metabolic syndrome ( ms ) is characterized by the presence of insulin resistance , low - degree inflammation , dysglycemia , low plasma high - density lipoprotein cholesterol ( hdl - c ) , increased triglycerides ( tg ) , elevated blood pressure , and abdominal obesity .
ms has been associated with an increased risk of type 2 diabetes mellitus ( dm2 ) and cardiovascular diseases ( cvds ) [ 1 , 2 ] .
the prevalence of ms varies between 15% and 40% , being greater in the population of hispanic origin .
abdominal obesity is considered a key characteristic of ms , which is related to decreased insulin - mediated glucose uptake .
adipose tissue is known to express and secrete a variety of adipokines , including leptin , adiponectin , resistin , and visfatin , as well as cytokines and chemokines such as tumor necrosis factor - alpha ( tnf- ) , interleukin-6 ( il-6 ) , and monocyte chemoattractant protein-1 ( mcp-1 ) [ 58 ] .
the release of adipokines by either adipocytes or adipose tissue - infiltrated macrophages plays a key role in the development of insulin resistance and dm2 , as well as the increased risk of cardiovascular disease associated with obesity .
renin - angiotensin system components are also activated in adipose tissue , leading to hypertension and insulin resistance .
adiponectin is considered to be a protective protein with antidiabetic , anti - inflammatory , and antiatherogenic effects .
reduced plasma adiponectin levels have been reported in obese individuals , particularly in those with visceral obesity , and have been negatively correlated with insulin resistance . furthermore , decreased adiponectin levels were found to be associated with a higher incidence of dm2 .
leptin was shown to promote the development of atherosclerosis by inducing oxidative stress in endothelial cells , increasing platelet aggregation , and hypertrophy and proliferation of vascular smooth muscle cells .
additionally , it was shown that a high leptin level predicts subsequent development of dm2 .
thus , leptin / adiponectin imbalance has a key role in the metabolic alterations associated with obesity [ 510 ] .
multiple therapeutic approaches such as renin - angiotensin system blockers and inhibitors , statins as well as nutrient and dietary interventions [ 1114 ] , have been proposed to reduce metabolic and cardiovascular risk in patients with ms .
garlic ( allium sativum l. ) has been used as a nutrient with beneficial cardiovascular effects .
however , the beneficial effects of garlic are offset by the fact that fresh garlic causes indigestion and that its pungent odor lingers on breath and skin .
an alternative source of garlic that is odorless and rich in antioxidants is aged garlic extract ( age ) .
age has shown beneficial effects in several alterations related to the development of cardiovascular diseases , such as antioxidant and antithrombotic properties [ 1820 ] .
thus , in the present study we aimed to investigate the effects of age on adipokines , inflammatory substances , endothelial function , and metabolic risk factors that constitute the cluster of metabolic syndrome in an urban colombian population .
double - blind , crossover , randomized , placebo - controlled clinical trial to assess the effect of age ( kyolic ) on the cardiovascular risk factors of subjects with ms .
men and women over 18 years old with diagnosis of ms , attending primary health care clinics from the metropolitan area of bucaramanga , colombia .
the ms diagnosis was based on the presence of central obesity ( waist circumference 90  cm ( male ) , 80  cm ( female ) ) and two of the following criteria : tg 150  mg / dl , hdl - c < 40  mg / dl ( male ) , < 50  mg / dl ( female ) , blood pressure 130/85  mmhg , and fasting plasma glucose 100  mg / dl .
the exclusion criteria were ( 1 ) allergies to garlic ; ( 2 ) current treatment with lipid - lowering drugs , antihypertensive drugs , and/or hypoglycemic medications ; ( 3 ) psychiatric disorders that prevent proper decision making ; ( 4 ) patients with infections or inflammatory assets ; ( 5 ) presence of coronary artery disease , with a current or past ischemic event ; ( 6 ) presence of severe chronic or terminal illnesses ; and ( 7 ) presence of diseases that compromise the immune system .
the study was approved by the ethical committee of the cardiovascular foundation in bucaramanga , colombia .
patients were randomly assigned by blocks to receive either 1.2  g / day of age ( kyolic ) or placebo , and after 12 weeks of supplementation , the treatment was invested for another 12 weeks ( figure 1 ) . each treatment was provided in an identical capsule that was taken twice daily with breakfast and dinner ( 2 capsules of each ) . all subjects received routine recommendations of lifestyle changes ( having a diet lower in fat and sugar and increasing physical activity with 30 minutes / day of moderate walking ) .
participants were followed up every four weeks with clinical evaluations and registration of potential undesirable effects and use of any other medication . during the baseline and at the end of each phase of treatment ( week 12 and week 24 ) , the following were determined .
weight , height , body mass index ( bmi ) , waist ( wc ) and hip circumferences ( hc ) , and blood pressure .
routine clinical tests were processed in the clinical research laboratory from the ophthalmological foundation of santander - foscal , floridablanca , colombia .
measurements of adipokines and inflammatory factors were performed at the department of physiology , faculty of medicine , complutense university of madrid , spain .
glycemia and lipid profile were quantified by using a routine colorimetric method ( biosystem bts-303 photometric , barcelona , spain ) .
interleukin-6 , adiponectin , and c - reactive protein were measured using an immunoassay ( r&d systems , mn , usa ) .
the fmv was performed using a high - resolution doppler ultrasound , measuring the changes in diameter of the brachial artery in response to increased blood flow ( reactive hyperemia ) .
the averages and proportions obtained in a descriptive analysis for all clinically relevant variables measured during the baseline evaluation were compared .
then , the treatment effect of the crossover design was evaluated through the difference in change between baseline versus posttreatment according to the intervention phase . based on the frequencies distribution of the outcome variables ,
the student 's t - test or wilcoxon signed - ranks test was used . in outcome variables where significant differences were observed , further analysis of changes was performed using analysis of covariance ( ancova ) , adjusting by phase , treatment , and their interaction ( treatment  phase ) to determine if changes were due to a carryover effect .
all analyses were conducted using stata statistical software , release 11.0 ( stata corporation , college station , tx , usa ) .
the 46 patients included in the study were distributed in two sequences of treatment : age - placebo and placebo - age .
three subjects ( all of them of the first group ) voluntarily discontinued the treatment during the phase 1 . demographic , anthropometric , and biochemical characteristics obtained in the 43 participants who completed the study are shown in table 1 . a significant difference in age
was found between the age - placebo and the placebo - age groups at the baseline . at the end of the study
the crossover analysis was conducted , and a significant difference in the adiponectin delta was found comparing age versus placebo ,  : 313.79 ( 95%ic : 48.34~675.92 ) versus  : 271.88 ( 95%ic :
the ancova confirmed that the significant difference in adiponectin was due to the treatment , not the phase of the study ( no carryover effect ) as no significant changes were observed in the interaction treatment phase ( table 3 ) .
no significant changes were observed in any of the other anthropometrical measurements , endothelial function , and biochemical variables ( table 2 ) .
the present study demonstrates for the first time that the administration of age to subjects with ms for 12 weeks increased adiponectin plasma concentrations .
our group previously reported that in dyslipidemic subjects , the presence of coronary artery disease is associated with an elevation of certain inflammatory markers but not with further endothelial dysfunction . in the present study ,
after the age intervention there were no significant changes either in endothelial function or in inflammation , which may relate both to the short period of intervention and the participation of subjects with low cardiovascular risk .
however , there was a significant increase in adiponectin , an anti - inflammatory adipokine with cardioprotective properties .
low adiponectin levels are observed in obese subjects with and without severe coronary atherosclerosis and in subjects with abdominal obesity [ 10 , 25 ] , and decreased adiponectin levels ( < 4  g / ml ) are associated with a twofold increase in the prevalence of coronary heart disease , independent of other cardiovascular risk factors .
moreover , hypoadiponectinemia is associated with insulin resistance and dm2 [ 27 , 28 ] , as well as atherosclerosis and hypertension .
adiponectin exerts an anti - inflammatory effect through activation of its three receptors ( adipor1 , adipor2 , and t - cadherin ) .
the activation of adipor1 and r2 results in increased hepatic and skeletal muscle fatty acid oxidation , increased skeletal muscle lactate production , reduced hepatic gluconeogenesis , increased cellular glucose uptake , and inhibition of inflammation and oxidative stress .
activation of t - cadherin is protective in vascular endothelial cells against oxidative stress - induced apoptosis .
several mechanisms have been suggested to explain the anti - inflammatory effects of adiponectin , including direct actions on inflammatory cells , actions on nf-b , and interaction with tnf- .
it has been demonstrated that adiponectin inhibits the expression of adhesion molecules in endothelial cells and inhibits smooth muscle cell proliferation , the differentiation of monocytes into macrophages , as well as the formation of foam cells and the secretion of tnf- by macrophages [ 3234 ] . also , increased adiponectin levels are related to improvement in the differentiation of preadipocytes into adipocytes , which is usually impaired in obese subjects .
in fact , 1,2-vinyldithiin ( 1,2-dt ) , a garlic - derived organosulfur compound , has been shown to affect the differentiation of human preadipocytes into adipocytes .
interestingly , a significant reduction of the expression of the two major adipogenic transcription factors , ppar2 and ccaat / enhancer binding protein ( c / ebp ) , was observed in 1,2-dt - treated preadipocytes . the 1,2-dt - mediated decrease in ppar2 expression
is associated with reduced ppar activity , suggesting that the negative effect of 1,2-dt on preadipocytes differentiation could be mainly due to an inhibitory effect on ppar2 , the master regulator of adipogenesis .
the role of these mechanisms of action of 1,2-dt in the beneficial effects of age increasing the levels of adiponectin remains to be elucidated .
additionally , our results showing that a short period of age administration increases the adiponectin level suggest that the effect of age improving the insulin resistance could be another new interesting mechanism to explain the well - known beneficial cardiometabolic effect of garlic .
another mechanism that could be associated with the adiponectin increase is the nitric oxide ( no ) pathway .
adiponectin increases the stability of enos mrna and half - life , enhances the association of enos with hsp90 , and stimulates the phosphorylation of enos , which together lead to increased no production [ 38 , 39 ] .
it has been suggested that age could increase no bioavailability [ 40 , 41 ] by ( a ) increasing cellular antioxidant capacity by providing cellular thiol antioxidants like cysteine and reduced glutathione , ( b ) maintaining functionally relevant levels of tetrahydrobiopterin and preventing oxidative inactivation of tetrahydrobiopterin , which prevents no synthase uncoupling and superoxide anion generation , and ( c ) maintaining no bioavailability in endothelial cells even under conditions of increased vascular oxidant stress .
age is rich in water - soluble organosulfur bioactive compounds such as s - allylcysteine and s - allylmercaptocysteine which are cellular donors of thiol containing reducing equivalents   and as such might explain the cardiovascular benefits of age . in summary
, we showed for the first time that age administration for 12 weeks increases adiponectin levels .
the importance of this observation in the prevention of cvd remains to be determined , and further and larger studies are needed .
 
 background . garlic ( allium sativum ) has been shown to have important benefits in individuals at high cardiovascular risk . 
 the aim of the present study was to evaluate the effects of the administration of aged garlic extract ( age ) on the risk factors that constitute the cluster of metabolic syndrome ( ms ) . 
 methods and design . 
 double - blind , crossover , randomized , placebo - controlled clinical trial to assess the effect of 1.2  g / day of age ( kyolic ) , for 24 weeks of treatment ( 12 weeks of age and 12 weeks of placebo ) , on subjects with ms . results . 
 the administration of age increased the plasma levels of adiponectin ( p = 0.027 ) . 
 no serious side effects associated with the intervention were reported . 
 conclusion . 
 the present results have shown for the first time that the administration of age for 12 weeks increased plasma adiponectin levels in patients with ms . 
 this suggests that age might be a useful , novel , nonpharmacological therapeutic intervention to increase adiponectin and to prevent cardiovascular ( cv ) complications in individuals with ms . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion