Blood Glucose Lowering Activity Research Articles

Effects of a triplex mixture of Peganum harmala, Rhus coriaria, and Urtica dioica aqueous extracts on metabolic and histological parameters in diabetic rats

Context: Several therapeutic effects such as antioxidant and blood glucose-lowering activities have been reported for Peganum harmala L (Zygophyllaceae) (PH) seeds, Rhus coriaria L (Anacardiaceae) (RC) fruits, and Urtica dioica L (Urticaceae) (UD) leaves.Objective: This study investigates the effects of a triplex mixture (1:1:1) of these medicinal plants on metabolic and histological parameters in diabetic rats.Materials and methods: Aqueous extracts of PH, RC and UD were administered as either monotherapy or in combination at a final dose of 200 mg/kg to alloxan-induced diabetic rats by daily gavage. Biochemical parameters including blood glucose, liver function-related enzymes, lipid profile, and creatinine were estimated by spectrophotometric methods. Tissues from the liver and kidney stained with hematoxylin/eosin were histologically examined. The results obtained from the exposure groups were compared to either healthy or diabetic control groups.Results: Compared with the diabetic control rats, all aqueous extracts (ED50 = 11.5 ± 2.57 mg/ml) led to significant decreases in the levels of ALP (1.39–2.23-fold, p < 0.05), low-density lipoprotein cholesterol (LDL-C) (1.79–3.26-fold, p < 0.05), and blood glucose (1.27–4.16-fold, p < 0.05). The serum concentrations of TG was decreased only by treatment with UD and triplex mixture (1.25- and 1.20-fold, respectively, p < 0.05). Among the studied parameters, alanine aminotransferase (ALT), LDL-C, TG, and creatinine recovered to healthy control levels after 4 weeks of treatment with the extract mixture.Conclusion: This study showed that PH, RC, and UD extracts, especially their combination, had significant antidiabetic, hypolipidemic, and liver and renal damage recovering effects.

Benzothiazole derivatives upregulate SIRT1 and relevant genes in high-fat fed C57BL/6J mice

SIRT1 is a protein deacetylase and regulates glucose and lipid metabolism through its deacetylase activity for a range of substrates. Growing evidence suggests that activation of SIRT1 can treat diseases such as type II diabetes and cardiovascular diseases. Therefore, novel activators of SIRT1 have aroused enormous interests among scientists. The aim of present study is to synthesize new compounds as SIRT1 activators and to investigate their effects on SIRT1 and relevant genes. The three compounds: (3-benzothiazol-2-yl) aniline (JHJ1), N-(3-(benzothiazol-2-yl)phenyl)-3,4,5-trimethoxybenzamide (JHJ2), and N-(3-(benzothiazol-2-yl)phenyl)-1H-pyrazo-3-carboxamide (JHJ3) were synthesized and their effects on SIRT1 and relevant genes to regulate glucose and lipid metabolism in high-fat diet fed C57BL/6J mice were also addressed. The results showed that relative mRNA expressions of SIRT1, FoxO1, PPARγ, and PGC-1α were significantly up-regulated in the liver, and the glucose, plasma total-cholesterol, hepatic cholesterol, and total triglyceride concentration were markedly lowered by JHJ1, JHJ2, and JHJ3 supplementation, respectively. These results suggest that benzothiazole derivatives HJ1, JHJ2, and JHJ3 supplementation could modulate the plasma lipids metabolism and blood glucose-lowering action in high-fat fed mice through regulation of SIRT1 and relevant genes.

Synthesis and oral hypoglycemic effect of novel thiazine containing trisubstituted benzenesulfonylurea derivatives

A new series of 3-(4-substituted phenyl)-1-(4-(4,6-dimethyl-6H-1,3-thiazin-2-yl)phenylsulfonyl)-1-substituted urea (5a–o) was synthesized by an effectual route via sulfonylcarbamates and explores the novel site for substitution in sulfonylurea as well as the way of thiazine can be prepared. The molecules were established by elemental analysis and spectroscopic viz. IR, 1H NMR, 13C NMR and MS techniques. All the fifteen derivatives were shown very prominent oral hypoglycemic effect at the dose of 40mg/kg body weight (p.o.) in respect of standard drug glibenclamide and control. The hypoglycemic effect was studied using oral glucose tolerance test in normal and NIDDM in STZ-rat model. The compounds 5a, 5d, 5f, 5i, 5k and 5n were dominant out of fifteen derivatives for blood glucose lowering activity (more than 80%) when comparing with NIDDM control. These derivatives were either containing simply phenyl ring (5a, 5f and 5k) on to the second amine of sulfonylurea (R′=H) or nitro group at the para position in compound 5d, 5i and 5n (R′=NO2) to produce significant oral hypoglycemic effect. Other structural activity relationship is also observed regarding the heteroaromatic and substituted aromatic group at R and R′ position respectively.

Differential hypoglycaemic, anorectic, autonomic and emetic effects of the glucagon-like peptide receptor agonist, exendin-4, in the conscious telemetered ferret.

BackgroundRodents are incapable of emesis and consequently the emetic potential of glucagon-like peptide-1 receptor (GLP-1R) agonists in studies designed to assess a potential blood glucose lowering action of the compound was missed. Therefore, we investigated if the ferret, a carnivore with demonstrated translation capability in emesis research, would identify the emetic potential of the GLP-1R agonist, exendin-4, and any associated effects on gastric motor function, appetite and cardiovascular homeostasis.MethodsThe biological activity of the GLP-1R ligands was investigated in vivo using a glucose tolerance test in pentobarbitone-anesthetised ferrets and in vitro using organ bath studies. Radiotelemetry was used to investigate the effect of exendin-4 on gastric myoelectric activity (GMA) and cardiovascular function in conscious ferrets; behaviour was also simultaneously assessed. Western blot was used to characterize GLP-1R distribution in the gastrointestinal and brain tissues.ResultsIn anesthetised ferrets, exendin-4 (30 nmol/kg, s.c.) reduced experimentally elevated blood glucose levels by 36.3%, whereas the GLP-1R antagonist, exendin (9–39) (300 nmol/kg, s.c.) antagonised the effect and increased AUC0–120 by 31.0% when injected alone (P < 0.05). In animals with radiotelemetry devices, exendin-4 (100 nmol/kg, s.c.) induced emesis in 1/9 ferrets, but inhibited food intake and decreased heart rate variability (HRV) in all animals (P < 0.05). In the animals not exhibiting emesis, there was no effect on GMA, mean arterial blood pressure, heart rate, or core body temperature. In the ferret exhibiting emesis, there was a shift in the GMA towards bradygastria with a decrease in power, and a concomitant decrease in HRV. Western blot revealed GLP-1R throughout the gastrointestinal tract but exendin-4 (up to 300 nM) and exendin (9–39), failed to contract or relax isolated ferret gut tissues. GLP-1R were found in all major brain regions and the levels were comparable those in the vagus nerve.ConclusionsPeripherally administered exendin-4 reduced blood glucose and inhibited feeding with a low emetic potential similar to that in humans (11% vs 12.8%). A disrupted GMA only occurred in the animal exhibiting emesis raising the possibility that disruption of the GMA may influence the probability of emesis occurring in response to treatment with GLP-1R agonists.

Blood glucose lowering activity of aloe based composition, UP780, in alloxan induced insulin dependent mouse diabetes model.

BackgroundThere are a few nutritional approaches to address the increased needs of managing diabetic conditions. Previously it has been reported that UP780, a standardized composition of aloe chromone formulated with an aloe polysaccharide, has a significant impact in reducing HbA1C, fasting blood glucose, fructosamine and plasma insulin level in humans and improved impaired glucose and insulin resistance in high-fat diet-induced and db/db non-insulin dependent diabetic mouse models. Here we describe activity of UP780 and its constituents to improve insulin sensitivity in alloxan induced insulin dependent diabetic mouse model.Materials and methodInsulin dependent diabetes was induced by administering a single intraperitoneal injection of alloxan monohydrate at a dose of 150 mg/kg to CD-1 mice. Aloesin (UP394) was formulated with an Aloe vera inner leaf gel powder polysaccharide (Qmatrix) to yield a composition designated UP780. Efficacy of oral administration of UP780 at 2000 mg/kg and its constituents (aloesin at 80 mg/kg and Qmatrix at 1920 mg/kg) were evaluated in this model. Glyburide, a sulfonylurea drug used in the treatment of type 2 diabetes, was used at 5 mg/kg as a positive control. Effect of UP780 on non-diabetic normal mice was also addressed.ResultsMice administered intraperitoneal alloxan monohydrate developed progressive type-1 diabetes like symptom. After 4 weeks of daily oral administration, reductions of 35.9%, 17.2% and 11.6% in fasting blood glucose levels were observed for UP780, the UP780 Aloe vera inner leaf gel polysaccharide preparation without chromone (Qmatrix), and Aloesin (UP394), treated animals respectively, compared to vehicle treated animals. UP780 has no impact on blood glucose level of non-diabetic healthy mice. UP780 showed statistically significant improvement for blood glucose clearance in oral glucose tolerance tests. Similarly, enhanced improvement in plasma insulin level and statistically significant reduction in triglyceride level was also observed for animals treated with the composition.ConclusionThese findings suggest that UP780, a chromone standardized Aloe based composition, could possibly be used as a natural supplement alternative to facilitate maintenance of healthy blood glucose levels.

Two new compounds from the aerial parts of Bergenia himalaica Boriss and their anti-hyperglycemic effect in streptozotocin-nicotinamide induced diabetic rats

Ethnopharmacological relevanceBergenia himalaica Boriss is mainly distributed in the temperate Himalayas between altitudes of 900 and 3000m ranging from the southeastern regions in central Asia and northern regions in South Asia. The plant has a long history of its use in traditional medicine for the treatment of various diseases such as diabetes, urinary complaints, kidney stones, hemorrhagic diseases and epilepsy. The aim of this study is to isolate pure compounds from Bergenia himalaica Boriss, elucidate their structures and determine their blood glucose lowering activity to obtain additional scientific evidence for its usage in traditional medicine for the management of diabetes. Materials and methodsThe crude methanolic extract from the aerial parts of Bergenia himalaica Boriss was separated into EtOAc and water sub-extracts and the EtOAc sub-extract was further divided into petroleum ether soluble and insoluble fractions. The pet-ether insoluble fraction was subjected to fractionation through column chromatography followed by prep. TLC. The blood glucose lowering activity of the 2 new compounds was evaluated in streptozotocin–nicotinamide induced diabetic rats. Additionally, glucose-stimulated insulin secretion was measured on isolated mice islets. ResultsTwo new compounds bergenicin and bergelin were isolated and their structures determined on the basis of spectral analysis. Significant decrease of blood glucose was observed at 1-h (1.0mg/kg) and 2-h (0.5mg/kg), after bergenicin administration to the diabetic rats and at 2-h (1.0mg/kg) and 3-h (0.5mg/kg), after bergelin administration. Bergenicin, but not bergelin, enhanced glucose-stimulated insulin secretion in isolated pancreatic islets. ConclusionsIn the present studies two new compounds, bergenicin and bergelin were isolated from Bergenia himalaica Boriss and their structures were elucidated. Both the compounds showed anti-hyperglycemic effects in streptozotocin–nicotinamide induced diabetic rats. Bergenicin showed insulinotropic effect; suggesting that the anti-hyperglycemic effect is mostly due to enhancement of insulin secretion from pancreatic β-cells.

Short-Term Caraway Extract Administration Improves Cardiovascular Disease Risk Markers in Streptozotocin-Induced Diabetic Rats: A Dose-Response Study

ABSTRACTObjective: This study examined the effects of caraway plant on blood levels of glucose, lipid profile, and C-reactive protein in diabetic rats. Methods: Thirty two male Wistar rats were randomly divided into four groups: group 1: nondiabetic control rats, group 2: diabetic rats, group 3, and 4 (caraway treated diabetic groups): each rat was treated with caraway at doses of 1 g/kg in group 3 and 2 g/kg in group 4. Diabetes was induced by a single intraperitoneal injection of 60 mg/kg streptozotocin. Caraway was administered as aqueous extract orally once a day for 3 weeks. Finally, blood samples were collected and fasting blood glucose, serum lipid profile, and C-reactive protein levels were determined. Data were analyzed statistically by one-way Analysis of Variance and considered to be significant when p < .05. Results: Diabetic rats receiving 1 and 2 g/kg caraway extracts had significantly lower total cholesterol (p = .036 and p = .010, respectively), low-density lipoprotein (p = .001 and p = .002, respectively), non-HDL-C (p = .003 and p = .007, respectively), LDL-C to HDL-C ratio (p = .002) and atherogenic index (p = .001) than that of diabetic control rats. Moreover, there were significant changes in fasting blood glucose in diabetic groups treated with 1 and 2 g/kg caraway extracts (p = .001 and p = .027, respectively) compared with the diabetic control. However, caraway did not have any significant effect on C-reactive protein level in diabetic rats. Conclusion: This study suggests that caraway can exhibit blood glucose and lipid lowering activities in diabetes, without any effect on C-reactive protein level.

Metformin: A Journey from countryside to the bedside

The discovery of metformin as an anti-diabetic drug spans three centuries-beginning in the herb, Galega officinalis in the 17 th century and ending in its launch as Glucophage in the 20 th century. Extract from the leaves of G. officinalis was used to treat many ailments such as fever, plague and symptoms of diabetes. The herbal extract contains guanidine and galegine as major chemical components. These compounds, although had an anti-diabetic effect, were too toxic for clinical use. Discovery of antimalarial drug, paludrine which also had blood glucose lowering activity, at the Imperial Chemical Industries, UK prompted evaluation of paludrine analogues, as potential anti-diabetic agents. This speculation was also based on the structure of paludrine, which partly resembled galegine, a compound present in the extract of G. officinalis. This development coupled with Garcia's positive results using flumamine, a guanidine analogue, on 'flu' fever accelerated the evaluation of guanidine and galegine analogues for anti-diabetic activity. These efforts culminated in the discovery of metformin, introduced as 'Glucophage', by Jean Sterne, in 1957. In this article, we have highlighted the journey of metformin from a common countryside herb to its present day status of a 'Wonder Drug' sitting at the bedside of diabetic patients.

Effect of Atorvastatin on Pharmacology of Sitagliptin in Streptozotocin-Nicotinamide Induced Type-II Diabetes in Rats

Prolonged type 2 diabetes mellitus (Type2DM) may lead to high risk of cardiovascular disease (CVD) requiring a global therapeutic approach. Statin therapy has proven its efficacy in reducing CVD events in Type2 DM patients. Dipeptidyl peptidase-4 inhibitors (gliptins), which are increasingly used to target hyperglycemia. In the present study type 2 DM in rats by i.p. Administration of Streptozotocin (STZ); (60 mg/kg) -Nicotinamide (120 mg/kg). Diabetes induced rats were divided into groups and treated with Sitagliptin alone and in combination with atorvastatin for 7 days. Blood samples were collected by retro orbital puncture. Mean glucose concentration was measured by GODPOD method using commercial glucose kits and sitagliptin in plasma was estimated by RP-HPLC method using methanol: water (60:40 v/v, containing 10 mM Tris and 10 mM Triethylamine) was adjusted to pH 9.0 using 1 mol/L hydrochloric acid. The blood glucose lowering activity of sitagliptin was increased by the presence of atorvastatin in diabetic rats. The pharmacokinetic (PK) and pharmacodynamic (PD) parameters of sitagliptin in diabetic rats were significantly changed in the presence of atorvastatin. The present study concludes that co-administration of atorvastatin with sitagliptin significantly improved the responses of sitagliptin in diabetic rats. Improved glucose metabolism and increased sitagliptin levels due to competitive inhibition of CYP 3A4 enzyme by atorvastatin may be responsible for the improved anti-hyperglycemic activity of sitagliptin

One-Step Production of Bioactive Proteins through Simultaneous PEGylation and Refolding

Production of protein therapeutics often involves in vitro refolding from bacterial inclusion bodies and subsequent PEGylation to improve protein stability and plasma half-life. Here, we devised a novel strategy for one-step production of site-specific mono-PEGylated proteins with good bioactivity and improved biostability by integrating PEGylation and protein refolding (IPPR). Using lysozyme and recombinant human fibroblast growth factor 21 (rhFGF21) as model proteins, we showed that both PEGylation and refolding of denatured proteins have been simultaneously accomplished by IPPR with high efficiency of refolding yield and bioconjugation. PEGylated rhFGF21 by IPPR has a similar capacity as the native rhFGF21 to stimulate glucose uptake in 3T3-L1 cells, but exhibits prolonged blood glucose and triglyceride lowering activity levels in the ob/ob diabetic mouse model. Hence, IPPR will significantly facilitate the generation of protein therapeutics.

Synthesis and blood glucose lowering activity of some novel benzenesulfonylthiourea derivatives substituted with 4-aryl-1-oxophthalazin-2(1H)yl-ones

Some new benzenesulfonylthiourea derivatives substituted with phthalazones (2a–q) were synthesized by refluxing the appropriate 4-aryl-1-oxophthalazin-2(1H)yl benzenesulfonamides with isothiocyanate in dry acetone over anhydrous K2CO3. All the synthesized compounds were characterized on the basis of IR, 1H NMR, MS data and elemental analysis. These synthesized compounds (2a–q) at the dose of 20 mg/kg were tested for antihyperglycemic activity in the glucose-fed hyperglycemic normal rat model and among these compounds 2f and 2m showed modest antihyperglycemic activity.

Tapping the Philippines' Rich Biodiversity for the Treatment of Diabetes

The Philippines is a mega-diverse country, and is one of the 17 countries that contain two-thirds of the entire biological diversity of the Earth [1]. This provides a fertile source of plant-derived bioactive agents for the treatment of diabetes, which is a disease that threatens a significant portion of the global population [2]. Employing the oral glucose tolerance test, the hypoglycemic activity, in normoglycemic mice, of methanolic extracts of ten Philippine plants (Syzygium cumini, Morinda citrifolia, Andropogon citratus, Ipomoea aquatica, Mimosa pudica, Averrhoa bilimbi, Polymnia sanchifolia, Benincasa hispida, Anacardium occidentale, Helianthus annuus) folklorically used for the treatment of diabetes was determined. To elucidate the mechanism of action, the alpha glucosidase inhibitory activity of the active plant extracts was evaluated employing a spectrophotometric technique. Among the plant extracts tested, Benincasa hispida, Morinda citrifolia, and Helianthus annuus were found to show promising results in significantly lowering blood glucose level with 47.80%, 40.10% and 36.69% hypoglycemic activity, respectively, when administered orally at a dose of 5 mg/20 g mouse. In comparison, metformin, administered at a dose of 3 mg/20 g mouse gave a 48.95% hypoglycemic activity. The same plant extracts did not exhibit inhibitory activity against alpha glucosidase at a concentration of 1000 µg/mL implying a different mechanism of action for the observed blood glucose lowering activity. Isolation and identification of the active principles from these active plants are being pursued. Acknowledgements: The authors would like to thank the funding agencies who made this work possible: National Institutes of Health through the FIRCA Grant Prime Award No. 1R03TW008213 – 01A1, Subaward No. 0000007997 and the University of the Philippines Diliman. Special acknowledgment to the University of Maryland Baltimore County, Maryland, USA, the Institute of Chemistry and the Natural Sciences Research Institute, University of the Philippines Diliman, Quezon City, Philippines where all research support and collaborative work were done.

Metformin in patients with ischemic heart disease and type 2 diabetes mellitus: mechanism of action and clinical efficiency

Diabetes mellitus is one of the leading causes of death in modern society, primarily due to its cardiovascular complications. This factor drives search for novel pharmacologic agents to affect not only glycemic levels, but also the cardiovascular prognosis in diabetic patients with ischemic heart disease. Recent studies demonstrate that aside from basic blood glucose lowering action, metformin shows beneficial influence on blood rheology and vascular tone, hemostasis, oxidative stress, lipid spectrum and delivers and an ant-ischemic effect. Here we review clinical and experimental evidence on cardio- and vasoprotective effects of metformin, highlighting their molecular mechanisms.

Evaluation of Tribal Medicinal Plants of Ramghat Region for their Antidiabetic Potential In Alloxan Induced Diabetic Rats

This study presents the rich resource of medicinal plants used by the tribes of Ramghat region of Western Ghats (Maharastra, India) against diabetes. It was aimed to identify and screen the important species used in the management of Diabeties and these plants create a basis for phytochemical evaluation which can lead to the discovery of biologically active compounds. In the present study, Pet-ether, Chloroform, Ethyl acetate and Ethanol extracts of fruits of Bredilia retusa, Habenaria rarifolia, Syzigium hemisphericum, Hydnocarpus pentandra were comparatively evaluated for their blood glucose lowering and hyperlipidaemic activity. The ethyl acetate and ethanolic extract showed significant activity in acute study as compare to diabetic control, but none of the extract showed significant results in prolonged study. The experiment also confirmed that ethyl acetate and ethanolic extracts significantly reduced the elevated total cholesterol, triglyceride level, SGOT, SGPT, ALD and Urea level. Our data suggests a significant antidiabetic and hyperlipidaemic effects of all the fruit extracts in alloxan diabetic rats.

Hypoglycemic and Antidiabetic Profile of the Aqueous Root Extracts of Leptadenia hastata in Albino Rats

This study was designed to evaluate the antidiabetic profile and the hypoglycaemic activity of aqueous root extracts of L. hastata in normal and alloxan-induced diabetic rats model. Eighty five albino rats were used for this study out of this thirty five were used subjected to experimental diabetes by the use of alloxan at a dose of 160 mg kg(-1) body weight. Seven experimental groups of five rats per group (A-G) were used for this study. A standard antidiabetic drug (insulin) group (B) and normal saline group (G) serves as positive control. The blood glucose lowering activity of the extract, insulin and normal saline groups were monitored at 0, 1, 3, 6, 12 and 18 hpost extract administration. On the other hand the remaining fifty albino rats were used to determine the acute toxicity and the hypoglycemic activity of the extract. The blood glucose levels of the rats were monitored at 0, 7, 14, 21 and 28 days post extract administration. Oral administration of aqueous root extract at 600 and 800 mg kg(-1) b.wt have significantly (p < 0.05) decreased the blood glucose in diabetic albino rats. On the other hand the hypoglycemic activity of the aqueous root extract on normal rats at dose of 1000 mg kg(-1) b.wt have significantly (p < 0.05) decreases blood glucose level in normal albino rats. The results of the current study have demonstrated the antidiabetic and hypoglycaemic effects of L. hastata aqueous root extracts and underscore its potentials in the management of diabetes mellitus especially following prolonged use in days.

Synthesis, characterization and biological evaluation of some novel 2,4-thiazolidinediones as potential cytotoxic, antimicrobial and antihyperglycemic agents

A series of some novel 2,4-thiazolidinediones (TZDs) (2a–x) have been synthesized and characterized by FTIR, 1H NMR, 13C NMR and LC mass spectral analysis. All the synthesized compounds were evaluated for their cytotoxicity, antimicrobial and in vivo antihyperglycemic activities. Among the tested compounds for cytotoxicity using Brine Shrimp Lethality assay, compound 2t ((Z)-5-(4-((E)-3-oxo-3-(thiophen-2-yl)prop-1-enyl)benzylidene)-1,3-thiazolidine-2,4-dione) exhibited significant inhibitory activity at ED50 value 4.00±0.25μg/mL and this level of activity was comparable to that of the reference drug podophyllotoxin with ED50 value 3.61±0.17μg/mL. Antimicrobial activity was screened using agar well diffusion assay method against selected Gram-positive, Gram-negative and fungal strains and the activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. From the results of antimicrobial activity compound 2s ((Z)-5-(4-((E)-3-(3,5-bis(benzyloxy)phenyl)-3-oxoprop-1-enyl)benzylidene)-1,3-thiazolidine-2,4-dione) was found to be the most active against all the tested strains of microorganisms with MIC value 16μg/mL. In vivo antihyperglycemic effect of twenty four TZDs (2a–x) at different doses 10, 30 and 50mg/kg b.w (oral) were assessed using percentage reduction of plasma glucose (PG) levels in streptozotocin-induced type II diabetic rat models. From the results, the novel compound 2x ((Z)-5-(4-((E)-3-(9H-fluoren-2-yl)-3-oxoprop-1-enyl)benzylidene)-1,3-thiazolidine-2,4-dione) exhibited considerably potent blood glucose lowering activity than that of the standard drug rosiglitazone and it could be a remarkable starting point to evaluate structure–activity relationships and to develop new lead molecules with potential cytotoxicity, antimicrobial and antihyperglycemic activities. In addition molecular docking studies were carried out against PPARγ molecular target using Molegro Virtual Docker v 4.0 to accomplish preliminary confirmation of the observed in vivo antihyperglycemic activity.

Synthesis and pharmacological evaluation of some novel 2-pyrazolines bearing benzenesulfonamide as anti-inflammatory and blood glucose lowering agents

A series of novel pyrazolines (2a–l) bearing benzenesulfonamide moiety were synthesized by condensing appropriate chalcone (1a–l) with 4-hydrazinobenzenesulfonamide hydrochloride. Structure of all novel synthesized compounds was characterized on basis of elemental analysis data and spectral data (IR, 1HNMR, MS). Compounds (2a–l) were screened for in vivo anti-inflammatory action in carrageenan-induced rat paw edema model and blood glucose lowering action in glucose fed hyperglycemic normal rats. Compounds 2a, 2e, and 2l showed significant anti-inflammatory action (more than 75 %) at 5 h and also showed superior gastrointestinal safety profiles as compared to celecoxib. One compound (2i) was found to exhibit significant blood glucose lowering activity.

The Lyn Kinase Activator MLR-1023 Is a Novel Insulin Receptor Potentiator that Elicits a Rapid-Onset and Durable Improvement in Glucose Homeostasis in Animal Models of Type 2 Diabetes

MLR-1023 [Tolimidone; CP-26154; 2(1H)-pyrimidinone, 5-(3-methylphenoxy)] is an allosteric Lyn kinase activator that reduces blood glucose levels in mice subjected to an oral glucose tolerance test (J Pharmacol Exp Ther 342:15-22, 2012). The current studies were designed to define the role of insulin in MLR-1023-mediated blood glucose lowering, to evaluate it in animal models of type 2 diabetes, and to compare it to the activities of selected existing diabetes therapeutics. Results from these studies show that in an acute oral glucose tolerance test MLR-1023 evoked a dose-dependent blood glucose-lowering response that was equivalent in magnitude to that of metformin without eliciting a hypoglycemic response. In streptozotocin-treated, insulin-depleted mice, MLR-1023 administration did not affect blood glucose levels. However, MLR-1023 potentiated the glucose-lowering activity of exogenously administered insulin, showing that MLR-1023-mediated blood glucose lowering was insulin-dependent. In a hyperinsulinemic/euglycemic clamp study, orally administered MLR-1023 increased the glucose infusion rate required to sustain blood glucose levels, demonstrating that MLR-1023 increased insulin receptor sensitivity. In chronically treated db/db mice, MLR-1023 elicited a dose-dependent and durable glucose-lowering effect, reduction in HbA1c levels and preservation of pancreatic β-cells. The magnitude of effect was equivalent to that seen with rosiglitazone but with a faster onset of action and without causing weight gain. These studies show that MLR-1023 is an insulin receptor-potentiating agent that produces a rapid-onset and durable blood glucose-lowering activity in diabetic animals.

Synthesis and blood glucose lowering activity of some novel benzenesulfonylurea derivatives substituted with 6-aryl-4,5-dihyropyridazin-3(2H)-ones

Five (2a–e) benzenesulfonylurea derivatives bearing pyridazinone were synthesized by refluxing the appropriate 6-aryl-2-(p-sulfamylphenyl)-4,5-dihydropyridazine-3(2H)-one with benzylisocyanate in dry acetone over anhydrous K2CO3. These compounds were characterized by elemental analysis and various spectroscopic techniques viz; IR, 1H NMR, 13C NMR, and MS data. These compounds (2a–e) at the dose of 20 mg/kg were tested for blood glucose lowering activity in glucose-fed hyperglycemic normal rats. Compound 2b showed more potent anti-hyperglycemic activity than the standard drug gliclazide. The compound 2b was also tested for its hypoglycemic effect in fasted normal rats. It also showed significant hypoglycemic effect (but less than that of gliclazide).

Feasibility of Structural Modification of Retinoid X Receptor Agonists to Separate Blood Glucose-Lowering Action from Adverse Effects: Studies in KKA&lt;sup&gt;y&lt;/sup&gt; Type 2 Diabetes Model Mice

Retinoid X receptor (RXR) agonists are reported to exhibit blood glucose-lowering action owing to peroxisome proliferator-activated receptor (PPAR)/RXR or liver X receptor (LXR)/RXR activation, but may also cause adverse effects such as blood triglyceride elevation. In order to examine the feasibility of separating the glucose-lowering action from the adverse effects, we examined the effects of RXR agonists (NEt-TMN), NEt-3IB, and NEt-3IP, which have different heterodimer-activating patterns, in KKA(y) type 2 diabetes model mice. We found that NEt-3IB induced lower degrees of hepatomegaly and blood triglyceride (TG) elevation than the other RXR agonists, even though all of them showed similar blood glucose-lowering action on repeated administration. These findings indicate that structural modification of RXR agonists is a potentially effective strategy to reduce adverse effects while retaining desired activities.