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Keywords:

  • dietary supplement;
  • overweight;
  • impaired fasting glycaemia;
  • Cynara scolymus

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conflict of Interest
  8. REFERENCES

The aim of this study is to evaluate the efficacy of a dietary supplementation with an extract from Cynara scolymus (Cs) on the glucose pattern in a group of patients with naïve impaired fasting glycaemia (IFG). A randomized, double-blind, placebo-controlled trial has been performed in 55 overweight subjects with IFG (fasting blood glucose [FBG]: 6.11 ± 0.56 mmol/l). These subjects were randomly assigned to supplement their diet with either an extract from Cs (600 mg/d) (26 subjects) or placebo (29 matched subjects) for 8 weeks. The decrease of FBG was the primary endpoint. The assessment of Homeostatic Metabolic Assessment (HOMA), glycosylated haemoglobin, A1c-Derived Average Glucose (ADAG), lipidic pattern and anthropometric parameters were the secondary endpoints. The within groups and percent changes from baseline were analyzed by the signed rank test. The comparison between groups was performed by Wilcoxon's two sample test. The supplemented group had significant decreases of: FBG (−9.6%), HOMA (−11.7%), glycosylated haemoglobin (−2.3%), ADAG (−3.1%) and lipidic pattern. The placebo group did not show any significant difference. Compared with the placebo, the supplemented group showed a significant difference in FBG, HOMA and lipidic pattern. These data demonstrate the efficacy of Cs extract on the reduction of glycometabolic parameters in overweight subjects with IFG. Copyright © 2013 John Wiley & Sons, Ltd.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conflict of Interest
  8. REFERENCES

Impaired fasting glycaemia (IFG) is a metabolic condition which increases the risk of developing type 2 diabetes (Unwin et al., 2002), one of major burdens in health care system in many industrialized countries (Shaw et al., 2010). A survey carried out in Copenhagen showed that 24.7% of males and 17% of females aged 60 years or more had IFG, indicating an increase of type 2 diabetes of 70% and 40%, respectively, over a 10-year period, as compared to normoglycaemic subjects (Glümer et al., 2003).

The proper management of IFG is the most cost-effective way to avoid the many sequelae of diabetes and primarily cardiovascular diseases (CVDs). If left untreated, most of the individuals with IFG will develop type 2 diabetes within 10 years, and a high proportion of them will suffer from micro- or macrovascular pathology (DECODE Study Group, the European Diabetes Epidemiology Group, 2001; Eastman et al., 1997; Saydah et al., 2001). Since long time, traditional phytotherapy has been used to treat IFG, as an alternative remedy to glucose-lowering drugs due to their frequent side effects, such as hypoglycaemia, lactic acidosis, idiosyncratic liver cell injury, permanent neurological deficit, digestive discomfort, headache and dizziness (Neustadt and Pieczenik, 2008). Hypoglycaemic herbal extracts are widely used as non-prescription treatment for diabetes (Hui et al., 2009). In particular, recent in vitro and animal studies support the hypoglycaemic effect of Cynara scolymus (Cs) extracts (Arion et al., 1997; Matsui et al., 2006; Fantini et al., 2010). This activity seems to be mainly related to the content of chlorogenic acid in Cs (Arion et al., 1997; Matsui et al., 2006; Fantini et al., 2010; Karthikesan et al., 2010). This compound is a potent inhibitor of glucose 6-phosphate translocase, an essential component of the hepatic glucose 6-phosphatase system which regulates the homeostasis of blood glucose (Arion et al., 1997). In addition, dicaffeoylchinic acid derivatives of Cs can also play a hypoglycaemic role in modulating the activity of alpha-glucosidase and consequently the catabolism of dietary carbohydrates (Matsui et al., 2006).

The favourable effects of Cs extracts on serum glucose regulation have been clearly demonstrated in animal studies, but intervention studies in humans are limited.

Only very recently, a highly standardized extract obtained from Cs flowering buds has been investigated (in combination with an extract from Phaseolus Vulgaris) in overweight subjects: after 8 weeks of treatment, a higher and significant reduction in glucose net change was observed in the supplemented group as compared to controls (Rondanelli et al., 2011).

Given this background, we investigated whether the highly standardized Cs extract could improve glycaemic control and insulin sensitivity in overweight subjects with newly diagnosed IFG.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conflict of Interest
  8. REFERENCES
Study design

A randomized, double-blind, placebo-controlledtrial was conducted in overweight and obese (body mass index (BMI) 25–35 kg/m2) men and women with newly detected IFG, as defined by American Diabetes Association (American Diabetes Association and National Institute of Diabetes, Digestive and Kidney Diseases, 2002).

The subjects were recruited from Pavia municipality by advertisement on a local newspaper and were screened by means of a clinical evaluation and plasma glycometabolic assessment. The study was carried out at the Dietetic and Metabolic Unit of the “Santa Margherita’ Institute, University of Pavia, Italy.

Fifty-five subjects, aged 18–60 years with BMI ranging from 25 to 35 kg/m2, with IFG (6.1–7.0 mmol/L), glycosylated haemoglobin <7.0% and no history of CVD, volunteered for the trial (Fig. 1). The subjects were not taking any medication likely to affect glucose or lipid metabolism (oral hypoglycaemic agents and statins) and were free of overt liver, renal and thyroid disease. The subjects who smoked or drank more than two standard alcoholic beverages/day (20 g of alcohol/day) were excluded from the study. Physical activity was recorded. Sedentary subjects were admitted to the study. The experimental protocol was approved by the Ethics Committee of the University of Pavia, and all the volunteers gave their written informed consent. Twenty-six subjects were randomized to Cs supplement and 29 to placebo. As subjects were enrolled, they were assigned a progressive subject number.

image

Figure 1. Flow diagram of a trial of supplementation versus placebo in the treatment of healthy overweight subjects.

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Identical products for each treatment group were assigned to a subject number according to a coded (AB) block randomization table prepared by an independent statistician. Investigators were blinded to the randomization table, the code assignments and the procedure. Independently by treatment (Cs supplement or placebo), the subjects followed a similar low-energy diet. The dietary treatment was associated to three daily oral assumptions (before breakfast, lunch and dinner) of film-coated tablets of 200 mg of standardized Cs flowering buds extract or placebo. The tablets were manufactured by Indena, Milan - Italy. The supplementation period was 8 weeks.

The Cs flowering heads extract was prepared through alcoholic extraction (EtOH 70%), and the extract was characterized by a high content in caffeoylquinic acid (high-performance liquid chromatography [HPLC] - % w/w between 30 and 60%) and flavonoids (expressed as luteolin glycosides; HPLC - % w/w between 2 and 5%). The yield expressed as drug/extract ratio is 120/1. Details of preparation have been described elsewhere (Fantini et al., 2010).

Compliance to the supplementation regimen was defined as the number of tablets actually taken by each subject, divided by the number of tablets that should have been taken over the course of the study. Adverse events (AEs) were based on spontaneous reporting by subjects as well as open-ended inquiries by members of the research staff. There were no study dropouts (Fig. 1).

Glycaemic and lipidic parameters

The glycaemic and lipidic parameters were assessed before the start of the study and at the end of treatment (EoT). Moreover, the fasting blood glucose (FBG) was evaluated 60 days after the end of the intervention. In order to avoid venipuncture stress, blood samples were obtained through an indwelling catheter inserted in an antecubital vein. Blood samples were immediately centrifuged and stored at −80 °C until assayed. FBG, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglyceride (TG) levels were measured by automatic biochemical analyzer (Hitachi 747, Tokyo, Japan). Serum concentration of haemoglobin A1c (HbA1c) was determined by high-performance liquid chromatographic method using automatic HbA1c analyzer (Tosoh HLC-723G7, Japan). A1c-Derived Average Glucose (ADAG) was calculated (Nathan et al., 2008). The serum insulin was evaluated by a double antibody RIA (Kabi Pharmacia Diagnostics AB, Uppsala, Sweden) and expressed as pmol/L. The intra- and inter-assay coefficients of variation were below 6%, and the low detection limit was 10.7 pmol/L. To determine insulin resistance, subjects were instructed to fast for 12 h before obtaining the blood sample. Furthermore, the subjects refrained from any form of physical exercise for 48 h before the study. Female subjects were tested during the early follicular phase of their menstrual cycles (days 3–10). Insulin resistance was evaluated using the Homeostasis Model Assessment (HOMA) (Haffner et al., 1996). Finally, for the assessment of safety, routine blood biochemistry parameters (blood count, serum protein elecrophoresis, creatinine, liver and thyroid function) were evaluated at the start and at the end of intervention.

Anthropometric measurements and dietary counselling

Nutritional status was assessed using anthropometric measurements before the start of the study and at EoT. Body weight and height were measured, and the BMI was calculated (kg/m2). Skinfold thicknesses (biceps, triceps, suprailiac, subscapular) were measured twice using a harpender skinfold caliper at 5 min intervals in each site following a standardized technique (Frisancho, 1984). Sagittal abdominal diameter at the L4–5 level in the supine position and waist girth was also measured. Anthropometric parameters were always collected by the same investigator.

Subjects were trained to follow a regimen that maintained a prudent balance of macronutrients: 28% of energy from fat (cholesterol < 200 mg), 57% of energy from carbohydrates (10% from simple carbohydrates), with 20–25 g of bran, and 15% of energy from protein. A registered dietician performed initial dietary counselling. Subjects were trained to restrict their daily energy intake by a moderate amount, 3344 kJ/d less than daily requirements based on WHO criteria (World Health Organization, 1985), with a regimen that maintained a prudent balance of macronutrients: 25–30% of energy from fat (cholesterol < 200 mg), 55–60% of energy from carbohydrates (10% from simple carbohydrates), with 25 g of bran and 15–20% of energy from protein. A registered dietician performed initial dietary counselling. A 3-day weighed-food record of 2 weekdays and 1 weekend day was performed during the first and the last weeks of the study. Dietary records were analyzed using a food-nutrient database (Rational Diet, Milan, Italy).

Satiating capacity

The satiating capacity was assessed using Haber's scale which is an analogue visual scale ranging from –10 (representing extreme hunger: painfully hungry) to +10 (representing extreme satiety: full to nausea) (Haber et al., 1977). Precisely, the subjects indicated the level of agreement in respect to hunger or satiety by pointing to an appropriate place along the graduated visual scale. The test was performed every day before lunch time by all the subjects included in the study during the entire period of treatment.

Psychodynamic pattern

A Beck Depression Inventory (BDI-II) was taken to assess depressive symptoms: a score of 10 to 30 was indicative of depressive symptoms (Steer et al., 1999). The BDI-II was performed by all the subjects at the start of the study and at EoT. The psychodynamic test was conducted under standardized conditions of comfort and silence, with a study technician always in attendance.

Statistical methods

All statistical analyses were performed by the SAS System version 9.2, choosing the 5% (p ≤ 0.05) as threshold value of statistical significance. The primary endpoint of the study was the supplemented versus placebo comparison of the change in fasting glucose blood levels between baseline and EoT. This was a single comparison; thus, there were no multiplicity concerns. In the case of the secondary endpoints, no adjustment of the 5% significance level was done for multiple comparisons/multiplicity due to their descriptive nature. Secondary efficacy endpoints were the changes between baseline and EoT of the other parameters of glycidic metabolism, lipidic pattern, psychodynamic test and anthropometric parameters.

Fasting glycaemia was also evaluated at the end of the follow-up (EoF) that is 60 days after the EoT. Differences in gender distribution between the two groups were assessed by the chi-square test. Due to the small sample size, distribution-free non-parametric tests have been adopted to analyze the discrete or continuous data. The within groups changes and percent changes from baseline were analyzed by the signed rank test (SR). At each assessment time, the comparison between groups was performed by the Wilcoxon's (W) two-sample test. The Haber scores recorded daily were averaged every ten days, producing six assessment occasions: days 1–10; 11–20; 21–30; 31–40; 41–50; 51–60. The average of the scores recorded over the two pre-treatment weeks was used as baseline. The pattern over time of the scores of each group was assessed by the Friedman's test. The comparisons within groups versus baseline and between groups at each assessment occasion were performed by the SR and W tests, respectively. It was also performed analysis of covariance with the delta fasting glycaemia, as an independent variable, and the treatment and delta BMI, as explanatory variables. The same model of ANCOVA was also applied to the delta of every lipidic parameter.

Safety was assessed by laboratory tests performed at baseline and EoT and by recording volunteered AEs.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conflict of Interest
  8. REFERENCES

All the 55 subjects completed the 60 days intervention trial and their characteristics at the baseline are shown in Table 1; the placebo and supplemented groups were homogeneous for all glyco-lipidic parameters.

Table 1. Demographics and baseline characteristics of the studied patients
Variablea Supplemented (N = 26)Placebo (N = 29)Total (N = 55)Pb
  1. a

    data are expressed as mean values and [SD], if otherwise not specified

  2. b

    Wilcoxon's two-sample test, if otherwise not specified

GenderF15 (58%)15 (52%)30 (54.5%)0.657
 M11 (42%)14 (48%)25 (45.5%)2)
AgeYears54.7 [11.6]53.6 [8.2]54.1 [9.8]0.821
BMIkg/m^231.74 [4.30]29.77 [3.08]30.70 [3.80]0.079
Glucosemmol/L6.049 [0.498]6.172 [0.607]6.114 [0.556]0.879
InsulinmcU/ml13.50 [5.33]12.83 [6.71]13.14 [6.05]0.241
HOMA index 3.671 [1.702]3.542 [1.799]3.603 [1.739]0.474
Glycosylated haemoglobin (%) Haemoglobin(%)6.59 [0.43]6.44 [0.74]6.50 [0.63]0.285
ADAG 142.4 [12.4]138.3 [21.2]140.0 [18.1]0.285
Total cholesterol (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L)mmol /L5.903 [1.018]6.050 [0.794]5.982 [0.899]0.415
HDL-cholesterol (mmol/L)mmol /L1.384 [0.430]1.529 [0.730]1.462 [0.608]0.386
Total/HDL-cholesterol ratiommol /L4.621 [1.636]5.055 [2.552]4.854 [2.168]0.755
LDL-cholesterol (mmol/L)(mmol/L)mmol /L3.976 [0.883]3.886 [0.449]3.928 [0.680]0.430
Triglyceridesmmol /L1.395 [0.559]1.380 [0.356]1.387 [0.459]0.686
BDI-II scalescore8.35 [7.68]7.93 [6.91]8.13 [7.22]0.979
Haber scalescore−1.630 [2.033]−1.880 [1.550]−1.760 [1.780]0.826

Glucose metabolism

The decrease in FBG was statistically significant in the supplemented group (−9.6%, p < 0.001), whereas it was not statistically significant in the placebo group. At the end of intervention, the difference between groups was statistically significantly (p = 0.001). The post-hoc power based on the observed treatments difference at EoT, with a pooled SD of 0.50 mmol/L and Alpha = 0.05, reaches the 99%. The changes from baseline in the insulin levels of two groups did not significantly differ. A statistically significant between groups difference was found in the percent changes from baseline (p = 0.044). At the end of intervention, the supplemented group showed a significant decrease in the glycosylated haemoglobin (−2.32%, p = 0.003), a significant decrease in the ADAG (−3.6%, p = 0.002) and a significant decrease in HOMA index (p < 0.001), whereas the placebo group did not show significant changes. These results have been shown in Table 2. There was no significant correlation within each group between delta BMI and fasting glycaemia: supplemented group (Pearson r = 0.074, p = 0.721; Spearman r = 0.003, p = 0.989); placebo group (Pearson r = −0.028, p = 0.888; Spearman r = 0.111, p = 0.575), as shown in Fig. 2. Moreover, the results of ANCOVA analysis demonstrated that changes in BMI did not affect changes in fasting glycaemia. Even, the interaction between treatment and BMI was not significant, indicating that the regression between delta fasting glycaemia and delta BMI was similar in both groups, as shown in Table 3.

Table 2. BMI and glucose metabolism. Mean changes from baseline
 Supplemented mean change and 95%CIPlacebo mean change and 95%CITreatment effect mean difference and 95%CI 
Variablep value
  • W = Wilcoxon's test

  • *

    p < 0.05; # p < 0.01; § p < 0.001 at the signed rank test

 Mean95%CIMean95%CIMean95%CI(W)
BMI (kg/m^2)−0.95§−1.27−0.64−0.41−1.450.63−0.54−1.620.530.001
Glucose (mmol/L)−0.62§−0.87−0.360.00−0.140.13−0.61−0.89−0.330.001
Insulin (mcU/ml)−0.47−1.210.280.45−1.061.97−0.92−2.580.740.057
Glycosylated haemoglobin−0.16#−0.25−0.06−0.08−0.240.08−0.08−0.260.110.153
ADAG−4.45#−7.22−1.68−2.28−6.822.27−2.17−7.383.040.178
HOMA index−0.54§−0.84−0.230.15−0.330.62−0.68−1.24−0.130.006
image

Figure 2. Scatter diagram of changes in blood glucose versus changes in BMI.

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Table 3. Results of ANCOVA
VariableSource of variationDFSum of squaresMean squareF valuePr > F
 Treatment12.300782.300788.730.005
Changes in glucoseChanges in BMI10.043110.043110.160.688
 Treatment* Changes in BMI10.055580.055580.210.648
 Treatment10.185840.185840.450.506
Changes in total cholesterolChanges in BMI11.867211.867214.500.039
 Treatment* Changes in BMI11.694421.694424.080.049
 Treatment10.018580.018580.590.445
Changes in HDL-cholesterolChanges in BMI10.000030.000030.000.976
 Treatment* Changes in BMI10.003330.003330.110.746
Changes in the ratioTreatment10.106450.106450.180.670
Total chol./HDL-chol.Changes in BMI11.120141.120141.930.171
 Treatment* Changes in BMI10.986760.986761.700.198
 Treatment10.579870.579871.370.248
Changes in LDL-cholesterolChanges in BMI12.017172.017174.750.034
 Treatment* Changes in BMI11.508121.508123.550.065
 Treatment10.000370.000370.000.958
Changes in triglyceridesChanges in BMI10.006690.006690.050.822
 Treatment* Changes in BMI10.062620.062620.480.493

Lipid parameters

TC significantly decreased in the supplemented group at the EoT (−6.30%, p = 0.001), but it did not change in the placebo group. HDL-C did not show any significant change from baseline at the EoT either in the supplemented group or in the placebo group. The ratio between total and HDL cholesterol significantly decreased from baseline in the supplemented group (−5.69%, p = 0.041). At EoT, blood LDL-C level significantly decreased in the supplemented group (−10.57%, p = 0.002), while it did not change significantly in the placebo group. TGs did not significantly change from baseline in both the intervention and control group. These results have been shown in Table 4. The ANCOVA results are in Table 3. They show that there was a significant relationship between decrease in TC and decrease in BMI (p = 0.039), but regression between delta TC and delta BMI was different in the two groups (interaction treatment by delta BMI, p = 0.049). The by group correlation between changes in TC and changes in BMI did not evidence any statistically significant relationship significant: supplemented group (Pearson r = 0.308, p = 0.135; Spearman r = 0.267, p = 0.198); placebo group (Pearson r = 0.086, p = 0.665; Spearman r = 0.105, p = 0.595). A significant relationship was also found between changes in LDL-C and changes in BMI (p = 0.034), but in this case, the interaction ‘Treatment by delta BMI’ was not significant (p = 0.065), the by groups correlation results being the following: supplemented group (Pearson r = 0.315, p = 0.125; Spearman r = 0.167, p = 0.425); placebo group (Pearson r = 0.186, p = 0.343; Spearman r = 0.043, p = 0.830).

Table 4. Lipids metabolism. Mean changes from baseline
 Supplemented mean change and 95%CIPlacebo mean change and 95%CITreatment effect mean difference and 95%CI 
Variablep value
  • W = Wilcoxon's test

  • *

    p < 0.05; # p < 0.01

 Mean95%CIMean95%CIMean95%CI(W)
Total cholesterol (mmol/L)−0.44#−0.82−0.060.07−0.030.18−0.52−0.91−0.130.001
HDL-cholesterol (mmol/L)0.00−0.070.07−0.04−0.110.030.04−0.060.130.399
Col/HDL ratio−0.35*−0.720.020.01−0.230.25−0.37−0.780.050.096
LDL-cholesterol (mmol/L)−0.50#−0.87−0.130.13−0.010.27−0.63−1.02−0.24<0.001
Triglycerides (mmol/L)−0.10−0.300.10−0.04−0.100.02−0.06−0.270.140.209

Anthropometric parameters

At EoT, the decrease in BMI was statistically significant in the supplemented group, while it did not significantly change in the placebo group, the between groups differences in changes from baseline being statistically significant (p = 0.001). At EoF, the differences versus baseline were statistically significant in the two groups, but the changes from baseline were more pronounced in the supplemented group when compared with placebo (p = 0.019 and p = 0.021 for changes and percent changes, respectively). The results regarding BMI have been reported in Table 2.

As concerns skinfold thickness, statistically significant reductions of baseline values of triceps, subscapular and suprailiac zones have been observed in the supplemented group whereas no statistically significant changes were found in the placebo group. Between groups statistically significant differences in the changes from baseline were observed for the subscapular zone (p = 0.007 for changes from baseline, p = 0.011 for percent changes from baseline). As concerns the other anthropometric parameters, statistically significant reductions of the baseline values have been observed in the supplemented group for arm circumference, AMA, AFA, MAC, waist, hips, calf and in the placebo group for brachial circumference and waist-hip ratio (WHR). The reductions versus baseline in the supplemented group were significantly more marked than placebo for: hips (p = 0.005 for both changes and percent changes from baseline) and calf (p = 0.020 for changes from baseline, p = 0.015 for percent changes from baseline); on the other hand, the reduction in WHR observed in the placebo group was significantly higher than in the supplemented group (p < 0.001 for both changes and percent changes from baseline). The results of the statistical analysis applied to the changes from baseline of anthropometric parameters are reported in Table 5.

Table 5. Anthropometric, satiety and depression parameters. Mean changes from baseline
 Supplemented mean change and 95%CIPlacebo mean change and 95%CITreatment effect mean difference and 95%CI 
Variablep value
  • W = Wilcoxon's test

  • *

    p < 0.05; # p < 0.01; § p < 0.001 at the signed rank test

 Mean95%CIMean95%CIMean95%CI(W)
Skinfold thickness: Biceps−0.96−1.930.0−0.95−2.060.17−0.01−1.461.430.648
Skinfold thickness: Triceps−0.81*−1.49−0.12−0.48−1.260.30−0.33−1.350.700.273
Skinfold thickness: Subscapular−1.40#−2.38−0.420.61−0.181.39−2.01−3.22−0.790.003
Skinfold thickness: Suprailiac−0.65*−1.27−0.04−0.41−1.760.94−0.24−1.731.240.271
Brachial circumference−1.06§−1.48−0.63−0.39*−0.71−0.07−0.66−1.18−0.150.002
AMA−3.13#−5.13−1.14−0.76−1.580.06−2.37−4.42−0.320.025
AFA−0.36§−0.58−0.14−0.05−0.170.06−0.31−0.54−0.070.006
MAC−0.80§−1.28−0.33−0.24−0.490.01−0.56−1.07−0.050.045
Waist−1.71§−2.55−0.88−0.71−1.730.30−1.00−2.290.300.102
Hips−1.63§−2.23−1.04−0.16−0.880.56−1.47−2.40−0.550.001
WHR−0.00−0.010.00−0.08§−0.11−0.060.080.060.110.000
Calf−0.65§−0.89−0.41−0.13−0.320.07−0.53−0.83−0.230.000
BDI-II0.08−1.771.92−0.18−0.750.390.26−1.572.080.780
HABER score0.09−0.851.03−0.38−1.320.560.47−0.831.770.443

Satiating capacity, psychodynamic pattern

The Haber test scores of the supplemented group did not show any statistically significant trend on time (Friedman test: 5.522; p = 0.479), while the scores of placebo group showed a statistically significant trend on time (Friedman test: 24.511; p < 0.001), the changes from baseline being significant in this group at ‘Days 11–20’ (p = 0.007). No between groups statistically significant differences in Haber scores have been detected. The changes from baseline analyzed at EoT are shown in Table 5.

As regards BDI, the scores of the two groups did not show any statistically significant change from baseline to EoT. No statistically significant differences between groups have been detected (Table 5).

Table 6 showed the results of a 3-day weighed-food record of 2 weekdays and 1 weekend day performed during the first week of intervention and during the last week of intervention in the two groups. No significant differences between treatment groups were shown.

Table 6. A 3-day weighed-food record of 2 weekdays and 1 weekend day was performed during the first week of intervention and during the last week of intervention
 First week of intervention (dietary supplement)Last week of intervention (dietary supplement)First week of intervention (placebo)Last week of intervention (placebo)
  1. *Mean (SD); Nutritional evaluation from Carnovale E, Marletta L: ‘Tabelle di composizione degli alimenti’, Istituto Nazionale della Nutrizione, Roma 1997

Energy (kJ)6772.6 (554.8)7485 (563.1)7580 (559.9)6083 (567.2)
Protein (g); (% energy)70.9 (5.4); 17.5 (1.1)80.3 (6.2); 18.0 (1.3)76.2 (6.6); 16.8 (1.1)66.0 (5.9); 18.2 (1.0)
Fat (g); (% energy)49.7 (4.5); 27.7 (1.3)54.8 (4.9); 27.6 (1.8)57.0 (5.2); 28.3 (2.0)47.6 (5.5); 29.5 (2.1)
Saturated fatty acids (g); (% energy)13.3 (1.2); 7.4 (0.5)15.2 (2.1); 7.6 (1.1)13.8 (1.4); 6.9 (0.9)12.9 (3.0); 8.0 (1.1)
Carbohydrate (g); (%)236.1 (22.5); 54.6 (1.7)259.5 (23.6); 54.4 (2.9)264.6 (24.4); 54.8 (2.0)202.6 (23.9); 52.3 (2.5)
Complex (g); (%)160.9 (24.2); 37.8 (2.8)184.4 (25.8); 38.7 (3.5)189.0 (23.3); 39.1 (3.0)131.6 (23.9); 34.0 (4.4)
Simple (g); (%)72.6 (7.4); 16.9 (1.8)75.1 (10.1); 15.8 (2.4)75.6 (12.5); 15.7 (2.9)71.2 (10.9); 18.3 (3.4)
Dietary fiber (g)23.9 (2.5)21.0 (3.6)25.7 (4.2)21.5 (5.1)
Cholesterol (mg)185.8 (31.1)207.4 (32.5)192.1 (32.4)184.9 (33.0)

AEs

No AEs were reported during the study in either group, and the values in routine blood biochemical parameters evaluated for the safety of the two groups did not show any statistically significant changes from baseline, nor statistically significant differences between groups.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conflict of Interest
  8. REFERENCES

The results of this double-blind, placebo-controlled, randomized clinical trial demonstrate that the treatment with a highly standardized extract from Cs flowering heads shows favourable glyco-metabolic effects in overweight subjects with naïve IFG. This is proven by the significant reduction of baseline values of FBG after 60 days of intervention with Cs extract, and this was the primary efficacy endpoint of the study. Moreover, a significant reduction of glycosylated haemoglobin, ADAG and HOMA has also been observed in the intervention group, thus confirming the efficacy of Cs extract in the control of glucose metabolism in IFG patients. On the contrary, insulinemia did not change significantly after treatment with Cs extract, and this is an expected observation due to the fact that insulin basal levels were within normal limits in our group of subjects. As a consequence, the significant reduction of HOMA observed only in the intervention group at the end of the study appears mainly correlated to the reduction of glycaemia. HOMA is an indirect index of insulin resistance, and its reduction supports the efficacy of supplementation with Cs extract in preventing the development of type 2 diabetes (Unwin et al., 2002).

This effect on glucose reduction is in agreement with the use of Cs extracts in traditional medicine as an antidiabetic remedy (Hernandez-Galicia et al., 2002). As a matter of fact, it is well known that the great problem of traditional herbal treatments is, in most of the cases, the lack of well standardized products and the lack of scientific evidence of efficacy, obtained by means of controlled clinical trials. On the contrary, this study has been conducted with a highly standardized Cs extract and with a double-blind, placebo-controlled, randomized design. The issue of standardization, characterization, preparation and toxicity of an herbal extract is crucial (Shan et al., 2007), and, as far as Cs extracts are considered, a relevant diversity has been shown when different dietary supplements were compared (Schütz et al., 2006). The Cs extract used in this study was highly standardized and characterized by a high content in caffeoylquinic acid and flavonoids, expressed as luteolin glycosides (Fantini et al., 2010). The daily doses of its polyphenolic components is in the range of the average food consumption in the Mediterranean population and in line with the one used in a recent study that evaluated the absorption and metabolism of bioactive molecules after oral consumption of cooked edible heads of Cs in human subjects (Azzini et al., 2007). Furthermore, this study showed biologically effective concentrations of artichoke markers in the human plasma (Azzini et al., 2007).

The mechanism of action of Cs extracts on glycaemia is multifactorial, as shown by various in vitro and animal studies (Arion et al., 1997; Matsui et al., 2006; Karthikesan et al., 2010; Hemmerle et al., 1997; Arion et al., 1998). Cs extracts have high antioxidant activity, primarily due to flavonoids and phenolic acids, and in particular chlorogenic acid (5-caffeoylquinic acid), dicaffeoylquinic acids and caffeic acid. Chlorogenic acid is a potent inhibitor of glucose 6-phosphate translocase, an essential component of the hepatic glucose 6-phosphatase system, which regulates the homeostasis of blood glucose (Arion et al., 1997). Moreover, it has been shown that, in rats, chlorogenic acid inhibits glucose absorption from the small intestine (Welsch et al., 1989). Furthermore, by inhibiting Glucose-6-Phospase (Glc-6-Pase) activity, chlorogenic acid may limit the release of glucose from glycogen into general circulation and prevents the increase of insulinemia, as reported in animal models, with the chlorogenic acid derivative (Herling et al., 1998; Simon et al., 2000). Diabetes causes a two- to threefold increase in Glc-6-Pase activity in the liver (Segal and Washko, 1959; Arion and Nordlie, 1965), making this enzyme system a potential target for compounds that are intended to suppress hepatic glucose production and to reduce hyperglycaemia. In addition, dicaffeoylchinic acid derivatives may favour the glycaemic control by modulating the activity of alpha-glucosidase and consequently the catabolism of dietary carbohydrates (Matsui et al., 2006).

The clinical impact that the results obtained in this study could play is of relevant interest due to the high prevalence in the western world of IFG (Shaw et al., 2010) with increased risk of developing type 2 diabetes (Unwin et al., 2002) and subsequently of developing various CVDs.

The potential use of a Cs extract as a treatment of IFG could represent an interesting alternative to the use of glucose-lowering drugs avoiding the risk of unwanted symptoms and complications, such as severe hypoglycaemia, lactic acidosis, idiosyncratic liver cell injury, permanent neurological deficit, digestive discomfort, headache and dizziness (Neustadt and Pieczenik, 2008; Arion and Nordlie, 1965; Modi, 2007; Hui et al., 2005; Garber and Spann, 2008). As a matter of fact, the intervention with Cs appears to be safe: no relevant side effects were observed in the intervention group.

Complementary medicine information needs to be incorporated into clinical practice and patient and professional education; awareness of the widespread use of complementary and alternative medicine by people with Type 2 diabetes is crucial for healthcare professionals (Thompson Coon and Ernst, 2003).

Another favourable effect observed in the present study regards the lipidic pattern. After 8 weeks of intervention with three daily doses of highly standardized extract from Cs flowering heads, a significant reduction of TC, total/HDL-C ratio and LDL-C was observed. The favourable effects of Cs supplementation on cholesterol metabolism, which are mostly mediated by its choleretic activity, have been already demonstrated in animal models (Saénz Rodriguez et al., 2002) as well as in humans (Lupattelli et al., 2004), so the results of this study confirm previous findings.

It is important to consider that weight loss could also have influenced the decrease of glucose and lipid values because a significant effect on weight reduction has been observed only in the intervention group, even though both groups were asked to follow a similar prudent diet. However, there was no significant correlation between the decrease in fasting glycaemia and weight loss in treated group, which demonstrated that the weight loss is not the cause of the decrease in fasting glycaemia. Moreover, both groups consumed the same prudent diet; probably, the more loss of weight observed in the treatment group was due to a decrease in appetite sensation. The losing weight effect of Cynara has been already demonstrated both in clinical research, although in combination with Phaseolus vugaris (Rondanelli et al., 2011), and in review of traditional use of Cs (Dickel et al., 2007).

These interesting results have been demonstrated in naïve overweight patients, but it is assumed that the same results can be evident in patients of normal weight, seen that the weight loss did not affect blood glucose. An interesting future study might involve association to hypoglycaemic therapy with the intake of this dietary supplement in severely ill patients with diabetes, with aim to improve glucose metabolism.

Further studies with a larger number of patients are clearly needed to confirm the effect of Cs extracts on FBG.

Moreover, it will be important to prove this hypoglycaemic effect in different study groups and not just in overweight patients with newly detected IFG, as it has been done in this study.

In conclusion, the supplementation with a highly standardized Cs extract is of great clinical interest for its potential role in the treatment of overweight patients with naïve IFG.

Conflict of Interest

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conflict of Interest
  8. REFERENCES

All authors declare no financial/commercial conflicts of interest.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conflict of Interest
  8. REFERENCES
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