Antidiabetic with antilipidemic and antioxidant effects of flindersine by enhanced glucose uptake through GLUT4 translocation and PPARγ agonism in type 2 diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants have been used by the people of developing countries to treat various diseases. WHO also recommends the use of medicines from plants source. In that, diabetes also one of the diseases that have been treated traditionally by several people all over the world. In India, Toddalia asiatica (L.) Lam. (Rutaceae) is also a medicinal plant used traditionally for the treatment of diabetes in Ayurveda. Moreover, T. asiatica is also used in a polyherbal formulation to treat diabetes. AIM OF THE STUDY: This study examined the antidiabetic with antilipidemic and antioxidant effects of flindersine isolated from T. asiatica leaves. MATERIALS AND METHODS: Diabetes was induced in Wistar rats by feeding a high-fat diet (HFD) for 15 days and injecting a single dose of 40 mg/kg b. wt. of Streptozotocin (STZ). Five days post-injection, the grouped diabetic rats were treated with 20 and 40 mg/kg of flindersine. RESULTS: Flindersine resulted in a clear decline of blood glucose levels during 28 days of treatment in two different doses. Flindersine also significantly (P ≤ 0.05; P ≤ 0.005) reduced the body weight gain, plasma insulin concentration, urea, creatinine, total cholesterol (TC), triglycerides (TG) and free fatty acids (FFA) levels and significantly increased (P ≤ 0.05; P ≤ 0.005) the total protein level, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities compared to the standard drug, pioglitazone. Additionally, flindersine restored the glucose transporter protein 4 (GLUT4), adenosine monophosphate protein kinase (AMPK) and peroxisome proliferator-activated receptor γ (PPARγ) expressions in adipose tissues and skeletal muscles. CONCLUSION: It has been found that flindersine has potent antilipidemic and antidiabetic activities by improving insulin sensitivity by enhancing the phosphorylation of AMPK, GLUT4 translocation, and PPARγ agonism on adipose tissue and skeletal muscles of diabetic rats.

Corrigendum to "In Vitro Wound Healing Potential of Stem Extract of Alternanthera sessilis".

[This corrects the article DOI: 10.1155/2018/3142073.].

Galangin controls streptozotocin-caused glucose homeostasis and reverses glycolytic and gluconeogenic enzyme changes in rats.

Galangin is a natural compound with anticancer, anti-inflammatory, and antioxidant properties. However, the ameliorating effect of streptozotocin (STZ)-induced glucose homeostasis has not yet been evaluated. Hence, this study was aimed at exploring the role of galangin in STZ-induced glucose homeostasis, glycolytic and gluconeogenic enzyme changes in rats. STZ-treated rats were characterised by increased plasma glucose and glycosylated haemoglobin and decreased plasma insulin and haemoglobin compared with the normal cage. Administration of galangin to STZ-treated rats effectively reversed the adverse biochemical and haematological changes. Significant alterations in glycogen levels as well as glycolytic and gluconeogenic enzyme activities were witnessed in STZ-treated rats, and these changes were reversed upon treatment with galangin. The compound exerts potent anti-hyperglycemic effects by regulating the glucose homeostasis and reversing the glycolytic and gluconeogenic enzyme changes in rats. However, the exact mechanism through which galangin prevents diabetic complications needs to be studied in detail.

Galangin ameliorates changes of membrane-bound enzymes in rats with streptozotocin-induced hyperglycemia

Objective: To assess the protective effect of galangin on membrane bound enzymes in rats with streptozotocin-induced diabetes. Methods: A single low dose of streptozotocin was injected to adult male albino rats to induce hyperglycemia. Galangin (8 mg/kg) or glibenclamide 600 μg/kg as a standard drug was given orally once daily for 45 days by gavage. Membrane-bound adenosine triphosphatases were determined including total ATPase, sodium-potassium-ATPase, calcium-ATPase and magnesium-ATPase in erythrocytes and tissues (kidney, liver, and heart). Results: The levels of total ATPases, sodium-potassium-ATPase, calcium-ATPase and magnesium-ATPase in erythrocytes and tissues were significantly altered in diabetic rats as compared to that in normal rats. After 45 days of treatment with galangin or glibenclamide, the levels of these enzymes were similar to that of normal control rats. Conclusions: Oral administration of galangin or glibenclamide can improve activities of these membrane-bound ATPases towards normal levels. Mechanism of galangin needs to be further explored in future.

In Vitro Wound Healing Potential of Stem Extract of Alternanthera sessilis.

Impaired wound healing is one of the serious problems among the diabetic patients. Currently, available treatments are limited due to side effects and cost effectiveness. In line with that, we attempted to use a natural source to study its potential towards the wound healing process. Therefore, Alternanthera sessilis (A. sessilis), an edible and medicinal plant, was chosen as the target sample for the study. During this investigation, the wound closure properties using stem extract of A. sessilis were analyzed. Accordingly, we analyzed the extract on free radical scavenging capacity and the cell migration of two most prominent cell types on the skin, human dermal fibroblast (NHDF), keratinocytes (HaCaT), and diabetic human dermal fibroblast (HDF-D) to mimic the wound healing in diabetic patients. The bioactive compounds were identified using gas chromatography-mass spectrometry (GC-MS). We discovered that the analysis exhibited a remarkable antioxidant, proliferative, and migratory rate in NHDF, HaCaT, and HDF-D in dose-dependent manner, which supports wound healing process, due to the presence of wound healing associated phytocompounds such as Hexadecanoic acid. This study suggested that the stem extract of A. sessilis might be a potential therapeutic agent for skin wound healing, supporting its traditional medicinal uses.

Influence of kaempferol, a flavonoid compound, on membrane-bound ATPases in streptozotocin-induced diabetic rats.

CONTEXT: Kaempferol is a flavonoid found in many edible plants (e.g. tea, cabbage, beans, tomato, strawberries, and grapes) and in plants or botanical products commonly used in traditional medicine. Numerous preclinical studies have shown that kaempferol have a wide range of pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, neuroprotective, and antidiabetic activities. OBJECTIVE: The present study investigates the effect of kaempferol on membrane-bound ATPases in erythrocytes and in liver, kidney, and heart of streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Diabetes was induced into adult male albino rats of the Wistar strain, by intraperitoneal administration of STZ (40 mg/kg body weight (BW)). Kaempferol (100 mg/kg BW) or glibenclamide (600 µg/kg BW) was administered orally once daily for 45 d to normal and STZ-induced diabetic rats. The effects of kaempferol on membrane-bound ATPases (total ATPase, Na(+)/K(+)-ATPase, Ca(2+)-ATPase, and Mg(2+)-ATPase) activity in erythrocytes and in liver, kidney, and heart were determined. RESULTS: In our study, diabetic rats had significantly (p < 0.05) decreased activities of total ATPases, Na(+)/K(+)-ATPase, Ca(2+)-ATPase, and Mg(2+)-ATPase in erythrocytes and tissues. Oral administration of kaempferol (100 mg/kg BW) or glibenclamide (600 µg/kg BW) for a period of 45 d resulted in significant (p < 0.05) reversal of these enzymes' activities to near normal in erythrocytes and tissues when compared with diabetic control rats. DISCUSSION AND CONCLUSION: Thus, obtained results indicate that administration of kaempferol has the potential to restore deranged activity of membrane-bound ATPases in STZ-induced diabetic rats. Further detailed investigation is necessary to discover kaempferol's action mechanism.

Ameliorative effect of kaempferol, a flavonoid, on oxidative stress in streptozotocin-induced diabetic rats.

OBJECTIVE: The aim of the present study was to evaluate the protective effect of kaempferol against oxidative stress in streptozotocin (STZ)-induced diabetic rats. METHODS: Diabetes was induced in male, adult albino rats of the Wistar strain, by intraperitoneal administration of STZ (40 mg/kg body weight (BW)). Kaempferol (100 mg/kg BW) or glibenclamide (600 µg/kg BW) was administered orally once daily for 45 days to normal and STZ-induced diabetic rats. RESULTS: The STZ-induced diabetic rats showed significantly increased levels of plasma glucose, thiobarbituric acid reactive substances, lipid hydroperoxides, and conjugated dienes in plasma, liver, kidney, and heart whereas they showed significantly decreased level of plasma insulin. The levels of non-enzymic antioxidants (vitamin C, vitamin E, reduced glutathione) in plasma, liver, kidney, and heart and the activities of enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase) in liver, kidney, and heart were significantly decreased in diabetic rats. Administration of kaempferol to diabetic rats was showed brought back in plasma glucose, insulin, lipid peroxidation products, enzymatic, and non-enzymatic antioxidants to near normal. CONCLUSION: The present study indicates that kaempferol has a good antioxidant property, as evidenced by its increase of antioxidant status and decrease of lipid peroxidation markers, thus providing protection from the risks of diabetic complications.

Morin, a flavonoid, on lipid peroxidation and antioxidant status in experimental myocardial ischemic rats.

BACKGROUND: Myocardial infarction affects a large population in the world. Lipid peroxide metabolism plays an important role in the pathology of myocardial infarction. OBJECTIVE: The present study was designed to investigate the antioxidant potential of morin, a flavonoid in isoproterenol (ISO)-induced myocardial infarction (MI), in rats. MATERIALS AND METHODS: Male albino Wistar rats were pre-treated with morin (40 mg/kg), daily for a period of 30 days. After the treatment period, ISO (85 mg/kg), was subcutaneously injected in rats at an interval of 24 h for 2 days. RESULTS: ISO-administered rats showed elevated levels of thiobarbituric acid reactive substances (TBARS), and lipid hydro-peroxide (LOOH), in plasma and heart. Pretreatment with morin, the above changes were significantly reduced to near normal level. ISO-administered rats showed decrease in the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) in heart. In addition, decrease the levels non enzymatic antioxidants such as reduced glutathione (GSH), vitamin C and vitamin E in plasma and heart while ceruloplasmin in plasma. CONCLUSION: Pretreatment with morin, reversed these above biochemical changes towards normalcy. These findings revealed that, the morin possess antioxidant activity in experimentally induced cardiac toxicity.

Protective effect of Cardiospermum halicacabum leaf extract on glycoprotein components on STZ-induced hyperglycemic rats.

OBJECTIVE: To investigate the protective role of Cardiospermum halicacabum (C. halicacabum) leaf extract on glycoprotein metabolism in streptozotocin (STZ)-induced diabetic rats. METHODS: Diabetes was induced in male albino Wistar rats by intraperitonial administration of STZ. The C. halicacabum leaf extract (CHE) was administered orally to normal and STZ-diabetic rats for 45 days. The effects of C. halicacabum leaf extract (CHE) on plasma and tissue glycoproteins (hexose, hexosamine, fucose and sialic acid) were determined. RESULTS: The levels of plasma and tissues glycoproteins containing hexose, hexosamine and fucose were significantly increased in STZ-induced diabetic rats. In addition, the level of sialic acid significantly increased in plasma and liver while decreased in kidney of STZ-induced diabetic rats. After administration of CHE to diabetic rats, the metabolic alteration of glycoprotein reverted towards normal levels. CONCLUSIONS: The present study indicates that the CHE possesses a protective effect on abnormal glycoprotein metabolism in addition to its antihyperglycemic activity.

Antihyperlipidemic effect of Melothria maderaspatana leaf extracts on DOCA-salt induced hypertensive rats.

OBJECTIVE: To investigate the antihyperlipidemic effect of crude ethanolic extract of Melothria maderaspatana (M. maderaspatana) leaf (CEEM) on deoxycorticosterone acetate (DOCA)-salt hypertensive rats. METHODS: A midscapular incision was made on each rat and the left kidney was excised after ligation of the renal artery. The surgical wound was closed using an absorbable suture. After one week recovery period, hypertension was induced by subcutaneous injection of DOCA-salt solution, twice a week, and the rats received a 1% sodium chloride solution as drinking water throughout the experimental period. CEEM or nifedipine was administered orally once a day for 6 weeks. RESULTS: In DOCA-salt hypertensive rats, the level of plasma and tissues of total cholesterol (TC), triglycerides (TG), free fatty acids (FFA) and phospholipids (PL) significantly increased and administration of CEEM significantly reduced these parameters towards normality. Further, the levels of low density lipoprotein-cholesterol (LDL-C) and very low density lipoprotein-cholesterol (VLDL-C) significantly increased while high density lipoprotein-cholesterol (HDL-C) decreased in hypertensive rats and administration of CEEM brought these parameters to normality which proved their antihyperlipidemic action. Histopathology of liver, kidney and heart on DOCA-salt induced rats treated with CEEM showed reduced the damages towards normal histology. CONCLUSIONS: These findings provided evidence that CEEM was found to be protecting the liver, kidney and heart against DOCA-salt administration and the protective effect could attribute to its antihyperlipidemic activities.

Preclinical evaluation and molecular docking of 4-phenyl-1-Napthyl phenyl acetamide (4P1NPA) from Streptomyces sp. DPTB16 as a potent antifungal compound.

The incidence of fungal disease has increased dramatically over the past decades, mainly due to the emergence and transmission of antifungal resistance within the fungal pathogens. The present study investigates the use of novel antifungal compound 4-Phenyl-1-Napthyl Phenyl Acetamide (4P1NPA), isolated from marine Streptomyces sp. DPTB16 as a potent antifungal drug. The preclinical studies and molecular docking for 4P1NPA against Cytochrome P450 51 (CYP 51) were performed using in silico pharmacology and docking tools. The finding reveals the drug likeliness of 4P1NPA and satisfactory interaction of 4P1NPA with CYP 51. These results collectively evidence the use of 4P1NPA as a drug to treat fungal infections. On the whole, we highlight the findings of this research will be helpful to design 4P1NPA as novel antifungal drug to defend the emerging antifungal resistance.

Protective effect of morin on cardiac mitochondrial function during isoproterenol-induced myocardial infarction in male Wistar rats.

Altered mitochondrial function and free radical-mediated tissue damage have been suggested as an important pathological event in isoproterenol (ISO)-induced cardiotoxicity. This study was undertaken to know the preventive effect of morin on mitochondrial damage in ISO-induced cardiotoxicity in male Wistar rats. Myocardial infarction (MI) in rats was induced by ISO (85 mg/kg) at an interval of 24 hours for 2 days. Morin was given to rats as pre-treatment for 30 days orally using an intragastric tube. ISO-treated rats showed a significant elevation of mitochondrial thiobarbituric acid reactive substances (TBARS) and hydrogen peroxide (HP) level and pre-treatment with morin significantly prevented the increase of TBARS and HP level to near normality. The level of enzymic and non-enzymic antioxidants was decreased significantly in ISO-treated rats and pre-treatment with morin significantly increased the levels of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, and reduced glutathione to normality. The activities of mitochondrial enzymes such as isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase were decreased significantly in ISO-treated myocardial ischemic rats and upon pre-treatment with morin restored these enzymes activity to normality. In addition, the decreased activities of cytochrome-C oxidase and NADH-dehydrogenases were observed in ISO-treated rats and pre-treatment with morin prevented the activities of cytochrome-C oxidase and NADH-dehydrogenase to normality. Pre-treatment with morin favorably restored the biochemical and functional parameters to near normal indicating morin to be a significant protective effect on cardiac mitochondrial function against ISO-induced MI in rats.

Protective effect of Melothria maderaspatana leaf fraction on electrolytes, catecholamines, endothelial nitric oxide synthase and endothelin-1 peptide in uninephrectomized deoxycorticosterone acetate-salt hypertensive rats.

This study was designed to investigate the protective effect of ethyl acetate fraction of Melothria maderaspatana (EAFM) leaf on electrolytes, catecholamines, endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) peptide in uninephrectomized deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Administration of DOCA-salt significantly increased the systolic and diastolic blood pressure and treatment with EAFM significantly lowered the blood pressure. In DOCA-salt rats, the levels of sodium and chloride increased significantly while potassium level decreased and administration of EAFM brought these parameters to normality. The levels of epinephrine and norepinephrine increased significantly in DOCA-salt rats and administration of EAFM significantly decreased these parameters to normality. DOCA-salt hypertensive rats exhibited significantly decreased L: -arginine and nitrite + nitrate levels and administration of EAFM brought these parameters to normality. DOA-salt hypertensive rats showed down-regulation of eNOS and up-regulation of ET-1 protein expressions in heart and kidney, and treatment with EAFM prevented down-regulation of eNOS and significantly down-regulated the ET-1 protein expressions. In conclusion, EAFM provides good blood pressure control by enhancing potassium and decreasing sodium levels, decreasing levels of epinephrine and norepinephrine, and preventing down-regulation of eNOS and significantly down-regulating ET-1 protein expression.

Antihypertensive effect of Melothria maderaspatana leaf fractions on DOCA-salt-induced hypertensive rats and identification of compounds by GC-MS analysis.

The present study was designed to investigate the antihypertensive effect of Melothria maderaspatana leaf fractions on deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats and to identify compounds from the active fraction by GC-MS analysis. Administration of DOCA salt significantly increased the systolic and diastolic blood pressure compared to sham-operated control rats. When treated with chloroform (CFM), ethyl acetate (EAFM) or methanol fractions of M. maderaspatana (MFM), EAFM alone significantly lowered the systolic and diastolic blood pressure. The levels of magnesium and copper significantly increased in plasma and decreased in tissues while the zinc level significantly increased in plasma and tissues, and administration of EAFM brought these parameters back to sham-operated control levels. By GC-MS analysis, phytochemicals such as coumarin, vallinic acid, p-coumaric acid, gallic acid, caffeic acid, and ferulic acid were identified in EAFM. In conclusion, the EAFM controls blood pressure in DOCA-salt hypertensive rats and reverts the metabolic alterations in magnesium, copper and zinc.

Pretreatment with morin, a flavonoid, ameliorates adenosine triphosphatases and glycoproteins in isoproterenol-induced myocardial infarction in rats.

The aim of this investigation was to evaluate the preventive role of morin, a flavonoid, on cardiac marker enzymes such as aspartate transaminase, lactate dehydrogenase, creatine kinase and creatine kinase-MB, membrane-bound enzymes such as sodium potassium-dependent adenosine triphosphatase, calcium-dependent adenosine triphosphatase and magnesium-dependent adenosine triphosphatase, and glycoproteins such as hexose, hexosamine, fucose and sialic acid in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Male albino Wistar rats were pretreated with morin (20, 40 and 80 mg/kg) daily for a period of 30 days. After the treatment period, ISO (85 mg/kg) was subcutaneously injected into the rats at an interval of 24 h for 2 days. ISO-induced rats showed significantly (P < 0.05) increased activities of cardiac marker enzymes in serum and decreased activities in the heart, and increased activities of calcium-dependent adenosine triphosphatase and magnesium-dependent adenosine triphosphatase in the heart, and the activity of sodium potassium-dependent adenosine triphosphatase decreased in the heart. ISO induction also showed a significant increase in the levels of glycoproteins in serum and the heart. Pretreatment with morin (40 mg/kg) daily for a period of 30 days exhibited significant (P < 0.05) effects and altered these biochemical parameters positively compared to the other two doses. Thus, our study shows that morin has a protective role in ISO-induced MI in rats. The observed effects might be due to the free radical-scavenging, antioxidant and membrane-stabilising properties of morin.

Effect of combination of edible oils on blood pressure, lipid profile, lipid peroxidative markers, antioxidant status, and electrolytes in patients with hypertension on nifedipine treatment.

OBJECTIVE: To determine the effect of combination of edible oils on blood pressure, anthropometric parameters, lipid profile, lipid peroxidative markers, antioxidant status and electrolytes in drug (nifedipine) taking patients with hypertension. METHODS: In this study, patients were separated into 4 groups. Normal (n=14), hypertensive patients (n=38), 38 patients under medication with nifedipine were divided into 2 groups nifedipine control (n=12) and nifedipine + oil combination (sesame + sunflower oil) groups (n=26). Sesame and sunflower oil combination was supplied to patients and instructed to use it as the only oil source for 45 days. Blood pressure and anthropometric parameters were measured at baseline and after 45 days. Lipid peroxidative markers, enzymatic and non-enzymatic antioxidants, lipid profile and electrolytes in blood were also measured. The study took place at Rajah Muthiah Medical College and Hospital, Annamalai University, Annamalainagar, India between January 2005 and December 2008. RESULTS: Nifedipine and oil-mix consumed patients significantly decreased the blood pressure, lipid peroxidative markers, lipid profile excluding the high density lipoprotein cholesterol (HDL-C), sodium, chloride, and increased enzymatic, non-enzymatic antioxidants, HDL-C and potassium levels when compared to nifedipine alone treated hypertensive patients. CONCLUSION: Nifedipine and oil-mix provided good protection over blood pressure and lipid peroxidation, and brought enzymatic and non-enzymatic antioxidants, lipid profile, and electrolytes towards normalcy in hypertensive patients.

Antihyperlipidemic activity of 3-hydroxymethyl xylitol, a novel antidiabetic compound isolated from Casearia esculenta (Roxb.) root, in streptozotocin-diabetic rats.

Casearia esculenta root (Roxb.) is widely used in traditional system of medicine to treat diabetes in India. An active compound, 3-hydroxymethyl xylitol (3-HMX), has been isolated, and its optimum dose has been determined in a short duration study and patented. In addition, the long-term effect of 3-HMX in type 2 diabetic rats on carbohydrate metabolism was investigated, and its antihyperglycemic effect was shown previously (Chandramohan et al., Eur J Pharmacol 2008;590:437-443). In this study we investigated the effect of 3-HMX on plasma and tissue lipid profiles in streptozotocin-induced diabetic rats. Diabetes was induced in adult male albino rats of the Wistar strain, weighing 180-200 g, by administration of streptozotocin (40 mg/kg of body weight) intraperitoneally. The normal and diabetic rats were treated with 3-HMX (40 mg/kg BW/day) for 45 days. The levels of total cholesterol, triglycerides, free fatty acids, and phospholipids were assayed in the plasma besides lipoprotein-cholesterol (high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and very low density lipoprotein-cholesterol (VLDL-C)) and tissues (liver, kidney, heart, and brain). Total cholesterol, triglyceride, free fatty acid, and phospholipid (LDL-C and VLDL-C in plasma only) levels increased in plasma and tissues significantly, whereas plasma HDL-C significantly decreased in diabetic rats. Treatment with 3-HMX or glibenclamide reversed the above-mentioned changes and improved toward normalcy. Histological study of liver also confirmed the biochemical findings. Thus administration of 3-HMX is able to reduce hyperglycemia and hyperlipidemia related to the risk of diabetes mellitus.

A novel compound from Casearia esculenta (Roxb.) root and its effect on carbohydrate metabolism in streptozotocin-diabetic rats.

Casearia esculenta root (Roxb.) is widely used in traditional system of medicine to treat diabetes in India. An active compound 3-hydroxymethyl xylitol (3-HMX) has been isolated and its optimum dose has been determined in a short duration study and patented. In the present study, the long-term effect of 3-HMX in type 2 diabetic rats has been investigated. An optimum dose of 3-HMX (40 mg/kg body weight) was orally administered for 45 days to streptozotocin-diabetic rats for the assessment of glucose, insulin, hemoglobin (Hb), glycated hemoglobin (HbA(1c)), hepatic glycogen, and activities of carbohydrate metabolizing enzymes, such as glucokinase, glucose 6-phosphatase, fructose 1,6-bisphosphatase and glucose-6-phosphate dehydrogenase and hepatic marker enzymes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gammaglutamyl transferase (GGT) in normal and streptozotocin-diabetic rats. 3-HMX at 40 mg dose produced similar effects on all biochemical parameters studied as that of glibenclamide, a standard drug. Histological study of pancreas also confirmed the biochemical findings. These results indicate that 3-hydroxymethyl xylitol, the compound from C. esculenta, possesses antihyperglycemic effect on long-term treatment also.