Treatment of diabetes with sulfonylurea drugs (glibenclamide) causes hypoglycemia followed by greater reduction in body weight, which are the most worrisome effects of these drugs. Stevia extract was found to antagonize the necrotic action of alloxan and thus had a re-vitalizing effect on β-cells of pancreas.
Stevia rebaudiana (Bertoni) is one of the 950
genera of the Compositae (Asteraceae). The plant was rediscovered by Dr.
Moises Santiago Bertoni in 1887. The plant was used extensively by
Gaurani Indians for more than 1500 years. [4] Stevia
has a long history of medicinal use in Paraguay and Brazil, and while
many of the therapeutic applications of Stevia are anecdotal, they must
be considered in that they have spanned generations. There are now known
to be more than 150 Stevia species but this is the only one
with significant sweetening properties; other species do contain other
biochemicals of interest. Leaves contain approximately 4–15% of
steviosides, which are intensely sweet compounds (150–300 times sweeter
than sugar). The leaves have been traditionally used for hundreds of
years in Paraguay and Brazil to sweeten local teas, medicines and as a
“sweet treat”. [5]
S. rebaudiana possesses various activities like antimicrobial, [6] antifungal, [7] hepatoprotective, [8] hypoglycemic (water extract), [9] antitumor, [6] antirotavirus, [10] anti-HIV, [11] anti-hypertension, [12,13] antiviral activity, [14] etc. Other folk applications of Stevia
and stevioside (primarily in Latin America and the Orient) include the
following: stimulate alertness and counter fatigue; facilitate digestion
and gastrointestinal functions; regulate blood glucose levels (BGLs);
nourish the liver, pancreas and spleen; help the body sustain a feeling
of vitality and well-being and external application for blemishes. Some Stevia
and stevioside users report a decrease in desire for sweets and fatty
foods. Additionally, some users have reported that drinking Stevia tea or Stevia enhanced teas helped to reduce their desire for tobacco and alcoholic beverages. [15] Stevia
and stevioside have been shown in studies to inhibit the growth and
reproduction of some bacteria that are responsible for tooth decay. [15,16]
Studies
on the comparative effects of leaves and stevioside on glycemia and
hepatic gluconeogenesis have already been reported. [17] Hypoglycemic effect [18] of stevioside has also been studied, together with protective effects of stevioside against the toxic actions of alloxan. [19] Chen et al.[18]
suggested that stevioside was able to regulate BGLs by enhancing not
only insulin secretion, but also insulin utilization in
insulin-deficient rats; the latter was due to decreased PEPCK gene
expression in rat liver by stevioside's action of slowing down
gluconeogenesis.Results and Discussion
Alloxan,
a β-cytotoxin, destroys β-cells of islets of Langerhans of pancreas,
resulting in a decrease in endogenous insulin secretion and paves the
way for the decreased utilization of glucose by the tissues. [29–31] In vitro studies have shown that alloxan is selectively toxic to pancreatic β-cells, leading to the induction of cell necrosis. [32,33]
The cytotoxic action of alloxan is mediated by reactive oxygen species,
with a simultaneous massive increase in cystolic calcium concentration,
leading to a rapid destruction of β-cells. [34] Decreased utilization of glucose by the tissues results in the elevation of BGL.
Expression
of elevated fasting BGL confirms induction of diabetes in
alloxan-induced experimental rats. The experiment focused on exploring
the competence of medium-polar (benzene:acetone, 1:1, v/v) extract from
the leaves of S. rebaudiana for medication of diabetes against
positive control reference drug glibenclamide. The difference in the
initial and final fasting BGLs of different groups in long-term (10-day)
studies exposed a significant elevation in BGL in diabetic controls as
compared with that of normal control, extract treated and glibenclamide
treated rats. Treatment of BGL with Stevia extract indicates the
effectiveness of the extract in experimental diabetic animals.
Medium-polar extract from leaves of S. rebaudiana, when administered orally (200 and 400 mg/kg) for 10 days, produced a significant (P < 0.01) dose-dependent reduction in BGL [Table 2] as well as in the body weight [Table 3], although body weight was regained by rats treated with both glibenclamide and Stevia extract. Stevia
extract exhibited a significant control of BGLs in diabetic rats,
together with lowest decrease in the body weight, as compared with
glibenclamide. Alternative exogenous treatments to diabetes include
dosage of insulin and sulfonylurea drugs (e.g., glibenclamide), which
cause hypoglycemia followed by greater reduction in body weight are the
most worrisome effects. Treatment with Stevia extract did not cause
hypoglycemia as well as significant decrease in body weight of diabetic
rats. Stevia extract was found to revitalize β-cells of pancreas, antagonizing β-necrotic action of alloxan.
Excessive hepatic glycogenolysis and gluconeogenesis
associated with decreased utilization of glucose by tissue is the
fundamental mechanism underlying hyperglycemia in the diabetic state. [35]
Aberration of liver glycogen synthesis or glycogenolysis in diabetes
may be due to lack of or resistance to insulin, which is essential to
activate glycogen synthase system. The significant increase of liver
glycogen level in Stevia extract-treated groups may be due to
reactivation of the glycogen synthase system by improving insulin
secretion. Diabetes is associated with weight loss. [36]
The reversal of weight loss in extract-treated diabetic group indicates
that the restorative effect of the extract may be due to the reversal
of gluconeogenesis and glycogenolysis.
Experimental results also reflect that the Stevia
extract is capable of reducing the oxidative state associated with
diabetes. Alloxan produces diabetes by liberating oxygen-free radicals
which cause lipid peroxide-mediated pancreatic injury. [37]
The extract may scavenge free radicals and facilitate reconstruction of
pancreatic cells to release more insulin and ultimately produces an
antidiabetic effect.
Effects on blood glucose level
Administration of benzene:acetone extract (200 and 400 mg/kg) produced a significant (P
< 0.01) dose-dependant reduction in BGL of alloxan-induced diabetic
rats. Alloxanized rats of group II (negative control) suffered from
hyperglycemia as they did not receive any drug, whereas alloxanized rats
of group III (positive control) treated with the reference antidiabetic
drug glibenclamide showed significant reduction in BGL to the required
standard blood glucose level on the 7th day and the levels were continuously maintained up to 10th day. Rats of group IV treated with Stevia extract (200 mg/kg) showed nearly normal BGL (99.00 ± 7.98 mg/dL) value on the 10 th day, whereas group V rats treated with Stevia
extract (400 mg/kg) also showed decrease in blood glucose level to
nearly normal (93.69 ± 9.33 mg/dL) value, which is very close to 0 day
BGL of group V. Table 2 shows that positive control glibenclamide treated rats attained normalized BGL on the 7th day of treatment, whereas Stevia extract treated rats attained nearby normal BGL on the 10th day.
