Traditional Antidiabetic Drugs Research Articles

Hepatoprotective Role of Aqueous Extract of Kasni Seeds in Alloxan-Induced Diabetic Mice

Background: Diabetes mellitus (DM) is a prevalent metabolic disorder characterized by chronic hyperglycemia, leading to various systemic complications, including liver damage. Traditional antidiabetic drugs are often associated with adverse effects, prompting interest in safer, natural alternatives like Kasni (Cichorium intybus) seeds, known for their hepatoprotective properties.Objective: This study aimed to evaluate the hepatoprotective effects of Kasni seed aqueous extract in alloxan-induced diabetic mice.Methods: Thirty-two male albino mice were divided into three groups: control, metformin-treated, and Kasni-treated. Diabetes was induced using alloxan monohydrate (150 mg/kg). The Kasni-treated group received 400 mg/kg of Kasni extract orally for 28 days. Blood glucose levels were monitored, and liver tissues were analyzed histologically to assess hepatocyte arrangement, central vein morphology, sinusoidal inflammation, and fatty globule presence.Results: The Kasni-treated group showed a significant reduction in blood glucose levels (140.2 ± 8.7 mg/dL) compared to the metformin group (180.4 ± 10.5 mg/dL) (p < 0.05). Histological analysis revealed restored hepatocyte arrangement, reduced fatty globules, and normalized central vein morphology in the Kasni-treated group.Conclusion: Kasni seed aqueous extract exhibits significant hepatoprotective effects in alloxan-induced diabetic mice, suggesting its potential as a natural therapeutic agent for managing liver complications in diabetes.

Recent drug development of dorzagliatin, a new glucokinase activator, with the potential to treat Type 2 diabetes: A review study.

Type 2 diabetes mellitus (T2DM) is a complicated disease related to metabolism that results from resistance to insulin and sustained hyperglycemia. Traditional antidiabetic drugs cannot meet the demand of different diabetes patients for reaching the glycemic targets; thus, the identification of new antidiabetic drugs is urgently needed for the treatment of T2DM to enhance glycemic control and the prognosis of patients suffering from T2DM. Recently, glucokinase (GK) has attracted much attention and is considered to be an effective antidiabetic agent. Glucokinase activators (GKA) represented by dorzagliatin could activate GK and mimic its function that triggers a counter-regulatory response to blood glucose changes. Dorzagliatin has shown great potential for glycemic control in diabetic patients in a randomized, double-blind, placebo-controlled Phase 3 trial (SEED study) and had a favorable safety profile and was well tolerated (DAWN study). In the SEED study, dorzagliatin significantly reduced glycosylated hemoglobin (HbA1c) by 1.07% and postprandial blood glucose by 2.83 mol/L, showing the great potential of this drug to control blood glucose in diabetic patients, with good safety and good tolerance. An extension of the SEED study, the DREAM study, confirmed that dorzagliatin monotherapy significantly improved 24-h glucose variability and increased time in range (TIR) to 83.7% over 46 weeks. Finally, the clinical study of dorzagliatin combined with metformin (DAWN study) confirmed that dorzagliatin could significantly reduce HbA1c by 1.02% and postprandial blood glucose by 5.45 mol/L. The current review summarizes the development of GK and GKA, as well as the prospects, trends, applications, and shortcomings of these treatments, especially future directions of clinical studies of dorzagliatin.

Dipeptidyl peptidase-4 inhibition of Peronema canescens Jack leaves and stems: Bioassay-guided fractionation, compound profiling by LC-MS/MS, and interaction mechanism

Sungkai (Peronema canescens Jack) has been used for generations as a traditional antidiabetic drug for the Borneo people, but scientific data as a dipeptidyl peptidase-4 (DPP-4) inhibitor has never been reported. This study aims to obtain the most active chromatographic fraction as a DPP-4 inhibitor and the profile of the compounds contained. Bioassay-guided fractionation was used in this study and bioassays using spectrofluorometric principles. Compound profiling is carried out using ultra-performance liquid chromatography coupled with electrospray ionization/quadrupole-time-of-flight mass spectrometry (UPLC-ESI-QToF-MS/MS), and molecular docking is used to investigate interactions between compounds and DPP-4. The study found that the most effective extracts were ethyl acetate and methanol extracts from the leaves, which showed inhibitory percentages of 70.0% ± 0.7233% and 59.69% ± 1.9394%, respectively, at a concentration of 100 μg/ml. The fractionation produces the most active fraction, the second fraction from P. canescens methanol extract (FPSM2 fraction), with a percent inhibition of 88.28% ± 2.1204%. The compounds contained in FPSM2 were identified through UPLC-ESI-QToF-MS/MS, including pectolinarigenin, glycitein, formononetin, latifoline, 3-oxo-alpha-ionol, moracin M, and loliolide. Assay results showed that P. canescens has been shown to have inhibitory activity against DPP-4, suggesting that this plant has excellent potential to be developed as a DPP-4 inhibitor.

ß- Caryophyllene Ameliorates Insulin Resistance in Liver of High Fat Diet and Fructose-Induced Type-2 Diabetic Rats

Insulin resistance may impact organs that transmit insulin signals, like skeletal muscle, adipose tissue, and the liver. Hyperglycemia and hypertriglyceridemia in the fasting state of type 2 diabetes mellitus are more significantly impacted by insulin resistance in the liver. Hypertriglyceridemia is the culprit behind beta-cell failure in type 2 diabetes. Treating insulin resistance in liver as a primary mechanism of traditional antidiabetic drugs, but unfortunately traditional drugs has unalterable advisory effect. In the present research, insulin resistance in the liver is addressed with the versatile natural phytonutrient beta-caryophyllene to demonstrate effectiveness in managing diabetes. An effective dose of -Caryophyllene taken by non-parental route (200 mg/kg b.wt) was given for 30 days to experimentally induced (high-fat diet and fructose-fed) type-2 diabetic rats to find out whether β-Caryophyllene regulates the IRS-2/akt pathway of insulin signaling. In the liver of diabetic rats, the data demonstrates that ß-caryophyllene treatment significantly increased the mRNA and protein expression of insulin receptor (IR) and GLUT-2. However, there was a significant variation in the mRNA expression of akt and insulin receptor-substrate-2 (IRS-2) between groups. Taking caryophyllene supplements can be beneficial for the control of type 2 diabetes. Studies conducted with this sesquiterpene could have tremendous potential and benefit for the treatment of type 2 diabetes.

Potential Mechanisms of Metformin-Induced Apoptosis in HeLa Cells

Metformin is a traditional antidiabetic drug that also shows potential antitumor effects in cervical cancer. However, some of its apoptosis-related mechanisms are still unclear. In this study, flow cytometry, western blotting, and RNA sequencing (RNA-seq) were used to evaluate the molecular mechanisms of metformin in HeLa cells. The results showed that metformin inhibited cell viability and promoted apoptosis, the protein expression level of Caspase-3 (CASP3) was increased and that of BCL-2 was decreased in HeLa cells treated with metformin. The RNA-seq results indicated a total of 239 differentially expressed genes between the metformin and control check (CK) groups, with 136 genes upregulated and 103 genes downregulated, and 14 of them were found to be associated with apoptosis signaling pathways. The DDIT3 and HRK genes were robustly upregulated in HeLa cells by the endoplasmic reticulum (ER) stress and the mitochondrial pathway of apoptosis. Metformin also affects the expression of PPP2R5C, PPP2R5A, and RRAGA, which participate in biological processes such as PI3K-AKT, mTOR, and AMPK signaling pathways. Metformin mediates the expression of related genes to induce apoptosis.

Biological Screening and Crystallographic Studies of Hydroxy γ-Lactone Derivatives to Investigate PPARγ Phosphorylation Inhibition.

PPARγ represents a key target for the treatment of type 2 diabetes and metabolic syndrome. To avoid serious adverse effects related to the PPARγ agonism profile of traditional antidiabetic drugs, a new opportunity is represented by the development of molecules acting as inhibitors of PPARγ phosphorylation by the cyclin-dependent kinase 5 (CDK5). Their mechanism of action is mediated by the stabilization of the PPARγ β-sheet containing Ser273 (Ser245 in PPARγ isoform 1 nomenclature). In this paper, we report the identification of new γ-hydroxy-lactone-based PPARγ binders from the screening of an in-house library. These compounds exhibit a non-agonist profile towards PPARγ, and one of them prevents Ser245 PPARγ phosphorylation by acting mainly on PPARγ stabilization and exerting a weak CDK5 inhibitory effect.

Hepatoprotective effect of gallic acid against type 2-induced diabetic liver injury in male rats through modulation of fetuin-A and GLP-1 with involvement of ERK1/2/NF-κB and Wnt1/β-catenin signaling pathways.

Gallic acid is a phenolic compound with biological and pharmacological activities. Therefore, our study aimed to examine whether gallic acid has a beneficial effect against type 2-induced diabetic hepatic injury in rats and attempt to discover its possible intracellular pathways. Adult male rats were subdivided into six groups: Control, DM (diabetes mellitus), GA (gallic acid)+DM, DM+GA, DM+MET (metformin) and DM+GA+MET. Type 2 diabetes mellitus (T2DM) induced a significant increase in the blood glucose, HOMA-IR, liver enzymes, fetuin-A, hepatic triglycerides content with diminished serum insulin and hepatic glycogen content associated with impairment of cellular redox balance. Administration of gallic acid successfully restored all these alterations which was confirmed by marked improvement of the histopathological changes of the liver. Significantly, gallic acid increased the expression of glucagon-like peptide-1 (GLP-1) immunoreactive cells in the terminal ileum with negative correlation observed between fetuin-A and GLP-1 cells. Furthermore, our results discovered that gallic acid could diminish the DM-induced hepatic damage via upregulated hepatic mRNA expression of GLUT-4, Wnt1 and β-catenin with inhibitory effects on the elevated expression of ERK1/2/NF-κB. In conclusion, this study suggests that gallic acid provides a significant protection against T2DM-mediated liver injury. The use of gallic acid with traditional anti-diabetic drug enhanced its efficiency compared with traditional drug alone.

548 ROLE OF NEW ANTIDIABETIC DRUGS IN THE PREVENTION OF CONTRAST-INDUCED NEPHROPATHY IN DIABETIC PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION

Abstract Background Contrast-Induced Acute Kidney Injury (CI-AKI) is a complication of patients undergoing percutaneous coronary intervention (PCI) associated with high morbidity and mortality and higher incidence is in patients with type II diabetes mellitus. Recently several randomized controlled trials have shown a clear benefit of new anti-diabetic drugs (GLP-1 analogues, DPP-4 inhibitors and SGLT-2 inhibitors) in the prevention of kidney damage but no study has evaluated their possible role in the prevention of CI-AKI in patients undergoing percutaneous coronary intervention. Methods The study enrolled 408 patients undergoing PCI and divided them into three groups: 136 with type 2 diabetes mellitus treated with new-antidiabetic drugs, 136 with type 2 diabetes mellitus treated with standard-antidiabetic therapy, and 136 non-diabetic patients. Patients were evaluated for serum creatinine (measured at the time of hospitalization, 24-hour and 48-hour post-PCI), glomerular filtration rate (eGFR) estimated using the Cockcroft-Gault equation before and after the procedure, and markers of myocardial damage at the admission and 24 hours after PCI. CI-AKI was defined as an increase in serum creatinine levels ≥ 0.3 mg / dL (26.5 μmol / L) or greater than 25% of the base value, occurred 24-48 hours after administration of the contrast medium. Results It was observed a significant increase in delta creatinine between pre and post PCI in the group treated with standard-antidiabetic therapy (0.91 ± 0.22 mg / dL vs 0.94 ± 0.23 mg / dL, p= 0.008), but not in the group treated with new-antidiabetic drugs that showed a delta creatinine close to zero (1.01 ± 0.33 mg / dL vs 1.01 ± 0.35 mg / dL, p = 0.945), similar to that observed in non-diabetic patients (1.01 ± 0.30 mg / dL vs 0.99 ± 0.31 mg / dL, p = 0.020). The patients treated with SGLT-2 inhibitors presented pre-PCI mean creatinine levels significantly lower (0.83 ± 0.16 mg / dL) than those treated with DPP-4 inhibitors (1.04 ± 0.34 mg / dL) and GLP-1 analogues (1.05 ± 0.39 mg / dL), (p for trend = 0.009). However, the creatinine delta between the pharmacological classes was similar (p = 0.881). The incidence of CI-AKI, defined as an increase ​​of serum creatinine 24-48 hours after contrast medium administration ≥ 25%, was 9.6% in patients treated with standard-antidiabetic therapy, 4.4% in patients treated with new-antidiabetic drugs and 3.7% in non-diabetic patients (p for trend = 0.080). The incidence of CI-AKI, defined as an increase of serum creatinine 24-48 hours after contrast medium administration ≥0.3 mg / dL, was 5.1% in the standard-antidiabetic therapy group, 3.8% in the new-antidiabetic drugs group and 2.9% in the non-diabetic patients (p for trend = 0.911). Conclusions The study demonstrated in diabetic patients undergoing PCI and in treatment with new anti-diabetic drugs (GLP-1 analogues, DPP-4 inhibitors, SGLT-2 inhibitors) a reduced incidence of CI-AKI compared to diabetic patients in treatment with traditional antidiabetic drugs (metformin, sulfonylureas, thiazolidinediones, insulin) and a similar incidence of CI-AKI compared to non-diabetic patients. The results of this study underline a possible protective role of new anti-diabetic drugs for the prevention of CI-AKI.

Probability Induction of Kratom Plant Bioactive Components in Antidiabetic and Antiobesity Studies

Background: Kratom (Mitragyna speciosa Korth.) is widely used by the surrounding community as a traditional antidiabetic and antiobesity drug due to its high content of secondary metabolite compounds. The purpose of writing this review is to find out the bioinduction influence of Bacillus thuringiensis and Pseudomonas fluorescens and to find out the presence of an increase in secondary metabolites. Method: Writing and assessing source problems related to using literature study methods. Results: Kratom leaf methanol extract contains secondary metabolites of alkaloid groups, flavonoids, steroids/terpenoids, phenols and saponins. The main compound content of kratom leaves classified as alkaloids is mitragynine that has not been found in other plants. The administration of non-pathogenic bacteria such as Bacillus thuringiensis and Pseudomonas fluorescens can induce plant defenses and can accumulate the production of phenol compounds and flavonoids in plants. Conclusion: Based on the literature search results, kratom can indeed function as an antidiabetic and antiobesity and induction of microbes, namely Bacillus thuringiensis and Pseudomonas fluorescens bacteria can increase the content of secondary metabolites of plants. Through the increase in secondary metabolites, the efficacy of plants is higher to overcome health problems, namely antidiabetics and antiobesity.

Evaluation of nootropic activity of telmisartan and metformin on diazepam-induced cognitive dysfunction in mice through AMPK pathway and amelioration of hippocampal morphological alterations

Cognitive impairments such as dementia are considered the biggest challenges for public health. Benzodiazepines are often prescribed for treatment of anxiety disorder but they are associated with elevated risk of dementia. The present study has been designed to evaluate the neuroprotective effect of telmisartan and metformin on diazepam-induced cognitive dysfunction in mice. Piracetam was used as an established nootropic agent. Mice were divided into 8 groups, group1; control group which received normal saline. groups 2, 3 and 4 were received telmisartan 0.3 mg/kg/day, metformin 100 mg/kg/day and piracetam 200 mg/kg/day respectively. group 5; DZP group that injected with diazepam 2.5 mg/kg, groups 6, 7 and 8 were received diazepam 2.5 mg/kg + telmisartan 0.3 mg/kg/day, metformin 100 mg/kg/day and piracetam 200 mg/kg/day respectively. All drugs were administrated for 15 successive days. Cognitive skills of the animals were examined with Elevated plus maze and Passive Shock Avoidance tests. Investigations of oxidative stress markers were performed. Gene expression levels of TNF-α, NFκB, Caspase 3 and AMPK were analyzed using RT-PCR. Histological and immunohistochemical techniques were performed in hippocampus using H&E, cresyl violet stain, anti GFAP and anti COX-2 immunostain. The study revealed that administration of diazepam increased initial and retention transfer latency as well as it decreased step down latency that means it caused memory impairment. There was a significant increase in hippocampal expression levels of TNF-α, NFκB, and Caspase 3 and downregulation of AMPK expression levels associated with increased neurodegeneration, astrocytes activation and COX-2 immunohistochemical staining. This study indicates that diazepam caused a decline in cognitive function depending on hippocampal activity. Telmisartan, a common antihypertensive agent and metformin, a traditional antidiabetic drug improved this cognitive dysfunction through their anti-oxidant and anti-inflammatory effect as they decreased initial and retention transfer latency as well as it increased step down latency. Also they decreased TNF-α, NFκB, and Caspase 3 and upregulated AMPK expression, moreover they ameliorated the hippocampal morphological alterations, GFAP and COX-2 immunoexpression.

Insights into the Role of DNA Methylation and Protein Misfolding in Diabetes Mellitus.

Diabetes mellitus is a metabolic disorder that is characterized by impaired glucose tolerance resulting from defects in insulin secretion, insulin action, or both. Epigenetic modifications, which are defined as inherited changes in gene expression that occur without changes in gene sequence, are involved in the etiology of diabetes. In this review, we focused on the role of DNA methylation and protein misfolding and their contribution to the development of both type 1 and type 2 diabetes mellitus. Changes in DNA methylation in particular are highly associated with the development of diabetes. Protein function is dependent on their proper folding in the endoplasmic reticulum. Defective protein folding and consequently their functions have also been reported to play a role. Early treatment of diabetes has proven to be of great benefit, as even transient hyperglycemia may lead to pathological effects and complications later on. This has been explained by the theory of the development of a metabolic memory in diabetes. The basis for this metabolic memory was attributed to oxidative stress, chronic inflammation, non-enzymatic glycation of proteins and importantly, epigenetic changes. This highlights the importance of linking new therapeutics targeting epigenetic mechanisms with traditional antidiabetic drugs. Although new data is evolving on the relation between DNA methylation, protein misfolding, and the etiology of diabetes, more studies are required for developing new relevant diagnostics and therapeutics.

Neurological Manifestation of Incretin-Based Therapies in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis.

As a new class of antidiabetic drug, incretin-based therapies, which include dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have raised concerns about symptoms of withdrawal in patients with type 2 diabetes mellitus (T2DM), such as dizziness and headache. To systematically evaluate whether incretin-based therapies may lead to dizziness and headache in patients with T2DM compared to other traditional antidiabetic drugs or placebo. We searched Medline, Embase, the Cochrane library, and clinicaltrials.gov from inception through June 23, 2017, to identify randomized controlled trials of the safety of DPP-4Is or GLP-1 RAs versus placebo or other antidiabetic drugs in T2DM patients. We used the network meta-analysis under the frequentist framework to compare the association between multiple antidiabetic drugs and dizziness and headache. A total of 233 clinical trials with nine treatments and 147,710 patients were included: two incretin-based therapies, one placebo, and six traditional antidiabetic drugs (metformin, insulin, sulfonylurea, thiazolidinediones, alpha-glucosidase inhibitor, and sodium-glucose co-transporter 2). Compared to insulin, thiazolidinediones, or placebo, GLP-1 RAs statistically significantly increased the risk of dizziness (odds ratios [ORs]: 1.92, 1.57, and 1.40, respectively) and headache (ORs: 1.34, 1.41, and 1.18, respectively). DPP-4Is increased the risk of headache (OR: 1.22, 95% confidence interval [CI]: 1.02 to 1.46; moderate quality) and dizziness (OR: 1.46, 95% CI: 1.05 to 2.03; moderate quality) compared to insulin. Of the incretin-based therapies, DPP-4Is had a lower risk of dizziness than GLP-1 RAs (OR: 0.76, 95% CI: 0.67 to 0.87; high quality). Ranking probability analysis indicated that GLP-1 RAs may have the greatest risk of both dizziness and headache among the nine treatments (22.5% and 23.4%, respectively), whereas DPP-4Is were in the middle (46.2% and 45.0%, respectively). Incretin-based therapies increase the risk of dizziness and headache compared to insulin, thiazolidinediones, and placebo.

Hypoglycemic effect of Phaleria macrocarpa (Scheff.) Boerl dry extract in healthy adults

BackgroundThe prevalence of diabetes in Indonesia continues to increase and causes many complications. Fruits of Phaleria macrocarpa (Scheff.) Boerl. (PM) are used in the traditional health system of the Indonesians, as effective remedy in the management of diabetes mellitus. The aim of this study was to evaluate the effect and magnitude of doses of PM dry fruit extract (PME) on blood glucose levels in healthy adults.MethodsThis research was of pre-posttest design involving 30 healthy volunteer subjects aged 20-55 years receiving glucose loads. At pre-test the subjects were given orally 75 g glucose, and at post-test they were given PME at doses of 125 mg and 250 mg. Data collection included anthropometric examination and blood glucose level. The area under the curve (AUC) of blood glucose levels was measured at 0, 15, 30, 60, 120 and 180 minutes. Data analysis was performed using paired t-test with p <0.05.ResultsThe percentage of reduction in AUC between pre- and post-test after administration of PME 125 mg was 12.1% and significant (p=0.000). But the percentage of reduction in AUC between pre- and post-test after administration of PME 250 mg was 4.07% and not significant (p=0.06). The reduction in AUC between post-test PME 125 mg vs PME 250 mg showed significant results (p=0.011).Conclusion This study demonstrated that a dose of 125 mg Phaleria macrocarpa (Scheff.) Boerl. dry extract has a hypoglycemic effect in healthy adults, and may therefore be suitable for use as traditional anti-diabetic drug.

Combined host-guest complex with coffee-ring effect for constructing ultrasensitive SERS substrate for phenformin hydrochloride detection in healthcare products.

Phenformin hydrochloride (PHE), once used as a traditional anti-diabetic drug, has now been banned due to significant side effects. However, the phenomenon of the illegal addition of PHE to hypoglycemic healthcare products is still rampant. Thus, the detection of illegally added PHE is urgently needed. Surface-enhanced Raman scattering (SERS) is a promising candidate for this purpose, but the weak affinity between PHE and bare metal (Au or Ag) limits direct SERS detection of PHE. In this paper, we prepared Ag nanoparticles coated with β-cyclodextrin (AgNP@β-CD), which display the coffee-ring effect, that can be used for PHE sensing. β-CD-functionalized nanoparticles could capture the analyte and fix the molecular orientation in the hydrophobic cavity. The coffee-ring effect could improve the SERS effect through a higher concentration of the analyte, higher density of nanoparticles, and more hot spots. The SERS performance of the AgNP@β-CD substrate was characterized by using o-phenylenediamine dihydrochloride as a probe molecule. The excitation wavelength and pH value were optimized. A linear response for PHE detection is in the 7.0 × 10-8-1.0 × 10-6molL-1 concentration range, and the limit of detection is as low as 8.0 × 10-9molL-1. This AgNP@β-CD coffee-ring effect substrate was applied to the detection of PHE in healthcare products, with recoveries between 95.3 and 105.0% and relative standard deviations of less than 5.16%. It is anticipated that the AgNP@β-CD substrate will also have great potential for the monitoring of other aromatic drugs in healthcare products.

The Effects of Exenatide and Metformin on Endothelial Function in Newly Diagnosed Type 2 Diabetes Mellitus Patients: A Case-Control Study.

IntroductionExenatide is a new antidiabetic glucagon-like peptide-1 receptor agonist. In addition to its hypoglycemic effect, exenatide may have a potential protective benefit on vascular endothelial function. This study attempted to compare the effects of exenatide and traditional antidiabetic drug metformin treatment on endothelial function in overweight patients with type 2 diabetes.MethodsNinety overweight patients with newly diagnosed type 2 diabetes were recruited; 45 patients received exenatide (Exe) treatment and 45 patients received metformin (Met) treatment for 12 weeks. The control groups included 37 overweight and 24 non-overweight individuals. The parameters of glucose and lipid metabolism and endothelial function were measured before and after treatment. Vascular endothelial dysfunction was measured by reactive hyperemia index.ResultsNewly diagnosed patients with type 2 diabetes had more serious vascular endothelial dysfunction than both overweight and normal-weight control groups. The levels of body mass index, glucose, HbA1c, homeostasis model assessment insulin resistance, and homeostasis model assessment β-cell function were improved significantly by both exenatide and metformin treatment. Both exenatide and metformin treatment can improve vascular endothelial function (Exe group: 1.67 ± 0.52 vs 1.98 ± 0.67, P < 0.05; Met group: 1.68 ± 0.29 vs 1.82 ± 0.24, P < 0.05). Exenatide treatment was no less effective than metformin in improving endothelial function (0.31 ± 0.70 vs 0.13 ± 0.24, P > 0.05).ConclusionsNewly diagnosed patients with type 2 diabetes may have vascular endothelial dysfunction. Both exenatide and metformin treatment can improve vascular endothelial dysfunction, and exenatide was no less effective than metformin treatment.

ROLE AND PLACE OF DAPAGLIFLOZIN IN THE MANAGEMENT OF 2nd TYPE DIABETES: FROM THEORY TO PRACTICE

A new approach to the treatment of the Type 2 diabetes mellitus (T2DM) based on drug-induced glycosuria and reduction in renal threshold of glucose, and drugs with a similar mechanism of action belong to an innovative class of antidiabetic drugs: inhibitors of 2nd type sodium-glucose cotransporter (GLT-2). In addition to improving glycemic control SGCT-2 inhibitors promote moderate weight loss and blood pressure (BP), increased sensitivity of tissues to insulin and improve β-cell function. Dapagliflozin an oral SGCT-2 inhibitor, which is due to the insulin independent mechanism of action is characterized by the minimal risk of hypoglycemia compared to traditional antidiabetic drugs, such as sulfonylurea and insulin. For this reason, the drug has the unique ability to combine with other oral hypoglycemic agents (OHGA). In addition, due to its natriuretic effect and ability to reduce body weight and blood pressure dapagliflozin is the drug of choice in patients with T2DM and cardiovascular diseases of atherosclerotic genesis. A combination of advantages, including a favorable safety profile of dapagliflozin allows extensive use of this drug for the initiation and intensification of T2DM treatment.

Metformin attenuates ER stress–induced mitochondrial dysfunction

Endoplasmic reticulum (ER) stress, a disturbance of the ER function, contributes to cardiac injury. ER and mitochondria are closely connected organelles within cells. ER stress contributes to mitochondrial dysfunction, which is a key factor to increase cardiac injury. Metformin, a traditional anti-diabetic drug, decreases cardiac injury during ischemia-reperfusion. Metformin also inhibits ER stress incultured cells. We hypothesized that metformin can attenuate the ER stress-induced mitochondrial dysfunction and subsequent cardiac injury. Thapsigargin (THAP, 3mg/kg) was used to induce ER stress in C57BL/6 mice. Cell injury and mitochondrial function were evaluated in the mouse heart 48hours after 1-time THAP treatment. Metformin was dissolved in drinking water (0.5g/250ml) and fed to mice for 7days before THAP injection. Metformin feeding continued after THAP treatment. THAP treatment increased apoptosis in mouse myocardium compared to control. THAP also led to decreased oxidative phosphorylationin heart mitochondria-oxidizing complex I substrates. THAP decreased the calcium retention capacity, indicating that ER stress sensitizes mitochondria to mitochondrial permeability transition pore opening. The cytosolic C/EBP homologous protein (CHOP) content was markedly increased in THAP-treated hearts compared to control, particularly in the nucleus. Metforminprevented the THAP-induced mitochondrial dysfunction and reduced CHOP content in cytosol and nucleus. Thus, metformin reduces cardiac injury during ER stress through the protection of cardiac mitochondria and attenuation of CHOP expression.

ANTIDIABETIC ACTIVITY OF EXTRACT, FRACTIONS, AND ASIATICOSIDE COMPOUND ISOLATED FROM CENTELLA ASIATICA LINN. LEAVES IN ALLOXAN-INDUCED DIABETIC MICE

Objective: Centella asiatica Linn. is known and used as traditional antidiabetic drug especially in ayurvedic traditional system in some countries. The main objective of this study was to evaluate antidiabetic activity of ethanolic extract, saponin-rich fraction (SRF), nonsaponin fraction (NSF), and asiaticoside compound isolated from C. asiatica Linn. leaves in alloxan-induced diabetic mice.Methods: Diabetes was induced in albino mice by administration of alloxan monohydrate (60 mg/kg i.v). Extract was administrated orally each in doses of 125, 250 and 500 mg/kg, the SRF and NSF were in doses of 75, 150 and 300 mg/kg, while the asiaticoside was administrated in doses of 1.4, 2.8 and 5.6 mg/kg for 21 days. Blood fasting glucose level, insulin level, and glycosylated hemoglobin level were measured, and histopathology of pancreas was observed to determine antidiabetic activity of each sample.Results: Decreased blood fasting glucose level, increased insulin, and decreased glycosylated hemoglobin were observed in diabetic mice treated with extract, SRF and asiaticoside. On 21st day, extract at dose 500 mg/kg, SRF at dose 300 mg/kg, and asiaticoside at dose 5.6 mg/kg gave lowest blood glucose level in their each group which were 239±8.0, 254±10.4, and 217±8.1 mg/dl, respectively, compared to control group at 290±14.8 mg/dl. Insulin level of these three groups was 19.4±0.59, 24.8±0.99, and 27.8±0.77 μIU/ml, respectively, the highest value in their each group compared to 7.28±0.34 μIU/ml in control group. Meanwhile glycated hemoglobin level of these groups was 2.040±0.08, 2.010±0.04, and 2.11±0.07 ng/ml, respectively, lowest value in their each group compared to control group at 2.76±0.06 ng/ml. However, histopathology study in these groups did not show any improvements in regeneration of β-cells of pancreas. In the other side, NSF treatment did not affect any the parameters mentioned above.Conclusions: It can be concluded that extract, SRF and asiaticoside isolated from C. asiatica Linn. possess significant antidiabetic activity in diabetic mice. Based on increased levels of insulin and histopathology studies of pancreatic tissue, antidiabetic activity of those samples was believed to occur through the mechanism of increasing secretion of healthy pancreatic β-cells without any ability to regenerate β-cells that were damaged by alloxan.

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells.

The traditional anti-diabetic drug, metformin, has been found to have anticancer effects. The Sonic hedgehog (Shh) signaling pathway is involved in the on cogenesis of gastric cancer. The aim of the present study was to investigate whether metformin has an effect on the Shh signaling pathway in gastric cancer cells. HGC‑27 and MKN‑45 human gastric cancer cells were treated with metformin at different concentrations and for different durations. Subsequently the mRNA and protein levels of Shh, Smoothened (SMO), and Glioma‑associated oncogene (Gli)‑1, Gli‑2 and Gli‑3 were examined using western blot and reverse transcription‑quantitative polymerase chain reaction analyses. RNA interference was used to detect whether the effects of metformin treatment on the Shh signaling pathway were dependent on AMP‑activated protein kinase (AMPK). The results revealed that the protein and mRNA levels of Shh and Gli‑1 were decreased by metformin treatment in the two cell lines in a dose‑ and time‑dependent manner. Metformin also significantly inhibited the gene and protein expression levels of SMO, Gli‑2 and Gli‑3. The small interfering RNA‑induced depletion of AMPK reversed the suppressive effect of metformin on recombinant human Shh‑induced expression of Gli‑1 in HGC‑27 gastric cancer cells. Therefore, metformin inhibited the Shh signaling pathway in the gastric cancer cell lines and the inhibitory effect of metformin on the Shh pathway was AMPK-dependent.

Cardiovascular effects of incretin-based therapies in patients with type 2 diabetes: a systematic review and network meta-analysis

BackgroundConcerns about the cardiovascular safety of incretin-based therapies, which include dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, in patients with type 2 diabetes have been raised. We aimed to systematically assess the cardiovascular effects of incretin-based therapies in patients with type 2 diabetes. MethodsIn this systematic review and network meta-analysis, we searched MEDLINE, Embase, the Cochrane library, and ClinicalTrials.gov from inception to April 28, 2016, for reports of randomised controlled trials. We included reports with available data comparing incretin-based therapies with placebo and traditional antidiabetic drugs in patients with type 2 diabetes, with a minimum follow-up period of 12 weeks, and we extracted data from these reports. The main outcome was a composite of major adverse cardiovascular events (including cardiovascular death, myocardial infarction, and stroke, as defined by the US Food and Drug Administration) and heart failure. We used a random-effects model to calculate odds ratios (ORs) with 95% CI, and did a network meta-analysis to supplement direct comparisons. This study is registered with PROSPERO, number CRD42015020395. FindingsOf 4873 trials identified in the search, 271 trials with eight treatments (incretin-based therapies, placebo, and six traditional antidiabetic drugs—metformin, insulin, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, and sodium-glucose co-transporter 2 inhibitors) and 162 729 patients were included in analysis. In pairwise meta-analysis, incretin-based therapies had a significantly decreased risk of cardiovascular events compared with placebo (OR 0·75, 95% CI 0·64–0·87) and sulfonylureas (0·78, 0·61–0·98). However, in network meta-analysis, the protective effect of incretin-based therapies on cardiovascular events was not detected compared with placebo (0·94, 0·87–1·02) and was evident only compared with sulfonylureas (0·77, 0·61–0·98). Incretin-based therapies did not have an increased cardiovascular risk compared with other traditional antidiabetic drugs in both pairwise and network meta-analyses. Ranking probability analysis showed that incretin-based therapies had the lowest cardiovascular risk among all eight treatments with a probability of 67·5%, followed by alpha-glucosidase inhibitors (65·2%) and sodium-glucose co-transporter 2 inhibitors (61·3%). InterpretationIncretin-based therapies seems to be associated with a decreased cardiovascular risk compared with placebo and sulfonylurea, and did not show any increased risk of cardiovascular events compared with other traditional antidiabetic drugs. FundingNational Natural Science Foundation of China (81302508).