Global study on the hypoglycemic effect of Stevia
Recent decades have seen a sharp rise in the incidence of type 2 diabetes and obesity as a result of dietary habits and reduced physical activity. These metabolic syndrome have become a significant public health problem in industrialized and developing countries. For the treatment of mild forms of diabetes are frequently used medicinal plants and means of alternative medicine. In South America, it was used in this extract from S.rebaudiana (Kinghorn, Soejarto, 2002). In addition, given that the main component of the extract, stevioside is sweet, but non-nutritive substance, it becomes a good substitute for sugar bodnyh diabetes.
Preliminary studies in Paraguay and Brazil established a hypoglycemic effect herb stevia. However, it was shown that no Stevia exerts hypoglycemic action in people without diabetes (Curi R. et al., 1986). This adaptogenic effect causes the safety of the plant.
When studying the hypoglycemic effect of an aqueous extract from the leaves of stevia (100 g of leaves and 1500 ml water) was administered per os to animals with alloxan diabetes, dose-dependent effect was detected. Adding to the diet of rats, containing large amounts of carbohydrates, 0.1% stevioside solution lowers the level of glycogen in the liver, but had no effect on blood glucose levels (Oliveira-Filho R. et al., 1986; Akashi H.et al ., 1977). When the experimental animals were given food with a high fat diet supplemented with 0.1% solution of stevioside, they found no change those parameters were observed in animals not receiving stevioside. A diet high in carbohydrates with 10% of the powder of the leaves of stevia (which corresponds to 0.5% stevioside in diet) caused a significant decrease in blood glucose level and glycogen in the liver within 4 weeks of administration (A. Viana, J. Metivier, 1980 ).
It is found that if the rats receive 0.5% stevioside or 10 g /% powder from Stevia leaves composed diets high in carbohydrate, high fat, then four weeks later there was a significant decrease in blood glucose levels (Susuki et al., 1977 ).
Upon receiving the extraction of stevia leaves (5 g /%) for three days every 6 hours. The healthy individuals showed significant decrease in plasma glucose levels during the test for glucose tolerance and fasting after sleep (Suri et al., 1986) . These observations confirm earlier data that stevioside, stevia extract can be used to treat diabetes.
It should be noted that the hypoglycemic effect of Stevia is not always observed, it is often short-lived and requires further study. However, it is clear that the product is useful for diabetics. Retaining usual flavor diet, stevia does not raise blood sugar levels even at a concentration of 10-15 times its average consumption (Ovide C. et al., 1971; Maier C. et al., 1997; P. Jeppsen P. et al., 2000).
Research conducted in the department of therapeutic and preventive power of the Ukrainian Institute of Food Hygiene (15 diabetic patients, 21 days), showed that the inclusion in the diet food saharola a positive effect on the patient's condition. But directly hypoglycemic effect was not recorded. Similar results were obtained in the Institute of Endocrinology and Metabolism, Academy of Medical Sciences in the Department of Clinical Pharmacology (30 patients, 30 days). Stevia showed no hypoglycemic action directly in diabetes, but has a positive effect when included in the diet diet.
Stevia normalize blood glucose levels
It is found that the effect of stevia on carbohydrate metabolism carried out in various ways. Impact stevioside, stevia extract on glucose uptake was investigated in vitro, using isolated small intestine (Toskulkao et al., 1995a). Thus stevioside high dose (5 mM) did not affect glucose absorption. However, at a concentration of 1 mM steviol inhibits glucose uptake by about 40%. It also reduces the accumulation of glucose in the tissue of the intestine, probably by affecting the membrane villi. Moreover, steviol altered morphology absorbent intestinal cells. These results suggest that possible place blockade action steviol mucosa can be and / or intracellular organelles absorbent intestinal cells (Toskulkao et al., 1995a). It is shown that at doses of 5 mM and 1 mM stevioside not inhibit absorption of glucose in the jejunum hamster, whereas 1 mM steviol 30% reduction in glucose uptake, but had no effect on the activity of Na + -K + -ATPase activity in the intestine (Toskulkao et al., 1995b). The observed decrease in ATP content in the intestinal mucosa and reduction of the area of the absorbing surface. The researchers suggest that delay the absorption of glucose by the action of steviol due to a decrease in the ATP level in the gut mucosa by reducing the enzyme activity in mitochondria level phosphorylation, as well as due to morphological changes in the intestinal cells.
Proved steviol inhibition of intestinal absorption of glucose into cells may lead to a reduction of its plasma concentration, which may not be desirable for healthy people. However, stevioside approved daily dose (ADI) of 5 mg / kg of body weight per day creates steviol concentration in plasma of about 20 uM (if all steviol in turn stevioside) (JECFA, 2006). This concentration steviol significantly below those levels which have been found inhibits glucose uptake in the intestine. It should be emphasized that stevioside does not interfere with the absorption of glucose.
Effects on the synthesis of glucose stevioside were studied in rats with experimental diabetes type 1 and type 2 (Chen et al., 2005). Type 1 diabetes induced by streptozotocin in rats (streptozotocin, STZ), and type 2 diabetes - by feeding rats a diet for two weeks with a high fructose (60%). Disease development was confirmed by measuring the level of fasting glucose, and in type 2 diabetes - sample introduction tolbutamide (10 mg / kg of body weight into the peritoneal cavity) (Shennan et al., 1987). It has been found that reduced stevioside high glucose levels in rats and in diabetes type 1 and type 2 diabetes stevioside Hypoglycemic effect in rats with streptozotocin diabetes was observed after oral administration of stevioside at doses of 1, 2 or 10 mg / kg body weight per day for 15 days. According to the study's authors observed may be mediated by the action of stevioside on the rate of gluconeogenesis, controlling the formation of glucose in the liver (Chen et al., 2005). Thus, in rats with streptozotocin diabetes observed overexpression fosfoenol-pyruvate kinase (Giffin et al., 1993; Chan et al., 2003), and the appointment stevioside dose-dependently reduced the concentration of mRNA encoding the enzyme (Chen et al., 2005). Therefore, it seems likely that the slow stevioside gluconeogenesis in the liver by inhibiting gene expression fosfoenolpiruvatkinazy and thus leads to a decrease in plasma glucose levels in rats with experimental diabetes.
Interesting results were obtained in a study that compared the impact of the extract of leaves of Stevia and stevioside on blood glucose and gluconeogenesis in normal rats (Ferreira et al., 2006). Feeding fasted male Wistar rats mixtures stevioside / stevia at a dose of 5.5 mg / kg of body weight per day for 15 days had no effect, whereas the leaves of Stevia powder receiving 20 mg / kg of body weight per day decreased the glucose concentration blood plasma, inhibiting the activity of pyruvate and fosfoenolpiruvatkinazy. Since the leaves of stevia contain many different steviolnyh glycosides, it remains to identify the active ingredient or active ingredients responsible for this effect.
Stevia stimulates the production of insulin by the pancreas
Effect on secretion and sensitivity to insulin. In studying the effect of stevioside and steviol on insulin release of islets isolated cells of the pancreas of mice found that both compounds stimulated hormone secretion (Jeppersen P. et al., 1996). Intravenous stevioside (2 g per 1 kg body weight) in rats with non-insulin dependent diabetes has led to an increase in insulin secretion (but not glucose) in the blood (Jeppersen P.et al. 1997).
Direct impact stevioside and steviol on insulin release was investigated in mouse islets and line pancreatic? -cells INS-1 (Jeppersen P. et al., 2000). In the presence of 16.7 mM glucose as a stevioside and steviol dose-dependent (1 nM to 1 mM), insulin secretagogues islets of Langerhans.
It was established that the insulinotropic / antihyperglycemic action inherent stevioside and steviol, however steviol is stronger than stevioside. To determine if there was observed effect on the whole organism, a test was conducted on glucose tolerance in rats Goto-Kakizaki (Goto-Kakizaki, GK) (rat non-obese type 2 diabetes) and normal rats in the presence or absence of stevioside (Jeppersen et al., 2002). Established that stevioside bolus (0.2 g / kg body weight) in parallel with glucose (2.0 g / kg body weight) stimulates insulin release, lowers plasma glucagon and reduces the blood glucose concentration during the tolerance test glucose. These results confirm the authors' opinion that stevioside inherent antihyperglycemic, insulinotropic and glyukagonostaticheskie properties (Jeppersen et al., 2002).
After repeated administration of stevioside GK rats with type 2 diabetes in the six weeks at a dose of 25 mg / kg of body weight per day, there was a decrease in insulin and glucagon in plasma, with increased insulin secretion (Jeppersen et al., 2003).
Long-term administration of soy protein persons with type 2 diabetes in mice and Zucker line with the metabolic syndrome, led to a decrease in total serum cholesterol by 19%, free fatty acids, - 15% and triglycerides - 47% (Jeppersen et al., 2006). When adding stevioside synergy observed in action on these indicators. In addition, their combined use is also improved first phase insulin response, lowers glucagon exhibits antihyperglycemic effect in rats and GK diabetic patients.
It is known that most cases of diabetes in the world to have type 2 diabetes (Kolterman et al., 1980), is accompanied by decreased sensitivity to insulin in the peripheral tissues, impaired glucose utilization efficiency, which gives rise to hyperglycemia. Therefore, studies have been conducted to study the effect of stevioside on insulin sensitivity in rats with insulin resistance, which is caused by the animals on a diet with 60% fructose content. Such animals impairs the ability of insulin to stimulate glucose uptake, suggesting that there is reduced sensitivity to insulin in the peripheral tissues (Elliott et al., 2002). When adding stevioside at a dose of 5.0 mg / kg of body weight to fructose-enriched food mixture was a marked improvement in insulin sensitivity (insulin ratio explored / glucose). As shown a test with tolbutamide, permanent assignment stevioside thrice daily alienated time of occurrence of insulin resistance (Chang et al., 2005).
Stevioside Effect on insulin sensitivity was also studied on insulinchuvstvitelnyh (thin) and insulin-resistant (obese) rats line Zucker (Zucker rats) (Lailerd et al., 2004). Oral administration of large doses of stevioside (500 mg / kg bw) increased in diabetic rats insulin sensitivity in all tissues of the body. It was established by determining the ratio of insulin / glucose after glucose loading. In addition, in vitro experiments studied the direct effect of stevioside on glucose uptake in skeletal muscle - the main site of accumulation of glucose. It found that stevioside at low concentrations (0.01-0.1 mM) may enhance glucose transport in skeletal muscle as the lean rats and rats Zucker obese line, confirming that the action is directed stevioside, apparently on the transport system glucose into skeletal muscle.
Thus, the effects of stevioside for stimulating insulin secretion (Jeppersen et al., 2000), as well as increase insulin sensitivity (Lailerd et al., 2004) confirms its beneficial effects on glucose metabolism. However, these results are raising the question of whether consumption can lead to stevioside fasting hypoglycemia, as is the case with a sulfonylurea, which stimulates the release of insulin. To answer this question, we administered stevioizid fasted Wistar rats and GK with normal or low plasma glucose (3.3 mM or lower), and wherein the insulinotropic effects of stevioside not found (Jeppersen et al., 2002).
The cells isolated islet tissue stevioside stimulated insulin release only at high glucose concentrations (more than 8.3 mM) (Jeppersen et al., 2000). Thus, stevioside, apparently exerts its beneficial effects, stimulating the release of insulin to the diabetic state only.
To assess the effect of stevia extract and stevioside glucose level in human blood a restricted number of experimental studies. Thus, adding 1 to the standard, the stevioside nutrition (in the control - 1 g starch) persons with type 2 diabetes was observed decrease of postprandial glucose by 18% (Gregersen et al., 2004). Also, there was a slight increase in blood insulin and glucagon levels decrease. Glyukozoinsulinogenny index characterizing insulin secretion after administration of stevioside increased by 40%. It is concluded that stevioside acts directly on peripheral glucose uptake influenced insulin, which causes the reduction of postprandial glucose.
This effect may be responsible for increasing glycogen storage in the liver (Hubler et al., 1994), as has been proven, that administration of 2mM stevioside drinking water expressed increased glycogen synthesis in the liver after 24 hr., And after 48 hours - If you give 1 mM. This steviol this has no effect (Hubler et al., 1994).
It has been shown that stevioside is also directly affects the secretion of glucagon (Hong et al., 2006). Addition of fatty acids to cultured cell adenoma of the pancreas of transgenic mice led to increased glucagon secretion and accumulation of triglycerides. Thus stevioside (from 10 ng to 1 .mu.M) reduced the release of glucagon. It is suggested that the observed effect is due to an increase in mRNA expression of carnitine palmitoyl transferase-activated proliferator? Receptor (RRAR?).
It is proved that the content of the second main component of the stevia leaf - A rebodiozid different from stevioside having one extra glucose residue has hypoglycemic effects similar to stevioside and stevia extract. It demonstrated that it dose-dependently enhances the release of insulin from the islet tissue in the presence of high glucose concentrations (> 6,6) (Abudula et al., 2004). This reaction requires the involvement of extracellular calcium. However, in the in vivo study it proved that long term administration to rats A rebodiozida not increased insulin secretion (Dyrskog et al., 2005).
Subsequent studies have shown that rebodiozid A stimulates insulin secretion from pakreaticheskih? -cells By blocking the ATP-dependent potassium channel, thus causing depolarization? -cells And activation of calcium channels. This inhibition of potassium channels requires the presence of glucose in a high concentration, which underlines the dependence of the action rebodiozida A glucose (Abudula et al., 2008). However, it does not set the signal path on which there is the effect of high glucose concentration in the plasma to the action rebodiozida A.
Similar results were obtained in long-term (16 weeks) appointment rebodiozida and patients with type 2 diabetes who have not observed its effects on glucose homeostasis, lipid profile and blood pressure (Maki et al., 2008). This study used rebodiozida A dose of 1000 mg / day, which is seven times the daily rate of its consumption as a sweetener for diabetics adults. The researchers concluded that rebodiazid A well tolerated and has no pharmacological effects in vivo in glucose homeostasis.
It is shown that a metabolite of stevioside, isosteviol, also improves the lipid profile improved and increased the expression of key genes? -cells. Its action is due to the influence of factors of the transcriptional regulation of insulin, which improves glucose homeostasis. It also improves insulin sensitivity, reducing plasma triglycerides and reducing weight in mice with experimental diabetes (Nordentoft et al., 2008).
The results obtained in experimental conditions in animals, served as the basis for research on humans. There have been a random, double-blind, placebo-controlled, long-term study of three groups of patients (76 persons). (Barriocanal L.A., 2008).
After a general survey, volunteers were enrolled according to the following criteria. Group 1: 16 patients with type 1 diabetes, men and women, age 20-60 years, disease duration of diabetes more than 5 years, with normal or high blood pressure with a glycosylated hemoglobin of less than 10%; body mass index - from 20 to 35 kg / m2, with no established kidney disease. Group 2: 30 patients with type 2 diabetes mellitus, male and female, age 40-70 years, the onset of diabetes over the age of 30 years, diabetes duration of more than 1 year and less than 10 years who were treated with diet and / or oral antidiabetic agents with normal or high blood pressure, with HbA. less than 10% and a BMI of 25 to 35 kg / m2, with no established kidney disease. Art.