A review of patent literature on the regulation of glucose metabolism by six phytocompounds in the management of diabetes mellitus and its complications / 中西医结合学报

Diabetes mellitus is a chronic disease, typified by hyperglycemia resulting from failures in complex multifactorial metabolic functions, that requires life-long medication. Prolonged uncontrolled hyperglycemia leads to micro- and macro-vascular complications. Although antidiabetic drugs are prescribed as the first-line treatment, many of them lose efficacy over time or have severe side effects. There is a lack of in-depth study on the patents filed concerning the use of natural compounds to manage diabetes. Thus, this patent analysis provides a comprehensive report on the antidiabetic therapeutic activity of 6 phytocompounds when taken alone or in combinations. Four patent databases were searched, and 17,649 patents filed between 2001 and 2021 were retrieved. Of these, 139 patents for antidiabetic therapeutic aids that included berberine, curcumin, gingerol, gymnemic acid, gymnemagenin and mangiferin were analyzed. The results showed that these compounds alone or in combinations, targeting acetyl-coenzyme A carboxylase 2, serine/threonine protein kinase, α-amylase, α-glucosidase, lipooxygenase, phosphorylase, peroxisome proliferator-activated receptor-γ (PPARγ), protein tyrosine phosphatase 1B, PPARγ co-activator-1α, phosphoinositide 3-kinase and protein phosphatase 1 regulatory subunit 3C, could regulate glucose metabolism which are validated by pharmacological rationale. Synergism, or combination therapy, including different phytocompounds and plant extracts, has been studied extensively and found effective, whereas the efficacy of commercial drugs in combination with phytocompounds has not been studied in detail. Curcumin, gymnemic acid and mangiferin were found to be effective against diabetes-related complications. Please cite this article as: DasNandy A, Virge R, Hegde HV, Chattopadhyay D. A review of patent literature on the regulation of glucose metabolism by six phytocompounds in the management of diabetes mellitus and its complications. J Integr Med. 2023; 21(3): 226-235.

Comparative Antidiabetic Potential Assessment Of Herbal Formulation Of Gymnemic Acid And Curcumin

Standardization of polyherbal formulations with respect to bioactive phytocompounds is the need of the time for registration and marketing authorization in developed countries. This has prompted to prepare and evaluate a standardized bioactive phyotcompounds conintaining formulation. The study aims at development and screening of a standardized antidiabetic suspension containing active isolated phytoconstituents targeting better therapeutic effect with reduced bioburden. Suspension of isolated gymnemic acid and curcumin (GCS) was prepared, evaluated and authenticated by TLC and HPTLC. Antidiabetic efficacy of GCS was screened against alloxan induced diabetes on rats following 28 days of treatment comparative to Hyponidd tablet and Madhumehari granules. Body weight, relative organ weight, blood glucose, cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) and very low density lipoprotein (VLDL) level was measured. The formulation having pH 6.0, refractive index 1.41 and 45.58 mg/ml total solid content showed high alcohol and water soluble extractive value. The GCS treatment normalized liver and kidney weight, decreased body weight gain, TC, TG, LDL and VLDL level along with an increase in HDL level. Study outcome signifies similar antidiabetic potential of standardized formulation GCS compared to marketed Polyherbal formulation with antihyperlipidemic activity signifying as a promising natural and safe remedy for the prevention of diabetic complications.

De novo in vitro shoot morphogenesis from shoot tip-induced callus cultures of Gymnema sylvestre (Retz.) R. Br. ex Sm

BACKGROUND: Gymnema sylvestre is a medicinal woody perennial vine known for its sweetening properties and antidiabetic therapeutic uses in the modern and traditional medicines. Its over-exploitation for the therapeutic uses and to meet the demand of pharmaceutical industry in raw materials supply for the production of anti-diabetic drugs has led to considerable decline in its natural population. RESULTS: An efficient system of shoot bud sprouting from nodal segment explants and indirect plant regeneration from apical meristem-induced callus cultures of G. sylvestre have been developed on Murashige and Skoog (MS) medium amended with concentrations of cytokinins. Of the three growth regulators tested, N6-benzylaminopurine (BAP) was the most efficient and 2.0 mg L-1 gave the best shoot formation efficiency. This was followed by thidiazuron (TDZ) and kinetin (Kin) but, most of the TDZ-induced micro shoots showed stunted growth. Multiple shoot formation was observed on medium amended with BAP or TDZ at higher concentrations. The produced micro shoots were rooted on half strength MS medium amended with auxins and rooted plantlets acclimatized with 87% survival of the regenerates. CONCLUSIONS: The developed regeneration system can be exploited for genetic transformation studies, particularly when aimed at producing its high yielding cell lines for the anti-diabetic phytochemicals. It also offers opportunities for exploring the expression of totipotency in the anti-diabetic perennial vine.

Attenuation of Neuronal Damage by Gymnemic acid in Experimentally Induced Cerebral Ischemia in Rats.

Gymnemic acid is obtained from the natural resource and has got antioxidant property, was investigated for the possible neuroprotective effect in experimentally induced cerebral ischemic rats. Carotid arteries clamped with the help of aneurysm clips to produce cerebral ischemia, the clips were removed from the arteries to allow the reflow of the blood through carotid arteries. It was observed that lipid peroxidation was increased significantly after bilateral common carotid artery occlusion. Brain endogenous antioxidant GSH and total protein levels were low. Administration of gymnemic acid in a dose of 250 mg/kg and 500 mg/kg b.w orally showed promising neuroprotective effect by reducing cerebral infarct size as well as improved all antioxidant levels showing activity against oxidative stress.

Effect of a deacyl gymnemic acid on glucose homeostasis & metabolic parameters in a rat model of metabolic syndrome.

Background & objectives: Metabolic syndrome (MS) comprises several cardio-metabolic risk factors, which include obesity, hypertension, hyperglycaemia, hypertriglyceridaemia and decreased HDL cholesterol. Leaf extract of Gymnema sylvestre has been shown to possess glucose lowering activity in animal models. This study was carried out to evaluate the efficacy of deacyl gymnemic acid (DAGA), active constituent of G. sylvestre, in a rat model of MS. Methods: Six groups consisting of six wistar rats in each, were studied. Group I received the normal diet, while the remaining five groups received high fructose diet (HFD ) for 20 days to induce MS. HFD was continued in these five groups for the next 20 days along with group II received vehicle solution, group III received pioglitazone and groups IV- VI received DAGA in variable doses. Systolic blood pressure (SBP) was measured using tail-cuff method. Oral glucose tolerance test (OGTT) was done at baseline and at days 20 and 40. Blood samples were collected for glucose, insulin and lipid profile. Results: Administration of HFD for 20 days resulted in weight gain (>10%), increase in SBP, fasting plasma glucose (FPG) and triglycerides fulfilling the criteria for MS. Administration of DAGA (200 mg/kg) reduced SBP and significantly improved the FPG and HOMA-IR (homeostatis model assessment-insulin resistance) with modest improvement in lipid profile without decrease in body weight similar to pioglitazone. Interpretation & conclusions: Our findings show that DAGA decreases SBP and improves parameters of glucose-insulin homeostasis in a rat model of MS induced by HFD. Further studies are required to elucidate the mechanism of action.

Gymnema sylvestre: An Alternative Therapeutic Agent for Management of Diabetes.

Gymnema sylvestre (Asclepiadaceae) also known as ‘gurmar’ or ‘sugar destroyer’ is a woody, climbing traditional medicinal herb which has many therapeutic applications in Ayurvedic system of medicine. It is used for lowering serum cholesterol, triglycerides and blood glucose level (hypoglycemic or antihyperglycemic), hypolipidaemic, weight loss, stomach ailments, constipation, water retention and liver diseases, either high or low blood pressure, tachycardia or arrhythmias, and used as aperitive, purgative, in eye troubles, antiinflammatory, smooth muscle relaxant, prevention of dental caries, cataract and as anticancer-cytotoxic agent. Its flowers, leaves, and fruits contains alkaloids, flavones, saponins, sapogenins, anthraquinones, hentri-acontane, pentatriacontane, α and β-chlorophylls, phytin, resins, d-quercitol, tartaric acid, formic acid, butyric acid, lupeol, β-amyrin related glycosides and stigmasterol having main principle bioactive compunds viz. gymnemic acids, gymnemasides, gymnemagenin, gurmarin, gymnemosides, gymnemanol, gymnemasins, gypenoside, and conduritol which act as therapeutic agent and play vital role in many therapeutic applications. Gymnemic acids are thought to be responsible for its antidiabetic activity and it is the major component of an extract shown to stimulate insulin release from the pancreas. Another anti-sweet agent gumarin is utilized as a pharmacological tool in the study of sweet-taste transduction. The commercial exploitation of this plant and their secondary metabolites are some of the major prospective of this rare medicinal herb. The focus of the present review is to achieve the potential of therapeutic value of this herb and mechanism and action of their secondary metabolites.

Anti-apoptotic potential of gymnemic acid phospholipid complex pretreatment in Wistar rats with experimental cardiomyopathy.

Cardiomyocyte apoptosis in heart failure has been the topic of research in many recent studies. In the present investigation, the potential cardioprotective effect of gymnemic acid phospholipid complex (GPC) on myocardial apoptosis and cardiac function was studied in doxorubicin (DOX; 30 mg/kg/ip/single dose)-induced cardiomyopathy model in rats. Doxorubicin induced cardiomyopathy was evidenced by significant hemodynamic changes (increased systolic, diastolic, mean arterial pressure and heart rate), decreased heart weight to body weight ratio, increase in serum lactate dehydrogenase (LDH) and Ca2+ levels and decrease in myocardial Na+/K+ ATPase levels along with caspase-3 activation. A marked reduction in glutathione, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, superoxide dismutase and catalase levels along with increase in the levels of thiobarbituric acids (TBARS) were also observed in rat myocardium. In addition, DNA laddering observed on agarose gel electrophoresis and cardiac histopathology study further supplemented myocardial apoptosis. Pre-treatment with GPC significantly reduced DOX-induced cardiac toxicity, including improvement of hemodynamic variables and heart weight to body weight ratio, decreased serum Ca2+ level and LDH levels, myocardial caspase-3 levels, increased Na+/K+ ATPase levels and decreased myocardial TBARS levels and elevated antioxidant enzymes as compared to pathogenic control group. Further, the anti-apoptotic effect of GPC was verified by prevention of internucleosomal DNA laddering on agarose gel electrophoresis and attenuation of histopathological perturbations by doxorubicin. These observations demonstrate that GPC might serve as a cardioprotective formulation in DOX-induced cardiomyopathy in rats.