0.01). The number of large HDL particles increased by 39%, while the number of medium HDL particles was reduced (P 0.01) and small HDL particles remained unchanged (P 0.05). This study provided novel information about the alterations in lipoprotein metabolism resulting from carbohydrate restriction. A 12-week carbohydrate-restricted diet resulted in significant reductions in triglycerides and apolipoproteins involved in triglyceride metabolism, leading to a decreased number of VLDL particles. This reduction in triglyceride-rich lipoproteins was associated with an increase in mean LDL particle size and a decrease in small and very small LDL particle quantity. Further, the changes in plasma triglycerides in combination with increased LCAT activity led to an increased mean HDL particle diameter. These results provide important information about the beneficial effects of a carbohydrate-restricted diet on cardiovascular risk. These results are limited to overweight and slightly obese men who are otherwise healthy and not taking lipid-lowering medication. The duration of the intervention was relatively short but tightly controlled, thus clearly representing the true biological adaptations to a carbohydrate-restricted diet. We conclude that the alterations in lipoprotein metabolism resulting from carbohydrate restriction are achieved through changes in VLDL, LDL, and HDL particle morphology and apolipoprotein concentrations. A comparison of the parameters that were modified in these two weight loss interventions is presented in Table 5. It is important to note here that there are other differences between these two studies, including gender and length of the intervention. However, the very-lowcarbohydrate diet (10%) proved to be more effective in improving the parameters associated with the metabolic syndrome compared with a moderate intake of carbohydrate (40%). In summary, there are many lifestyle factors that can be modified and have an impact on the metabolic syndrome. However, weight reduction and diet modifications are the best alternatives. Among the dietary interventions, carbohydrate restriction appears to have the greatest impact. Figure 1. Low-density lipoprotein (LDL) subclass quantity. Nutrition Reviews, Vol. 65, No. 6 S33

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