Green tea constituent to benefit human health
Teavigo provides EGCG which is safe, well tolerated and has a good bioavailability, writes Peter Weber
The metabolic syndrome is a concurrence of distributed glucose and insulin metabolism, overweight and abdominal fat distribution, mild dyslipidemia, and hypertension. It is characterised by insulin resistance. The pathogenesis of the syndrome has multiple origins, but obesity and sedentary lifestyle coupled with diet and still largely unknown genetic factors clearly interact to produce the syndrome.
The prevalence of the metabolic syndrome among US adults, based on the definition of the National Cholesterol Education Program is 23.7 per cent. However, the unrelenting increase in the prevalence of obesity in the US suggests that the current prevalence of the metabolic syndrome is now very likely to be higher than estimated from the 1988 to 1994 National Health and Nutrition Examination Survey III data.
The cornerstone of treatment are weight management and appropriate levels of physical activity. The health benefits of green tea have been known for centuries. People have been drinking tea from the leaves of the Camellia sinesis plant for more than 2000 years. Health benefits have been attributed to tea consumption ever since including anti-obesity and anti-diabetic effects.
Epidemiological studies have associated green tea drinking with a reduced risk of several diseases including cardiovascular diseases and cancer. The body of evidence regarding the health benefits of green tea has grown considerably during the last decade by numerous studies using green tea extracts, which contained various mixtures of mainly four catechins: epigallocatechin-3-gallate (EGCG), epicatechin (EC), epigallocatechin (EGC) and epicatechin gallate (ECG).
EGCG is the most abundant catechin in green tea, and most of the putative health benefits are attributed to EGCG. In the context of the metabolic syndrome it is noteworthy that green tea extracts or EGCG, respectively exert anti-obesity and hypolipidemic effects in humans, as well as anti-diabetic effects in animals and in vitro.
DSM Nutritional Products has developed a method to purify EGCG from green tea extracts and to produce batches with a constant concentration of more than 90 per cent crystalline pure EGCG (Teavigo). This allows for manufacturing of hard-gelatin capsules with a defined and stable EGCG content.
We investigated the safety, tolerability and plasma-kinetic behaviour of Teavigo as well as the anti-obesity, anti-diabetic and cardio-protective effects of this product.
Teavigo provides EGCG which is safe, well tolerated and has a good bioavailability.
In a randomised, double-blind, placebo-controlled study the safety, tolerability and plasma kinetic behaviour of a single oral intake of Teavigo was assessed in 60 healthy male volunteers. Single doses of 50, 100, 200, 400, 800, 1600 mg of Teavigo or placebo were administered.
Blood samples were taken at intervals until 26 h later. EGCG kinetic profiles revealed rapid absorption with a one-peak plasma concentration versus time course, followed by a multiphasic decrease consisting of a distribution phase and an elimination phase in all dosage groups. The mean AUC(0µ) of total EGCG varied between 442 and 10,368 ng.h/ml. The according mean Cmax values ranged from 130-3392 ng/ml and were observed after 1.2-2.2 h (Figure 1).
A dose linearity for rate and extent can be assumed. The mean t1/2z were seen between 1.8 and 4.9h. Single oral doses of Teavigo upto 1600 mg were safe and very well tolerated.
Another randomised, double-blind, placebo-controlled study assessed the safety, tolerability and plasma-kinetic behaviour of Teavigo after ten days of repeated intake in 36 healthy male volunteers. 200, 400, 800 mg of Teavigo or placebo were administered daily. Blood samples for plasma-kinetic EGCG characterisation were taken on day 1 and day 10.
Kinetic parameters were determined and compared between day one and day 10. EGCG plasma-kinetic evaluation showed dose linearity for single dose application (day one). After repeated intake (day 10) dose linearity was applied between the 200mg and 400mg group. Intake escalation to 800mg was more than dose-proportional in rate and extent. Ten days of repeated administration of oral doses of Teavigo of upto 800 mg per day were found to be safe and very well tolerated.
Teavigo was safe and very well tolerated even though the highest dose tested was significantly higher than the reported daily intake from green tea.
Reduces adipose tissue
We investigated the anti-obesity effect of Teavigo in a mouse model of diet-induced obesity. Body weight gain as well as changes in body fat, blood glucose, and lipids were measured.
One month old mice were randomly assigned to groups (n=8) receiving either a low fat diet or high fat (20 per cent) diet with or without 1 per cent EGCG for five months. Consumption of the high fat diet resulted in a significant increase in body weight when compared to the low fat diet. Weights of subcutaneous and epidydimal adipose tissues rose 61 per cent and 88 per cent in the high fat group, respectively. Supplementation of one per cent Teavigo to the high fat diet completely abolished both the increase in body weight and the rise in adipose tissue weights (Figure 2).
A similar study was conducted in the NZB mouse model of diet-induced obesity. Teavigo supplementation (0.5 per cent and 1 per cent w/w of diet) for four weeks selectively reduced the increase in adipose tissue mass in a dose-dependent manner (Figure 3) and thereby prevented diet-induced obesity. In the ob/ob mouse model, the dose response of Teavigo on the development of obesity was investigated. A modified AIN-93 diet was supplemented without or with Teavigo providing 0.25 per cent, 0.5 per cent and one per cent EGCG. Body weight was measured and body composition was accessed by NMR.
Teavigo at a dose of 0.5 per cent and one per cent significantly influenced body weight and body composition. Body weight and adipose tissue mass of control mice increased 6.9 per cent, and 4.7 per cent respectively, during the 21 days of intervention. Body weight and adipose tissue mass of 0.5 per cent.
Teavigo supplemented mice increased to a significantly lesser extent (3.0 per cent and 2.5 per cent respectively). Body weight and adipose tissue mass of one per cent Teavigo supplemented mice decreased markedly (-5.8 per cent and -9.6 per cent, respectively). These data indicate that Teavigo exerts a dose-dependent effect on body weight and body composition.
Several mechanisms are being suggested by which Teavigo may impact on adipose tissue and body weight. Our data indicate that these effects are at least partially mediated via a direct effect of Teavigo on adipose tissue. We found a potent inhibitory effect of Teavigo on the adipogenic transformation of C3H10T1/2 cells in an in vitroadipocyte differentiation assay.
This suggests that the observed decrease in adiposity of animals supplemented with Teavigo can be attributed to inhibition of adipocyte growth. Furthermore, Teavigo supplementation markedly decreased the expression of several lipogenic enzymes including fatty acid synthase (FAS) in adipose tissue and it affected thermogenesis and substrate oxidation in a dose-dependent manner. Our study results with Teavigo support the fact that EGCG is the active constituent in green tea which not only increases 24-hour energy expenditure and fat oxidation but also reduces the abdominal fat depot.
Improves glucose tolerance
The anti-diabetic activity of Teavigo was determined by the oral route and in a feeding experiment in the db/db mouse model of non-insulin dependent diabetes mellitus (NIDDM). In the feeding experiment db/db mice were randomly assigned to groups receiving a modified AIN-93 diet supplemented with or without one per cent Teavigo for five weeks.
Fed and fast state blood glucose levels, food intake, and body weight were monitored.
Glucose and insulin tolerance tests were performed after four and five weeks of treatment, respectively. Compared to control mice, Teavigo supplementation resulted in a pronounced and dose-dependent decrease in the levels of both fed (-57.3 per cent) and fast (-50.0 per cent) state blood glucose (Figure 4). Fed state plasma triglyceride and free fatty acid levels were reduced by 67.0 per cent and 30.3 per cent, respectively, due to Teavigo supplementation.
The effects of a short-term treatment with low doses of Teavigo on glucose tolerance was investigated in two-months-old db/db mice. The animals received Teavigo orally per gavage for 11 days. Administration of Teavigo at 30 and 100 mg/kg/day resulted in a dose-dependent reduction of fasted state blood glucose levels (-16.4 per cent and -32.2 per cent, respectively). Similarly, Teavigo caused a dose-dependent improvement of oral glucose tolerance as indicated by a 7.5 per cent and 19.6 per cent decrease in area under the curve (Figure 5). The animals on Teavigo showed also a dose-dependent increase in plasma insulin levels suggesting improved insulin secretion in response to feeding.
The mechanism by which Teavigo may improve glucose metabolism includes regulation of genes that encode gluconeogenic enzymes and protein-tyrosine phosphorylation by modulating the redox state of the cell.
In rat H4IIE hepatoma cells, Teavigo caused a pronounced decrease in the mRNA expression of gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase).
This effect was also apparent in the livers of db/db mice supplemented with Teavigo suggesting that it effectively reduces hepatic glucose production in diabetes mellitus.
Furthermore, we found that Teavigo increases the mRNA expression of the glycolytic enzyme glucokinase (GK) in animals resulting in enhanced hepatic glucose metabolism and improved glucose-stimulated insulin secretion by the pancreas.
Therefore, our data indicate that Teavigo is beneficially influencing the metabolic syndrome by enhancing both hepatic glucose metabolism and pancreatic insulin secretion.
In conclusion, our data demonstrate that Teavigo is safe and very well tolerated in humans. Furthermore, our study results strongly suggest that Teavigo has pronounced anti-obesity effects by a direct inhibition of adipose tissue enlargement probably via enhancing fat oxidation and by reducing lipogenesis. In addition, Teavigo markedly improves the postprandial glucose response and stimulates insulin secretion.
Our data are very encouraging that Teavigo may benefit human health by reducing several risk factors of the metabolic syndrome, which is highly prevalent in industrialised countries.
The writer is with DSM Nutritional Products, Basel, Switzerland. For details contact: DSM Nutritional Products India Pvt Ltd
Tel: 022-56924082, Fax: 56924091