What are the possible pharmacologic mechanisms of action (MOA) of GlucoMedix® in reducing glucose, lipids, triglycerides, and blood pressure in the rat animal models?
Stevia and steviol glycosides might down-regulate the levels of glucose and lipids in blood, as well as arterial hypertension. Stevia phytochemicals or steviol glycosides were known in human clinical trials to affect type 2 diabetes (11, 15). There is evidence of a possible benefit regarding hypertension in humans (5). However, another study of only 7 patients per group yielded a negative result for hypertension (4), although statistically significant reductions in cholesterol, LDL, and glucose were observed.
The Stevia-derived ingredients were also effective in rat models in alloxan-induced hyperglycemia (13, 14, 17), streptozotocin-induced hyperglycemia (18), and cholesterol-induced hyperlipidemia (12). Another rat study showed that stevioside and powdered Stevia leaves in high-carbohydrate and high-fat diets caused a significant reduction in blood glucose level after 4 weeks of treatment (40). Our studies in three rat efficacy models are consistent with these prior findings, presuming that the steviol glycosides are contributing to the overall efficacy of GlucoMedix®.
Uncaria extracts have been found to reduce glucose levels in mice and rat animal models (32, 33). A hydro-alcoholic extract of Uncaria containing POAs (29.1 mg/g) in a streptozotocin-induced mouse model, showed a reduction in glycemic levels (33). Likewise, rats treated with 75 and 150 mg/kg of Uncaria tomentosa dry extract showed a reduction in blood glucose (32). One possible MOA for this glucose down-regulation is explained by alpha-glucosidase and alpha-amylase inhibitory activities within Uncaria extracts (41, 42). These enzymes catalyze the hydrolysis of complex polysaccharides, such as dietary starch and endogenous glycogen. This enzymatic antagonism of biodegradation of polysaccharide precursors might reduce blood glucose, and thus possibly contribute to the overall glycemic regulatory efficacy of GlucoMedix®.
Steviol glycosides and/or Uncaria phytochemicals might be affecting the endocrine and/or neuro-endocrine system, and in particular the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol levels might be a possible mediator under the influence of these bioactive compounds. Cortisol is known to play a key role in glucose utilization. Patients with Metabolic Syndrome exhibit elevated HPA axis properties leading to hypercortisolism (43, 44). Future studies of GlucoMedix® could assess levels of cortisol and insulin.
Another possible MOA is that the Uncaria POAs are affecting the immune system (33, 36, 45, 46). However, it should be noted that the subacute toxicology study at doses as high as 2000 mg/kg for four weeks did not reveal any significant alterations in white blood cell numbers or ratios (i.e., Tables 1 and 2). If the MOA is immunomodulatory, it is not being achieved by altering the number of white blood cells.
Regardless of the MOA, one significant factor to consider is that the three rodent efficacy models involved experimental induction agents (i.e., alloxan, L-NAME, and cholesterol) that result in parameters exceeding normal physiologic levels, whereas the acute and subacute toxicology models were not dependent on any induction events. In other words, the toxicity model was performed in a natural physiologic state. The 28-day toxicity studies further underscore that any efficacy benefit in hyper-normal physiological states (e.g., induced states or disease states) is not expected to result in any adverse outcome extending below baseline parameters in normal laboratory animals (or humans).
A beneficial aspect of these animal model efficacy and toxicity studies run in parallel is the establishment of a favorable therapeutic index. In other words, GlucoMedix® achieved the desired efficacy endpoints without any observable toxicity at or above the effective dose(s) and at coincident time points (i.e., at 3-4 weeks).
Toxicologic studies in rodents have demonstrated the safety of extracts and isolated compounds of Uncaria tomentosa and Stevia rebaudiana (13, 25, 47). Our study shows that GlucoMedix® has an LD50 in rats greater than 5,000 mg/kg of body weight, and well-being parameters such as sleep, behavior pattern, motor activity, skin, coat, and appetite were normal. No weight loss was observed after two weeks of observation.
Metabolic Syndrome is often associated with type 2 diabetes, but it can exist in patients lacking this comorbidity. In the US a diagnosis typically involves any three of five comorbidities, as per the NCEP-ATP III criteria. Although type 2 diabetes is common, it is not the essential factor driving the pathophysiology of Metabolic Syndrome in all patients.
Although some articles assert that alloxan induction is an experimental model for type 2 diabetes (14, 17), it should be noted that the alloxan-induced and glibenclamide-controlled rat model is more closely related to type 1 diabetes (insulin insufficiency), rather than type 2 diabetes (insulin resistance). This suggests that GlucoMedix® might be stimulating production of insulin from the remaining pancreatic beta cells following toxic damage to the tissue by alloxan. Thus, this animal model does not provide a precise correlate for type 2 diabetes within Metabolic Syndrome. Beyond the scope of the present experiment, two relevant rodent models for consideration in the future are C57BL6J male mice on high fat diet and Zucker Diabetic Fatty (ZDF) rats.
Stevia extract has long been used for the treatment of diabetes in South America (48). Furthermore, stevioside is a potent sweetener with no calories. Thus, Stevia-derived products can achieve reductions in blood glucose in humans by two means: (a) as a substitute for dietary sugars, thus reducing ingested sugars; and (b) as a pharmacologic active ingredient affecting glucose homeostasis.
The GlucoMedix® extract of Uncaria and Stevia shows anti-hyperglycemic activity in alloxan-induced rats treated at doses of 250 - 1000 mg/Kg of body weight. GlucoMedix® might regulate the level of glucose by increasing insulin secretion and/or by a better utilization of glucose by peripheral tissues and muscles in diabetic rats.
One of the most common complications of diabetes mellitus is cardiovascular disease. Other studies have suggested that Uncaria, Stevia, and their metabolites promote cardiovascular health and reduce hypertension. Our results with GlucoMedix® show a decrease in cholesterol and triglyceride levels in hyperlipidemic rats at 21 days and a decrease in blood pressure induced by L-NAME in hypertensive rats at 28 days of treatment with doses of 250 - 1000 mg/Kg.
What bearing might these rodent doses have if GlucoMedix® is administered to humans? If the 250, 500, and 1,000 mg/Kg daily doses in rats (ca. 0.24 Kg) are extrapolated via allometric dosage conversion for oral administration in humans (65 Kg and 0.75 exponent), the corresponding allometric daily doses of GlucoMedix® required in an adult for “similar” pharmacologic effects would be 4, 8, and 16 g (wet weight). The highest daily dose of 16 g should be essentially equipotent to the pharmaceutical positive controls of glibenclamide, atorvastatin, and enalapril.
Given that the extract mixture contains ca. 2.56 mg/100 ml of POAs, then these human allometric doses would contain only 0.10, 0.20, and 0.41 mg of POAs. Note that few active pharmaceutical ingredients (APIs) in the pharmacopeia are effective in the sub-milligram level in human adults. However, predicate examples do exist; an example is the phytochemical scopolamine that is effective at 0.1 - 0.5 mg in humans (49, 50). If the POAs are contributing to the efficacy endpoints, then they would by necessity be highly potent phytochemicals.
Allometric dosage conversion presumes similarities between the two species regarding pathophysiology, pharmacokinetics, and pharmacodynamics. A suggested human starting oral daily dose of GlucoMedix® that might be effective within 4 weeks at treating Metabolic Syndrome or its comorbidities is 4 g. Given that the IC50 values for glucose and lipids (cholesterol and triglycerides) were below 250 mg/kg in rats, then it is reasonable to speculate that adult doses lower than 4 g (and/or with longer duration of treatment) might also be effective in humans.