THE POSSIBILITY OF ADJUVANT PHYTOCHEMICAL THERAPIES AGAINST DIABETES
The virtues of Gymnema
Diabetes mellitus (DM) is the most common chronic endocrine disorder (3% of world population at least), which is characterized by a defective or deficient insulin secretary process, glucose underutilization, and hyperglycemia. All tissues have energy requirement that is usually supported by metabolizing glucose; the entry of glucose from the blood into the cells of liver, skeletal muscle, adipose tissue etc. is promoted by insulin: in the case of diabetics, these tissues cannot normally assimilate glucose and hence it accumulates within the blood, promoting the genesis of the problems that characterize diabetes. The diagnosis of diabetes is sure with at least 200 mg/dl of glycemia, detected at any time of day or 2 hours after a load of glucose.
The management of diabetes without any side effect is still a challenge, with a therapy that consists on insulin and oral hypoglycaemic drugs; but there is certainly one aspect of therapy which can bring benefits to the patients: herbal drugs, which are prescribed widely because of their effectiveness, fewer side effects and relatively low cost. Indeed, the first-line hypoglycemic drug metformin is itself derived from Galega officinalis.
Humankind has a long history in the use of herbal medicines; however, the scientific literature on the efficacy of complementary and alternative medicine in the treatment of diabetes is relatively sparse and heterogeneous.
Medicinal Plants, 1998
Medicinal plants of India with antidiabetic properties, 2002
Use of alternative medicine in diabetes mellitus, 2001
The prevalence and pattern of complementary and alternative medicine use in individuals with diabetes, 2002
Use of complementary and alternative medicine among persons with diabetes mellitus: results of a national survey, 2002
World ethnobotanical information about medicinal plants reports that about 800 plants are used in the control of diabetes mellitus: about 400 of them have been experimentally proved, but the complete mechanism of action is available only for about 100 plants. The main active constituents of these plants include alkaloids, glycosides, polysaccharides, peptidoglycans, glycopeptides etc.; these molecules affect various metabolic cascades and pathways, which directly or indirectly affect the level of glucose in the human body.
Herbal medicines for diabetes can be classified into four categories according to their mode of action:
- Drugs acting like insulin (e.g. Momordica charantia [bitter melon])
- Drugs acting on insulin secreting β-cells (e.g. Allium cepa [onion])
- Drugs acting by modifying glucose utilization (e.g. Zingiber officinale [ginger])
- Drugs acting by miscellaneous mechanisms (e.g. Panax ginseng [ginseng])
Study of the anti-hypoglycemic effect of plants used as anti-diabetics, 1998
Biological Complementary Therapies - A focus on botanic products in diabetes, 2001
Systematic Review of Herbs and Dietary Supplements for Glycemic Control in Diabetes, 2003
Medicinal Plants With Hypoglycemic/Anti-Hyperglycemic Properties: A Review, 2005
Anti-Diabetic Potential and Indian medicinal Plants, 2008
A Target Based Therapeutic Approach Towards Diabetes Mellitus Using Medicinal Plants, 2008
Hypoglycemic herbs and their action mechanisms, 2009
Medicinal plants used for the treatment of diabetes and its long-term complications, 2010
Even if there are many suitable plants for a review rather than a thorough investigation, here, a focus on Gymnema sylvestre is presented. The choice has been made on the basis of the amount of literature available on pubmed and choosing different aspects of the treatment on the basis of the mechanisms of action and the pathways involved.
Three presentations of G. sylvestre:
Gymnema sylvestre (GS) is a slow growing, perennial, woody climbing plant (Asclepiadaceae family), which grows in tropical forests of central and southern India. Leaves are opposite, usually elliptic or ovate (1.25–2.0 inch × 0.5–1.25 inch); flowers are small, yellow, in umbellate cymes.
It is used in folk, ayurvedic and homeopathic systems of medicine because of believed potent antidiabetic effect; the leaves of this plant have been used in India for over 2000 years to treat in particular madhu meha [honey urine]. According to common folklore, chewing the leaves causes a loss of the ability to discriminate the “sweet” taste, hence the popular Hindi name gurmar [sugar destroyer].
PART USED & PHARMACEUTICAL PREPARATIONS
- Leaves, with a bitter acrid taste.
- Dry-extracted spray, titrated in gymnemic acids (containing about 25% of gymnemic acids)
In market, G. sylvestre is available in the form of crude plant, powder, extract paste and solid in standardized form. The plant material is also available in the form of capsule or tablets in combination with other herbal plants.
According to the Italian Society of Natural Medicine (SIMN), GS daily dosage ranges are 8–14 mg/kg, divided into two doses to be taken about 10 minutes before the two main meals. If we analyse clinical trials, we can see that a typical dose is from 400 to 600 mg standardized to contain about 25% of gymnemic acids and divided into two or three parts, based on the number of main meals (the aspect of dividing is not clear from examining the studies but because it is being used to regulate blood sugar, divided doses with meals would seem ideal). There is insufficient evidence about its uses for pediatric population, so it cannot be recommended for them. Moreover, the product should not be used without medical supervision, since there is the possibility of increasing hypoglycemia when GS is used with insulin or antidiabetic drugs, so that doses may have to be adjusted.
GS leaves contain triterpene saponins belonging to oleanane and dammarene classes:
- Oleanane saponins are gymnemic acids and gymnemasaponins
- Dammarene saponins are gymnemasides
The most representative are gymnemic acids (GA), which contain several acylated derivatives of deacylgymnemic acid (DAGA): more than 20 homologues of GA are found in the leaves; the highest properties are shown by gymnemic acids I--IV. They all contain a glucuronic acid moiety and the gymnemagenin aglycone esterified at position C-21 and C-28.
Basic molecular structure of Gymnemic acid
Molecular structure of Gymnemic acid I
Isolation and structure elucidation of gymnemic acids, antisweet principles of Gymnema sylvestre, 1992
Antihyperglycemic effects of gymnemic acid IV, a compound derived from Gymnema sylvestre leaves in streptozotocindiabetic mice, 2000
Isolation and Characterization of Gymnemic Acid from Gymnema sylvestre R.Br. In Control of Diabetes, 2012
Besides this, other plant constituents are flavones, anthraquinones, tartaric acid, formic acid, butyric acid, stigmasterol (there are many more). The plant extract also tests positive for alkaloids.
Gymnemic acids have antidiabetic, antisweetener and anti-inflammatory activities. The antidiabetic array of molecules has been identified as a group of closely related gymnemic acids after it was successfully isolated and purified from the leaves of GS. Later, the phytoconstituents of GS were isolated, and their chemistry and structures were studied and elucidated.
MOLECULAR MECHANISM & ACTION
The variety of theorized mechanisms is a based on the fact that the atomic arrangement of gymnemic acid molecules is similar to that of glucose molecules. There are some possible mechanisms by which the leaves extract of GS or gymnemic acid possess their hypoglycemic acid effects.
- It causes inhibition of glucose absorption from intestine: gymnemic acid molecules fill the receptor location in the absorptive external layers of the intestine thereby preventing the sugar molecules absorption by the intestine, which results in low blood sugar level. Receptor blockade is established quickly and persists for about 5 hours, decreasing sugar absorption of about 50%.
- It increases utilization of glucose as it increase the activities of enzymes responsible for utilization of glucose by insulin-dependent pathways, determines an increase in phosphorylase activity and decrease in gluconeogenic enzymes and sorbitol dehydrogenase; moreover increases cell permeability to insulin.
- It increases secretion of insulin by stimulating β-cells and/or increasing their number (in pancreatectomized animals it has no hypoglycemic effect, indicating that its effect may require some residual β-cell function).
- It promotes regeneration of islet cells, ensuring adequate hormonal support and response.
Besides all that, gymnemic acids and gurmarin (another constituent of the leaves) have been shown to block sweet taste in humans: almost certainly gymnemic acid molecules fill the receptor locations on the taste buds thereby preventing its activation by sugar molecules present in the food, thereby curbing the sugar craving.
Enzyme changes and glucose utilisation in diabetic rabbits: the effect of gymnema sylvestre, 1983
Possible regeneration of the islets of Langerhans in streptozotocin-diabetic rats given Gymnema sylvestre leaf extracts, 1990
Gymnema sylvestre stimulates insulin release in vitro by increased membrane permeability, 1999
In vitro callus and in vivo leaf extract of Gymnema sylvestre stimulate β-cells regeneration and anti-diabetic activity in Wistar rats, 2010
A novel Gymnema sylvestre extract stimulates insulin secretion from human islets in vivo and in vitro, 2010
Effect of OSA (an aqueous extract of GS leaves) on insulin secretion and cell viability is shown.
MIN6 β-cells (rodent insulin-secreting cell line) were incubated for 30 minutes in the presence of 0.06-2mg/ml OSA at 2mM glucose (panel A) or 20mM glucose (panel B) and insulin secretion (bars) was measured by radioimmunoassay. MIN6 cell membrane integrity (▲) was measured in parallel by exposing MIN6 cells to 0.06-2mg/ml OSA at 2mM and 20mM glucose for 30 minutes and quantifying Trypan blue-stained cells using a haemocytometer. Secretion data are means ± SEM, n = 8–10 separate wells of cells, representative of three separate experiments. Trypan blue uptake data are means ± SEM of 4 separate MIN6 cell samples, with an average of 268 and 283 cells analysed per sample at 2mM and 20mM glucose respectively.
p<0.0001 by ANOVA at 2mM and 20mM glucose, for both insulin secretion and Trypan blue uptake.
Static incubation experiments with MIN6 β-cells indicated that OSA (0.06-2mg/ml) significantly stimulated insulin secretion at 2mM glucose (A) and potentiated 20mM glucose-stimulated insulin secretion (B) with maximal stimulatory effects at 0.25-0.5mg/ml. The figure also indicates that >90% of cells restricted entry of Trypan blue after 30 minutes exposure to ≤0.25mg/ml OSA at both 2mM and 20mM glucose, but higher concentrations of OSA caused progressive reductions in cell viability.
OSA also stimulated insulin secretion from isolated human islets of Langerhans in vitro. Thus, it can be seen from this figure (panel A) that the profile of insulin release from human islets at 2mM glucose in response to 0.125 mg/ml OSA was rapid in onset, sustained, and fully reversible upon the withdrawal of OSA. Panel B demonstrates that human islets showed a significant further increase in insulin secretion in response to 20mM glucose following a sustained secretory response to 0.125 mg/ml OSA at 2mM glucose.
The stimulatory effects of OSA in human islets at 20mM glucose are shown in panel C where insulin secretion was stimulated approximately 10-fold when the glucose concentration was increased from 2mM to 20mM, and this glucose-induced secretory response was potentiated in a sustained manner in the presence of 0.125 mg/ml OSA.
p<0.05 for all panels; data are means ± SEM, n=3.
Panel D shows micrographs of Trypan blue-stained human islets after incubation for 30 minutes in control buffer, 2mM glucose, or in buffers supplemented with 0.25mg/ml OSA or 0.25mg/ml GS4.
Two separate fields of view are shown for each condition. Control and OSA-treated islets showed minimal Trypan blue uptake, with staining restricted to cells on the islet periphery, whereas GS4-treated islets showed extensive uptake of Trypan blue by cells throughout the islets. Scale bars show 50μm.
Characterisation of the Insulinotropic Activity of an Aqueous Extract of Gymnema Sylvestre in Mouse β-Cells and Human Islets of Langerhans, 2009
RELEVANT SELECTED CLINICAL TRIALS
Two small open-label trials have yielded promising results.
- 22 patients with type 2 DM were given either 200 mg of an ethanolic extract daily or their usual treatment for 18 to 20 months. Significant improvements in FBG and HbA1c levels (p<0.001 for both) were noted in the test group.
- The other trial was uncontrolled, but reported that 3 months of treatment with 800 mg daily of a similar extract reduced FBG levels by 11% and HbA1c levels by 0.6% in a mixed population of 65 patients with type 1 and type 2 diabetes.
No adverse effects were reported in either trial. Preliminary evidence of any benefit is probably insufficient to support the widespread use of GS for diabetes management at this time. The significant improvements in HbA1c levels definitely warrant further study as well as judicious use in selected patients.
Complementary and alternative medicine for the treatment of DM2, 2009 (ref. 86 and 87)
Other two studies can be considered; however they do not report important design details, such as blinding or randomization (as we can often see in trials about these classes of substances).
- One study was conducted in type 1 diabetic patients on insulin, 27 of whom took 200 mg gymnema capsules after breakfast and supper and 37 of whom took insulin only for a period of 6–30 months. After 6–8 months, mean HbA1c decreased in the gymnema group from a baseline of 12.8 to 9.5% (p<0.001). After 16–18 months, 22 patients remaining on gymnema had a mean HbA1c of 9% (p values not given). At the end of 26–30 months, six patients remaining on gymnema had a mean HbA1c of 8.2% (p values not given). Mean fasting blood glucose (FBG) also decreased from a baseline of 232 to 177 mg/dl after 6–8 months, 150 mg/dl after 16–18 months and 152 mg/dl after 20–24 months (p values not given). The mean insulin dose decreased from a baseline of 60 to 45 units/day after 6–8 months and to 30 units/day at 26–30 months (p values not given). Patients on placebo had no significant changes from baseline.
Use of Gymnema sylvestre leaf extract in the control of blood glucose in insulin-dependent diabetes mellitus, 1990
- Another study was conducted in patients with type 2 diabetes on sulfonylureas; 22 took 400 mg/day of gymnema capsules in addition to sulfonylurea treatment and 25 took a placebo and sulfonylureas for a period of 18–20 months. Mean HbA1c decreased from a baseline of 11.9 to 8.48% (p<0.001). Mean FBG decreased from 174 to 124 mg/dl after 18–20 months (p<0.001). Five patients were able to discontinue sulfonylureas. In this study, lipids also decreased significantly. Patients on placebo had no significant changes in HbA1c, FBG, or lipids.
Antidiabetic effect of a leaf extract from Gymnema sylvestre in non-insulin-dependent diabetes mellitus patients, 1990
SIDE EFFECTS & TOXICITY
No side effects have been reported secondary to gymnema use, at least on a large scale (see the link below), even if hypoglycemia is the first potential side effect. Anyway, because other uses for gymnema leaf extract are based on its ability to act as a laxative and diuretic suppressant, these phenomena would be considered adverse reactions when Gymnema s. is used for its glucose lowering effect in diabetes. Moreover hypersensitivity can be a possible reason for problems.
Safety in pregnancy has not been established (caution).
Toxic hepatitis induced by Gymnema sylvestre, a natural remedy for type 2 diabetes mellitus, 2010
No “serious” [use alternative] neither “significant" [monitor closely] interaction have been reported. Drug interactions may occur from the additive effects of using concomitantly more than one hypoglycemic agent. In fact, “minor” interactions has been revealed, involving at least 36 substances; most of them are antidiabetic drugs, such as:
Gymnema increases their efftects by pharmacodynamic synergism.
Others are generally involved, anyway often in the same background:
- acarbose, used to treat diabetes and obesity; gymnema increases effects of acarbose by pharmacodynamic synergism
- carbonyl iron, used to treat iron deficiency and as an iron dietary supplement; gymnema decreases levels of carbonyl iron by inhibition of GI absorption (applies only to oral form of both agents).
RESISTANCE, DEPENDENCE AND WITHDRAW
There are a number of plants which have the capacity to reduce the glucose production, induce the utilization of glucose and combat with secondary complications. Only a fraction of these have been screened pharmacologically. If we think that the most commonly used drugs of modern medicine such as aspirin, digitalis, reserpine, vinblastine etc. have originated from plant sources, evidently it is prudent to look for options in herbal medicine for diabetes, since it is proven that medicinal plants have potential effectiveness against diabetes.
A fundamental aspect is the fact that many herbal therapies have not undergone proper scientific assessment for their potential to cause serious toxic effects and major drug-to-drug interaction. So continued research is necessary to elucidate the pharmacological activities of herbal remedies being used to treat diabetes mellitus.
Potential future research challenges can be schematized into some points:
- Identify phytochemical compounds directly associated with hypoglycemia and antihyperglycemia
- Conduct extensive large-population clinical studies for selected species
- Determine the mechanisms behind hypoglycemic and antihyperglycemic activity for the selected medicinal plant species
- Assess the inter- and intra-specific variation in secondary metabolite production in response to environmental and production inputs for most species
- Investigate combination dosages of natural plant product and synthetic drugs to determine the optimal combination for cost-effective therapies
- Determine the long-term side effects of natural herbal product formulations individually and in combination with synthetic drugs
- Develop easy to consume food products fortified with extracts of this clinically tested plant species that can be incorporated into diabetic diets or create diets which contain the tested constituents
Although biological complementary therapies have been studied in human clinical trials, as we can see, there are many problems with study design, study endpoints, numbers of patients and study duration. There is insufficient evidence to recommend generalized use for patients with diabetes. Furthermore, these products have some or many side effects (or they could have them) and may potentially interact with traditional diabetes medications.
Ultimately, what can be said is that it is absolutely desirable to establish guidelines and care/treat pathways for phytochemicals, to have them included in the diabetes standards of care.