Beneficial Effects Of Metformin Research Articles

COVID-19 and Diabetes: A Narrative Review

The pandemic of the novel human coronavirus disease 2019 (COVID‐19) has become an evolving global health issue due to the high morbidity and mortality rate. Patients who have comorbidities (e.g., diabetes, hypertension, obesity, cancer, and cardiovascular disease) are significantly at increased risk for admission into the intensive care unit, and this situation could affect the survival of the infected patients. Among the various comorbidities in this review, we focused on the diabetic patients who were highly affected because of increased viral entry into the cell via angiotensin-converting enzyme 2 (ACE2) in the respiratory system, leading to decreased immunity. Furthermore, several studies have been conducted on the beneficial effects of metformin in diabetic patients with COVID-19, but other studies have demonstrated the severe course of COVID-19 disease. Hence, further comprehensive studies are necessary in this regard. For these reasons, the prevention and management of COVID-19 in diabetic patients are essential and play a key role in reducing the fatality rate.

Beneficial Effects of Metformin on the Central Nervous System, with a Focus on Epilepsy and Lafora Disease.

Metformin is a drug in the family of biguanide compounds that is widely used in the treatment of type 2 diabetes (T2D). Interestingly, the therapeutic potential of metformin expands its prescribed use as an anti-diabetic drug. In this sense, it has been described that metformin administration has beneficial effects on different neurological conditions. In this work, we review the beneficial effects of this drug as a neuroprotective agent in different neurological diseases, with a special focus on epileptic disorders and Lafora disease, a particular type of progressive myoclonus epilepsy. In addition, we review the different proposed mechanisms of action of metformin to understand its function at the neurological level.

Protective effect of metformin against ovariectomy induced depressive- and anxiety-like behaviours in rats: role of oxidative stress.

Several studies have shown that low estrogen levels can lead to an increase in the incidence of depression and anxiety during menopause. The hippocampus and prefrontal cortex are parts of the brain involved in depressive- and anxiety-like behaviors. Recent studies have revealed that metformin has neuroprotective effects mainly due to its antioxidant properties. The aim of the present study was to examine the therapeutic potential of metformin in depressive- and anxiety-like behavior as well as oxidative stress in the prefrontal cortex and hippocampus of ovariectomized rats. Young female Wistar Albino rats were distributed into four groups (n:8): control, metformin-administered control, ovariectomized and metformin administered ovariectomized groups. Metformin (25 mg/kg) was administered daily by oral gavage for 2 weeks. Forced swimming test and open field test were performed to evaluate depression- and anxiety-like behaviors, respectively. Following the treatment with metformin, the tissues of the hippocampus and prefrontal cortex were isolated for the measurement of malondialdehyde, reduced glutathione and ascorbic acid contents. Ovariectomy resulted in depressive- and anxiety-like behaviors, and besides, increased content of malondialdehyde in both prefrontal cortex and hippocampus. The levels of ascorbic acid and glutathione were found to be reduced in ovariectomized rats. Metformin treatment significantly decreased depressive behaviour and malondialdehyde content in the prefrontal cortex. Reducing oxidative stress of the prefrontal cortex was suggested as a possible mechanism implicated in the beneficial effects of metformin on ovariectomy-induced depressive-like behaviour. We believe that the therapeutic efficiency of metformin needs to be tested for potential clinical use in surgical menopause or gonadal hormone deficiency women with depression.

Impact of Concurrent Coincident Use of Metformin During Lung Stereotactic Body Radiation Therapy.

IntroductionRecent data suggest synergy of chemoradiotherapy and metformin in locally-advanced non-small cell lung cancer (NSCLC). It remains unclear if similar synergy exists with stereotactic lung body radiation therapy (SBRT) and metformin. We analyzed the role of metformin on progression-free survival (PFS) and toxicity in the setting of lung SBRT.MethodsWe identified 31 patients on metformin-treated with SBRT for early-stage NSCLC. Eighty-nine similarly treated patients were chosen as controls. Kaplan-Meier method was used to estimate cumulative PFS probabilities.ResultsMedian follow-up was 30.7 months. Forty-two patients had diabetes, 31 (74%) of which were taking metformin concurrent with SBRT. Median PFS for metformin-users vs. metformin non-users was 36.4 months vs 48.9 months, respectively (p = 0.29). Among diabetic patients, median PFS for metformin users was 36.4 months and was unobserved for non-users (p= 0.40). On univariable analysis, male sex (p = 0.03) and tumor size (p = 0.01) were associated with the risk of progression or death; use of metformin was not significant (p = 0.34). There was no difference in grade ≥2 radiation pneumonitis between metformin users vs non-users (p = 0.51)ConclusionIn this retrospective sample of lung SBRT patients, we did not detect a meaningful effect of concurrent metformin use on PFS. Since SBRT and conventional RT may have different cell kill mechanisms, the previously described beneficial effects of metformin may not apply in a hypofractionated setting. These results should be validated in an independent dataset, and we await the results of ongoing clinical trials.

Metformin - its anti-cancer effects in hematologic malignancies.

The main anti-diabetic effect of metformin mediated through stimulation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) is the inhibition of hepatic gluconeogenesis and triggering glucose uptake in skeletal muscles. Additionally, some new pathways, besides the AMPK activation, were discovered, that can explain wide-range properties of metformin. All these properties are now attracting the attention of researchers in the fields other than diabetes and the drug has been reported to have anti-cancer, immunoregulatory and anti-aging effects. Among others, the beneficial effects of metformin in hematological disorders like leukemias, lymphomas, and multiple myeloma were reported. Despite a great progress in therapy, these diseases are still incurable in most cases. Thus, there is an urgent need to discover novel, less toxic and more effective drugs especially for older or chemotherapy-resistant patients. In this review article, the current findings on the anti-cancer effect of metformin together with underlying possible mechanisms in blood cancers are discussed. However. to evaluate precisely these promising effects of metformin, more studies are required, because many of the published results are preclinical.

A new aspect of an old friend: the beneficial effect of metformin on anti-tumor immunity

T-cell-based cancer immunotherapies, such as immune checkpoint blockers (ICBs) and chimeric antigen receptor (CAR)-T-cells, have significant anti-tumor effects against certain types of cancer, providing a new paradigm for cancer treatment. However, the activity of tumor infiltrating T-cells (TILs) can be effectively neutralized in the tumor microenvironment (TME) of most solid tumors, rich in various immunosuppressive factors and cells. Therefore, to improve the clinical outcomes of established T-cell-based immunotherapy, adjuvants that can comprehensively relieve multiple immunosuppressive mechanisms of TME are needed. In this regard, recent studies have revealed that metformin has several beneficial effects on anti-tumor immunity. In this mini-review, we understand the immunosuppressive properties of TME and how metformin comprehensively enhances anti-tumor immunity. Finally, we will discuss this old friend’s potential as an adjuvant for cancer immunotherapy.

Metformin improves cognition of aged mice by promoting cerebral angiogenesis and neurogenesis.

Metformin is a widely used drug for type 2 diabetes that is considered to have potential anti-aging effects. However, the beneficial effects of metformin in middle-aged normoglycemic mice are less explored. Here, we report that metformin treated by tail vein injection improved cognitive function of aged mice better than oral administration, which seem to show a dose-dependent manner. Correspondingly, long-term oral administration of metformin was associated with significant disability rates. Further, metformin restored cerebral blood flow and brain vascular density and promoted neurogenic potential of the subependymal zone/subventricular zone both in vivo and in vitro. RNA-Seq and q-PCR results indicated that metformin could enhance relative mRNA glycolysis expression in blood and hippocampal tissue, respectively. Mechanistically, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a key enzyme in glycolysis pathway, may contribute to angiogenic and neurogenic potentials of NSCs. Interestingly, the relative GAPDH mRNA expression of peripheral blood mononuclear cell was gradually decreased with aging. Meanwhile its expression level positively correlated with cognitive levels. Our results indicated that metformin represents a candidate pharmacological approach for recruitment of NSCs in aged mouse brain by enhancing glycolysis and promoting neurovascular generation, a strategy that might be of therapeutic value for anti-aging in humans.

Delayed metformin treatment improves functional recovery following traumatic brain injury via central AMPK-dependent brain tissue repair

Accumulating evidence suggests that chronic metformin posttreatment offers potent neuroreparative effects against acute brain injury. However, in previous studies, metformin was not initially administered beyond 24 h postinjury, and the effects of delayed metformin treatment in traumatic brain injury (TBI) and other types of acute brain injury and the related mechanisms are unclear. To test this, male C57BL/6 mice received once daily metformin treatment (20, 50 or 100 mg/kg/d, i.p.) at day 1–14, day 1–2, day 1–10, day 3–10, day 5–12 or day 5–28 after cryogenic TBI (cTBI). The results showed that 100 mg/kg/d metformin administered at day 1–14 postinjury significantly promoted motor functional recovery in the beam walking and gait tests and reduced the infarct volume. Metformin (100 mg/kg/d) administered at day 1–10 or day 3–10 but not day 1–2 or day 5–12 after cTBI significantly improved motor functional outcomes at day 7 and 14, and reduced the infarct volume at day 14. Interestingly, the therapeutic time window was further expanded when the duration of metformin treatment starting at day 5 postinjury was extended to 2 weeks. Furthermore, compared with cTBI, the administration of metformin at day 3–10 or day 5–28 after cTBI significantly elevated the expression of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and growth associated protein 43 (an axonal regeneration marker) and the number of vascular branch points and decreased the area of glial scar and the number of amoeboid microglia in the peri-infarct area at day 14 or 28 postinjury. The above beneficial effects of metformin were blocked by the intracerebroventricular injection of the AMPK inhibitor compound C (40 μg/mouse/d). Our data provide the first evidence that metformin has a wide therapeutic time window for at least 5 days after cTBI, during which it can improve functional recovery by promoting tissue repair and inhibiting glial scar formation and microglial activation in a central AMPK-dependent manner.

Metabolic Alterations Predispose to Seizure Development in High-Fat Diet-Treated Mice: the Role of Metformin.

The link between epilepsy and type 2 diabetes (T2DM) and/or metabolic syndrome (MetS) has been poorly investigated. Therefore, we tested whether a high-fat diet (HFD), inducing insulin-resistant diabetes and obesity in mice, would increase susceptibility to develop generalized seizures induced by pentylentetrazole (PTZ) kindling. Furthermore, molecular mechanisms linked to glucose brain transport and the effects of the T2DM antidiabetic drug metformin were also studied along with neuropsychiatric comorbidities. To this aim, two sets of experiments were performed in CD1 mice, in which we firstly evaluated the HFD effects on some metabolic and behavioral parameters in order to have a baseline reference for kindling experiments assessed in the second section of our protocol. We detected that HFD predisposes towards seizure development in the PTZ-kindling model and this was linked to a reduction in glucose transporter-1 (GLUT-1) expression as observed in GLUT-1 deficiency syndrome in humans but accompanied by a compensatory increase in expression of GLUT-3. While we confirmed that HFD induced neuropsychiatric alterations in the treated mice, it did not change the development of kindling comorbidities. Furthermore, we propose that the beneficial effects of metformin we observed towards seizure development are related to a normalization of both GLUT-1 and GLUT-3 expression levels. Overall, our results support the hypothesis that an altered glycometabolic profile could play a pro-epileptic role in human patients. We therefore recommend that MetS or T2DM should be constantly monitored and possibly avoided in patients with epilepsy, since they could further aggravate this latter condition.

Metformin during Pregnancy: Effects on Offspring Development and Metabolic Function.

Maternal obesity during pregnancy and gestational diabetes mellitus (GDM) are both associated with of several postnatal diseases in the offspring, including obesity, early onset hypertension, diabetes mellitus, and reproductive alterations. Metformin is an oral drug that is being evaluated to treat GDM, obesity-associated insulin resistance, and polycystic ovary syndrome (PCOS) during pregnancy. The beneficial effects of metformin on glycemia and pregnancy outcomes place it as a good alternative for its use during pregnancy. In this line of thought, improving the metabolic status of the pregnant mother by using metformin should avoid the consequences of insulin resistance on the offspring's fetal and postnatal development. However, some human and animal studies have shown that metformin during pregnancy could amplify these alterations and be associated with excessive postnatal weight gain and obesity. In this minireview, we discuss not only the clinical and experimental evidence that supports the benefits of using metformin during pregnancy but also the evidence showing a possible negative impact of this drug on the offspring's development.

2311-PUB: Metformin Improves Hepatic Inflammation in Diet-Induced Obese Mice through Downregulating CYP7B1

Metformin is an antidiabetic drug widely used to treat type 2 diabetes. Although it has been found for a very long time, its mechanism remains to be discovered. Recently, metformin has been reported to be effective in other disease, such as obesity and tumor. However, whether metformin is beneficial in nonalcoholic fatty liver disease remains controversial. CYP7B1, a cholesterol hydroxylase, has been reported to be upregulated in the inflammatory diseases. We investigated whether CYP7B1 plays an important role in the effect of metformin on the hepatic inflammation in diet-induced obese mice. In this study, eight-week-old C57BL/6 mice were subjected to a chow diet or a high fat diet (HFD) for 12 weeks. After the diet intervention, mice on an HFD were randomly divided into HFD group and HFD+Metformin group (HFDM group) for 4 weeks. The results showed that the body weight, fasting blood glucose, body fat mass, glucose metabolism and insulin sensitivity were remarkably improved by metformin. The histological results including H&E staining and oil red O staining showed that metformin significantly ameliorated fatty liver induced by HFD. And the quantification of liver triglyceride also proved that. The histological results also revealed that adipocytes of epididymal adipose tissue and subcutaneous adipose tissue were smaller after metformin treatment. Meanwhile, metformin also ameliorated the whitening of brown adipose tissue according to the H&E staining. Compared to HFD group, the mRNA levels of CYP7B1 and pro-inflammatory markers (TNFα, IL-1, F4/80 and MCP1) in liver were downregulated in HFDM group. How CYP7B1 functions in the beneficial effect of metformin on improving hepatic inflammation is going to be further studied. Disclosure W. Guo: None. W. Wang: None. X. Zheng: None. F. Xu: None.

Possible Beneficial Effect of Metformin Alone or in Combination with Methotrexate in Rheumatoid Arthritis Induced Rat Model

Background: Rheumatoid arthritis (RA) is a chronic, relapsing inflammatory and autoimmune multisystem illness that affects the joints. Methotrexate (MTX) is considered by many rheumatologists to be the most important and useful [DMARDs]. Metformin an antidiabetic medication has been reported to exert an anti-inflammatory effect. The rationale of this study is to test the effect of monotherapy with metformin alone or in comparison with methotrexate monotherapy on Adjuvant-induced arthritis (AIA). Aim of the study: The present study was designed to evaluate the effect of metformin alone and during basal treatment with methotrexate on rheumatoid factor, C-reactive protein, reduced glutathione, tumor necrosis factor- α, arthritis score and histopathological changes. Materials and methods: Rats were classified into: Group I: control normal group. Group II: was not treated (diseased group). Group III was treated with methotrexate (MTX). Group IV: was treated with metformin. Group V: was treated with combination of MTX with metformin. All treated groups received drugs for 4 weeks. Results: All groups showed significant improvement in all parameters and improvement of the histopathology of the joint. A significant reduction in the score was seen in all treated group at the end of 3rd and 4th weeks. Conclusion: All tested drugs alone or in combination showed improvement of parameters of RA. It is found that all combinations show more efficacy than each drug alone.

Effects of metformin alone and in combination with spironolactone on hyperandrogenism in polycystic ovarian syndrome

Objective To evaluate the efficacy of combined therapy with metformin and low-dose spironolactone as compared with metformin alone on the clinical and endocrine-metabolic alterations of patients with polycystic ovarian syndrome (PCOS). Background PCOS is the most common endocrinological disorder in reproductive-age women. Thus, at least theoretically, metformin plus spironolactone therapy may be an effective and safe combination for PCOS. Patients and methods A prospective randomized comparative study was carried out on 48 patients with the PCOS in Obstetrics and Gynecology Department, Menoufia University Hospital, and Al-Shohadaa Hospital, Egypt, from the period of May 2016 till January 2018. Detailed history, laboratory investigations, obstetric examination, and follow-up were done. Results Mean hirsutism score and BMI (kg/m2) were 10.8 ± 3.9 and 26.8 ± 2.2, respectively, before treatment, which decreased significantly to 7.6 ± 2.4 and 22.10 ± 1.92, respectively, after 6 months of treatment. Luteinizing hormone, follicle-stimulating hormone, free testosterone, dehydroepiandrosterone sulfate, fasting glucose, fasting insulin, and homeostasis model assessment of insulin resistance were decreased significantly after 6 months of treatment as compared with before treatment among women who received metformin + hypocaloric diet and received metformin + spironolactone + hypocaloric diet before treatment. Free testosterone was decreased in group B (58.2 ± 9.1) more than group A (73.6 ± 12. 9). Conclusion The results confirm the beneficial effects of metformin in patients with PCOS. It also proves that the addition of low-dose spironolactone induces a more marked reduction of clinical and biochemical hyperandrogenism in patients with PCOS present with hyperandrogenic conditions.

Could metformin be therapeutically useful in Huntington's disease?

Emerging evidence suggest that dimethylbiguanide (metformin), a first-line drug for type 2 diabetes mellitus, could be neuroprotective in a range of brain pathologies, which include neurodegenerative diseases and brain injury. However, there are also contraindications that associate metformin treatment with cognitive impairment as well as adverse outcomes in Alzheimer's disease and Parkinson's disease animal models. Recently, a beneficial effect of metformin in animal models of Huntington's disease (HD) has been strengthened by multiple reports. In this brief review, the findings associated with the effects of metformin in attenuating neurodegenerative diseases are discussed, focusing on HD-associated pathology and the potential underlying mechanisms highlighted by these studies. The mechanism of action of metformin is complex, and its therapeutic efficacy is therefore expected to be dependent on the disease context. The key metabolic pathways that are effectively affected by metformin, such as AMP-activated protein kinase activation, may be altered in the later decades of the human lifespan. In this regard, metformin may nonetheless be therapeutically useful for neurological diseases with early pathological onsets, such as HD.

Metformin reduces lipid accumulation in HepG2 cells via downregulation of miR-33b

Introduction Here, we aimed to investigate whether the beneficial effects of metformin on lipid accumulation is mediated through regulation of miR-33b. Methods The expression of the genes and miRNAs and protein levels were evaluated using real-time PCR and western blot, respectively. To investigate the potential role of miR-33b in lipid accumulation, the mimic of the miR-33b was transfected into HepG2 cells. Results We found that metformin reduces high glucose-induced lipid accumulation in HepG2 cells through inhibiting of SREBP1c and FAS and increasing the expression of CPT1 and CROT. Overexpression of miR-33b significantly prevented the decreasing effect of metformin on lipid content and intra and extra triglyceride levels. Importantly, miR-33b mimic inhibited the increasing effects of metformin on the expression of CPT1 and CROT. Conclusion These findings suggest that metformin attenuates high glucose-induced lipid accumulation in HepG2 cell by downregulating the expression of miR-33b.

P5006Metformin reduces the risk of hospitalization for heart failure in type 2 diabetes patients: a retrospective cohort analysis

Abstract Background A beneficial effect of metformin on heart failure requires confirmation. Purpose To investigate whether metformin might affect the risk of heart failure hospitalization in type 2 diabetes patients. Methods Patients with new-onset type 2 diabetes during 1999–2005 were enrolled from the reimbursement database of Taiwan's National Health Insurance and followed until December 31, 2011. Analyses were conducted in a propensity score (PS) matched-pair cohort (42,367 ever users and 42,367 never users) and hazard ratios were estimated by Cox's hazard regression analysis incorporated with the inverse probability of treatment weighting using the PS. Results A total of 1,592 never users and 987 ever users were hospitalized for heart failure for the first time during follow-up, with a respective incidence of 843.34 and 499.18 per 100,000 person-years. The overall hazard ratio was 0.588 (95% confidence interval: 0.543–0.637), and the hazard ratios for the first (<29.13 months), second (29.13–61.63 months), and third (>61.63 months) tertiles of cumulative duration were 1.018 (0.914–1.135), 0.575 (0.511–0.647), and 0.340 (0.297–0.390), respectively. Sensitivity analyses conducted in an unmatched cohort before and after excluding patients who received an irregular refill of metformin or who were treated with incretin-based therapies during follow-up consistently supported such a protective effect of metformin on heart failure. Conclusion Metformin use is associated with a lower risk of hospitalization for heart failure. Acknowledgement/Funding The study was partly supported by the Ministry of Science and Technology (MOST 107-2221-E-002-129-MY3) of Taiwan.

The effect of metformin on lipid parameters and on cardiovascular risk in patients with type 2 diabetes without statin therapy

Introduction: Some meta-analyses suggested a positive effect of metformin therapy on lipid parameters, but the potential beneficial effect of metformin on cardiovascular risk in type 2 diabetes is not entirely clear. Aim: We investigated the effect of metformin therapy on lipid parameters and cardiovascular risk in patients with type 2 diabetes. Method: In a cross-sectional, monocentric study, 102 patients with type 2 diabetes without lipid-lowering medication were analysed for lipid profile and cardiovascular risk (United Kingdom Prospective Diabetes Study Risk Calculator) depending on metformin therapy. The patients were divided into two subgroups regarding with (n = 52) or without metformin therapy (n = 50). Results: Patients with metformin therapy had significantly lower total cholesterol and LDL cholesterol levels than patients without metformin (p<0.01 and p<0.05). This effect was independent from glucose control. No intrinsic effect of metformin could be found on systolic blood pressure, HDL cholesterol, triglycerides, and long-term cardiovascular risk using a multivariable risk assessment score. Conclusion: Metformin therapy has beneficial effects on cholesterol levels without improving cardiovascular risk in patients with type 2 diabetes. Orv Hetil. 2019; 160(34): 1346-1352.

PCN173 EFFECT OF METFORMIN ON SURVIVAL AMONG OVARIAN CANCER PATIENTS WITH COMORBID DIABETES: A SYSTEMATIC REVIEW AND META-ANALYSIS

Metformin has anticancer properties and has been associated with decreased incidence and improved survival among patients with several cancers. Inconsistent evidence exists regarding the beneficial effects of metformin in women with ovarian cancer. We updated the evidence by performing a systematic review and meta-analysis to examine the effect of metformin on all-cause mortality among ovarian cancer patients with comorbid diabetes. Original articles published in English until December 2018 were searched in Medline-Ovid, PubMed, The Cochrane Library, and also searched the conference abstracts presented at the conferences at the International Society for Pharmacoeconomics and Outcomes Research, National Comprehensive Cancer Network and American Society of Clinical Oncology, for studies on metformin use in ovarian cancer with comorbid diabetes. Meta-analysis was performed using RevMan to determine the pooled hazard ratio (pHR) and its 95% confidence interval (CI). I2 statistics was examined to evaluate heterogeneity between the studies. Study quality assessment was conducted using the Cochrane Risk of Bias tool for the randomized controlled trial (RCT) and Newcastle-Ottawa Quality Assessment Scale for cohort studies. Four studies, one RCT and three retrospective cohort studies, met the inclusion criteria and were included in the meta-analysis. Compared to women who had no metformin use, those who used metformin had lower all-cause mortality, however the association was not significant (pHR=0.47, 95% CI=0.21-1.09, p=0.08, I2=79%). A subgroup analysis of retrospective cohort studies also did not change the findings. Metformin has a marginal yet nonsignificant beneficial effect on overall survival in women with ovarian cancer with comorbid diabetes. Due to the possible selection bias in the observational studies, RCTs should be designed to evaluate the efficacy of metformin use in ovarian cancer.

Increased beneficial outcome of metformin by co-enzyme Q10 against experimentally-induced hind limb ischemia reperfusion injury in normal and diabetic rats

Background: Skeletal muscles are susceptible for ischemic reperfusion injury especially in settings in order to achieve homeostasis in traumatic injury and vascular surgery. This study aimed at investigating the implication of induction of diabetes on generation of ischemic reperfusion injury in rat gastrocnemius muscle. In addition, the possible beneficial effect of metformin and co-enzyme q10 was investigated.Methods: About 80 male adult Sprague Dawley rats divided into 10 groups. Metformin was administrated as continuous oral dose for 28 days. Coenzyme q10 was administrated parenterally 2 and 24 hours before induction of ischemia in diabetic and non-diabetic animals.Results: In diabetic ischemic groups, tested drugs either singly or in combination significantly reduce HB1cA and plasma levels of muscle specific enzyme CPK and muscle myokin IL6, raised natural antioxidant GSH and reduced oxidative stress parameters (SOD and MDA), apoptotic (caspase-3) and inflammatory parameters TNF-α and TGFβ were reduced. Continuous oral metformin for 28 days was more powerful than parenteral short-term coenzyme q10 as regards all tested parameters except for GSH and caspase-3 both drugs were equi-effective. Combined drugs have more powerful ameliorating effect than either drug singly except for HB1cA which was equi-effective with that of metformin. Regarding non diabetic ischemic groups, metformin was more powerful in reduction of caspase-3, IL6 and TNF- α while coenzyme q10 was more powerful in elevating GSH.Conclusions: Co-enzyme q10 can be used as add on therapy with metformin in order to decrease the deleterious effects resulted from hind limb ischemia reperfusion in normal and diabetic rats.

Metformin Prevents High Glucose Induced Disruption of Coronary Artery Endothelial Barrier Function and Accelerates Wound Healing Via Regulating Junctional Protein, VE‐Cadherin

Despite the great strides have been made in treating diabetes induced vascular endothelial barrier dysfunction, current treatments have shown limited success in reversing vascular pathologies. Increase in endothelial permeability via modification of endothelial junctional proteins, such as vascular endothelial cadherin (VE‐Cadherin), leads to the formation of minute inter‐endothelial gaps, and the infiltration of protein‐rich fluid in the interstitial space. If remained unchecked, the persistent buildup of edema underlying the endothelial lining sets the stage for the serious life‐threatening complications. Hyperglycemia‐induced endothelial dysfunction contributes vascular complications of diabetes. Moreover, wound healing impairment is also increasingly recognized to be a consequence of hyperglycemia‐induced dysfunction of endothelial in type 2 diabetes mellitus (T2DM). Metformin, an oral anti‐hyperglycemic agent, is the first‐line drug in the clinic for patients with T2DM. Clinical studies suggested that the beneficial effect of metformin on the incidence of diabetes complications was not only related to its action on blood glucose normalization. We hypothesized that the metformin prevents high glucose‐induced endothelial barrier dysfunction and accelerates wound healing process in human coronary endothelial cells (HCAE) via preventing the destabilization of VE‐cadherin. Endothelial permeability was evaluated by using Electric Cell‐substrate Impedance Sensing (ECIS) mechanism, a measure of trans‐endothelial electrical resistance (TEER) across the endothelial monolayers using TEER electrodes. Wound healing assay was performed by employing electric signals to both wound and monitor the healing process in endothelial monolayer. Our data show that 25mM glucose concentration increased endothelial permeability and abrogated the wound healing process. Metformin at the dose of 10mM significantly prevented alteration of endothelial barrier function and enhances wound healing process in the presence of high glucose concentration. To investigate the signaling mechanism involved in the protection offered by metformin, we found that metformin prevented myosin light chain kinase (MYLK) phosphorylation and increased in VE‐cadherin expression, suggesting abrogation of increase endothelial contractility and dismantling the junctional proteins in presence of high glucose concentration. In conclusion, our study shows that metformin maintained endothelial barrier function and improved the process of wound healing in endothelial cells exposed to high glucose. Thus, metformin is emerging as a potential therapeutics in improving coronary endothelial barrier function in diabetes mellitus.Support or Funding InformationThis work was supported by funding from CTRE SEED Grant Award to Mohammad Tauseef.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.