Glucose Tolerance In Diabetic Rats Research Articles

The neuroprotective role of celastrol on hippocampus in diabetic rats by inflammation restraint, insulin signaling adjustment, Aβ reduction and synaptic plasticity alternation

Celastrol, the primary constituent of Tripterygium wilfordii, has demonstrated neuroprotective properties in rats with dementia by reducing inflammation. A high-fat diet and streptozotocin injection were utilized to establish a diabetic rat model, which was then employed to investigate the possible protective effect of celastrol against the development of diabetes-induced learning and memory deficits. Afterwards, the experimental animals received a dose of celastrol by gavage (4 mg/kg/d). An animal study showed that celastrol enhanced insulin sensitivity and glucose tolerance in diabetic rats. In the Morris water maze test, rats with diabetes performed poorly in terms of spatial learning and memory; treatment with celastrol improved these outcomes. Additionally, administration of celastrol downregulated the expression of inflammatory-related proteins (NF-κB, IKKα, TNF-α, IL-1β, and IL-6) and greatly reduced the generation of Aβ in the diabetic hippocampus tissue. Moreover, the insulin signaling pathway-related proteins PI3K, AKT, and GSK-3β were significantly upregulated in diabetic rats after celastrol was administered. Also, celastrol prevented damage to the brain structures and increased the synthesis of synaptic proteins like PSD-95 and SYT1. In conclusion, celastrol exerts a neuroprotective effect by modulating the insulin signaling system and reducing inflammatory responses, which helps to ameliorate the cognitive impairment associated with diabetes.

Chinese herb couple against diabetes: integrating network pharmacology and mechanism study

Cassia twig is a dry twig of Cinnamomum cassia Presl, a Lauraceae plant. Astragalus L is one of the largest genuses of flowering plants in the Leguminosae family. Roots of A. membranaceus Bge. var. mongholicus (Bge.) Hsiao, A. membranaceus (Fisch.) Bge. Chinese herb couple refers to the matching of two herbs in pairs, mostly with synergistic effects or toxicity reduction. This Chinese herb couple (Cassia twig-Astragalus) come from the classic famous book “Zhang Xichun’s book on Chinese herb couple”, which is widely used to treat diabetes. Moreover, both Cassia twig and Astragalus belong to the homology of medicine and food. However, its mechanism is still unclear. The study identified the effective components of Cassia twig-Astragalus by UPLC-Q-TOF-MS/MS and investigated the mechanism of Cassia twig-Astragalus in treating diabetes by virtue of network pharmacology, molecular docking and experimental verification. Firstly, based on UPLC-Q-TOF-MS/MS and network pharmacology, a total of 10 active ingredients of Astragalus and 6 active ingredients of Cassia twig were screened, and a total of 13 key targets were obtained. There were 64 targets at the intersection of Cassia twig-Astragalus with diabetes, mainly including IL-17, TNF, NF-κβ, AGE-RAGE signaling pathway, etc. It mainly involves the response of cells to insulin stimulation, the response to insulin and the positive regulation of cell adhesion. Secondly, molecular docking results showed that quercetin has good binding activities with AKT1 and TNF. Calycosin has good binding activities with AKT1, TNF and CAV1. Formononetin has good binding activities with TNF and IL-6. Isorhamnetin has good binding activities with AKT1, TNF and IL-6. Finally, the animal experiments showed that Cassia twig-Astragalus could improve the body weight, blood glucose and glucose tolerance in diabetic rats. After the intervention with Cassia twig-Astragalus, the inflammatory factors (IL-10, TNF-α, IL-6) were significantly improved in diabetic rats, which also effectively reduced TG and TC. Communicated by Ramaswamy H. Sarma

EDEM1 regulates the insulin mRNA level by inhibiting the endoplasmic reticulum stress-induced IRE1/JNK/c-Jun pathway

Pancreatic beta cells produce and secrete insulin as a response to rises in blood glucose. Despite the advances in understanding glucose-regulated insulin transcription and translation the mechanisms triggering the synthesis of new insulin molecules are still incompletely described. In this report, we identify EDEM1 as a new modulator of insulin synthesis and secretion. In the presence of EDEM1, INS-1E cells secrete significantly more insulin upon glucose stimulation compared to control cells. We found that overexpression of EDEM1 inhibited the IRE1/JNK/c-Jun pathway, leading to an increase in the insulin mRNA level. Similarly, EDEM1 transduced human islets secreted significantly more insulin upon stimulation. Furthermore, EDEM1 improved insulin secretion restoring normoglycemia and glucose tolerance in diabetic rats. We propose EDEM1 as a regulator of the UPR via IRE1/XBP1s and IRE1/JNK/c-Jun signaling cascades and insulin transcription in pancreatic β-cells, supporting EDEM1 as a potential target for the treatment of diabetes.

Safety and antidiabetic activity of Lagenaria siceraria (Molina) Standl. juice in streptozotocin -induced diabetic rats

Ethnopharmacological relevanceDiabetes and its complications have overwhelmed India's healthcare system. Current therapies are expensive and have adverse side effects, thus dietary changes and alternative treatments are needed. Lagenaria siceraria (Molina) Standl. Juice is used mainly for its nutritional and medicinal values, however toxicity of the juice and antidiabetic effects have been poorly characterized. Aim of the studyTo investigate the toxicity, anti-diabetic and anti-inflammatory efficacy of Lagenaria siceraria (Molina) Standl. (LS) juice. Materials and methodsIn vitro antidiabetic (α-glucosidase, α-amylase and DPP-4 inhibitory) activities were screened using standard procedures. The glucose uptake test was carried out by using L6 rat skeletal muscle cell line. In vivo sub-acute toxicity of LS juice was assessed on Wistar rats. Wistar rats were induced with diabetes by a single intraperitoneal (I.P) injection of freshly prepared streptozotocin (55 mg/kg body weight). The animals were randomly divided into 6 groups: normal control, untreated diabetic control, diabetic rats. Different dose of 200 mg/kg, 400 mg/kg and 600 mg/kg body weight of LS juice were administered, one group of diabetic rats were administered with 2 IU/mL insulin. The rats were sacrificed on the 31st day of the experiment and various in vivo biochemical parameters were evaluated in the serum and tissue homogenates of diabetic rats. ResultsSignificant dose-dependent inhibition of α-amylase (22.6%), α-glucosidase (50.13%), and DPP-4 (61.50%) activity was observed by LS juice. LS juice (10 μg/mL) increased insulin-mediated 2NBDG (2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) Amino)-2-Deoxyglucose) absorption in L6 cells. Animals treated with LS juice showed no toxicity or unfavorable pharmacological effects. Lagenaria siceraria (Molina) Standl. Juice improved glucose tolerance in diabetic rats with reduced fasting blood glucose. Lipopolysaccharide induced NF-κB, TNF-α and IL-1β production was also decreased in rats fed with LS juice. ConclusionLagenaria siceraria (Molina) Standl. Juice has demonstrated promising anti-inflammatory properties as well as the capacity to inhibit the digestion enzymes glucosidase and amylase. Our findings thus open new avenues for further research into the antidiabetic potential of LS juice.

Ameliorative effects of phlorotannin-rich fraction of Sargassum tenerrimum in high-fat diet and low dose streptozotocin-induced metabolic changes and oxidative stress in diabetic rats

Introduction: Type 2 diabetes mellitus (T2D) is a progressing polygenic disease demanding a multitargeted treatment strategy. Sargassum tenerrimum (ST) is a marine brown alga with potentially bioactive chemicals that could be used as innovative biotherapeutics for diabetes treatment. The current research examined the potential of the phlorotannin-rich fraction from S. tenerrimum (PST) to mitigate diabetes in Wistar albino rats induced with high-fat diet (HFD) and streptozotocin (STZ) administration. Methods: Diabetic rats were given PST (200 and 400 mg/kg) or metformin (250 mg/kg) orally three weeks, and followed by the measurements of insulin, glycemic factors, biological markers of oxidative stress, tumor necrosis factor-alpha (TNF-α), as well as hepatic and pancreatic histopathological changes. Results: PST treatment significantly decreased fasting blood glucose, insulin resistance, lipid profile, hepatic profile, and TNF- α levels and improved serum insulin and glucose tolerance in diabetic rats. In the skeletal muscles of diabetic rats, PST led to a significant rise in antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) reductase, and a decrease in lipid peroxidation. Furthermore, PST treatment significantly reduced pancreatic-cell damage and hepatic fatty accumulation. PST was more efficacious at 400 mg/kg exhibiting a dose-dependent effect. Conclusion: PST improves glucolipid metabolism in HFD and STZ-induced diabetic rats, probably by reducing hyperglycemia, insulin resistance, dyslipidemia, oxidative stress, inflammation, and damage to pancreatic and hepatic architectures. The findings suggest that PST has a curative impact on diabetes mellitus type 2 and represents a new subject of study for the treatment of diabetes naturally.

Dual A1 and A2A adenosine receptor antagonists, methoxy substituted 2-benzylidene-1-indanone, suppresses intestinal postprandial glucose and attenuates hyperglycaemia in fructose-streptozotocin diabetic rats

Background/AimRecent research suggests that adenosine receptors (ARs) influence many of the metabolic abnormalities associated with diabetes. A non-xanthine benzylidene indanone derivative 2-(3,4-dihydroxybenzylidene)-4-methoxy-2,3-dihydro-1 H-inden-1-one (2-BI), has shown to exhibit higher affinity at A1/A2A ARs compared to caffeine. Due to its structural similarity to caffeine, and the established antidiabetic effects of caffeine, the current study was initiated to explore the possible antidiabetic effect of 2-BI.MethodsThe study was designed to assess the antidiabetic effects of several A1 and/or A2A AR antagonists, via intestinal glucose absorption and glucose-lowering effects in fructose-streptozotocin (STZ) induced diabetic rats. Six-week-old male Sprague-Dawley rats were induced with diabetes via fructose and streptozotocin. Rats were treated for 4 weeks with AR antagonists, metformin and pioglitazone, respectively. Non-fasting blood glucose (NFBG) was determined weekly and the oral glucose tolerance test (OGTT) was conducted at the end of the intervention period.ResultsDual A1/A2A AR antagonists (caffeine and 2-BI) decreased glucose absorption in the intestinal membrane significantly (p < 0.01), while the selective A2A AR antagonist (Istradefylline), showed the highest significant (p < 0.001) reduction in intestinal glucose absorption. The selective A1 antagonist (DPCPX) had the least significant (p < 0.05) reduction in glucose absorption. Similarly, dual A1/A2A AR antagonists and selective A2A AR antagonists significantly reduced non-fast blood glucose and improved glucose tolerance in diabetic rats from the first week of the treatment. Conversely, the selective A1 AR antagonist did not reduce non-fast blood glucose significantly until the 4th week of treatment. 2-BI, caffeine and istradefylline compared well with standard antidiabetic treatments, metformin and pioglitazone, and in some cases performed even better.Conclusion2-BI exhibited good antidiabetic activity by reducing intestinal postprandial glucose absorption and improving glucose tolerance in a diabetic animal model. The dual antagonism of A1/A2A ARs presents a positive synergism that could provide a new possibility for the treatment of diabetes.

Astragaloside IV ameliorates insulin induced insulin resistance in HepG2 cells through reactive oxygen species mediated c-Jun N-terminal kinase pathway.

To investigate the effects and elucidate the mechanism of Astragaloside IV (AS-IV) for insulin resistance (IR) and type 2 diabet es mellitus (T2DM). CCK8 kit was used to detect cell viability, glucose detection kit was used to detect the concentration of glucose in cell supernatant, reactive oxygen species (ROS) detection kit and Western blot were used to explore the mechanism of Astragaloside IV (AS-IV) in improving IR. A diabetic rat model was also established by feeding high sugar and fat diet and streptozotocin (STZ) injection. After treatment with AS-IV, rosiglitazone (ROZ), or normal saline, the fasting blood glucose (FBG), C peptide (C-P), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and the glucose tolerance were assessed. AS-IV could effectively reduce the content of ROS and increase the glucose uptake in high insulin-treated IR-type HepG2 cells. The results of molecular mechanisms indicated that AS-IV could improve insulin resistance by reducing JNK phosphorylation and regulating c-Jun N-terminal kinase (JNK) downstream protein expression. Additionally, AS-IV could significantly reduce the levels of FBG, TNF-α, IL-6 and the glucose tolerance in diabetic rats ( < 0.05 or < 0.01). The high and medium dose groups of AS-IV could significantly increase the C-P levels in diabetic rats ( < 0.05 or < 0.01). Our results indicated that AS-IV improve liver IR through the JNK pathway and ROS, which meant a new molecular target for the treatment of diabetes. The AS-IV also helped to prevent and improved the insulin resistance of rats.

A study on dislipidemic and hyper glycemic activities of Aloe vera

Aloe, a popular plant, has a long history as a versatile folk remedy. The plant can be alienated mainly into two products: gel and latex. Aloe vera gel is the leaf pulp or mucilage, aloe latex, commonly referred to as “aloe juice,” is a bitter yellow exudate from the pericyclic tubules just underneath the external skin of the leaves. Extracts of aloe gum efficiently improves glucose tolerance in diabetic rats as well as in normal rats. Treatment of long term however not solitary dose of exudates of Aloe barbadensis leaves impart hypoglycemia in alloxanized diabetic rats. Solitary as well as long term doses of acrimonious component of the same plant also displayed hypoglycemic effect in diabetic rats. This response of Aloe vera and its acrimonious component is by the stimulus of synthesis and/or release of insulin from pancreatic beta cells. Aloe vera also have got the anti-inflammatory potential in a dose reliant way and relieves wound in diabetic mice by healing activity. The current article highlights the biological activities of Aloe Vera.

Hepatic Oxidative Damages and Glucose Tolerance in Diabetic Rats Exposed to Repeated Oral Doses of Diazinon

Background: Environmental pollutants including organophosphate insecticides impair glucose metabolism by altering hepatic oxidation and play an important role in the development of diabetes and its complications. The aim of this study was to assess the impacts of repeated oral doses of Diazinon, an organophosphate insecticide, which is known to impair the glucose metabolism and its tolerance through oxidative stress in the rat liver. Methods: Diabetes was induced in rats by a single dose of freshly prepared Streptozotocin at 60 mg/kg. Both normal and diabetic rats were exposed to daily oral Diazinon at 20 mg/kg for 21 days. Subsequently, the effects on the rats’ liver were assessed by glucose tolerance test, histopathology examinations and antioxidant capacity measurement. Results: The glucose tolerance tests showed impairment in the non-diabetic rats exposed to Diazinon, while the difference in glucose tolerance between the diabetic rats treated with or without Diazinon was not significant. Diazinon in diabetic rats caused greater histopathological changes along with significant elevations in the lipid peroxidation and antioxidant enzymes, including superoxide dismutase and catalase in the liver tissue. Conclusion: Subacute exposure to Diazinon exacerbated hepatotoxicity by inducing oxidative stress in diabetic rats. The superoxide dismutase and catalase activities increased due to the oxidative damages in rats’ liver caused by Diazinon.

Antidiabetic activity and metabolite profiles of ascidian Halocynthia roretzi

• Consumption of ascidian of H. roretzi tissues significantly improves the glucose tolerance in diabetic rats. • Consumption of ascidian H. roretzi tissue significantly reduces plasma cholesterol and triglyceridesin levels in diabetic rats. • Ascidian H. roretzi tissue is a rich source of amino acid, unsaturated fatty acids, vitamins, and bioactive compounds. • Ascidian H. roretzi tissue contain 11 anti-diabetes molecules and high levels of natural astaxanthin. Halocynthia roretzi has been cultured and utilized as a nutritious seafood in Southeastern Asia for many years because of its abundance active molecules. Here, we reported that feeding of H. roretzi tissues resulted in improving oral glucose tolerance in rats. To screen the active components, we identified 950 chemical compounds from H. roretzi metabolome. Furthermore, 11 molecules with the activity of regulating blood glucose and lipids were selected based on structural identity. Among them, two natural products, hesperetin and astaxanthin were selected for further quantitative detection. The results showed that concentrations of hesperetin and astaxanthin in the tissues of H. roretzi were calculated to be 13.7 ± 9.5 and 167.9 ± 48.4 µg/100 g, respectively. The high content of astaxanthin in H. roretzi indicates its potential roles and functions in anti-diabetes activity. Taken together, our results showed that H. roretzi could be used as a functional food supplement for regulating lipid/glucose metabolism.

ViphyllinTM, a Standardized Black Pepper Extract Exerts Antihyperglycemic Effect and Improves Sciatic Nerve Conduction in High Fat Diet/Streptozotocin-Induced Diabetic Model Rats.

PurposeResearch on plant-based formulations has drawn considerable attention in the management of diabetic neuropathy (DN) for having lesser side effects than the synthetic counterparts. Here, we have investigated for the first time the therapeutic effects of a standardized Piper nigrum L., (black pepper) seed extract, ViphyllinTM in mitigating hyperglycemia and neuropathic pain of type 2 diabetes model rats.MethodsType 2 diabetes was induced in male Wistar rats using high fat diet and a single dose of streptozotocin (60 mg/kg i.p.). The diabetic rats were orally administered with Viphyllin containing not less than 30% β-caryophyllene (BCP), at 25 mg, 50 mg and 100 mg/kg/day doses for 6 weeks. Changes in body weight, fasting blood glucose (FBG), glucose tolerance, and blood biochemical parameters were measured. The nociceptive response to thermal stimulus (tail flick test) and sciatic nerve conduction velocity (NCV) were recorded at the end of study.ResultsViphyllin treatment markedly improved the body weight and glucose tolerance in diabetic rats. Also, the extract could significantly reduce the diabetes-induced elevation in FBG, liver and kidney indices. Further, Viphyllin dose-dependently increased the nociception latency in tail flick test compared to untreated diabetic rats (p<0.05). Viphyllin at 100 mg/kg significantly increased the NCV (44.12±1.91*** m/s vs diabetic control 25.80±1.88 m/s). The antioxidant enzyme activities in sciatic nerve tissue were considerably increased in Viphyllin-treated groups compared to diabetic control. A 6-week treatment with Viphyllin markedly reversed the pathological manifestations of diabetes in vital organs such as liver, kidney and pancreas.ConclusionThe study concludes that Viphyllin exerts antidiabetic effects and improves nerve conduction to mitigate neuropathic pain.

Therapeutic Effects of Milk Thistle (Silybum marianum L.) and Artichoke (Cynara scolymus L.) on Nonalcoholic Fatty Liver Disease in Type 2 Diabetic Rats.

Background At present, nonalcoholic fatty liver disease (NAFLD) does not have an approved pharmacologic therapy. The present study investigated the protective effects and possible mechanisms of milk thistle (Silybum marianum L.) and artichoke (Cynara scolymus L.) in treating NAFLD in type 2 diabetic rats. Methods The NAFLD was established in rats after four weeks of type 2 diabetes induction. The animals were treated with pharmaceutical preparations of milk thistle (Livergol®) and artichoke (Atheromod-B®) extracts for eight weeks. After the end of the intervention, oral glucose tolerance, the serum parameters of oxidative stress, liver functional tests, and lipid profiles were evaluated. Histopathological changes were assessed by hematoxylin and eosin staining. Results Treatment with preparations of milk thistle and artichoke nonsignificantly improved glucose tolerance in diabetic rats. Both preparations significantly improved serum superoxide dismutase activity and the level of malondialdehyde. Although treatment with milk thistle reduced serum activity of aspartate aminotransferase and serum levels of triglyceride (TG), total cholesterol, and low-density lipoprotein-cholesterol, artichoke extracts only attenuated the serum level of TG. Milk thistle also effectively protected the liver from histological changes. Conclusions Milk thistle could be a promising pharmacological option for the treatment of NAFLD. Nonetheless, long-term randomized clinical trials are necessary to confirm the observed results.

Endoplasmic reticulum stress-dependent activation of TRB3-FoxO1 signaling pathway exacerbates hyperglycemic nephrotoxicity: Protection accorded by Naringenin

Endoplasmic reticulum (ER) dysfunction contributes greatly to the pathophysiology of hyperglycemic nephrotoxicity. This study unravels the critical role of Tribbles 3 (TRB3)-Forkhead box O1 (FoxO1) signaling pathway during hyperglycemic renal toxicity. It also uncovers the novel role of Naringenin, a flavanone, in regulating ER stress in proximal tubular cells, NRK 52E, and kidneys of streptozotocin/nicotinamide induced experimental diabetic Wistar rats. Results demonstrate that expression of ER stress marker proteins including phosphorylated protein kinase ER like kinase (p-PERK), phosphorylated eukaryotic Initiation Factor 2α (p-eIF2α), X Box Binding Protein 1 spliced (XBP1s), Activating Transcription Factor 4 (ATF4) and C/EBP Homologous Protein (CHOP) were upregulated in diabetic kidneys indicating the activation of ER stress response due to nephrotoxicity. Treatment with Naringenin reduced the expression of TRB3, an ER stress-inducible pseudokinase, both in vitro and in vivo. Gene silencing of TRB3 enhanced Akt and FoxO1 phosphorylation and alleviated FoxO1 mediated apoptosis during hyperglycemic nephrotoxicity. Notably, TRB3 gene silencing effects were comparable to the response with Naringenin treatment. Prevention of nuclear colocalization of ATF4 and CHOP in Naringenin treated cells was evident. Naringenin also reduced insulin resistance, apoptosis and glycogen accumulation along with enhancement of glucose tolerance in diabetic rats. Prevention of ultrastructural aberrations in the ER of hyperglycemic renal cells by Naringenin confirmed its anti-ER stress effects. These findings affirm that activation of TRB3-FoxO1 signaling is critical in the pathogenesis of hyperglycemia-induced renal toxicity and protective effect of Naringenin via modulation of ER stress may be exploited as a novel approach for its management.

Swimming training and Plantago psyllium ameliorate cognitive impairment and glucose tolerance in streptozotocin–nicotinamide-induced type 2 diabetic rats

Brain malfunction is common in diabetic patients. On the other hand, a growing body of research points to the beneficial effect of medicinal plants and exercise training on insulin sensitivity and brain function. Therefore, the aim of the present study was to investigate the effect of co-administration of swimming training and Plantago psyllium (mixed with standard pelleted food at a weight ratio of 5%) on learning and memory impairment and glucose tolerance in type 2 diabetic rats. For this purpose, 10 healthy and 40 rats with type 2 diabetes were randomly allocated to five groups: healthy sedentary control group (Con), sedentary diabetic group (D), diabetic group subjected to swimming training (D + Tr), diabetic group receiving P. psyllium (D + Ps), and diabetic group subjected to swimming training and receiving P. psyllium (D + Ps + Tr). Diabetes was induced by a single intraperitoneal injection of nicotinamide (120 mg/kg) and streptozotocin (65 mg/kg) separately with 15 min intervals. Experimental groups were treated with swimming training and P. psyllium independently and simultaneously for 12 weeks. Lipid profile and food intake were measured and also, glucose tolerance was evaluated by glucose area under the curve (AUCg) using an oral glucose tolerance test. Passive avoidance learning (PAL) and memory were evaluated by shuttle box test and cognitive memory was assessed by novel object recognition (NOR) and elevated plus-maze (EPM) tests. Diabetic rats exhibited a significant increase in food intake, lipid profile, and AUCg compared to healthy rats. Step-through latency in the PAL acquisition trial (STL-a) and retention test (STL-r) were significantly lower in diabetic rats than in the control group. In the diabetic group without treatment, time spent in the dark compartment increased compared to the control group in the shuttle box test. Discrimination index and distance traveled reduced in diabetic rats. On the other hand, swimming training and P. psyllium alleviated food intake, lipid profile, and glucose tolerance in diabetic rats. Also, the STL-a, STL-r, discrimination index, and distance travelled in the D + Ps + Tr group were significantly more than the diabetic group. Results showed that 12 weeks of swimming training and receiving P. psyllium improved memory deficit in streptozotocin–nicotinamide-induced type 2 diabetic rats possibly through hypolipidemic and hypoglycemic effects. These results suggest that the administration of swimming training and P. psyllium simultaneously might be an effective intervention for the treatment of diabetes-induced behavioral deficits.

Design and Identification of a GPR40 Full Agonist (SCO-267) Possessing a 2-Carbamoylphenyl Piperidine Moiety.

GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic β-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and incretin, both of which are the pivotal regulators of glycemic control. Therefore, a GPR40 agonist is an attractive target for the treatment of type 2 diabetes mellitus. Using the reported biaryl derivative 1, we shifted the hydrophobic moiety to the terminal aryl ring and replaced the central aryl ring with piperidine, generating 2-(4,4-dimethylpentyl)phenyl piperidine 4a, which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with N-alkyl-N-aryl benzamides to lower the lipophilicity and restrict the N-alkyl moieties to the presumed lipophilic pocket using the intramolecular π-π stacking of cis-preferential N-alkyl-N-aryl benzamide. Among these, orally available (3S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (SCO-267) effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism.

Antihyperglycemic Effect of the Aqueous Extract of Foeniculum vulgare in Normal and Streptozotocin-induced Diabetic Rats.

Diabetes mellitus is associated with high blood glucose levels due to insulin shortcoming (insulinopenia) or defective insulin action. The objective of the study was to investigate the antidiabetic and antioxidant effects of Foeniculum vulgare in streptozotocin-induced diabetic rat. The effects of the leaves aqueous extract (LAE) of Foeniculum vulgare (F. vulgare) at a dose of 10 mg/kg on blood glucose levels were evaluated in normal and streptozotocin (STZ)- induced diabetic rats. Histopathological changes were also evaluated in liver in STZ-induced rats. Single oral administration of F. vulgare LAE reduced blood glucose levels 6 h after administration in STZ diabetic rats (p<0.0001). Furthermore, blood glucose levels were decreased in both normal (p<0.05) and STZ diabetic rats (p<0.0001) after the fifteenth day of treatment. During this test, both groups did not show any significant change in their body weight. Moreover, this aqueous extract improved oral glucose tolerance in diabetic rats and revealed a positive effect on liver histology. On the other hand, the extract used in this experiment showed an inhibitory concentration (IC50) of 50% of free radicals with a concentration of 43±1.19 µg/ml. While the synthetic antioxidant (BHT) had an IC50 equal to 22.67±2.17µg /ml. This study demonstrates the antihyperglycemic, hypoglycemic and antioxidant effects of the leaves of F. vulgare in normal and diabetic rats.

ε-Viniferin, a promising natural oligostilbene, ameliorates hyperglycemia and hyperlipidemia by activating AMPK in vivo.

ε-Viniferin (VNF), a naturally occurring oligostilbene (a resveratrol dimer), is mainly found in grapes and red wines. However, unlike resveratrol, the biological activity of VNF has not been widely studied. This study was conducted to investigate the beneficial effects of VNF on hyperglycemia and hyperlipidemia and further to reveal the underlying mechanism. The ameliorative effects of VNF in high-fat-diet and streptozotocin-induced type 2 diabetic rats were assessed physiologically, biochemically and histologically after oral administration of VNF (30 mg kg-1 and 60 mg kg-1) for 8 weeks. Western blotting and immunohistochemistry experiments were performed to determine the effects of VNF on the AMPK phosphorylation levels in the livers of diabetic rats. Molecular docking and molecular dynamics simulation were further performed to study the molecular-level interaction between VNF and AMPK. Meanwhile, the protective effects of VNF on the liver and kidney were also evaluated. The results showed that the VNF treatment caused a significant decrease in the concentrations of fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), and low density lipoprotein-cholesterol (LDL-C), and improved the glucose tolerance of diabetic rats. In addition, the liver and kidney damage indices such as alanine aminotransferase (ALT), aspartate aminotransaminase (AST), creatinine (CR), and blood urea nitrogen (BUN) were also lowered and improved. Moreover, VNF could increase the AMPK activation and attenuate histopathological changes in the liver of diabetic rats. The molecular docking and molecular dynamics simulation results revealed for the first time that VNF bound to the hinge region between the α- and β-units of AMPK and interacted with the active site of AMPK. In conclusion, VNF can effectively improve hyperglycemia and hyperlipidemia and exhibit protective effects on the liver and kidney functions. The underlying mechanism of VNF in hyperglycemia and hyperlipidemia may be related to the activation of AMPK in vivo. Our findings indicate that VNF is a potentially useful natural agent for the treatment of metabolic diseases, especially type 2 diabetes and hyperlipidemia.

Antidiabetic Activity of Root Tubers of Cyanotis tuberosa in Streptozotocin Induced Diabetic Rats

Diabetes mellitus arising due to insufficient insulin production or its action or both is characterized by hyperglycemia. According to WHO it ranks as the third leading cause of death. Presently available antidiabetic drugs have one or more side effects. There is a need for new antidiabetic agents that will have therapeutic effect with fewer side effects. Cyanotis tuberosa is traditionally used as ethno medicine for curing several ailments in India. The objective of this study was to evaluate the antihyperglycemic activity of root tubers of Cyanosis tuberosa (Commelinaceae) in STZ induced diabetic rats. Different doses of aqueous suspension and different solvent extracts (made by soxhlation) were given to the Streptozotocin induced diabetic rats orally by using oral gavage. After treatment aqueous suspension at the dose of 250 mg/kg b.w has markedly (69%) decreased the fasting blood glucose levels after 6 hours of treatment. Whereas among the solvents extracts hexane extract at the dose of 750mg/kg b.w has produced highest (87%) anti hyperglycemic activity than the other solvent extracts and it is higher than that of the standard drug glibenclamide (20 mg/kg b.w). No hypoglycemic effects were observed in the diabetic rats after the treatment. And Cyanosis tuberosa improves the oral glucose tolerance of diabetic rats when given the hexane extract at the dose of 750mg/kg b.w. Phytochemical analysis of the hexane extract revealed the presence of bioactive secondary metabolites such as flavonoids, tannins, saponins, terpenoids, phenolics, and triterpenes which are responsible for antihyperglycemic activity. In conclusion our findings suggest that the hexane extract of Cyanotis tuberosa can decrease the hyperglycemia in diabetic rats most efficiently without any side effects.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Trigonella Foenum Graecum Extract Benefits on Hematological, Biochemical and Male Reproductive System of as a Complementary Therapy with Glimepiride in Treating Streptozotocin Induced Diabetic Rats

Diabetes mellitus (DM) is a chronic metabolic disorder. Streptozotocin is a naturally occurring cytotoxic chemical, particularly toxic to the pancreas and insulin producing beta cells in mammals and induces diabetes. Glimepiride is a second generation sulfonylurea, used as second-line or add-on treatment options for type 2 diabetes. Fenugreek (Trigonellafoenum graecum) seeds have been documented as a traditional plant treatment for diabetes. Soluble dietary fiber of Fenugreek significantly improved oral glucose tolerance in diabetic rats. It also exerts anti-diabetic effects mediated through the inhibition of carbohydrate digestion and absorption and the enhancement of peripheral insulin action. Most herbal remedies can interact with allopathic drugs resulting in altered activity and toxicity. At the same time, herbal remedies might produce the same kind of effects as the drug produce. Current published research information on herb-drug interactions is scanty. So, the aim of this study was to investigate the possible interaction between conventional drug used for the management of diabetes; (Glimepiride) and a traditional herbal remedy; Fenugreek aqueous extract in Streptozotocin induced diabetic male albino rats. In conclusion, combination therapy induces better hematological, biochemical effects and improves the oxidative stress biomarkers and antioxidant enzymes. Histological studies showed better results on some organ functions. The results emphasize the benefit of using the combination of Fenugreek seeds aqueous extracts as supportive complementary anti-diabetic therapy.

Buxus sempervirens L Improves Streptozotocin-induced Diabetes Mellitus in Rats.

Buxus sempervirens L. (Boxwood) is a medicinal plant used in Moroccan traditional medicine for diabetes treatment in Morocco. However; there is no experimental support of this ethnopharmacological use. The present investigation is aimed at studying the antidiabetic and the preliminary phytochemical of the aqueous extract of the leaves of Buxus sempervirens (AELBS). AELBS (5 mg/kg) was administered by gavage to normal and streptozotocin-induced diabetic rats and blood glucose levels were measured for 6 hours (acute study) and 15 days (chronic study). Oral glucose test tolerance (OGTT) and histopathological examination of liver and pancreas were carried out using standard methods. Furthermore, preliminary phytochemical screening and quantification of phenolic and flavonoid contents were also realized. AELBS reduced the blood glucose of both healthy and diabetic rats. This extract was also able to improve oral glucose tolerance in diabetic rats and it ameliorated hepatic histology, however, no enhancement was noticed in pancreatic histology. Preliminary phytochemical study revealed that AELBS possesses many chemical compounds such as alkaloids, phenolic compounds (flavonoids, tannins, and cyanidins), carbohydrates, reducing sugars and mucilage. Additionally, this extract is rich in phenolic compounds including flavonoids. According to all these findings, we conclude that AELBS at a low dose demonstrated a potent antihyperglycemic effect in streptozotocin rats and further investigations should be necessary for supporting the use of this plant in the management of diabetes by the Moroccan population.