In the present work, we investigated the hypoglycemic and anti-lipemic effects of the aqueous extract from C. sicyoides in the model of alloxan-induced diabetes in rats. Alloxan causes diabetes through its ability to destroy the insulin-producing beta cells of the pancreas [24, 25]. In vitro studies have shown that alloxan is selectively toxic to pancreatic beta cells, leading to the induction of cell necrosis . The cytotoxic action of alloxan is mediated by reactive oxygen species, with a simultaneous massive increase in cytosolic calcium concentration, leading to a rapid destruction of beta cells .
We showed that the aqueous extract from C. sicyoides (AECS, 100 and 200 mg/kg), administered orally for 7 days, produced significant decreases in plasma glucose in the model of alloxan-induced diabetes in rats, by comparing the results before and after the AECS treatment. A similar effect was observed after a shorter (4 days) treatment with the higher dose of AECS (200 mg/kg). However, AECS had no effect on glycemia in normal rats. Besides, no significant decrease was detected in diabetic animals administered with distilled water, for the same period of time (controls). Although the alloxan group (controls) presented a dramatic body weight reduction, weight losses were lower in the alloxan plus AECS-treated group, indicating another potential benefit of AECS.
Our findings that the extract of C. sicyoides reduces the glycemia of alloxan-induced diabetic rats, but had no effect on that of normal rats, are in agreement with a very recent work . These authors also showed that the leaf decoction from C. sicyoides significantly reduced the intake of both food and fluid, and the volume of urine excreted, as well as the levels of blood glucose, urinary glucose and urinary urea, as compared to controls. Others  showed that, after oral administration, the leaf extract from C. sicyoides presented a potential hypoglycemic activity in hereditary diabetic mice, normal rats and rats with streptozotocin-induced diabetes. The authors showed that the extract, administered for 4 weeks, significantly lowered the mean plasma glucose level of mice, under feeding conditions. Besides, a single oral administration significantly lowered the plasma glucose level, 1 h after sucrose loading, in normal rats and rats with streptozotocin-induced diabetes.
However, Beltrame et al., 2001  failed to show any anti-diabetic activity in the hydroalcoholic extract obtained from the leaves of C. sicyoides, which instead intensified the decreased glucose tolerance promoted by dexamethasone, in rats. It is worthwhile to point out that the plant is popularly used as a decoction, which is similar to the aqueous extract used in the present work. Active principles responsible for the hypoglycemic activity presented by C. sicyoides are possibly better extracted by aqueous and more polar solvents.
We found that the aqueous extract is rich in carbohydrate type compounds, which are easily precipitated by ethanol (results not shown). Besides, recently  a new coumarin glycoside was obtained from the aerial parts of C. sicyoides. Glycosides are sugar derivatives, and an overwhelming number of glycosides occur in nature, mainly in plants, and such compounds have received much attention for possessing a variety of biological activities. Thus, flour prepared from C. rotundifolia was shown to contain significant amounts of non-starch polysaccharides , the major fraction of which was water-soluble. These authors verified that, in humans, the species elicited significant reductions in plasma glucose levels, at post-prandial time points and for the area-under-the-curve (AUC) values. Significant reductions in plasma insulin levels, at various post-prandial time points and for AUC values, were also seen after C. rotundifolia administration. Water-soluble non-starch polysaccharides are certainly one of the components responsible for the glucose and insulin lowering effects.
Although, in the present work, we showed no changes in total cholesterol levels, a significant decrease was observed in plasma triglyceride levels in the alloxan-induced diabetic rats, after 4 and 7-day treatments with AECS administered orally. On the other hand, another work  did not find any alteration in lipid metabolism, nor in levels of hepatic glycogen in streptozotocin-diabetic rats, after C. sicyoides treatment. According to them, these results indicate that the mechanism responsible for the improvement in carbohydrate metabolism, observed in animals treated with C. sicyoides decoction, does not involve inhibition of glycogenolysis and/or stimulation of glycogenesis.
We also measured plasma levels of AST and ALT, hepatic enzyme markers, and showed that these enzyme levels were significantly increased after AECS treatment. However, these effects were also observed in controls and, under both conditions, the values are in the range of those shown by our normal control rats. Elevated activities of serum aminotransferases are a common sign of liver disease, and are more frequently observed among people with diabetes, than in the general population. Furthermore, diabetic complications such as limited joint mobility, retinopathy and neuropathy are associated with liver enzyme activities, independently of alcohol consumption, body mass index, and metabolic control of diabetes . Besides, it has been shown that the alloxan injection causes a significant increase in the activity of several enzymes, such as beta-glucuronidase, N-acetyl-beta-glucosaminidase, lysosomal acid phosphatase, leucine aminopeptidase, and cathepsin D . Moreover, the activities of the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes, among others, have been used as indicators of tissue toxicity in experimental diabetes. For instance, Mori et al., 2003  reported that levels of AST, ALT and alkaline phosphatase (ALP) were higher in streptozotocin-induced diabetic rats, over a 53-day period.
The duration of the alloxan-induced diabetic state is still a matter of concern. An earlier work  showed that alloxan-induced diabetes of 4-day duration produced metabolite changes in the brain, compatible with severe reduction of cerebral metabolism and reduced phosphofructokinase activity. Alloxan-treated animals were also severely dehydrated. A more recent work  showed disease-related abnormalities, such as ATPase activities in sciatic nerves, from rats with alloxan-induced diabetes of various durations (2 weeks up to 6 months). Others observed high glucose levels even after 2 weeks of alloxan injection . Under the conditions of the present investigation, diabetes was well maintained up to the 7th-day treatment with AECS, which began 48 h after a single alloxan injection.
Levels of glucose, insulin, triglycerides and total cholesterol were also shown to increase in experimental models of chemically-induced diabetes, including that with alloxan. A recent work  reported the reversibility of the diabetic state, 12 days after the alloxan injection, as demonstrated by the reduction of glucose and triglyceride concentrations, and a positive reaction of the anti-insulin antibodies in the pancreatic tissue. In the present investigation, we followed the hepatic enzymes and lipid profile, for 4 and 7 days, when the diabetic state was still well maintained.
AECS administration to normal animals caused no changes in any of the measured parameters, similarly to results observed by others . Their data and ours suggest that the mode of action of AECS in diabetic animals does not resemble those of sulfonyl ureas or insulin. It may, however, act in a similar way to biguanides, via the inhibition of gluconeogenesis.