Effect of ketogenic mediterranean diet with phytoextracts and low carbohydrates/high-protein meals on weight, cardiovascular risk factors, body composition and diet compliance in Italian council employees

  • Antonio Paoli1Email author,

    Affiliated with

    • Lorenzo Cenci2 and

      Affiliated with

      • Keith A Grimaldi3

        Affiliated with

        Nutrition Journal201110:112

        DOI: 10.1186/1475-2891-10-112

        Received: 13 July 2011

        Accepted: 12 October 2011

        Published: 12 October 2011

        Abstract

        Background

        There has been increased interest in recent years in very low carbohydrate ketogenic diets (VLCKD) that, even though they are much discussed and often opposed, have undoubtedly been shown to be effective, at least in the short to medium term, as a tool to tackle obesity, hyperlipidemia and some cardiovascular risk factors. For this reason the ketogenic diet represents an interesting option but unfortunately suffers from a low compliance. The aim of this pilot study is to ascertain the safety and effects of a modified ketogenic diet that utilizes ingredients which are low in carbohydrates but are formulated to simulate its aspect and taste and also contain phytoextracts to add beneficial effects of important vegetable components.

        Methods

        The study group consisted of 106 Rome council employees with a body mass index of ≥ 25, age between 18 and 65 years (19 male and 87 female; mean age 48.49 ± 10.3). We investigated the effects of a modified ketogenic diet based on green vegetables, olive oil, fish and meat plus dishes composed of high quality protein and virtually zero carbohydrate but which mimic their taste, with the addition of some herbal extracts (KEMEPHY ketogenic Mediterranean with phytoextracts). Calories in the diet were unlimited. Measurements were taken before and after 6 weeks of diet.

        Results

        There were no significant changes in BUN, ALT, AST, GGT and blood creatinine. We detected a significant (p < 0.0001) reduction in BMI (31.45 Kg/m2 to 29.01 Kg/m2), body weight (86.15 kg to 79.43 Kg), percentage of fat mass (41.24% to 34.99%), waist circumference (106.56 cm to 97.10 cm), total cholesterol (204 mg/dl to 181 mg/dl), LDLc (150 mg/dl to 136 mg/dl), triglycerides (119 mg/dl to 93 mg/dl) and blood glucose (96 mg/dl to 91 mg/dl). There was a significant (p < 0.0001) increase in HDLc (46 mg/dl to 52 mg/dl).

        Conclusions

        The KEMEPHY diet lead to weight reduction, improvements in cardiovascular risk markers, reduction in waist circumference and showed good compliance.

        Background

        Obesity has become a health emergency in Western countries [1, 2]. As is well known, obesity and in particular abdominal obesity is one of the principle risk factors for cardiovascular disease and along with dyslipidemia, hypertension and diabetes contributes to the metabolic syndrome [3]. Even though weight loss is a desired goal for most overweight individuals, and its health benefits have been clearly determined [4, 5], there are still no definitive data on what dietary protocols are most effective in both the short and long term [6] or even what is the correct nutritional approach in general [7].

        The most commonly accepted dietary strategy is based on relatively high levels of carbohydrates and low fat content but according to some studies these low fat diets yield only modest weight loss and suffer from low long-term compliance [8]. In fact adherence of overweight/obese individuals to high carbohydrate/low fat nutrition is often a problem because the majority have been shown to have dietary preferences for foods with a rich fat content. Furthermore rather than consume complex carbohydrates there is a tendency to prefer highly processed food containing simple sugars [911] such that a low fat diet can actually encourage the consumption of sugars and refined carbohydrates that can worsen weight problems and also facilitate dyslipidemia especially in insulin resistance individuals [12, 13]. As a consequence of the relative inefficacy of these types of diet there has been increased interest in recent years in very low carbohydrate ketogenic diets (VLCKD) [14] that, have undoubtedly been shown to be effective, at least in the short to medium term, as a tool to tackle obesity, hyperlipidemia and some cardiovascular risk factors [1518]. The Mediterranean diet is often proposed as the healthy standard but many of the advantages associated with it can actually be linked to life style and the true original Mediterranean diet did not contemplate the current high levels of refined carbohydrates on which the typical Italian diet is based [19, 20]. For this reason the standard ketogenic diet is not associated with high compliance in populations, like the Italian, that are used to carbohydrate based diets. The objective of the present study, which was devised as a case pilot trial, is to assess the safety, compliance and effects of a "Mediterranean style" ketogenic diet that utilizes very low carbohydrate ingredients formulated to simulate the aspect and taste of common carbohydrate rich foods (e.g. pasta) and which contain phytoextracts intended to add beneficial effects of important vegetable components. The aim of using herbal extracts during the diet period was to reduce some commonly reported light side effects of ketogenic diets. The parameters measured include blood biomarkers, body composition, weight loss and compliance in a cohort of council employees in Rome, Italy.

        Methods

        Subjects

        The pilot study group consisted of 106 Rome council employees (19 males and 87 female; mean age 48, 49 ± 10, 33). Inclusion criteria were: BMI ≥ 25, age > 18 years and < 65 years, currently on a carbohydrate rich diet (> 50% energy), [21] desire to lose weight and health status suitable for a modified ketogenic diet (Tisanoreica®) [22] i.e. normal renal function, not pregnant or lactating. After the start of the experimental protocol the subjects who began new exercise programs or pharmaceutical treatments would be excluded. A small rise in transaminase was not considered a condition for exclusion since mild alterations in GOT and GPT values are common in obese individuals. Subjects eligible for the study were invited to the IPA clinic (Istituto di Previdenza ed Assistenza - health services for public sector employees) to attend an orientation session. At the first visit it was explained that during the first three weeks it was necessary to almost totally exclude carbohydrates and a detailed menu containing permitted and non-permitted foods was provided to each participant, along with the components of the ketogenic Mediterranean with phytoextracts (KEMEPHY) diet described below. Anthropometric measures were performed and blood samples were taken from the subjects two-three days before and after they began the diet. Subjects received no monetary compensation for their participation and signed a voluntary consent form before initiating the diet. The ethical and clinical review committee of IPA and the European Nutrition Society approved the study protocol, informed consent form and information material provided to subjects.

        Diet

        The KEMEPHY (ketogenic Mediterranean with phytoextracts) diet protocol was ketogenic during the first 3 weeks with approximately 34 g of CHO daily, using low carbohydrate high-protein meals and herbal teas [22] (Tisanoreica® by Gianluca Mech SpA, Orgiano VI) (Table 1 and 2).
        Table 1

        diet composition in KEMEPHY (ketogenic Mediterranean with phytoextracts) diet.

         

        KEMEPHY Week 1-3

        KEMEPHY Week 4-6

        Energy Kcal

        1098 ± 21.3

        1186 ± 107

        Protein, g/day

        (% daily Energy)

        99 (36)

        91 (31)

        Carbohydrate, g/day (% daily Energy)

        34 (12)

        74 (25)

        Fat, g/day

        (% daily Energy)

        63 (52)

        58 (44)

        Mean Kcal/die of the two phases of KEMEPHY

        1146 ± 88.8

        Kcal values are expressed in mean per day and SD. Other values are expressed in mean per day.

        Table 2

        Plant extracts used in KEMEPHY (ketogenic Mediterranean with phytoextracts) diet

        Plant extracts

        Week 1-3

        Week 4-6

        Composition

        Extracts A, ml/day

        20

        20

        Durvillea antarctica, black radish, mint, liquorice, artichoke, horsetail, burdock, dandelion, rhubarb, gentian, lemon balm, chinaroot, juniper, spear grass, elder, fucus, anise, parsley, bearberry, horehound

        Extracts B, ml/day

        20

        20

        Serenoa, Red clover, Chervil, Bean, Elder, Dandelion, Uncaria, Equisetum, Horehound, Rosemary

        Extracts C, ml/day

        50

        50

        Horsetail, asparagus, birch, cypress, couch grass, corn, dandelion, grape, fennel, elder, rosehip, anise

        Extracts D, ml/day

        (only weeks 1 and 2)

        40

        0

        Eleuthero, eurycoma longifolia, ginseng, corn, miura puama, grape, guaranà, arabic coffee, ginger

        The permitted foods were: cooked or raw green vegetables (200 g/meal), meat, fish and eggs (2 times/day), olive oil 40 g/day. Integration with a dish (PAT® i.e. porzione alimentare tisanoreica = tisanoreica nutritional portion) composed of high quality proteins (equivalent to 18 grams) and virtually zero carbohydrate (but that mimic their taste) was provided for every meal, for a maximum of four PATs per day. During the last three weeks complex carbohydrates were introduced (50-80 g/day), cheese (60 g/day), PAT was reduced from four to two, while the other indications remained unchanged. The distribution of nutrients (proteins, carbohydrates and fats) in terms of percentage of total caloric intake was 36%, 12% and 52%, respectively (weeks 1 to 3) and 31%, 25% and 44% (weeks 4 to 6). During the 6 weeks, the patients in the study group consumed 20 ml of extract A, 20 ml of extract B and 50 ml of extract C. During the first two weeks, before breakfast and lunch, they also consumed 40 ml of extract D (Tables 2 and 3).
        Table 3

        Main actives ingredients of used phytoextracts, their reported beneficial effects and related references

        Extract

        Main Active ingredients

        Reported beneficial effects

        Refs

        A

        Mint

        black radish

        burdock

        - indigestion

        - antioxidant

        - choleretic, increases bile secretion helping digestion

        [69]

        [70]

        B

        Serenoa Repens (saw palmetto)

        hormonal regulating effects

        [71]

         

        White bean

        alpha-amylase inhibitory properties and has been reported to aid weight loss and glycemic control

        [72]

        [73]

        C

        Equisetum

        Antioxidant

        diuretic

        glycemic control

        [74]

        [75]

         

        Dandelion (Taraxacum officinale

        diuretic

        [76]

        D

        Ginseng

        Miura Puama

        Guaranà

        Ameliorate the commonly reported symptoms of weakness and tiredness during the 1st phase of ketosis (1/2 weeks)

        [77]

        [78]

        [79]

        Supplements

        Subjects also took a daily (1 caplet each morning) multivitamin supplement [23] (containing Magnesium19 mg, Calcium 16 mg, Phosphorus 8 mg, Zinc 4.5 mg, Iron 4.62 mg, Manganese 1 mg, Potassium 0.5 mg, Copper 0.4 mg, Chromium 28.55 μg, Selenium 4 μg, Niacin 10 mg, Beta carotene 1.8 mg, Folic Acid 66 μg, Biotin 30 μg, Vitamin C 19.8 mg, Vitamin E 3.3 mg, Pantothenic Acid 1.98 mg, Vitamin B6 0.66 mg, Vitamin B2 0.53 mg, Vitamin B1 0.426 mg, Vitamin D3 1.65 μg, Vitamin B12 0.33 μg (Multivitaminico Balestra e Mech, Gianluca Mech SpA, Orgiano VI).

        Measurements

        Subjects were weighed at the same time of day at the start and after 6 weeks of the diet, using the same weighing scales (Digital Scale Joycare® Jc431). Fasting venous blood samples were collected at weeks 0 and 6 for total cholesterol (CHOLt), triacyglicerol (TG) high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), glucose, blood urea nitrogen (BUN), uricemia, VES, creatinine, ALT, AST, GGT. Blood was collected in EDTA treated vacutainer tubes. To avoid interassay variation all blood samples were stored at -80° and analysed together at the end of the study. A separate sample of blood was clotted and serum analyzed for total cholesterol and triacylglycerols by photometric assay with an intra-assay and interassay CV values of 2% and 4%, respectively.

        HDL cholesterol was determined using a homogenous enzyme immunoassay. The intra-assay and interassay CV values were both < 4%. Plasma glucose was determined colorimetrically using glucose oxidase methodology. Plasma urea nitrogen were measured using an enzymatic (urease), colorimetric method. Creatinine was measured colorimetrically using the picric acid assay, and uric acid was determined using a modified Trinder peroxide assay. LDLc fraction was calculated from Friedewald's formula: LDLc = TC - HDLc - (TG/5) [24]. Body composition was assessed using bioelectrical impedance analysis (BIA Akern Bioresearch, Pontassieve, FI, Italy) which is a non-invasive and portable method for the estimation of fluid compartments, fat and fat-free mass in healthy subjects. Bioelectrical impedance analysis was chosen for the analysis of body composition due to its reliability, safety, convenience and non-invasiveness making it optimal for the routine monitoring of body composition during the ketogenic diet [25, 26]. The experimental design is showed in Figure 1.
        http://static-content.springer.com/image/art%3A10.1186%2F1475-2891-10-112/MediaObjects/12937_2011_440_Fig1_HTML.jpg
        Figure 1

        Experimental design.

        Statistical analysis

        We tested the normality and the assumption of homoscedasticity of all parameters at the start of the trial using the Kolmogorov-Sminorv and Shapiro-Wilk tests. To study changes over time and the effects of gender, we added an appropriate interaction analysis. As there were no significant gender interactions, the data of each group were pooled and analyzed together. A Student's t test was used to compare parameters before and after 6 weeks of the KEMEPHY diet using Statistica Software, ver. 8.0 (Tulsa, USA) and the software package GraphPad Prism version 4.00 for Windows, GraphPad Software, San Diego California USA. All data are expressed as mean ± standard deviation.

        Results

        Of the 106 persons recruited 87 completed the study (83, 6% compliance). Of the 19 subjects that withdrew 4 were for family/personal reasons, 8 subjects were lost to follow up and only 7 withdrew due to inadequate compliance to the diet protocol. Adjusted for causes of withdrawal only 7 of 104 were not able to follow the KEMEPHY diet for an adjusted compliance of 93.4%

        Blood analysis did not reveal significant modification in ALT, AST, GGT and bilirubin values, nor were there significant variations in creatinine, uric acid, nitrogen and electrolytes (NA, K, Cl, Ca, Mg). There were significant changes in lipid profiles with reductions in triglycerides, total cholesterol and LDL along with a rise in HDL levels which all reached significance - see Table 4 and 5.
        Table 4

        Blood biomarker, anthropometric and body composition values, separated for male and female, before and after 6 weeks KEMEPHY diet. Values are expressed in mean and SD.

         

        Pre diet female

        Post diet female

        Pre diet

        male

        Post diet

        male

        BUN (mg/dl)

        33.4 ± 9.5

        33.2 ± 8.7

        35.2 ± 6.0

        33.8 ± 7.0

        Uric acid (mg/dl)

        5.0 ± 1.3

        5 ± 1.2

        4.8 ± 1.3

        5.0 ± 1.3

        VES (mm/hour)

        14 ± 7.3

        12.7 ± 7.6

        16 ± 7.3

        14.4 ± 6.3

        Creatinine (mg/dL)

        0.84 ± 0.15

        0.77 ± 0.11

        0.83 ± 0.2

        0.85 ± 0.2

        Total Cholesterol (mg/dl)

        206.2 ± 41.4

        182.8 ± 34.3

        199.2 ± 29.8

        176.9 ± 26.1

        HDLc (mg/dl)

        46.7 ± 7.2

        52.6 ± 9.5

        43.9 ± 8.5

        50.1 ± 9.1

        LDLc (mg/dl)

        151.8 ± 28.3

        137.1 ± 24.8

        140.9 ± 32.9

        130.4 ± 25.9

        TG (mg/dl)

        119.9 ± 60.3

        94.2 ± 41.8

        114.1 ± 61.8

        93.9 ± 46.2

        ALT (U/l)

        20.5 ± 10.9

        17.3 ± 5.1

        18.4 ± 4.6

        19.1 ± 6.8

        AST (U/l)

        18.5 ± 5.4

        17.1 ± 4.7

        17.8 ± 3.8

        17 ± 5.1

        GGT (U/l)

        20.5 ± 10.9

        17.3 ± 5.1

        21.5 ± 11.7

        15.4 ± 4.1

        Glucose (mg/dl)

        95.7 ± 12.5

        90.5 ± 9.8

        95.9 ± 11.2

        90.6 ± 8

        Weight Kg

        82.6 ± 12.7

        76.3 ± 12.1

        102.4 ± 22.2

        93.4 ± 21

        BMI (Kg/m 2 )

        31 ± 4.8

        28.7 ± 4.6

        33.6 ± 6.2

        30.6 ± 5.8

        % Fat

        42.3 ± 6, 8

        36 ± 6, 9

        37 ± 4.3

        30.6 ± 4.1

        Waist circumference cm

        103.5 ± 14

        94, 3 ± 10.3

        120.8 ± 15.1

        109.7 ± 14.1

        Hip circumference cm

        114.9 ± 11.6

        107.2 ± 10.5

        117.3 ± 9.9

        111.2 ± 10.4

        Table 5

        Blood biomarker values (all subjects) before and after the 6 week KEMEPHY diet. Values are expressed in mean and SD.

         

        Pre KEMEPHY diet

        Post KEMEPHY diets

        p

        BUN (mg/dl)

        33.8 ± 8.9

        33.4 ± 8.4

        n.s.

        Uric acid (mg/dl)

        4.9 ± 1.3

        5 ± 1.2

        n.s.

        VES (mm/hour)

        14.2 ± 7.2

        12.8 ± 7.4

        n.s.

        Creatinine (mg/dL)

        0.83 ± 0.16

        0.78 ± 0.13

        n.s.

        Total Cholesterol (mg/dl)

        204.2 ± 40

        181.1 ± 33.4

        P < 0.0001

        HDLc (mg/dl)

        46.2 ± 7.4

        52.1 ± 7.4

        P < 0.0001

        LDLc (mg/dl)

        149.7 ± 29.1

        135.8 ± 24.8

        P < 0.0001

        TG (mg/dl)

        118.6 ± 59.9

        93.8 ± 42.2

        P < 0.0001

        ALT (U/l)

        20.7 ± 9.1

        18.2 ± 6.7

        n.s.

        AST (U/l)

        18.4 ± 5.1

        17 ± 5

        n.s.

        GGT (U/l)

        21 ± 11

        17 ± 5

        n.s.

        Glucose (mg/dl)

        96 ± 12

        91 ± 9

        P < 0.0001

        Anthropometric and body composition measurements revealed an average weight loss of 6.72 kg or 7.8% (pre 86.15 ± 16.38 vs post 79.43 ± 15.31; p < 0.0001). Fat mass was reduced from 41.24 ± 6.74 to 34.99 ± 6.74, a fall of 15.1% (p < 0.0001). As in previous studies no significant differences were observed in total body water expressed as percent of body weight [22, 27]. Waist circumference was reduced by an average of 9.46 cm from 106.56 ± 15.38 to 97.10 ± 12.69, a fall of 8.9% (p < 0.0001). There were also significant reductions in hip and thigh circumferences of 7.41 cm (from 115 ± 11.24 to 107.78 ± 10.39; p < 0.0001) and 3.32 cm respectively (from 58.65 ± 5.43 to 55.32 ± 4.90). Anthropometric and body composition results are showed in tables 6.
        Table 6

        Anthropometric and body composition measures (all subjects) pre and post diet

         

        Pre KEMEPHY diet

        Post KEMEPHY diets

        p

        BMI (Kg/m 2 )

        31.5 ± 5.1

        29. ± 4.8

        P < 0.0001

        Weight Kg

        86.2 ± 16.4

        79.4 ± 15.3

        P < 0.0001

        % Fat

        41.2 ± 6.7

        35 ± 6.7

        P < 0.0001

        Waist circumference cm

        106.6 ± 15.4

        97.1 ± 12.7

        P < 0.0001

        Hip circumference cm

        115 ± 11.3

        107.8 ± 10.4

        P < 0.0001

        Discussion

        Many weight loss diet procedures continue to focus on the reduction of fat content and controlled protein intake, however our results appear to demonstrate that the KEMEPHY diet, which is a modification of the VLCKD, is effective not only for weight and fat loss but also leads to improvements in the values of various biomarkers which are associated with increased risk of metabolic and cardiovascular disease. The weight loss effect of VLCKD diets may be caused by several factors:
        1. 1.

          Satiety effect of proteins leading to appetite reduction [2836] in which also ketone bodies may have a role [37, 38], although the mechanism is not clear [39];

           
        2. 2.

          Reduction in lipid synthesis and increased lipolysis mechanisms [4044];

           
        3. 3.

          Reduction in at rest respiratory quotient and therefore an increase in fat metabolism for energy use [22, 45];

           
        4. 4.

          Increased metabolic expenditure caused by gluconeogenesis and the thermic effect of proteins [4651]

           

        The beneficial effects on cardiovascular risk factors involve the reduction of blood triglycerides [17, 18, 22] and also the reduction of total and LDL cholesterol along with a rise in HDL cholesterol [17, 18, 22, 5254]. Furthermore the VLCKD can cause modifications in LDL-C particles leading to increased size [53] which may reduce cardiovascular risk since smaller LDL particles have been shown to be more atherogenic [55].

        The cholesterol lowering effect of VLCKD is also mediated by the well known facilitating action of insulin on HMGCoA reductase and inhibition of the latter by cholesterol and fats [56]. Insulin then increases the production of endogenous cholesterol while exogenous cholesterol has the opposite effect [56].

        The KEMEPHY diet protocol used in this study maintains some advantages of the Mediterranean diet such as the use of olive oil [21] and some vegetables [19] (selected to avoid stimulating insulin production) but at the same time by inducing a physiological ketosis [57] promotes beneficial modifications in cardiovascular risk factors and body composition [22]. The use of the phyoextracts in this study may have contributed to the absence of commonly reported mild effects of ketosis (e.g. weakness, constipation, bad breath, headache). During the first three weeks of the KEMEPHY diet subjects avoided fructose completely and during the second three weeks only a moderate amount of fructose, exclusively from fruit, and therefore together with starch, was permitted. As a matter of fact fructose may stimulate fat biosynthesis via mechanisms which are not yet fully characterised [58], also several studies have reported that excessive concentrations of fructose can induce some or all of the features of metabolic syndrome independently of energy intake. Clinical and epidemiologic data further suggest that excessive fructose intake can contribute to the causes of metabolic syndrome [59].

        Adjusted compliance in this study was 93.4% which is higher than reported compliances of standard VLCK diets (in the 20% to 58% range). [22, 60, 61]. It is tempting to speculate that the inclusion of "carbohydrate-like" formulated foods is one of the reasons for high compliance - however this, along with the potential benefits of the phytoextracts, requires further verification in a future study with a matched control group.

        Safety considerations

        If we assimilate de facto, which is not always correct, ketogenic diets with high protein diets then the risks proposed by critics of this type of dietary approach are essentially those of possible kidney damage due to high levels of nitrogen excretion during protein metabolism which can cause an increase in glomerular pressure and hyper-filtration [27]. There is not wide agreement between studies however, some infer the possibility of renal damage from animal studies [62, 63] while others, looking at both animal models and human studies propose that even high levels of protein in the diet do not damage renal function [64, 65]. In subjects with intact renal function higher dietary protein levels caused some functional and morphological adaptations without negative effects [66]. Also it should be underlined that ketogenic diets are only relatively high in protein [49, 67] and that some recent studies have demonstrated that VLCKD can even cause a regression of diabetic nephropathy in mice [68]. With regard to possible acidosis during VLCKD since the concentration of ketone bodies never rises above 8 mmol/l [40, 42] this risk is virtually inexistent in subjects with healthy insulin function.

        Conclusions

        Some limitations to this study include the lack of a matched control group and the short trial period. There are though many studies that demonstrate that VLCK diets are more effective than low fat or standard Mediterranean diets, at least over the short term [21], and the main aims of the present initial study were to assess safety aspects, acceptance & palatability and weight loss & biomarker changes. We are able to conclude that at least in the short term it was able to lead to positive changes including the reduction of fasting blood glucose, improvements in lipid profiles, significant and rapid weight and fat loss with the preservation of lean mass. We also note a high level of compliance, whether this was due to specific unique features of the present diet requires confirmation in a future matched control trial.

        Abbreviations

        KEMEPHY: 

        ketogenic Mediterranean with phytoextracts

        VLCKD: 

        very low carbohydrate ketogenic diet

         : 

        high-density lipoprotein cholesterol

        LDLc: 

        low-density lipoprotein cholesterol

        TG: 

        Triglycerides

        GLU: 

        Glucose

        BUN: 

        Blood Urea Nitrogen

        UA: 

        Uric acid

        ALT: 

        Alanine aminotransferase

        AST: 

        Aspartate Aminotransferase

        GGT: 

        Gamma-glutamyl transpeptidase

        Cr: 

        Creatinine.

        Declarations

        Acknowledgements

        The authors thank the men and women who participated in this investigation.

        Authors’ Affiliations

        (1)
        Department of Human Anatomy and Physiology, University of Padova
        (2)
        Nutrition and Dietetic Service, San Bortolo Hospital
        (3)
        Biomedical Engineering Laboratory, Institute of Communication and Computer Systems, National Technical University of Athens

        References

        1. Finkelstein EA, Ruhm CJ, Kosa KM: Economic causes and consequences of obesity. Annu Rev Public Health 2005, 26:239–257.View Article
        2. Olshansky SJ, Passaro DJ, Hershow RC, Layden J, Carnes BA, Brody J, Hayflick L, Butler RN, Allison DB, Ludwig DS: A potential decline in life expectancy in the United States in the 21st century. N Engl J Med 2005, 352:1138–1145.View Article
        3. Koh-Banerjee P, Wang Y, Hu FB, Spiegelman D, Willett WC, Rimm EB: Changes in body weight and body fat distribution as risk factors for clinical diabetes in US men. Am J Epidemiol 2004, 159:1150–1159.View Article
        4. Appel LJ, Champagne CM, Harsha DW, Cooper LS, Obarzanek E, Elmer PJ, Stevens VJ, Vollmer WM, Lin PH, Svetkey LP, Stedman SW, Young DR, Writing Group of the PREMIER Collaborative Research Group: Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. JAMA 2003, 289:2083–2093.View Article
        5. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM, Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002, 346:393–403.View Article
        6. Nordmann AJ, Nordmann A, Briel M, Keller U, Yancy WS Jr, Brehm BJ, Bucher HC: Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials. Arch Intern Med 2006, 166:285–293.View Article
        7. Chahoud G, Aude YW, Mehta JL: Dietary recommendations in the prevention and treatment of coronary heart disease: do we have the ideal diet yet? Am J Cardiol 2004, 94:1260–1267.View Article
        8. Brehm BJ, Seeley RJ, Daniels SR, D'Alessio DA: A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J Clin Endocrinol Metab 2003, 88:1617–1623.View Article
        9. Yeomans MR: Psychological approaches to under standing satiation and satiety. Agro Food High tech 2010, 21:16–19.
        10. Power ML, Schulkin J: Anticipatory physiological regulation in feeding biology: cephalic phase responses. Appetite 2008, 50:194–206.View Article
        11. Drewnowski A, Krahn DD, Demitrack MA, Nairn K, Gosnell BA: Taste responses and preferences for sweet high-fat foods: evidence for opioid involvement. Physiol Behav 1992, 51:371–379.View Article
        12. Feinman RD, Volek JS: Carbohydrate restriction as the default treatment for type 2 diabetes and metabolic syndrome. Scand Cardiovasc J 2008, 42:256–263.View Article
        13. Lankinen M, Schwab U, Gopalacharyulu PV, Seppanen-Laakso T, Yetukuri L, Sysi-Aho M, Kallio P, Suortti T, Laaksonen DE, Gylling H, Poutanen K, Kolehmainen M, Oresic M: Dietary carbohydrate modification alters serum metabolic profiles in individuals with the metabolic syndrome. Nutr Metab Cardiovasc Dis 2010, 20:249–257.View Article
        14. Atkins RC: Dr. Atkins' diet revolution; the high calorie way to stay thin forever. New York: D. McKay Co; 1972.
        15. Al-Khalifa A, Mathew TC, Al-Zaid NS, Mathew E, Dashti HM: Therapeutic role of low-carbohydrate ketogenic diet in diabetes. Nutrition 2009, 25:1177–1185.View Article
        16. Dashti HM, Mathew TC, Khadada M, Al-Mousawi M, Talib H, Asfar SK, Behbahani AI, Al-Zaid NS: Beneficial effects of ketogenic diet in obese diabetic subjects. Mol Cell Biochem 2007, 302:249–256.View Article
        17. Adam-Perrot A, Clifton P, Brouns F: Low-carbohydrate diets: nutritional and physiological aspects. Obes Rev 2006, 7:49–58.View Article
        18. Sharman MJ, Kraemer WJ, Love DM, Avery NG, Gomez AL, Scheett TP, Volek JS: A ketogenic diet favorably affects serum biomarkers for cardiovascular disease in normal-weight men. J Nutr 2002, 132:1879–1885.
        19. Bellisle F: Infrequently asked questions about the Mediterranean diet. Public Health Nutr 2009, 12:1644–1647.View Article
        20. Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, O'Keefe JH, Brand-Miller J: Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr 2005, 81:341–354.
        21. Perez-Guisado J, Munoz-Serrano A, Alonso-Moraga A: Spanish Ketogenic Mediterranean Diet: a healthy cardiovascular diet for weight loss. Nutr J 2008, 7:30.View Article
        22. Paoli A, Cenci L, Fancelli M, Parmagnani A, Fratter A, Cucchi A, Bianco A: Ketogenic diet and phytoextracts Comparison of the efficacy of Mediterranean, zone and tisanoreica diet on some health risk factors. Agro Food Ind Hi-Tech 2010, 21:24–29.
        23. Zupec-Kania B, Zupanc ML: Long-term management of the ketogenic diet: seizure monitoring, nutrition, and supplementation. Epilepsia 2008,49(Suppl 8):23–26.View Article
        24. Gazi IF, Elisaf M: LDL-cholesterol calculation formulas in patients with or without the metabolic syndrome. Int J Cardiol 2007, 119:414–415.View Article
        25. Saunders NH, al-Zeibak S, Ryde SJ, Birks JL: The composition of weight loss in dieting obese females by electrical methods. Int J Obes Relat Metab Disord 1993, 17:317–322.
        26. Piccoli A, Pastori G, Codognotto M, Paoli A: Equivalence of information from single frequency v. bioimpedance spectroscopy in bodybuilders. Br J Nutr 2007, 97:182–192.View Article
        27. Kreider RB, Rasmussen C, Kerksick CM, Wilborn C, Taylor L, Campbell B, Magrans-Courtney T, Fogt D, Ferreira M, Li R, Galbreath M, Iosia M, Cooke M, Serra M, Gutierrez J, Byrd M, Kresta JY, Simbo S, Oliver J, Greenwood M: A carbohydrate-restricted diet during resistance training promotes more favorable changes in body composition and markers of health in obese women with and without insulin resistance. Phys Sportsmed 2011, 39:27–40.View Article
        28. Westerterp-Plantenga MS, Nieuwenhuizen A, Tome D, Soenen S, Westerterp KR: Dietary protein, weight loss, and weight maintenance. Annu Rev Nutr 2009, 29:21–41.View Article
        29. Paddon-Jones D, Westman E, Mattes RD, Wolfe RR, Astrup A, Westerterp-Plantenga M: Protein, weight management, and satiety. Am J Clin Nutr 2008, 87:1558S-1561S.
        30. Soenen S, Westerterp-Plantenga MS: Proteins and satiety: implications for weight management. Curr Opin Clin Nutr Metab Care 2008, 11:747–751.View Article
        31. Veldhorst M, Smeets A, Soenen S, Hochstenbach-Waelen A, Hursel R, Diepvens K, Lejeune M, Luscombe-Marsh N, Westerterp-Plantenga M: Protein-induced satiety: effects and mechanisms of different proteins. Physiol Behav 2008, 94:300–307.View Article
        32. Vogels N, Westerterp-Plantenga MS: Successful long-term weight maintenance: a 2-year follow-up. Obesity (Silver Spring) 2007, 15:1258–1266.View Article
        33. Bravata DM, Sanders L, Huang J, Krumholz HM, Olkin I, Gardner CD, Bravata DM: Efficacy and safety of low-carbohydrate diets: a systematic review. JAMA 2003, 289:1837–1850.View Article
        34. Astrup A: The satiating power of protein--a key to obesity prevention? Am J Clin Nutr 2005, 82:1–2.
        35. Soenen S, Plasqui G, Smeets AJ, Westerterp-Plantenga MS: Protein intake induced an increase in exercise stimulated fat oxidation during stable body weight. Physiol Behav 2010, 101:770–774.View Article
        36. Soenen S, Westerterp-Plantenga MS: Changes in body fat percentage during body weight stable conditions of increased daily protein intake vs. control. Physiol Behav 2010, 101:635–638.View Article
        37. Johnstone AM, Horgan GW, Murison SD, Bremner DM, Lobley GE: Effects of a high-protein ketogenic diet on hunger, appetite, and weight loss in obese men feeding ad libitum. Am J Clin Nutr 2008, 87:44–55.
        38. McClernon FJ, Yancy WS Jr, Eberstein JA, Atkins RC, Westman EC: The effects of a low-carbohydrate ketogenic diet and a low-fat diet on mood, hunger, and other self-reported symptoms. Obesity (Silver Spring) 2007, 15:182–187.View Article
        39. Cabeza De Vaca S, Holiman S, Carr KD: A search for the metabolic signal that sensitizes lateral hypothalamic self-stimulation in food-restricted rats. Physiol Behav 1998, 64:251–260.View Article
        40. Cahill GF Jr: Fuel metabolism in starvation. Annu Rev Nutr 2006, 26:1–22.View Article
        41. Sato K, Kashiwaya Y, Keon CA, Tsuchiya N, King MT, Radda GK, Chance B, Clarke K, Veech RL: Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J 1995, 9:651–658.
        42. Robinson AM, Williamson DH: Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 1980, 60:143–187.
        43. Veldhorst MA, Westerterp-Plantenga MS, Westerterp KR: Gluconeogenesis and energy expenditure after a high-protein, carbohydrate-free diet. Am J Clin Nutr 2009, 90:519–526.View Article
        44. Vazquez JA, Kazi U: Lipolysis and gluconeogenesis from glycerol during weight reduction with very-low-calorie diets. Metabolism 1994, 43:1293–1299.View Article
        45. Langfort J, Pilis W, Zarzeczny R, Nazar K, Kaciuba-Uscilko H: Effect of low-carbohydrate-ketogenic diet on metabolic and hormonal responses to graded exercise in men. J Physiol Pharmacol 1996, 47:361–371.
        46. Feinman RD, Fine EJ: Nonequilibrium thermodynamics and energy efficiency in weight loss diets. Theor Biol Med Model 2007, 4:27.View Article
        47. Feinman RD, Fine EJ: Whatever happened to the second law of thermodynamics? Am J Clin Nutr 2004, 80:1445–6. author reply 1446
        48. Feinman RD, Fine EJ: "A calorie is a calorie" violates the second law of thermodynamics. Nutr J 2004, 3:9.View Article
        49. Feinman RD, Fine EJ: Thermodynamics and metabolic advantage of weight loss diets. Metab Syndr Relat Disord 2003, 1:209–219.View Article
        50. Fine EJ, Feinman RD: Thermodynamics of weight loss diets. Nutr Metab (Lond) 2004, 1:15.View Article
        51. Jequier E: Pathways to obesity. Int J Obes Relat Metab Disord 2002,26(Suppl 2):S12–17.View Article
        52. Lofgren I, Zern T, Herron K, West K, Sharman MJ, Volek JS, Shachter NS, Koo SI, Fernandez ML: Weight loss associated with reduced intake of carbohydrate reduces the atherogenicity of LDL in premenopausal women. Metabolism 2005, 54:1133–1141.View Article
        53. Volek JS, Sharman MJ, Forsythe CE: Modification of lipoproteins by very low-carbohydrate diets. J Nutr 2005, 135:1339–1342.
        54. Volek JS, Sharman MJ, Gomez AL, Scheett TP, Kraemer WJ: An isoenergetic very low carbohydrate diet improves serum HDL cholesterol and triacylglycerol concentrations, the total cholesterol to HDL cholesterol ratio and postprandial pipemic responses compared with a low fat diet in normal weight, normolipidemic women. J Nutr 2003, 133:2756–2761.
        55. Austin MA, King MC, Vranizan KM, Krauss RM: Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation 1990, 82:495–506.View Article
        56. Siliprandi N, Tettamanti G: Biochimica medica: strutturale, metabolica e funzionale. Padova: Piccin; 2005.
        57. Krebs HA: The regulation of the release of ketone bodies by the liver. Adv Enzyme Regul 1966, 4:339–354.View Article
        58. Samuel VT: Fructose induced lipogenesis: from sugar to fat to insulin resistance. Trends Endocrinol Metab 2011, 22:60–65.View Article
        59. Madero M, Arriaga JC, Jalal D, Rivard C, McFann K, Perez-Mendez O, Vazquez A, Ruiz A, Lanaspa MA, Jimenez CR, Johnson RJ, Lozada LG: The effect of two energy-restricted diets, a low-fructose diet versus a moderate natural fructose diet, on weight loss and metabolic syndrome parameters: a randomized controlled trial. Metabolism; 2011:in press.
        60. Klein P, Janousek J, Barber A, Weissberger R: Ketogenic diet treatment in adults with refractory epilepsy. Epilepsy Behav 2010, 19:575–579.View Article
        61. Mosek A, Natour H, Neufeld MY, Shiff Y, Vaisman N: Ketogenic diet treatment in adults with refractory epilepsy: a prospective pilot study. Seizure 2009, 18:30–33.View Article
        62. Jia Y, Hwang SY, House JD, Ogborn MR, Weiler HA, O K, Aukema HM: Long-term high intake of whole proteins results in renal damage in pigs. J Nutr 2010, 140:1646–1652.View Article
        63. Wakefield AP, House JD, Ogborn MR, Weiler HA, Aukema HM: A diet with 35% of energy from protein leads to kidney damage in female Sprague-Dawley rats. Br J Nutr 2011, (106):656–63.
        64. Skov AR, Haulrik N, Toubro S, Molgaard C, Astrup A: Effect of protein intake on bone mineralization during weight loss: a 6-month trial. Obes Res 2002, 10:432–438.View Article
        65. Martin WF, Armstrong LE, Rodriguez NR: Dietary protein intake and renal function. Nutr Metab (Lond) 2005, 2:25.View Article
        66. Welle S, Nair KS: Relationship of resting metabolic rate to body composition and protein turnover. Am J Physiol 1990, 258:E990–998.
        67. Westerterp-Plantenga MS: How are normal, high- or low-protein diets defined? Br J Nutr 2007, 97:217–218.View Article
        68. Poplawski MM, Mastaitis JW, Isoda F, Grosjean F, Zheng F, Mobbs CV: Reversal of diabetic nephropathy by a ketogenic diet. PLoS One 2011, 6:e18604.View Article
        69. Lugasi A, Blazovics A, Hagymasi K, Kocsis I, Kery A: Antioxidant effect of squeezed juice from black radish (Raphanus sativus L. var niger) in alimentary hyperlipidaemia in rats. Phytother Res 2005, 19:587–591.View Article
        70. Lou Z, Wang H, Li J, Chen S, Zhu S, Ma C, Wang Z: Antioxidant activity and chemical composition of the fractions from burdock leaves. J Food Sci 2010, 75:C413–419.
        71. Di Silverio F, D'Eramo G, Lubrano C, Flammia GP, Sciarra A, Palma E, Caponera M, Sciarra F: Evidence that Serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy patients. Eur Urol 1992, 21:309–314.
        72. Barrett ML, Udani JK: A proprietary alpha-amylase inhibitor from white bean (Phaseolus vulgaris): a review of clinical studies on weight loss and glycemic control. Nutr J 2011, 10:24.View Article
        73. Celleno L, Tolaini MV, D'Amore A, Perricone NV, Preuss HG: A Dietary supplement containing standardized Phaseolus vulgaris extract influences body composition of overweight men and women. Int J Med Sci 2007, 4:45–52.View Article
        74. Mimica-Dukic N, Simin N, Cvejic J, Jovin E, Orcic D, Bozin B: Phenolic compounds in field horsetail (Equisetum arvense L.) as natural antioxidants. Molecules 2008, 13:1455–1464.View Article
        75. Safiyeh S, Fathallah FB, Vahid N, Hossine N, Habib SS: Antidiabetic effect of Equisetum arvense L. (Equisetaceae) in streptozotocin-induced diabetes in male rats. Pak J Biol Sci 2007, 10:1661–1666.View Article
        76. Clare BA, Conroy RS, Spelman K: The diuretic effect in human subjects of an extract of Taraxacum officinale folium over a single day. J Altern Complement Med 2009, 15:929–934.View Article
        77. Pieralisi G, Ripari P, Vecchiet L: Effects of a standardized ginseng extract combined with dimethylaminoethanol bitartrate, vitamins, minerals, and trace elements on physical performance during exercise. Clin Ther 1991, 13:373–382.
        78. Piato AL, Detanico BC, Linck VM, Herrmann AP, Nunes DS, Elisabetsky E: Anti-stress effects of the "tonic"Ptychopetalum olacoides (Marapuama) in mice. Phytomedicine 2010, 17:248–253.View Article
        79. Lima WP, Carnevali LC Jr, Eder R, Costa Rosa LF, Bacchi EM, Seelaender MC: Lipid metabolism in trained rats: effect of guarana (Paullinia cupana Mart.) supplementation. Clin Nutr 2005, 24:1019–1028.View Article

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