Therapeutic Effects Of Metformin Research Articles

Metformin prevents the onset and progression of intervertebral disc degeneration: New insights and potential mechanisms (Review).

Metformin has been the go‑to medical treatment for addressing type 2 diabetes mellitus (T2DM) as a frontline oral antidiabetic. Obesity, cancer and bone deterioration are linked to T2DM, which is considered a metabolic illness. Numerous diseases associated with T2DM, such as tumours, cardiovascular disease and bone deterioration, may be treated with metformin. Intervertebral disc degeneration (IVDD) is distinguished by degeneration of the spinal disc, accompanied by the gradual depletion of proteoglycans and water in the nucleus pulposus (NP) of the IVD, resulting in lower back pain. The therapeutic effect of metformin on IVDD has also attracted much attention. By stimulating AMP‑activated kinase, metformin could enhance autophagy and suppress cell senescence, apoptosis and inflammation, thus effectively delaying IVDD. The present review aimed to systematically explain the development of IVDD and mechanism of metformin in the treatment and prevention of IVDD to provide a reference for the clinical application of metformin as adjuvant therapy in the treatment of IVDD.

Microalgae‐Based Dual Drug Delivery System with Enhanced Articular Cavity Retention for Osteoarthritis Treatment

AbstractOsteoarthritis (OA) is a prevalent degenerative joint disease globally, and the availability of effective treatments for OA remains limited. Recent research has shown that metformin offers pleiotropic advantages in the development of OA. However, the therapeutic effects of metformin are hindered by inadequate residence time within the joints, instability, and low bioavailability. In this study, the utilization of natural microalgae S. platensis (SP) is proposed as carriers for metformin, resulting in the development of a metformin delivery system (SP@Met) as a dual drug delivery system that exhibits responsive dual drug cascade release and improved retention within the articular cavity. The local administration of SP@Met has demonstrated efficacy in extending the drug retention time within the articular cavity, while also enabling cascade release of both metformin and phycocyanin. SP@Met can effectively eliminate reactive oxygen species, reduce the expression of pro‐inflammatory cytokines, and restore the balance of cartilage anabolism and catabolism, thereby impeding the progression of OA. This therapeutic approach utilizes a natural microalgae carrier to facilitate efficient delivery of metformin to the articular cavity, resulting in synergistic therapeutic efficacy and offering a promising avenue for the management of OA for potential clinical application.

Revealing the role of metformin in gastric intestinal metaplasia treatment.

Gastric intestinal metaplasia (IM) is a precancerous stage associated with gastric cancer. Despite the observed beneficial effects of metformin on IM, its molecular mechanism remains not fully elucidated. This study aims to reveal the effects and potential mechanisms of metformin in treating IM based on both bioinformatics and in vivo investigations. The seven public databases (GeneCards, DisGeNET, OMIM, SuperPred, Pharm Mapper, Swiss Target Prediction, TargetNet) were used in this work to identify targeted genes related to intestinal metaplasia (IM) and metformin. The shared targeted genes between metformin and IM were further analyzed by network pharmacology, while the interactions in-between were investigated by molecular docking. In parallel, the therapeutic effect of metformin was evaluated in IM mice model, while the core targets and pathways effected by metformin were verified in vivo. We screened out 1,751 IM-related genes and 318 metformin-targeted genes, 99 common genes identified in between were visualized by constructing the protein-protein interaction (PPI) network. The top ten core targeted genes were EGFR, MMP9, HIF1A, HSP90AA1, SIRT1, IL2, MAPK8, STAT1, PIK3CA, and ICAM1. The functional enrichment analysis confirmed that carcinogenesis and HIF-1 signaling pathways were primarily involved in the metformin treatment of IM. Based on molecular docking and dynamics, we found metformin affected the function of its targets by inhibiting receptor binding. Furthermore, metformin administration reduced the progression of IM lesions in Atp4a-/- mice model significantly. Notably, metformin enhanced the expression level of MUC5AC, while inhibited the expression level of CDX2. Our results also showed that metformin modulated the expression of core targets in vivo by reducing the activity of NF-κB and the PI3K/AKT/mTOR/HIF-1α signaling pathway. This study confirms that metformin improves the efficacy of IM treatment by regulating a complex molecular network. Metformin plays a functional role in inhibiting inflammation/apoptosis-related pathways of further IM progression. Our work provides a molecular foundation for understanding metformin and other guanidine medicines in IM treatment.

Preventive and Therapeutic Effect of Metformin in Head and Neck Cancer: A Concise Review.

Head and neck cancer (HNC) is a complex affection. Nowadays, conventional treatments are associated with many side effects, reducing the patient's quality of life. Recent studies suggest that metformin, a first-line treatment for diabetes, could decrease cancer incidence and improve cancer-related survival rates. This systematic review summarizes important data from studies evaluating metformin's contribution to preventing and treating HNC. The results suggest a protective effect of metformin in HNC. However, no consensus has been found on its therapeutic effects. Metformin seems to confer an improved cancer-related survival rate in a diabetic population, but compared to a non-diabetic population, the review could not identify any advantages. Nevertheless, no studies presented a negative impact. In conclusion, the results of this systematic review suggest that HNC patients may benefit from metformin. Indeed, it would reduce the HNC incidence. However, more studies are required to evaluate the effect on cancer-related survival rates.

Metformin induces tolerogenicity of dendritic cells by promoting metabolic reprogramming

Dendritic cells (DCs) can mediate immune responses or immune tolerance depending on their immunophenotype and functional status. Remodeling of DCs’ immune functions can develop proper therapeutic regimens for different immune-mediated diseases. In the immunopathology of autoimmune diseases (ADs), activated DCs notably promote effector T-cell polarization and exacerbate the disease. Recent evidence indicates that metformin can attenuate the clinical symptoms of ADs due to its anti-inflammatory properties. Whether and how the therapeutic effects of metformin on ADs are associated with DCs remain unknown. In this study, metformin was added to a culture system of LPS-induced DC maturation. The results revealed that metformin shifted DC into a tolerant phenotype, resulting in reduced surface expression of MHC-II, costimulatory molecules and CCR7, decreased levels of proinflammatory cytokines (TNF-α and IFN-γ), increased level of IL-10, upregulated immunomodulatory molecules (ICOSL and PD-L) and an enhanced capacity to promote regulatory T-cell (Treg) differentiation. Further results demonstrated that the anti-inflammatory effects of metformin in vivo were closely related to remodeling the immunophenotype of DCs. Mechanistically, metformin could mediate the metabolic reprogramming of DCs through FoxO3a signaling pathways, including disturbing the balance of fatty acid synthesis (FAS) and fatty acid oxidation (FAO), increasing glycolysis but inhibiting the tricarboxylic acid cycle (TAC) and pentose phosphate pathway (PPP), which resulted in the accumulation of fatty acids (FAs) and lactic acid, as well as low anabolism in DCs. Our findings indicated that metformin could induce tolerance in DCs by reprogramming their metabolic patterns and play anti-inflammatory roles in vitro and in vivo.

Metformin alleviates liver fibrosis in mice by enriching Lactobacillus sp. MF-1 in the gut microbiota

BackgroundLiver fibrosis is associated with gut dysbiosis. Metformin administration has emerged as a promising method for the treatment of organ fibrosis. We aimed to investigate whether metformin ameliorates liver fibrosis by enhancing the gut microbiota in mice with carbon tetrachloride (CCl4)-induced liver fibrosis and the underlying mechanism. Materials and methodsA liver fibrosis mouse model was established, and the therapeutic effects of metformin were observed. We administered antibiotic treatment and performed fecal microbiota transplantation (FMT), and 16S rRNA-based microbiome analysis to evaluate the effects of the gut microbiome on metformin-treated liver fibrosis. We isolated the bacterial strain preferably enriched by metformin and assessed its antifibrotic effects. ResultsMetformin treatment repaired the gut integrity of the CCl4-treated mice. It reduced the number of bacteria in colon tissues and reduced the portal vein lipopolysaccharide (LPS) levels. The FMT performed on the metformin-treated CCl4 mice alleviated their liver fibrosis and reduced their portal vein LPS levels. The markedly changed gut microbiota was screened out from the feces and named Lactobacillus sp. MF-1 (L. sp. MF-1). In the CCl4-treated mice, daily gavage of L. sp. MF-1 maintained gut integrity, inhibited bacterial translocation, and reduced liver fibrosis. Mechanistically, metformin or L. sp. MF-1 inhibited the apoptosis of intestinal epithelial cells and restored CD3+ intestinal intraepithelial lymphocytes in the ileum and CD4+Foxp3+ lamina propria lymphocytes in the colon. ConclusionsMetformin and its enriched L. sp. MF-1 can reinforce the intestinal barrier to alleviate liver fibrosis by restoring immune function.

Netrin-1 Monoclonal Antibody-Functionalized Nanoparticle Loaded with Metformin Prevents the Progression of Abdominal Aortic Aneurysms.

Abdominal aortic aneurysms (AAAs) are a global health and economic burden. Therapeutic strategies to inhibit the progression of AAAs are currently lacking. Recently, the therapeutic effect of metformin on aneurysms has attracted considerable interest. However, the unfavorable pharmacokinetic properties of metformin limit its feasibility for AAA treatment. We constructed a metformin-loaded netrin-1-responsive AAA-targeted nanoparticle (Tgt-NP-Met) for AAA management. Evaluation of the therapeutic effect of Tgt-NP-Met was performed by in vitro and in vivo experiments. Our results showed that the binding of netrin-1 monoclonal antibodies enhanced the AAA-targeting capability of nanoparticles (NPs). Moreover, Tgt-NP-Met administration prevented AAA development and reduced the aneurysm diameter in apolipoprotein E (ApoE)-deficient (ApoE-/-) mice that received continuous infusion of angiotensin II. Furthermore, metformin prevented AAA progression by inhibiting the transformation of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a synthetic phenotype, which is mediated by macrophage infiltration and activation. Our findings identify metformin as a functional suppressor for macrophage-mediated phenotypic transformation of VSMCs and Tgt-NP-Met as an efficient therapeutic strategy for AAA management.

The role of circulating miRNAs in mechanism of action and prediction of therapeutic responses of metformin in polycystic ovarian syndrome

To study the involvement of microribonucleic acids (miRNAs) in the pathogenesis of chronic anovulation and mechanism of metformin treatment in polycystic ovary syndrome (PCOS). Case-control and prospective validation cohort study. Tertiary university hospital. A total of 146 patients with PCOS and chronic anovulation and 20 non-PCOS controls were enrolled. Patients who resumed ovulation after metformin treatment (MET-OV) and remained anovulatory after metformin treatment (MET-AO) were assigned to MET-OV and MET-AO groups, respectively. All patients with PCOS received metformin treatment for 6 months. Baseline and chronological changes in the plasma levels of 14 miRNAs (miR-21, 93, 132, 193b, 221, 222, 223, 27a, 125b, 200b, 212, 320a, 429, and 483) selected by literature review, anthropometric data, and hormonal as well as metabolic profiles were measured. Predictive modeling based on baseline circulatory miRNA levels and clinical parameters was performed to predict ovulation recovery after metformin treatment. No significant differences were observed in the baseline hormonal and metabolic profiles between the MET-OV and MET-AO groups. However, the expression of miR-27a, miR-93, and miR-222 was significantly higher in the MET-OV group than that for the MET-AO and control groups. After 6 months of metformin treatment, the levels of insulin, luteinizing hormone, and 6 circulating miRNAs (miR-21, 27a, 93, 221, 222, and 223) and homeostatic model assessment for insulin resistance decreased significantly in the MET-OV group, but remained unchanged in the MET-AO group. The area under curve, sensitivity, and specificity of the adjusted prediction model, based on miRNA levels and clinical parameters using logistic regression analysis for predicting ovulatory response after metformin treatment, were 0.807, 0.892, and 0.632, respectively. The present study demonstrated a distinct pattern of baseline expression and chronological changes in the levels of several circulatory miRNAs between the MET-OV and MET-AO groups, suggesting that aberrantly overexpressed diabetogenic miRNAs are involved in the pathophysiology of chronic anovulation in PCOS, and their down-regulation might contribute toward the therapeutic effects of metformin. This could provide new insights into the mechanism of action and applicability of individualized metformin therapy in women with PCOS.

Research progress on the therapeutic effect and mechanism of metformin for lung cancer (Review).

Lung cancer is the most common type of cancer and the leading cause of cancer‑associated death worldwide. Despite the availability of various treatments such as surgery, chemoradiotherapy, targeted drugs and immunotherapy, treatment is expensive and the prognosis remains poor. At present, lung cancer drugs and treatment programs remain in a state of continuous exploration and research to improve the prognosis, and to reduce the pain and economic burden for the patients. Type2 diabetes is a common chronic disease in middle‑aged and elderly patients, leading to significantly increased complications of cardiovascular and cerebrovascular diseases. Epidemiology shows that type2 diabetes also increases the incidence of malignant tumors, including lung, liver, colorectal and pancreatic cancer. Metformin is a biguanide, widely used as a first‑line oral drug in treating type2 diabetes. Metformin has a hypoglycemic effect and a biological antitumor impact, reducing the incidence of various tumors, including lung cancer, and improving the prognosis of patients with tumors. The anti‑lung cancer effect of metformin involves a variety of mechanisms that can improve the therapeutic effect and prognosis of lung cancer, as a single drug or in combination with other therapies. The present study aims to review the associated literature and the therapeutic effects of metformin on lung cancer.

Metformin alleviates long-term high-fructose diet-induced skeletal muscle insulin resistance in rats by regulating purine nucleotide cycle

Nutrient excess caused by excessive fructose intake can lead to insulin resistance and dyslipidemia, which further causes the development of metabolic syndrome. Metformin is a well-known AMPK activator widely used for the treatment of metabolic syndrome, while the mechanism of AMPK activation remains unclear. The present study aimed to investigate the pharmacological effects of metformin on fructose-induced insulin resistance rat, and the potential mechanism underlying AMPK activation in skeletal muscle tissue. Results indicated that metformin significantly ameliorated features of insulin resistance, including body weight, Lee's index, hyperinsulinemia, dyslipidemia, insulin intolerance and pancreatic damage. Moreover, treatment with metformin attenuated the inflammatory response in serum and enhanced the antioxidant capacity in skeletal muscle tissue. The therapeutic effects of metformin on fructose-induced insulin resistance may be related to the activation of AMPK to regulate Nrf2 pathway and mitochondrial abnormality. Additionally, metformin suppressed the expression of adenosine monophosphate deaminase 1 (AMPD1) and up-regulated the expression of adenylosuccinate synthetase (ADSS) in the purine nucleotide cycle (PNC), which facilitated the increase of AMP level and the ratio of AMP/ATP. Therefore, we proposed a novel mechanism that metformin activated AMPK via increasing AMP by regulating the expression of AMPD1 and ADSS in PNC pathway.

TRH and TRH-like peptide levels covary with caloric restriction and oral metformin in rat heart and testis

BackgroundObesity, type 2 diabetes, and major depression are common comorbidities in aging populations. Metformin (MF) mimics effects of caloric restriction (CR) which increases health and life spans. CR suppresses central TRH activity resulting in bradycardia and suppression of energy expenditure. TRH and TRH-like peptides with sequence pGlu-X-Pro-NH2, (X-TRH) where ‘X’ can be any amino acid residue, have anorectic, antidepressant, anxiolytic, analeptic, anti-epileptic, neuroprotective and anti-aging effects. The present studies compare the effects of CR and oral MF on expression of TRH and TRH-like peptides. CR experiment: Sixteen male Sprague-Dawley rats divided into 4 groups: ad libitum fed (CR-CON), 24 h fasted (CR-AC), fed (ADF1) or fasted (ADF2) 24 h after 10 days of alternate day fasting. MF experiment: Sixteen rats divided into 4 groups: water (MF-CON), 6 mg MF/ml water 24 h (MF-AC), 10 days MF (CHR) or 8 days MF then 48 h water (WD). ResultsComparison of chronic MF and ADF2 treatment effects on TRH and TRH-like peptide levels in testis revealed a consistent pattern for peptide responses observed in the two experiments with Glu-TRH > Val-TRH > TRH > Peak 2 > Trp-TRH > Phe-TRH > Tyr-TRH. TRH levels increased in heart during CR and MF treatment consistent with cardiac responses to congestive heart failure and infarction. ConclusionsBecause TRH reverses aging-induced testicular degeneration and mediates the pathophysiology of congestive heart failure these tripeptides may participate in the therapeutic effects of MF in ameliorating the cardiometabolic risk factors and fertility impairments associated with type 2 diabetes.

The lactate receptor GPR81 mediates hepatic lipid metabolism and the therapeutic effect of metformin on experimental NAFLDs

The lactate receptor G protein-coupled receptor 81 (GPR81) has been recently implicated in lipolysis in adipose tissue. In this study, we accidently discovered the role of GPR81 in hepatic lipid metabolism. Data clearly showed that hepatic GPR81 was markedly up-regulated in fasted mice, whereas it was severely down-regulated in obese mice. Genetic deficiency of GPR81 impaired ketogenic response, enhanced hepatic lipid accumulation, and exacerbated hepatosteatosis under acute fasting conditions. Mechanically, we demonstrated that hepatic GPR81 might function as a modulator of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), activate the downsream transcription of liver carnitine o-palmitoyltransferase 1(L-CPT1), and thereby control the influx of fatty acids into mitochondria for β-oxidation. Importantly, metformin improved experimental nonalcoholic fatty liver disease (NAFLDs) in a GPR81-dependent manner. Collectively, GPR81 was critical for hepatic lipid homeostasis and activation of hepatic GPR81 might represent a promising strategy for the treatment of obesity and its associated metabolic disorders.

Expression of Caspase-3 in Circulating Innate Lymphoid Cells Subtypes Is Altered by Treatment with Metformin and Fluvastatin in High-Fat Diet Fed C57BL/6 Mice.

The current study aimed to determine the expression levels of caspase-3 in circulating innate lymphoid cell subtypes (ILCs) in a high-fat diet (HFD)-induced prediabetes mouse model. Another critical point was to assess the therapeutic effects of metformin and fluvastatin in modulating caspase-3 activation in ILCs within these HFD-fed mice. Prominent results showed that mice exposed to HFD for 14 weeks displayed impaired glucose tolerance that was accompanied by elevated levels of low-density lipoprotein cholesterol (LDL-c) and altered haematological profile as characterised by significantly increased concentrations of red blood cell count, white cell count and lymphocytes when compared to those fed a low-fat diet (LFD). Moreover, the expression of caspase-3 in ILC1 and ILC3 was significantly increased in the HFD groups in comparison to the LFD-fed group. Notably, six-week treatment with metformin and fluvastatin reduced the caspase-3 activation in ILC subtypes. The reduced caspase-3 activation in ILC1 was inversely associated with HDL-c levels following metformin treatment. Interestingly, the reduced caspase-3 activation in ILC3 was associated with lower total cholesterol following fluvastatin treatment in these HFD-fed mice. However, there were no differences in activation of caspase-3 on ILC2 or any association between caspase-3 activation and changes in body weight or fasting blood glucose. Thus, while HFD-feeding clearly modulates ILCs, potentially leading to pro-apoptotic mechanisms, metformin and fluvastatin may play a major role in protecting against such metabolic disturbances.

Effect of Metformin on Myocardial Injury Induced by Hepatic Ischemia-Reperfusion in Rats.

Background: There is no effective medication for treatment or prevention of hepatic ischemia-reperfusion (HIR) injury caused by liver transplantation and hepatectomy. This study aimed to investigate the therapeutic effects of metformin on HIR injury and related myocardial injury in rats. Methods: Wistar male rats were randomly divided into four groups: sham group, ischemia-reperfusion group, and IR group treated with metformin 150 mg/kg and 100 mg/kg. Wistar male rats were administered metformin 150 mg/kg, 100 mg/kg or saline 30 min pre-operative and underwent 15 min ischemia and 6 h reperfusion (n = 4). Results: Metformin significantly alleviates the injury caused by HIR. Administration of metformin resulted in a significant reduction in the serum levels of alanine transaminase and aspartate transaminase and the activity of malondialdehyde, creatine kinase-MB, and lactate dehydrogenase but maintained high catalase and superoxide dismutase activity. Metformin significantly inhibited the IR-induced elevation of tumor necrosis factor-α in liver and heart tissue. Conclusion: Metformin can alleviate hepatic and myocardial injury induced by IR by inhibiting oxidative stress.

Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice

BackgroundMetformin exhibits therapeutic potential in behavioural deficits induced by methamphetamine (METH) in rats. Emerging studies suggest gut microbiota may impact psychiatric symptoms, but there is no direct evidence supporting metformin’s participation in the pathophysiology of withdrawal symptoms via modulation of gut microbiota. MethodsIn order to define the functional impacts of gut microbiota and metformin to the behavioural deficits during METH withdrawal, we utilized a combination of fecal microbiota transplantation (FMT), high-throughput sequencing, and untargeted metabolomics technologies. ResultsFirst, METH addicts exhibited higher α diversity and distinct microbial structures compared to healthy controls. In particular, the relative abundance of Rikenellaceae was positively correlated with the severity of anxiety and depression. Second, both human-to-mouse and mouse-to-mouse FMTs confirmed that METH-altered-microbiota transplantation is sufficient to promote anxiety and depression-like behaviours in recipient germ-free mice, and these behavioural disturbances could be ameliorated by metformin. In-depth analysis revealed that METH significantly altered the bacterial composition and structure as well as relative abundance of several bacterial taxa and metabolites, including Rikenellaceae and inosine, respectively, whereas add-on metformin could remodel these alterations. Finally, the inosine complementation successfully restored METH-induced anxiety and depression-like behaviours in mice. ConclusionThis study demonstrates that METH withdrawal-induced anxiety and depression-like behaviours are reversible and transmissible via gut microbiota in a mouse model. The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota-derived metabolites, highlighting the role of the gut microbiota in substance use disorders and the pathophysiology of withdrawal symptoms.

Numb/Notch/PLK1 signaling pathway mediated hyperglycemic memory in pancreatic cancer cell radioresistance and the therapeutic effects of metformin

BackgroundDiabetes mellitus has presented a positive role in the progression of pancreatic cancer and “Hyperglycemic memory” could be an important cause for diabetic damage. While limited information is available regarding the role of “hyperglycemic memory” in the pancreatic cancer and its radio-resistance. We therefore investigated correlation among hyperglycemic memory, Numb and metformin in pancreatic cancer radio-resistance. MethodsHigh glucose and hyperglycemic memory models were established in vitro and in vivo. Western blot, real-time PCR were accordingly used to detect Numb /Notch/ Polo-like kinase1 (PLK1) signaling at the level of molecular, cellular and experimental animal model, respectively. The apoptosis rate was evaluated by TUNEL assay and Capase-3 activity. The therapeutic effect of metformin was revealed by detecting the level of Numb / Notch /PLK1 through Western blot and real-time PCR. ResultsInactivation of Numb promotes the pancreatic cancer radio-resistance through hyperglycemic memory and metformin could suppress the radio-resistance by activating Numb in vitro and in vivo. In addition, PLK1 and Notch signaling pathway (Notch1, HEY1) elevated in pancreatic cancer radio-resistance condition, which was induced by hyperglycemic memory. Moreover, Numb overexpression or metformin could suppress Notch pathway to alleviate pancreatic cancer radio-resistance. ConclusionsOur data demonstrated that Numb might be a promising target for the improvement of hyperglycemic memory damage and the effect of metformin deserved urgent attention on pancreatic cancer radio-resistance therapy.

AMPK/mTOR-mediated therapeutic effect of metformin on myocardial ischaemia reperfusion injury in diabetic rat

Background The autophagy associated signalling pathways such as AMPK/mTOR previously were suggested to play a crucial role in protecting from ischaemia–reperfusion injury (IRI). The objective of this study was to evaluate the effect of metformin (DMBG) on autophagy during myocardial IRI with diabetes mellitus (DM). Methods The DM rat model was established using streptozocin, and further induced ischaemia model via transitory ligation of the left anterior coronary artery and following reperfusion. The model rats were treated with 400 mg/kg/day DMBG for 1 week. Autophagosomes were investigated using transmission electron microscopy. Autophagy-associated signalling pathways were detected by western blot. Results The myocardial infarct size was shown to significantly increase in the DM rats exposed to IRI compared to negative control, but decrease in DMBG treated. The mature autophagosomes were elevated in infarction and marginal zones of DM + IRI + DMBG compared to DM + IRI. Furthermore, the increasing protein levels of LC3-II, BECLIN 1, autophagy related 5 (ATG5) and AMP-activated protein kinase suggested activated autophagy-associated intracellular signalling AMPK and mTOR pathways upon DMBG treated. Conclusions Taken together, the outcomes determinate a novel mechanism that DMBG could activate autophagy process to provide a cardio-protective effect against DM induced myocardial IRI.

Comparative Evaluation of the Effect of Metformin and Insulin on Gut Microbiota and Metabolome Profiles of Type 2 Diabetic Rats Induced by the Combination of Streptozotocin and High-Fat Diet.

Lately, an increasing number of studies have investigated the relationship between metformin and gut microbiota, suggesting that metformin exerts part of its hypoglycemic effect through the microbes. However, its underlying mechanism remains largely undetermined. In the present study, we investigated the effects of metformin on gut microbiota and metabolome profiles in serum and compared it with insulin treatment in rats with type 2 diabetes mellitus (T2DM). Diabetic rats (DM group) were induced by a combination of streptozotocin and high-fat diet (HFD). After 7 days, DM rats were treated with metformin (MET group) or insulin (INS group) for 3 weeks. The 16S rRNA sequencing of the gut microbiota and non-targeted metabolomics analysis of serum were conducted. A total of 13 bile acids (BAs) in serum were further determined and compared among different groups. The rat model of T2DM was well established with the typical diabetic symptoms, showing significantly increased blood glucose, AUC of OGTT, HOMA-IR, TC, TG, LDL-C and TBA. Metformin or insulin treatment could ameliorate symptoms of diabetes and partly recover the abnormal biochemical indicators. Compared with DM rats, the relative abundances of 13 genera were significantly changed after metformin treatment, while only three genera were changed after insulin treatment. The metformin and insulin treatments also exhibited different serum metabolome profiles in T2DM rats. Moreover, 64 differential metabolites were identified between MET and DM groups, whereas 206 were identified between INS and DM groups. Insulin treatment showed greater influence on amino acids, glycerophospholipids/glycerolipids, and acylcarnitine compared with the metformin treatment, while metformin had an important impact on BAs. Furthermore, metformin could significantly decrease the serum levels of CA, GCA, UDCA, and GUDCA, but increase the level of TLCA in DM rats. Insulin treatment significantly decreased the levels of CA, UDCA, and CDCA. Besides, several metabolites in serum or microbiota were positively or negatively correlated with some bacteria. Collectively, our findings indicated that metformin had a stronger effect on gut microbiota than insulin, while insulin treatment showed greater influence on serum metabolites, which provided novel insights into the therapeutic effects of metformin on diabetes.

Metformin attenuates H2O2-induced osteoblast apoptosis by regulating SIRT3 via the PI3K/AKT pathway.

Osteoporosis is a common metabolic disease that has a high incidence in postmenopausal women. Studies have indicated that oxidative damage plays an important role in the development of postmenopausal osteoporosis. Metformin has been showed to have the ability to relieve excessive oxidation. The aim of the present was to determine the therapeutic effect and potential mechanism of metformin in postmenopausal osteoporosis. Oxidative damage was stimulated in vitro by the addition of H2O2 to MC3T3-E1 cells and a mouse menopausal model was also constructed. Cell viability and flow cytometry experiments were performed to determine the effects of H2O2 and metformin treatment on apoptosis. Mitochondrial membrane potential was tested by JC-1 assays. Western blotting was used to detect the expression of mitochondrial apoptosis markers and antioxidant enzymes. Small interfering RNA was used to knockdown sirtuin3 (SIRT3), which was verified at the mRNA and protein levels. Bilateral ovariectomy was used to prepare menopausal mice, which were analyzed using micro-computed tomography. The results indicated that metformin is able to repair mitochondrial damage and inhibit the apoptosis of osteoblasts induced by H2O2, and also reverse bone mass loss in ovariectomized mice. Western blotting results demonstrated the involvement of SIRT3 in the production of antioxidant enzymes that are essential in protecting against mitochondrial injury. In addition, experiments with SIRT3 knockdown indicated that metformin reverses H2O2-induced osteoblast apoptosis by upregulating the expression of SIRT3 via the PI3K/AKT pathway. The results of the present reveal the pathogenesis of oxidative damage and the therapeutic effect of metformin in postmenopausal osteoporosis. They also suggest that SIRT3 is a potential drug target in the treatment of osteoporosis, with metformin being a candidate drug for modification and/or clinical application.

Metformin promotes microglial cells to facilitate myelin debris clearance and accelerate nerve repairment after spinal cord injury.

Spinal cord injury (SCI) is one kind of severe trauma for central nervous system. Myelin debris clearance and axon regeneration are essential for nerve regeneration after SCI. Metformin, a glucose-lowering drug, has been demonstrated to promote the locomotor functional recovery after SCI. In this study, we investigated the role and molecular mechanism of metformin on myelin preservation in a rat SCI model. SCI was induced in rats by compression at T9 level using a vascular clip. We showed that administration of metformin (50 mg·kg-1·d-1, ip) for 28 days significantly improved locomotor function in SCI rats. Metformin also ameliorated SCI-induced neuronal apoptosis and promoted axon regeneration in the spinal cord. Using co-immunofluorescence of IBa-1 and MBP, and luxol fasting blue (LFB) staining, we demonstrated that metformin promoted the transformation of M1 to M2 phenotype polarization of microglial cells, then greatly facilitated myelin debris clearance and protected the myelin in SCI rats. Furthermore, metformin ameliorated SCI-induced blockade of autophagic flux in the spinal cord, and enhanced the fusion of autophagosome and lysosome by inhibiting the AMPK-mTOR signaling pathway. Moreover, metformin significantly attenuated inflammatory responses in the spinal cord. In LPS-treated BV2 cells, pretreatment with metformin (2 mM) significantly enhanced autophagy level, suppressed inflammation and cell apoptosis. The protective effects were blocked in the presence of an autophagy inhibitor 3-methyladenine (3-MA, 5 mM), suggesting that the effect of metformin on autophagy in microglial cells is essential for the myelin preservation during nerve recovery. This study reveals a novel therapeutic effect of metformin in SCI recovery by regulating the activation of microglial cells and enhancing its autophagy level.