Blood Glucose Lowering Activity Research Articles

Blood glucose-lowering activity of protocatechuic acid is mediated by inhibiting α-glucosidase

α-Glucosidase inhibitors are effective in controlling postprandial hyperglycemia, which play crucial roles in the management of type 2 diabetes. Protocatechuic acid (PCA) is one of phenolic acids existing not only in various plant foods but also as a major microbial metabolite of dietary anthocyanins in the large colon. The present study investigated the inhibitory mechanism of PCA on α-glucosidase in vitro and examined its effect on postprandial blood glucose levels in vivo. Results from in vitro experiments demonstrated that PCA was a mix-type inhibitor of α-glucosidase. Driven by hydrogen bonds and van der Waals interactions, PCA reversibly bound with α-glucosidase to form a stable α-glucosidase-PCA complex in a spontaneous manner. The computational simulation found that PCA could insert into the active cavity of α-glucosidase and establish hydrogen bonds with catalytic amino acid residues. PCA binding aroused the steric hindrance for substrates to enter active sites and caused the structural changes of interacted catalytic amino acid residues. PCA also exhibited postprandial hypoglycemic capacity in diabetic mice. This study may provide the theoretical basis for the application of PCA as an active ingredient of functional foods in dietary management of diabetes.

BLOOD GLUCOSE LOWERING EFFECT OF ETHANOL LEAF EXTRACT OF HYMENODICTYON FLORIBUNDUM (RUBIACEAE)

In developing countries, and some developed nations, diseases are managed using complementary medicine with the aid of preparations from a single or mixture of herbs. Diabetes mellitus, described by persistently high blood glucose levels, owing to abnormalities in insulin secretion, is among such disorders. Hymenodictyon floribundum has been reported to be used in ethnomedicine to manage diabetes. This study aimed to investigate the blood glucose-lowering activity of the ethanol extract of Hymenodictyon floribundum leaves in adult Wistar rats. Elemental analysis, preliminary phytochemical screening, and acute toxicity test were carried out. Oral glucose tolerance test (OGTT) was performed using five groups of adult Wistar rats administered graded doses (375, 750, and 1500 mg/kg) of the extract, distilled water (1 mL/kg) as negative control, and metformin (500 mg/kg) as positive control. Measurement of glucose levels in blood was performed at 0, 30, 60, and 120 minutes of extract administration, respectively. The result of the elemental analysis indicated the presence of Ca, Mg, K, Na, Fe, Mn, Cu, Cr, Ni, and Pb. Preliminary phytochemical screening revealed tannins, steroids, triterpenes, saponins, alkaloids, anthraquinones, and flavonoids. The Median lethal dose (LD50) of the extract was estimated to be higher than 5000 mg/kg orally. The animals treated with the extract showed a significant (p<0.05) decrease in blood glucose levels compared to the negative control. Blood glucose levels dropped below baseline in the animals treated with the highest dose (1500 mg/kg) of the extract. The study therefore revealed that Hymenodictyon floribundum has the potential to produce a blood glucose-lowering effect and corroborates the claim of antidiabetic activity of the plant.

BLOOD GLUCOSE LOWERING EFFECT OF ETHANOL LEAF EXTRACT OF HYMENODICTYON FLORIBUNDUM (RUBIACEAE)

In developing countries, and some developed nations, diseases are managed using complementary medicine with the aid of preparations from a single or mixture of herbs. Diabetes mellitus, described by persistently high blood glucose levels, owing to abnormalities in insulin secretion, is among such disorders. Hymenodictyon floribundum has been reported to be used in ethnomedicine to manage diabetes. This study aimed to investigate the blood glucose-lowering activity of the ethanol extract of Hymenodictyon floribundum leaves in adult Wistar rats. Elemental analysis, preliminary phytochemical screening, and acute toxicity test were carried out. Oral glucose tolerance test (OGTT) was performed using five groups of adult Wistar rats administered graded doses (375, 750, and 1500 mg/kg) of the extract, distilled water (1 mL/kg) as negative control, and metformin (500 mg/kg) as positive control. Measurement of glucose levels in blood was performed at 0, 30, 60, and 120 minutes of extract administration, respectively. The result of the elemental analysis indicated the presence of Ca, Mg, K, Na, Fe, Mn, Cu, Cr, Ni, and Pb. Preliminary phytochemical screening revealed tannins, steroids, triterpenes, saponins, alkaloids, anthraquinones, and flavonoids. The Median lethal dose (LD50) of the extract was estimated to be higher than 5000 mg/kg orally. The animals treated with the extract showed a significant (p<0.05) decrease in blood glucose levels compared to the negative control. Blood glucose levels dropped below baseline in the animals treated with the highest dose (1500 mg/kg) of the extract. The study therefore revealed that Hymenodictyon floribundum has the potential to produce a blood glucose-lowering effect and corroborates the claim of antidiabetic activity of the plant.

Fluorinated thiazole–thiosemicarbazones hybrids as potential PPAR-γ agonist and α-amylase, α-glucosidase antagonists: Design, synthesis, in silico ADMET and docking studies and hypoglycemic evaluation

In addition to Peroxisome Proliferator-Activated Receptor-gamma (PPAR-γ), which is essential for controlling type-2 diabetes mellitus, α-amylase and α-glucosidase inhibition is a key strategy in managing postprandial hyperglycemia. In this work a series of 2-(1-(2-((4-fluorophenyl)amino)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carbothioamide derivatives (3–6) was designed and synthesized through theiosemicarbazide derivatives, the structural elucidation of the new synthesized compounds was established using elemental and spectroscopic analyses. The antidiabetic activities of the new thiazole-thiosemicarbazone hybrids were screened in vivo for blood glucose lowering activity in normal rats and compared with pioglitazone as antidiabetic standard. Male Sprague-Dawley rats had reduced blood sugar levels after exposure to compounds 5 and 6 compared to pioglitazone. Additionally, the PPAR-γ agonist activity of compounds 5 and 6 as well as their ability to inhibit α-amylase and α-glucosidase were assessed. When compared to standard acarbose, which had an IC50 value of 0.74 ± 0.15 mM/mL, compound 5 showed the highest α-glucosidase inhibitory activity with IC50 value of 0.446 ± 0.01 mM/mL, while compound 6 showed good activity with an IC50 value of 1. 914 ± 0.04 mM/mL. However, compound 5 and compound 6 had weak α-amylase inhibitory activity, with IC50 values of 11.78 ± 0.58 and 24.18 ± 1.2 µg/mL respectively. Furthermore, Peroxisome proliferator activated receptor γ [PPAR-γ] agonist activity for compound 5 and compound 6 was assessed and gave promising result as [PPAR-γ] agonist with IC50 value of 0.938 ± 0.023 and 0.947 ± 0.024 ng/mL respectively superior to that of pioglitazone with IC50 value of 1.912 ± 0.11 ng/mL. All the results supported compound 5 as promising candidates for construction of new antidiabetic agents. Also, in silico ADMET and docking studies for the most promising derivatives 5, 6, Acarbose, and Pioglitazone were done.

A gut microbial metabolite of linoleic acid ameliorates liver fibrosis by inhibiting TGF-β signaling in hepatic stellate cells

The antidiabetic drug pioglitazone ameliorates insulin resistance by activating the transcription factor PPARγ. In addition to its blood glucose–lowering action, pioglitazone exerts pleiotropic effects including amelioration of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). The mechanism by which pioglitazone achieves this latter effect has remained unclear, however. We here show that pioglitazone administration increases the amount of linoleic acid (LA) metabolites in adipose tissue of KK-Ay mice. These metabolites are produced by lactic acid bacteria in the gut, and pioglitazone also increased the fraction of Lactobacillus in the gut microbiota. Administration of the LA metabolite HYA (10-hydroxy-cis-12-octadecenoic acid) to C57BL/6 J mice fed a high-fat diet improved liver histology including steatosis, inflammatory cell infiltration, and fibrosis. Gene ontology analysis of RNA-sequencing data for the liver revealed that the top category for genes downregulated by HYA treatment was related to extracellular matrix, and the expression of individual genes related to fibrosis was confirmed to be attenuated by HYA treatment. Mechanistically, HYA suppressed TGF-β–induced Smad3 phosphorylation and fibrosis-related gene expression in human hepatic stellate cells (LX-2). Our results implicate LA metabolites in the mechanism by which pioglitazone ameliorates liver fibrosis, and they suggest that HYA is a potential therapeutic for NAFLD/NASH.

Inhibition of Key Digestive Enzymes Linked to Type 2 Diabetes Mellitus by Piper betle L. Leaf Extracts to Manage Diabetes in an Alternative Way

Background: Diabetes mellitus is a chronic metabolic disorder. The therapeutic approaches for treating diabetes are to decrease the absorption of glucose through the inhibition of carbohydrate hydrolyzing enzymes like α-amylase and α-glucosidase or to use medications for lowering the blood glucose level. Objective: The current study aimed to investigate the inhibitory potentials of the key digestive enzymes, α-amylase and α-glucosidase, by betel leaf extracts and blood glucose lowering activities using diabetic mice. Methods: In vitro inhibitory potentials of the key enzymes linked to type 2 diabetes mellitus (viz. α-amylase and α-glucosidase) by the betel leaf (Piper betle) extracts, including the study on the mode of enzyme inhibition, were evaluated spectrophotometrically and in vivo blood glucose lowering activities were assessed using alloxan-induced diabetic mice. Results: Betel leaf extracts showed potential α-amylase and α-glucosidase inhibition activities and blood glucose lowering activities. Among the extracts, young deshi betel leaf extract demonstrated the highest α-amylase inhibition activity, while young khasia betel leaf extract exhibited the lowest α-amylase inhibition activity. Young khasia betel leaf extract showed the maximum α-glucosidase inhibition activity. However, the lowest α-glucosidase inhibition activity was found with deshi betel leaf extracts. Betel leaf extract inhibited α-amylase and α-glucosidase activities through competitive inhibition. In vivo study revealed that among the extracts, young deshi and khasia leaf extract reduced blood glucose levels in all doses. Young deshi leaf extract exhibited significant (p<0.05) antidiabetic activity to reduce blood glucose level ˂ 6.9 mmol/L at a lower concentration. Conclusion: This study would open a new window for the researcher to find new antidiabetic bioactive compounds that would be cost-effective and without any adverse effects.

Transfer of Proteins from Cultured Human Adipose to Blood Cells and Induction of Anabolic Phenotype Are Controlled by Serum, Insulin and Sulfonylurea Drugs.

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are anchored at the outer leaflet of eukaryotic plasma membranes (PMs) only by carboxy-terminal covalently coupled GPI. GPI-APs are known to be released from the surface of donor cells in response to insulin and antidiabetic sulfonylureas (SUs) by lipolytic cleavage of the GPI or upon metabolic derangement as full-length GPI-APs with the complete GPI attached. Full-length GPI-APs become removed from extracellular compartments by binding to serum proteins, such as GPI-specific phospholipase D (GPLD1), or insertion into the PMs of acceptor cells. Here, the interplay between the lipolytic release and intercellular transfer of GPI-APs and its potential functional impact was studied using transwell co-culture with human adipocytes as insulin-/SU-responsive donor cells and GPI-deficient erythroleukemia as acceptor cells (ELCs). Measurement of the transfer as the expression of full-length GPI-APs at the ELC PMs by their microfluidic chip-based sensing with GPI-binding α-toxin and GPI-APs antibodies and of the ELC anabolic state as glycogen synthesis upon incubation with insulin, SUs and serum yielded the following results: (i) Loss of GPI-APs from the PM upon termination of their transfer and decline of glycogen synthesis in ELCs, as well as prolongation of the PM expression of transferred GPI-APs upon inhibition of their endocytosis and upregulated glycogen synthesis follow similar time courses. (ii) Insulin and SUs inhibit both GPI-AP transfer and glycogen synthesis upregulation in a concentration-dependent fashion, with the efficacies of the SUs increasing with their blood glucose-lowering activity. (iii) Serum from rats eliminates insulin- and SU-inhibition of both GPI-APs' transfer and glycogen synthesis in a volume-dependent fashion, with the potency increasing with their metabolic derangement. (iv) In rat serum, full-length GPI-APs bind to proteins, among them (inhibited) GPLD1, with the efficacy increasing with the metabolic derangement. (v) GPI-APs are displaced from serum proteins by synthetic phosphoinositolglycans and then transferred to ELCs with accompanying stimulation of glycogen synthesis, each with efficacies increasing with their structural similarity to the GPI glycan core. Thus, both insulin and SUs either block or foster transfer when serum proteins are depleted of or loaded with full-length GPI-APs, respectively, i.e., in the normal or metabolically deranged state. The transfer of the anabolic state from somatic to blood cells over long distance and its "indirect" complex control by insulin, SUs and serum proteins support the (patho)physiological relevance of the intercellular transfer of GPI-APs.

In vitro and in vivo Pharmacological Studies of Leaves of Staurogyne argentea Wall.

Staurogyne argentea Wall. (Family: Acanthaceae) is an important medicinal plant that has many traditional uses in tribal areas of Bangladesh. The current study emphasizes the pharmacological investigations of n-hexane, chloroform and aqueous soluble fractions of ethanol extract of leaves of S. argentea to justify the traditional uses of this plant species in Bangladesh. In vitro anti-inflammatory activity of S. argentea was confirmed by inhibition of egg albumin denaturation and erythrocyte membrane stabilizing methods. In both experiments, the aqueous fraction at concentration of 160 μg/ml exhibited significant inhibition of egg albumin denaturation by 76.91% with IC50 value of 24.22 μg/ml compared to standard Diclofenac-Na. In membrane stabilization assay, the aqueous fraction showed prominent anti-inflammatory activity by protecting the human erythrocyte membrane against hypotonic solution induced lysis. In addition, among all the aqueous fraction at 100 μg/ml also showed maximum antioxidant potential via the inhibition of DPPH scavenging by 75.05% (IC50= 42.92 μg/ml). The test materials were subjected to evaluate for the anti-diabetic activity by both in vitro starch iodine method as well as by oral glucose tolerance test in Swiss albino mice. In both experiments, the aqueous fraction showed maximum blood glucose lowering activity which is comparable to standard glibenclamide. The chloroform fraction (Conc. 500 mg/kg bw) exhibited moderate inhibition of both acetic acid-induced writhing reflex and yeast-induced pyrexia in mice. During sedative activity screening, different solvent fractions produced mild to moderate activity in comparison with standard diazepam. These findings revealed that S. argentea is a valuable source of bioactive compounds with diverge pharmacological actions, which validates its use in Bangladesh folk medicinal practices. Bangladesh Pharmaceutical Journal 26(1): 89-98, 2023 (January)

HYPOGLYCAEMIC AND ANTIHPERGLYCAEMIC ACTIITIES OF AQUEOUS EXTRACT OF FICUS CARICA IN DIABETIC RATS

The Ficus carica ( fig ) is an important harvest worldwide for its dry and fresh consumption. Its common edible part is the fruit which is fleshy, hollow, and receptacle . The dried fruits of Ficus carica have been reported as an important source of vitamins, minerals, carbohydrates, sugars, organic acids, and phenolic compounds A short study was undertaken as a preliminary investigation to evaluate the antidiabetic effect of the aqueous leave extract by oral glucose tolerance test (OGTT) , normoglycemic and antihyperglycemic activity in streptozotocin (STZ)-nicotinamide in a dose of 120 mg kg induced non insulin-dependent diabetes mellitus Wister albino rats. Graded doses (250 and 500 mg/kg) of the aqueous leave extract suspended in gum acacia were administered to normal and experimental diabetic Wister albino rats. Effect on glucose tolerance test showed a significant reduction in the blood glucose level of extract treated animals after 1 hr, indicating its hypoglycemic activity. Continuous blood glucose lowering activity was observed till 4 hr of administration in normoglycemic and diabetic rats. The results were compared with standard drug glibenclamide. Also the extract showed a high LD50 value and could be used safetly.

The alpha-7 nicotinic acetylcholine receptor agonist GTS-21 engages the glucagon-like peptide-1 incretin hormone axis to lower levels of blood glucose in db/db mice.

To establish if alpha-7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a blood glucose-lowering action in db/db mice, and to test if this action requires coordinate α7nAChR and GLP-1 receptor (GLP-1R) stimulation by GTS-21 and endogenous GLP-1, respectively. Blood glucose levels were measured during an oral glucose tolerance test (OGTT) using db/db mice administered intraperitoneal GTS-21. Plasma GLP-1, peptide tyrosine tyrosine 1-36(PYY1-36), glucose-dependent insulinotropic peptide (GIP), glucagon, and insulin levels were measured by ELISA. A GLP-1R-mediated action of GTS-21 that is secondary to α7nAChR stimulation was evaluated using α7nAChR and GLP-1R knockout (KO) mice, or by co-administration of GTS-21 with the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the GLP-1R antagonist, exendin (9-39). Insulin sensitivity was assessed in an insulin tolerance test. Single or multiple dose GTS-21 (0.5-8.0mg/kg) acted in a dose-dependent manner to lower levels of blood glucose in the OGTT using 10-14 week-old male and female db/db mice. This action of GTS-21 was reproduced by the α7nAChR agonist, PNU-282987, was enhanced by sitagliptin, was counteracted by exendin (9-39), and was absent in α7nAChR and GLP-1R KO mice. Plasma GLP-1, PYY1-36, GIP, glucagon, and insulin levels increased in response to GTS-21, but insulin sensitivity, body weight, and food intake were unchanged. α7nAChR agonists improve oral glucose tolerance in db/db mice. This action is contingent to coordinate α7nAChR and GLP-1R stimulation. Thus α7nAChR agonists administered in combination with sitagliptin might serve as a new treatment for type 2 diabetes.

The Impact of GLP1 Agonists on Bone Metabolism: A Systematic Review.

Background and Objectives: The association between diabetes mellitus and increased risk of bone fractures has led to the investigation of the impact of antidiabetic drugs on bone metabolism. Glucagon-like peptide-1 receptor agonists (GLP1RAs) are a relatively novel and promising class of anti-hyperglycemic drugs. In addition to their blood glucose lowering action, GLP1RAs seem to have additional pleiotropic properties such as a beneficial skeletal effect; although the underlying mechanisms are not completely understood. The present systematic review summarizes current evidence about GLP1RAs and their effects on bone metabolism and fracture. Methods: An extensive literature search was conducted based on electronic databases namely, PubMed, Google Scholar and Cochrane Central Register of Controlled Trials (CENTRAL) through October 2019 to January 2020 for articles related to bone mineral density, diabetes mellitus and GLP1RAs. We included articles published in English. Finally, we included four randomized controlled trials, three meta-analyses, a case-control study and a population-based cohort analysis. Results: Based on the articles included, the animal studies indicated the salutary skeletal effects of GLP1RAs in opposition to what has been commonly observed in human studies, showing that these agents have no impact on bone mineral density (BMD) and the turnover markers. Moreover, it was demonstrated that GLP1 was not associated with fracture risk as compared to other anti-hyperglycemic drugs. Conclusions: Findings from this systematic review have demonstrated the neutral impact of GLP1RAs on BMD. Moreover, further double-blind randomized controlled trials are needed to draw more meaningful and significant conclusions on the efficacy of GLP1RAs on BMD.

Nutritional Characteristics, Glycaemic Index and Blood Glucose Lowering Property of Gluten-Free Composite Flour from Wheat (Triticum aestivum), Soybean (Glycine max), Oat-Bran (Avena sativa) and Rice-Bran (Oryza sativa)

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by increased blood glucose levels due to either lack of insulin production or inefficient as in the activity of insulin. Hence, this study aimed to produce and evaluate nutritional quality, glycaemic index, carbohydrate hydrolyzing enzymes and blood glucose lowering potential of composite flour samples from wheat, soybeans and rice-bran and oat-bran. The precooked wheat, soycake, rice-bran and oat-bran flour samples were blended (wheat 70% and soycake 30% (WSC); wheat 70%, soycake 25% and rice bran 5% (WSR); wheat 70%, soycake 25% and oat bran 5% (WSO); and wheat 70%, soycake 20%, rice bran 5% and oat bran 5% (WSRO) using material balance equation with reference to 25% of daily requirement for protein (14 g/day) and fibre (5 g/day) for adults. Formulated foods and controls (Cerolina (CERO) & 100% wheat (WF)) were evaluated for nutritional quality, glycaemic index, carbohydrate hydrolyzing inhibitory and antidiabetic potentials using standard methods. Nutritional parameters of formulated composite flour samples showed that WSRO exhibited higher protein content (23.94 g/100g), biological value (98.01%) and growth performance in rats than other food samples including controls, i.e., WF (14.56 g/100g; 66%) and CERO (17.59 g/100g; 97.59%). The α-amylase and α-glucosidase enzyme inhibitory activity of the experimental food samples ranged from 49.25% - 66.75% and 37.53% 57.40% in WS and WSRO, respectively. While glycaemic load and glycaemic index of the food samples varied from 24.64 - 28.50% and 40.03 - 46.41%, while that of CERO were 25.63% and 40.05%, respectively. Antidiabetic potential of experimental foods showed that WSRO (79.62%) had the highest blood glucose lowering activity; while those rats fed on WS sample (65.65%) had the least activity. However, the antidiabetic activity of WSRO was significantly (p<0.05) higher than that of ACAR (Acarbose) (75.07%), CERO (73.87%) and WF (59.10%), respectively. In conclusion, sample WSRO exhibited high nutritional quality, low glycaemic index and ability to lower blood glucose concentration. Hence, this formulated food mighty be suitable as an alternate to synthetic antidiabetic agent in managing diabetes.

Evaluation of Antidiabetic and Antioxidant Activity of Leaf Extract and Solvent Fractions of Hypoestes forskaolii (Val) (Acanthaceae) in Mice.

BackgroundCurrently, there is a demand for new antidiabetic drugs from natural therapeutic agents, and diabetes mellitus disease is global epidemic. The leaf of Hypoestes forskaolii has been used in the traditional health system for the management of diabetes mellitus in Ethiopia and Eritrea. The aim of this study was to evaluate in vivo antidiabetic, antihyperlipidemic and in vitro antioxidant activity of leaf extract and solvent fractions of the leaf of H. forskaolii (Vahl) in mice.MethodsThe blood glucose-lowering activities of leaf extract and solvent fractions of the leaf of H. forskaolii were screened in the normoglycemic, glucose loaded, and streptozotocin-induced diabetic mice models. In the treatment of streptozotocin-induced diabetic mice with leaf extract and solvent fractions, weight and lipid profile was measured. Antioxidant activity of the plant leaf extract was determined using DPPH assay.ResultsThe leaf extract of H. forskaolii showed significant blood glucose reduction in the normoglycemic model and glucose loaded test at doses of 200 mg/kg (34.1%, p < 0.001 and 55.5%, p < 0.001), respectively, as compared to the normal control. In the streptozotocin-induced diabetic model, extract and solvent fractions significantly (p < 0.001) reduced blood glucose level at all tested doses (100mg/kg, 200mg/kg and 400mg/kg) on the 14th day as compared to diabetic control. In addition, a significant reduction (p < 0.001) of serum TC, VLDL, LDL, TG was observed. In the antioxidant activity test, the IC50 values of extract and a standard drug (ascorbic acid) were 4.87µg/mL and 15.7µg/mL, respectively.ConclusionThe present study showed that the methanolic leaf extract and solvent fractions of H. forskaolii have antidiabetic, and antioxidant activity that provides a scientific support for the local use of the plant leaves in the treatment of diabetes.

Evaluation of the anti-hyperglycemic and antioxidant activities of a novel phytochemical formulation

BackgroundOne of the major characteristics of Diabetes Mellitus (DM) is high blood glucose levels and impairment of insulin production, which can lead to serious complications, so the main aim of treating patients with diabetes, is to maintain normal levels of glycaemia control. With the adverse effects and limitations of the existing drugs, scientists have been in search for safer and more efficient and affordable alternative treatments. In this backdrop, search for a new generation of antidiabetic drugs is a priority in recent years. PurposeNatural products base drugs were used in traditional systems of medicine for diabetes. The introduction of drugs based on natural products is usually considered to be safer, cheaper, easily available and sometimes more efficacious than purely synthetic ones. In addition, the synergetic effect of the constituent agents could be better than a single agent acting alone. Accordingly, the aim of the present study was to develop a phytochemical formulation including bioavailable curcuminoids, extracts of Gymnema sylvestre, Emblica officinalis and Salacia reticulata based on traditional knowledge and to evaluate its anti-hyperglycemic and antioxidant activities. MethodsThe phytochemical formulation was prepared by using encapsulation technology and the bioactive components were estimated using UPLC. Physical parameters, total phenolic and flavonoid content, antioxidant (DPPH, FRAP, SOD scavenging activity), α-amylase inhibition and blood glucose lowering activity in rats were also evaluated. ResultsOral supplementation at a dosage of 200 mg/kg and 400 mg/kg of phytochemical formulation for a duration of 21 days resulted in a 77.8% and 76.1% reduction in the blood glucose level. The total flavonoid content of 42.92 ± 0.028% QE, DPPH activity showed an IC50 of 93.59 ± 0.88 µg/mL, superoxide radical scavenging activity showed an IC50 of 45.71 ± 0.17 μg/ml, α-amylase inhibitory activity exhibited IC50 value of 1053 ± 1.41 µg/mL all showed promising results for the efficacy of the formulation. ConclusionBased on the results, the novel phytochemical formulation has potent antidiabetic and antioxidant efficacy, and which can be a promising candidate for the development of new generation antidiabetic drugs.

Evaluation of Antidiabetic, Antidiarrheal and Sedative Effects of the Methanolic Extract of Clerodendrum viscosum Roots in Mice

Background: Clerodendrum viscosum is one of the most well-known plants in traditional practices. The study aims to explore the antidiabetic, antidiarrheal and sedative effects of methanolic extract of Clerodendrum viscosum roots (MECV) in mice. Methods: For each experiment, four groups of animals were used consisting of three mice per group. Each group was treated individually: group I treated as negative control, Group II received reference drug of each experiment, Group III and IV received MECV at 200 and 400 mg/kg body weight, respectively. Antidiabetic effect of MECV was evaluated by oral glucose tolerance test. Antidiarrheal activity was examined by the method of castor oil induced diarrhea and reduction in amount of diarrheal feces was determined. To assess the sedative activity of MECV, total sleeping time was determined in phenobarbitone induced mice. Results: MECV showed statistically significant (p&lt;0.05) blood glucose lowering activity which was comparable to the standard drug, glibenclamide and the effect was found to be dose dependent. The extract reduced the diarrheal feces in mice by 51.85% and 65.56% at 200 and 400 mg/kg doses, respectively. The observed activity was found significant (p&lt;0.05) in comparison to the positive control. Also, the test extract showed significant (p&lt;0.05) sedative activity with respect to the control suggesting that the extract potentiated the phenobarbitone induced sleeping time. Conclusion: This is the first report on the therapeutic importance of methanolic extract of Clerodendrum viscosum roots in diabetes, diarrhea and sedation and thus supporting the uses of the plant in traditional medicine.

Synthesis and biological evaluation of thiazolidinedione derivatives of chalcones and flavones as antihyperglycemic and antidyslipidemic agents

A series of chalcone and flavone derivatives (6a-d, 9a-f) based on 2,4-thiazolidinedione have been synthesized and evaluated for in vivo antihyperglycemic activity in sucrose loaded (SLM) and streptozotocin (STZ) induced diabetic animal models and also for antidyslipidemic activity in the triton model. Compounds 9d, 9e, and 9f exhibited potent blood glucose-lowering activity in both SLM and STZ models. Compounds 6c, 6d, and 9c, 9e, and 9f showed moderate lipid-lowering activity. The selected most potent compounds 6d and 9e were also studied in db/db mice for both antihyperglycemic and antidyslipidemic activity.

Canagliflozin ameliorates aortic and hepatic dysfunction in dietary-induced hypercholesterolemia in the rabbit

AimsCanagliflozin is an antidiabetic agent which lowers blood glucose levels by inhibiting the glucose reabsorption machinery in the proximal tubules. There have not been conducted any study on its direct impact on hypercholesterolemia and associated vascular disorders independently of blood glucose lowering activity. Materials and methodsRabbits were arranged in 3 groups: Group 1 (Control): regular rabbit chow; Group 2 (HCD): 1% cholesterol-enriched chow was given to rabbits for 4 weeks; Group 3 (HCD-CANA): 1% cholesterol-enriched chow was fed to rabbits concurrently with canagliflozin (10 mg/kg/day, orally) for 4 weeks. At the end of experiment, blood and tissue samples were obtained for biochemical, histological, immunohistochemical, and vascular reactivity assessment. Key findingsWhen statistically compared to Control (P < 0.05), HCD showed a significant increase in the serum triglycerides, low-density lipoprotein, total cholesterol, C-reactive protein, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase. Furthermore, a significant decrease was seen in both liver and aortic levels of glutathione peroxidase and superoxide dismutase concurrently with a significant elevation in malondialdehyde levels. Aortic levels of nitrate/nitrite ratio were significantly elevated. Acetylcholine-induced relaxation was impaired as the Emax decreased significantly in aortae. Moreover, a significant increase was seen in the level of aortic intima/media ratio. Canagliflozin treatment significantly improved vascular function, lipid profile and inflammation and reduced liver injury. SignificanceOur data suggest that SGLT-2 inhibition via canagliflozin not only possesses an antihyperglycemic activity, but also improves hypercholesterolemia, vascular and liver function in dietary-induced hypercholesterolemia in the rabbit.

659-P: Cotadutide (MEDI0382) Is Well Tolerated at Doses Up to 600 µG with Blood Glucose-Lowering Activity in Japanese Patients with T2DM

Background: This study examined the safety and efficacy of cotadutide, a dual receptor agonist with activity on receptors for glucagon-like peptide-1 and glucagon, at doses up to and including 600 µg in patients with T2DM and obesity in Japan.Methods: During this double-blind, phase 1b study, adults with T2DM (HbA1c 6.5-8.5%) and obesity were randomized to two cohorts of once-daily cotadutide (n = 6 each) or placebo (n = 2 each) for 70 days. A dose-escalation committee (DEC) approved titrations > 400 µg following a safety data review.Results: The DEC approved titrations up to 600 µg. Gastrointestinal disorders were the most frequently reported AE with 9 patients on cotadutide (75%) reporting at least 1 event. No SAEs were reported. There was a significant reduction from baseline in 7-day average glucose measured by CGM with cotadutide: mean change (SD) to final week of treatment -62.79 mg/dL (35.66) vs. an increase of 28.52 mg/dL (9.16) with placebo. Cotadutide treatment reduced HbA1c by 1.13% (0.64) at end of treatment from a baseline of 7.41% (0.67). On day 70, the cotadutide group demonstrated a -6.93% (3.44) reduction from baseline in body weight, compared with -1.23% (1.2) in the placebo group.Conclusions: Cotadutide was well tolerated at doses up to 600 µg in Japanese patients and promoted a generalized reduction in blood glucose and body weight.View largeDownload slideView largeDownload slide DisclosureM. Asano: Employee; Self; AstraZeneca K. K. A. Sekikawa: Employee; Self; AstraZeneca K. K. M. Sugeno: Employee; Self; AstraZeneca K. K. H. Shimada: None. D. Robertson: Employee; Self; AstraZeneca, Employee; Spouse/Partner; GlaxoSmithKline plc., Stock/Shareholder; Self; AstraZeneca. L. Hansen: Employee; Self; AstraZeneca.

Evaluation of Antidiabetic Activity of Ajuga integrifolia (Lamiaceae) Root Extract and Solvent Fractions in Mice.

Traditional healers and the community have used the roots of Ajuga integrifolia for the treatment of diabetes mellitus. It is not scientifically validated for its antidiabetic activity previously. Therefore, the objective of the present study was to determine the hypoglycemic and antidiabetic activity of Ajuga integrifolia. Ajuga integrifolia roots' crude extract and solvent fractions were prepared. The doses of 100 mg/kg, 200 mg/kg, and 400 mg/kg of crude root extract and solvent fractions were used on normoglycemic, oral glucose loaded, and streptozotocin-induced diabetic mice models to determine their hypoglycemic and antihyperglycemic activities. The crude extract and solvent fractions' effect on bodyweight was also evaluated on streptozotocin-induced diabetic mice. A standard drug in all cases was glibenclamide (5 mg/kg), and the blood glucose level was measured by using a glucose meter. Data analysis was performed by using Statistical Package for Social Sciences version 21. One-way analysis of variance followed by Tukey's post hoc multiple comparison test was used to analyze the data. p value < 0.05 was considered statistically significant. Hydromethanolic crude extract and its aqueous fraction of Ajuga integrifolia root showed a considerable blood glucose lowering activity at all doses. Both the repeated daily doses of the crude extract and the repeated daily doses of the aqueous fraction of Ajuga integrifolia root extract revealed the similar effect in lowering the fasting blood glucose level in streptozotocin-induced diabetic mice models. It was also found that groups treated with the Ajuga integrifolia at the doses of 200 mg/kg and 400 mg/kg showed significant (p < 0.05) bodyweight improvement at the 14th day of treatment compared to the respective baseline bodyweight, and the diabetic control group showed significant (p < 0.01) reduction in bodyweight at the 14th day compared to the baseline. This study revealed that crude extract and solvent fractions of Ajuga integrifolia root possess significant antidiabetic activity which supports its traditional use for the treatment of diabetes mellitus.

SYNTHESIS, BIOLOGICAL EVALUATION AND DOCKING STUDIES OF NON HEPATOTOXIC 5-SUBSTITUTED THIAZOLIDINE-2, 4-DIONES AS ANTIDIABETIC, ANTI-HYPERLIPIDEMIC, ANTI-OXIDANT AND CYTOTOXIC AGENTS

A series of eleven thiazolidine-2, 4-dione (TZD) derivatives, were synthesized and characterized by FT-IR, 1 H NMR and mass spectral analysis. All the synthesized TZD derivatives were screened for their in vitro and in vivo anti-diabetic and antioxidant, activities and cytotoxicity. In vivo antihyperglycemic effect was assessed by measuring plasma glucose (PG) levels in alloxan-induced type II diabetic rat models. The compound 4h exhibited better blood glucose lowering activity than the standard drug rosiglitazone. The synthesized TZD derivatives were evaluated for hepatotoxicity and pancreatic tissue studies. Antioxidant activity was evaluated by DPPH method and H2 O2 method. Compounds 4a and 4b exhibited potent antioxidant activity. Among the tested compounds for cytotoxicity using MTT assay method, compound 4i exhibited better viability and cytotoxicity activity. Thiazolidinedione derivatives were evaluated for their affinity towards target PPARg, using rosiglitazone as the reference compound molecular docking visualization through FlexX docking program. From selected anti-diabetic targets, the proposed derivatives exhibited better interaction with PPARγ receptor, where rosiglitazone showed docking score of -19.891 kJ/ mol, compound 4h exhibited highest docking score of -31.6068 kJ/mol. The study showed that all the studied compounds were showing higher docking score when compared to control drug rosiglitazone and it could be a remarkable starting point to evaluate structure activity relationships to develop new lead molecules with potential anti-diabetic activities.