Results of this preliminary study demonstrate, for the first time, the beneficial effects of WBG in Taiwanese adult subjects with MetS. A daily dose of 4.8 grams lyophilized WBG powders in capsules significantly decreased the incidence of MetS after three months of supplementation and the improved status remained after stopping the supplementation for one month, but not for two and three months. This indicates that the washout period should be at least one month if a crossover study is to be conducted. Our results show that it is worth to conduct further randomized-placebo controlled trials to confirm the benefits of WBG on metabolic disorders.
MetS is a spectrum of metabolic disorders that project to high risk of type 2 DM and cardiovascular diseases. MetS subjects defined by at least three out of the five risk factors are thus a heterogeneous population. The most common characteristic of our study subjects is abdominal obesity, based on the large waist circumference (40 out of the 42 subjects). In this regard, we did observe a significant decrease in waist circumference after the supplementation of WBG. On the other hand, the number of subjects with high serum glucose(≥100 mg/dL) and triglyceride(≥150 mg/dL), low HDL-c and high blood pressure (SBP ≥130 or DBP≥ 85 mmHg) were 26 (61.9%), 34 (81.0%), 25 (59.5%) and 36 (85.7%), respectively. The relatively small sample size together with the heterogeneity might have limited our power to detect differences in these metabolic endpoints.
Insulin resistance is regarded to play a central role in MetS and abdominal obesity has been associated with insulin resistance. Despite that the insulin resistance indicators logHOMA, McAuley, and Quicki showed ameliorated trends after one to three months of WBG supplementation, there were no statistical significance due to the small sample size and heterogeneous characteristics of our study subjects. Indeed, our original goal was to recruit 45 MetS subjects based on the sample size estimation with a 15% decrease in the MetS incidence rate after WBG supplementation and 5% dropout rate. Fortunately, a 19% decrease in the MetS incidence rate was observed despite that only 42 subjects were recruited and 4 (9.5%) of them have dropped out.
In addition to the individual differences in MetS risk factors, the heterogeneity of our study subjects also arisen from the great range of their ages (23-63 years) and BMI (22.3-45.2). Moreover, both men and women (irrespective of whether they are post- or pre- menopause) were included. Besides, subjects previously diagnosed with type 2 DM, hyperlipidemia or hypertension were not excluded and were all advised to maintain their prescribed medication. These further increased the heterogeneity of our study subjects. All these heterogeneities should be avoided if a randomized controlled trial is to be carried out in the future.
The regulation of glucose metabolism by BG or it extracts/components has been extensively reviewed and various active compounds and action mechanisms have been proposed [3
]. Early study isolated a Polypeptide-P, the so-called "plant insulin" from BG and demonstrated its insulin-like activity [25
]. D-(+)-trehalose isolated from BG was shown to inhibit α-glucosidase [26
] and delayed the digestion and absorption of dietary carbohydrates. Recently, cucurbitane-type triterpenoids isolated from BG were shown to increase glucose transporter 4 translocation through activation of AMPK [27
], inhibit α-glucosidase [28
], and modulate insulin secretion activity [29
]. 9c,11t,13t-conjugated linolenic acid [30
] and momordin [31
] from BG were noted to activate PPAR α, γ and PPAR β/δ respectively. It has been shown that PPARγ agonist induced uncoupling protein-1 expression and increased oxygen consumption in the white adipose tissue cells [32
]. In addition, PPARβ/δ has been shown to play a critical role in the body fat reduction in an animal model [33
studies using animal models also provided evidences that BG ameliorated metabolic disorders through the regulations of PPARs as one of the mechanism [18
]. The Hualien No.4 WBG used in this study is a hybrid variety of WBG being selected for its high PPAR activating activity. Other proposed mechanisms for actions of BG include stimulation of pancreatic insulin secretion [35
], decreased hepatic gluconeogenesis, increased hepatic glycogen synthesis, metformin- and sulfonylurea-like glycemic control activities [5
Almost all the human studies associated with metabolic disorder using bitter gourd were focused on controlling type 2 DM [3
]. The beneficial effects of BG on type 2 DM have not been firmly established. Most non-controlled, and 2 randomized controlled trials [20
] showed statistically significant reduction of fasting blood glucose, but other controlled trials showed no significant effect [20
Among the five criteria of MetS, only waist circumference was found to be significantly reduced after supplementation in this study. This trend of change in the waist circumference was similar to the decline in the incidence rate of MetS, despite that lowering of waist circumference to less than 90/80 cm were not the main contributors for subjects that showed a release from having MetS after three months of BG supplementation. Abdominal obesity is well recognized as a potential etiologic factor of MetS [38
]; hence, reverted central obesity is of significance for overall MetS management. This finding from our study is particularly important for Asians, a population that is likely to have metabolic obesity [39
In general, lyophilized WBG powder capsule preparations in our study were well tolerated. There were few adverse events and these were generally mild. In previous human trials, the most commonly reported side effects are abdominal pain and diarrhea [24
]. Our study showed that adverse effects were mostly moderate, including one and two subjects with abdominal pain and bloat respectively. To our knowledge, this is the first human trial to evaluate the effects of WBG on MetS.
Our study, however, has certain limitations. The relatively small sample size and substantial heterogeneity of the studied subjects limited our power to detect differences in many metabolic endpoints. This was an uncontrolled trial, so we cannot exclude the placebo effect. Nevertheless, after discontinuing the supplementation agent, our subjects were followed up for MetS over an additional three-month period. On the other hand, a recent study demonstrated that taking dietary supplements may create an illusory sense of invulnerability that disinhibits unhealthy behaviors because such supplements are perceived as conferring health advantages [40
]. This might also be a concern as we did not monitor diets and other life-style factors of our subjects throughout the study period. Generalizability (external validity) of the trial findings were not defined due to the WBG capsules used were prepared from a specific variety of WBG provided by Hualien District Agricultural Research and Extension Station, Council of Agricultural, Executive Yuan, Taiwan.