Acidosis láctica en un paciente usuario de metformina / Metformin-associated lactic acidosis

Metformin is a hypoglycemic agent used as the first line for the treatment of non-insulin dependent Diabetes Mellitus. While it is a generally safe drug, it has an infrequent adverse reaction called lactic acidosis. We report a 49 year-old patient with non-insulin-requiring type 2diabetes who developed an acute kidney failure injury along with severe metabolic acidosis secondary to pneumonia during treatment.

La metformina es un agente hipoglucemiante que se ocupa de primera línea para el tratamiento de la Diabetes Mellitus no insulino dependiente. Si bien es un medicamento bien tolerado, tiene una reacción adversa bastante infrecuente que es la acidosis láctica. Reportamos el caso de una paciente de 49 años insulino no dependiente que desarrolló una injuria renal aguda junto con acidosis metabólica severa secundaria a una neumonía en tratamiento.

Effective Inhibition of TNFalpha/mTOR Axis-Mediated Liver Inflammation and Fibrosis Induced by TAA Using a Combination of Metformin and Resveratrol in Association with the Inhibition of the Profibrotic Gene and Protein Expression / Inhibición Efectiva de la Inflamación Hepática Mediada por el Eje TNF-alfa/mTOR y la Fibrosis Inducida por TAA Utilizando una Combinación de Metformina y Resveratrol en Asociación con la Inhibición del Gen Profibrótico y la Expresión de Proteínas

SUMMARY: The response of the immune system to harmful stimuli leads to inflammation, and the adverse effects of the toxic hepatitis chemical, thioacetamide (TAA) on the human body are well documented. This article investigated the degree of protection provided by the combined pleotropic drug, metformin (Met) and the plant polyphenolic and the antiinflammatory compound, resveratrol (Res) on liver tissue exposed to TAA possibly via the inhibition of the inflammatory cytokine, tumor necrosis factor-α (TNF-α) / mammalian target of rapamycin (mTOR) axis-mediated liver fibrosis, as well as amelioration of profibrotic gene and protein expression. Rats were either given TAA (200 mg/kg via intraperitoneal injection) for 8 weeks beginning at the third week (experimental group) or received during the first two weeks of the experiment combined doses of metformin (200 mg/kg) and resveratrol (20 mg/kg) and continued receiving these agents and TAA until experiment completion at week 10 (treated group). A considerable damage to hepatic tissue in the experimental rats was observed as revealed by tissue collagen deposition in the portal area of the liver and a substantial increase (p<0.0001) in hepatic levels of the inflammatory marker, tumor necrosis factor-α (TNF-α), as well as blood levels of hepatocellular injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). TAA also augmented hepatic tissue levels of the signalling molecule that promotes liver fibrosis (mTOR), and profibrogenic markers; alpha-smooth muscle actin (α-SMA) protein, tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA, and matrix metalloproteinase-9 (MMP-9) mRNA. All these parameters were protected (p≤0.0016) by Met+Res. In addition, a significant correlation was detected between liver fibrosis score and inflammation, liver injury enzymes, mTOR, and profibrogenesis markers. Thus, these findings suggest that Met+Res effectively protect the liver against damage induced by thioacetamide in association with the downregulation of the TNF-α/mTOR/fibrosis axis.

La respuesta del sistema inmunológico a estímulos dañinos conduce a la inflamación y los efectos adversos de la tioacetamida (TAA), una sustancia química tóxica para el hígado, están bien documentadas. Este artículo investigó el grado de protección proporcionado por el fármaco pleotrópico combinado metformina (Met), el polifenólico vegetal y el compuesto antiinflamatorio resveratrol (Res) en el tejido hepático expuesto a TAA, posiblemente a través de la inhibición de la citoquina inflamatoria, factor de necrosis tumoral α (TNF-α)/objetivo de la fibrosis hepática mediada por el eje de rapamicina (mTOR), así como mejora de la expresión de genes y proteínas profibróticas. Las ratas recibieron TAA (200 mg/kg mediante inyección intraperitoneal) durante 8 semanas a partir de la tercera semana (grupo experimental) o recibieron durante las dos primeras semanas del experimento dosis combinadas de metformina (200 mg/kg) y resveratrol (20 mg/kg) y continuaron recibiendo estos agentes y TAA hasta completar el experimento en la semana 10 (grupo tratado). Se observó un daño considerable al tejido hepático en las ratas experimentales, como lo revela el depósito de colágeno tisular en el área portal del hígado y un aumento sustancial (p<0,0001) en los niveles hepáticos del marcador inflamatorio, el factor de necrosis tumoral-α (TNF- α), así como los niveles sanguíneos de biomarcadores de lesión hepatocelular, alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST). TAA también aumentó los niveles en el tejido hepático de la molécula de señalización que promueve la fibrosis hepática (mTOR) y marcadores profibrogénicos; proteína actina del músculo liso alfa (α- SMA), inhibidor tisular de las metaloproteinasas-1 (TIMP-1) mRNA y matriz metaloproteinasa-9 (MMP-9) mRNA. Todos estos parámetros fueron protegidos (p≤0.0016) por Met+Res. Además, se detectó una correlación significativa entre la puntuación de fibrosis hepática y la inflamación, las enzimas de lesión hepática, mTOR y los marcadores de profibrogénesis. Por lo tanto, estos hallazgos sugieren que Met+Res protege eficazmente el hígado contra el daño inducido por la tioacetamida en asociación con la regulación negativa del eje TNF-α/mTOR/fibrosis.

miR-139-5p enhances the inhibition effect of metformin on cell proliferation of pancreatic cancer cell line PANC-1 cultured in normal-glucose medium / 基础医学与临床

Objective To investigate the effects of metformin(Met)on the proliferation of pancreatic cancer cells under different glucose concentration culture conditions,and to find the potential role of miR-139-5p in the process.Methods PANC-1 cells were treated with different concentrations of metformin(0/5/10/20 mmol/L)in 25 mmol/L(high-glucose group,HG)or 5 mmol/L(normal-glucose group,NG)glucose culture,cell proliferation,apoptosis,migration and cell cycle were detected after 48 h.The expression of miR-139-5p was quantitatively detected by RT-qPCR,and the miR-139-5p mimics were transfected into PANC-1 cells to clarify the role of miR-139-5p.Results Metformin inhibited the proliferation,promoted apoptosis,and induced S phase and G2/M phase arrest of PANC-1 cells under in high glucose and normal glucose culture conditions,and its anti-proliferation and pro-apoptosis effects were more significant in the normal glucose groups.The expression of miR-139-5p was up-regu-lated by metformin treatment in normal but not in high glucose culture.Further studies showed that miR-139-5p mimics inhibited of PANC-1 cells proliferation without metformin pre-incubation and enhanced the anti-prolifera-tion effect of 5 mmol/L metformin.The pro-apoptotic effect of 10 mmol/L metformin in normal glucose culture conditions.Conclusions In normal-glucose culture conditions,metformin can inhibit proliferation,induce apop-tosis and cell cycle arrest of PANC-1 cells more significantly than in higher-glucose culture,which may be partly related to the up-regulation of miR-139-5p.

Preparation,characterization,and in vitro biological performance evaluation of PLGA electrospinning membranes doped with metformin-loaded hollow mesoporous silica nanoparticles / 实用口腔医学杂志

Objective:To prepare PLGA electrospinning membranes doped with hollow mesoporous silica nanoparticles loaded with metformin and investigate their biological properties.Methods:PLGA(Control group)and PLGA/HMSN/Met electrospun membranes(Experimental group)were prepared by electrospinning technology.The microscopic morphology of the 2 groups of electrospun mem-branes was observed by SEM.The hydrophilicity,elemental composition and in vitro drug release were detected by contact angle meas-urement,EDS,and drug release test,respectively.SEM and laser scanning confocal microscope(LSCM)were used to observe the growth of periodontal ligament stem cells(PDLSCs)on the 2 groups of electrospun membranes,and CCK-8 assay was used to detect the cell proliferation.Results:Both electrospun membranes had extracellular matrix(ECM)-like fiber structures.The PLGA/HMSN/Met electrospun membranes could slowly release Met for up to 35 days,and the hydrophilicity of PLGA membranes was improved by HMSN-Met doped.The composite electrospun membranes had good cell biocompatibility in vitro,and could promote cell proliferation.Conclu-sion:Modification of PLGA with HMSN-Met can improve the hydrophilicity of PLGA electrospun membranes,continuously release Met,and have good cell biocompatibility.

Metformin pretreatment induces cardiac autophagy to reduce myocardial injury in septic mice / 中国组织工程研究

BACKGROUND:Sepsis complicated by myocardial injury is characterized by a high mortality.Metformin can prevent sepsis-induced myocardial dysfunction by exerting anti-inflammatory effects,improving oxidative stress,and reducing apoptosis.However,it is unclear whether metformin-induced autophagy plays an important role in the protective effect against sepsis-induced myocardial injury. OBJECTIVE:To explore the effect of metformin pretreatment on myocardial injury in septic mice. METHODS:A total of 40 male Kunming mice were randomly divided into sham operation group,model group,metformin group,and metformin+ 3-methyladenine group,with 10 mice in each group.The latter two groups were intraperitoneally injected with metformin for 14 days at a fixed time every day,and the metformin+3-methyladenine group was intraperitoneally injected with 3-methyladenine 1 hour before modeling.Twenty-four hours after the last injection of metformin,cecal ligation and perforation were used to construct a model of myocardial injury in septic mice.The sham operation group was not ligated and perforated.All mice were sacrificed 24 hours after surgery,and blood and myocardial specimens were collected.The levels of inflammatory factors and myocardial injury markers in serum were detected by ELISA.The mRNA expression of autophagy markers LC3B and p62 in myocardial tissue was detected by RT-qPCR.The protein expression of LC3B,Beclin-1,p62,p-AMPK,and AMPK in myocardial tissue was detected by western blot.The pathological changes in myocardial tissue were detected by hematoxylin-eosin staining. RESULTS AND CONCLUSION:Autophagy was inhibited in septic mice with myocardial injury.Compared with the sham operation group,the levels of serum tumor necrosis factor-α,interleukin-1β,interleukin-6,creatine kinase isoenzyme,and troponin T were increased in the model group(P<0.05),but there was no significant difference in p62,LC3Ⅱ/LC3Ⅰ,and p-AMPK/AMPK between the two groups(P>0.05).Compared with the model group,the levels of tumor necrosis factor-α,interleukin-6,creatine kinase isoenzyme,troponin T,and p62 were decreased in the metformin group(P<0.05),while LC3Ⅱ/LC3Ⅰ,p-AMPK/AMPK and Beclin-1 level were increased(P<0.05).Compared with the metformin group,the levels of tumor necrosis factor-α,interleukin-6,creatine kinase isoenzyme,troponin T,and p62 were increased in the metformin+3-methyladenine group(P<0.05),while LC3Ⅱ/LC3Ⅰ and Beclin-1 level were decreased(P<0.05).Myocardial hematoxylin-eosin staining indicated that myocardial fibers arranged normally in the sham operation group,but disorderedly in the model group,with interstitial edema and a large number of infiltrated inflammatory cells.A small amount of vacuolar changes were observed in the metformin group.The arrangement of myocardial fibers in the metformin+3-methyladenine group was slightly disordered,with more vacuolar changes.To conclude,metformin pretreatment may reduce myocardial injury in septic mice by activating the AMPK signaling pathway and inducing autophagy.

Metformin:A promising clinical therapeutical approach for BPH treatment via inhibiting dysregulated steroid hormones-induced prostatic epithelial cells proliferation / 药物分析学报

The occurrence of benign prostate hyperplasia(BPH)was related to disrupted sex steroid hormones,and metformin(Met)had a clinical response to sex steroid hormone-related gynaecological disease.How-ever,whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear.Here,our clinical study showed that along with prostatic epithelial cell(PEC)proliferation,sex steroid hormones were dysregulated in the serum and prostate of BPH patients.As the major contributor to dysregulated sex steroid hormones,elevated dihydrotestosterone(DHT)had a significant positive rela-tionship with the clinical characteristics of BPH patients.Activation of adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor(AR)-mediated Yes-associated protein(YAP1)-TEA domain transcription factor(TEAD4)heterodimers.Met's anti-proliferative effects were blocked by AMPK inhibitor or YAP1 over-expression in DHT-cultured BPH-1 cells.Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

Efficacy of the combination of semaglutide, insulin degludec, and metformin in the treatment of type 2 diabetes mellitus and poor glycemic control accompanied by overweight or obesity / 中国基层医药

Objective:To investigate the efficacy of the combination of semaglutide, insulin degludec, and metformin in the treatment of type 2 diabetes mellitus and poor glycemic control accompanied by overweight or obesity.Methods:A total of 160 patients with type 2 diabetes mellitus and poor glycemic control accompanied by overweight or obesity were included in this case-control study after receiving treatment at Bayannur Hospital from April 2022 to March 2023. These patients were divided into a control group and an observation group based on different treatment regimens, with 80 patients in each group. The control group was treated with degludec insulin combined with metformin, while the observation group was treated with semaglutide, degludec insulin, and metformin. The treatment lasted for 12 weeks in both groups. The changes in fasting plasma glucose, 2-hour postprandial blood glucose (2 h PG), glycosylated hemoglobin, time in range for 2 h PG, fasting insulin, Homeostatic Model Assessment for Insulin Resistance index, body mass index, and visceral fat area and adverse reactions were monitored.Results:The overall response rate in the observation group was 100% (80/80), which was significantly higher than 97.5% (78/80) in the control group (χ 2 = 11.03, P < 0.05). After treatment, the levels of 2 h PG, glycosylated hemoglobin, fasting insulin, Homeostatic Model Assessment for Insulin Resistance index, body mass index, visceral fat area in the observation group were (7.35 ± 0.17) mmol/L, (6.08 ± 0.24)%, (10.30 ± 2.58) μU/mL,(2.69 ± 0.66), (24.40 ± 0.68) kg/m 2, (80.20 ± 8.94) cm 2, respectively, which were significantly lower than (7.92 ± 0.24) mmol/L, (6.34 ± 0.27)%,(13.71 ± 3.13) μU/mL,(3.57 ± 0.83), (26.77 ± 3.49) kg/m 2, (116.12 ± 34.09) cm 2 respectively in the control group ( t = -0.73, -3.74, -4.20, -4.15, -3.35, -5.10, all P < 0.05). The time in range for 2 h PG in the observation group was (72.68 ± 4.09)%, which was significantly higher than (50.16 ± 10.00)% in the control group ( t = -10.42, P < 0.05). The incidence of adverse reactions in the observation group was 3.8% (3/80), which was slightly, but not significantly, higher than 2.5% (2/80) in the control group ( P > 0.05). Conclusion:The combination of semaglutide, degludec insulin, and metformin demonstrates an ideal clinical effect in the treatment of type 2 diabetes mellitus and poor glycemic control accompanied by overweight or obesity. This combined approach can effectively regulate fasting and postprandial blood glucose levels, markedly decrease the body mass index and visceral fat levels, and improve insulin resistance while not significantly increasing the incidence of adverse reactions.

Antitumor Effect of Metformin on Ovarian Cancer Cells / 肿瘤防治研究

Objective To explore the antitumor effects of metformin on ovarian cancer cells in vitro, particularly on tumor cell proliferation, cell cycle, apoptosis, migration, and possible mechanism. Methods Ovarian cancer cell lines (A2780, CAOV3, and SKOV3) were treated with different concentrations of metformin. Their proliferation was explored using the MTT and clone formation assays, cell migration was examined using the scratch and Transwell assays, and cell cycle and apoptosis were examined using flow cytometry. In addition, metformin’s effects on the phosphorylation of AMPK and mTOR and the expression of CXCR4 and Wnt/β-catenin protein was measured by Western blot. Results The survival rates of ovarian cancer cells decreased significantly with increasing metformin concentration and metformin treatment time. The IC50 values of metformin at 48 h for A2780, CAOV3, and SKOV3 cells were 16.36, 36.65, and 43.44 mmol/L, respectively. Compared with the control group, the clone formation ability and cell migration ability of ovarian cancer cells were significantly inhibited by metformin treatment and cell cycle arrested at the G0/G1 phase, and the apoptosis rate increased. As metformin concentration increased, the expression of phosphorylated AMPK protein gradually increased, and the expression levels of phosphorylated mTOR, CXCR4, Dvl3, β-catenin, cyclin D1, and CDK1 decreased. Conclusion Metformin exerts an antitumor effect on ovarian cancer cells, which is related to the activation of AMPK to inhibit CXCR4-mediated Wnt/β-catenin signaling pathway.

Tratamiento con metformina previene la adiposidad de la médula ósea femoral inducida por un síndrome metabólico experimental en ratas / Metformin treatment prevents experimental metabolic syndrome-induced femoral bone marrow adiposity in rats

RESUMEN Objetivo. Determinar el efecto de un tratamiento con metformina (MET) sobre la predisposición adipogénica de células progenitoras de médula ósea (CPMO), adiposidad de la médula ósea y propiedades biomecánicas óseas. Materiales y métodos. 20 ratas Wistar machos adultos jóvenes fueron separados en cuatro grupos, recibiendo en agua de bebida: 100% agua (C); 20% de fructosa (F); metformina 100 mg/kg peso/día (M); o fructosa más metformina (FM). Tras cinco semanas se sacrificaron los animales, se diseccionaron ambos húmeros para obtener CPMO, y ambos fémures para evaluar adiposidad medular (histomorfometría) y propiedades biomecánicas (flexión a 3 puntos). Las CPMO se cultivaron in vitro en medio adipogénico para evaluar expresión de RUNX2, PPAR-γ y RAGE por RT-PCR, actividad de lipasa y acumulación de triglicéridos. Resultados. La dieta rica en fructosa (grupo F) produjo un aumento tanto de triglicéridos in vitro, como de la adiposidad medular in vivo; siendo parcial o totalmente prevenido por un co-tratamiento con metformina (grupo FM). No se observaron diferencias en las pruebas biomecánicas femorales in vivo, ni en actividad de lipasa y relación RUNX2/PPAR-γ in vitro. La DRF aumentó la expresión de RAGE en CPMO, siendo prevenido por co-tratamiento con MET. Conclusiones. El síndrome metabólico inducido por una dieta rica en fructosa aumenta la adiposidad medular femoral y, en parte, la predisposición adipogénica de las CPMO. A su vez, esto puede ser prevenido total o parcialmente por un co-tratamiento oral con MET.

ABSTRACT Objective. To determine the effect of metformin (MET) treatment on adipogenic predisposition of bone marrow progenitor cells (BMPC), bone marrow adiposity and bone biomechanical properties. Materials and methods. 20 young adult male Wistar rats were sorted into four groups. Each of the groups received the following in drinking water: 100% water (C); 20% fructose (F); metformin 100 mg/kg wt/day (M); or fructose plus metformin (FM). After five weeks the animals were sacrificed. Both humeri were dissected to obtain BMPC, and both femurs were dissected to evaluate medullary adiposity (histomorphometry) and biomechanical properties (3-point bending). BMPC were cultured in vitro in adipogenic medium to evaluate RUNX2, PPAR-γ and RAGE expression by RT-PCR, lipase activity and triglyceride accumulation. Results. The fructose-rich diet (group F) caused an increase in both triglycerides in vitro, and medullary adiposity in vivo; being partially or totally prevented by co-treatment with metformin (group FM). No differences were found in femoral biomechanical tests in vivo, nor in lipase activity and RUNX2/PPAR-γ ratio in vitro. DRF increased RAGE expression in BMPC, being prevented by co-treatment with MET. Conclusions. Metabolic syndrome induced by a fructose-rich diet increases femoral medullary adiposity and, in part, the adipogenic predisposition of BMPC. In turn, this can be totally or partially prevented by oral co-treatment with MET.

Protective mechanism of metformin-induced cardiomyocyte autophagy on myocardial injury in septic mice / 安徽医科大学学报

Objective @#To investigate the possible mechanism of metformin (Met) -induced cardiomyocyte autoph- agy in protecting myocardial injury in septic mice．@*Methods @# The model of myocardial injury in septic mice was es- tablished by cecal ligation and puncture ( CLP) ．Sixty Kunming mice were randomly divided into sham operation group (Sham group) ，model group ( CLP group) ，model + dimethyl sulfoxide ( DMSO) group ( CLP + DMSO group) ，model + metformin (Met) group (Met group) ，model + Met + 3-methyladenine (3-MA) group (Met + 3- MA group) ，model + Met + compound C ( CC) group (Met + CC group) ，with 10 mice in each group．The Met， Met + 3-MA and Met + CC groups were intraperitoneally injected with Met (200 mg / kg) once a day for 2 weeks be- fore modeling．The Met + 3-MA group was intraperitoneally injected with 3-MA ( 10 mg / kg) 1 h before surgery. The Met + CC group was intraperitoneally injected with CC (20 mg / kg) 30 min before surgery．The model was es- tablished 24 h after the last injection of Met．The heart and blood of all mice were collected 24 h after surgery．The Western blot technique was employed to assess the relative expression levels of microtubule-associated protein 1 light chain 3 (LC3) isoforms，namely LC3 I and LC3 II，autophagy effector protein 1 (Beclin-1) ，ubiquitin-bind- ing protein 62 (p62) ，B-cell lymphoma / leukemia-2 (Bcl-2) ，Bcl-2-associated X protein (Bax) ，adenosine mono- phosphate (AMP) kinase (AMPK) and phosphorylated AMPK (p-AMPK) ．Myocardial pathological changes were observed by hematoxylin-eosin (HE) staining．The changes of myocardial mitochondria and autophagosomes were observed by electron microscopy．Hematoxylin-eosin (HE) staining was used to observe the pathological changes of myocardium． Electron microscopy was used to observe the changes of myocardial mitochondria and autophago- somes. @*Results @# Compared with Sham group，the relative protein expression of Beclin-1，p62，p-AMPK / AMPK and LC3 II / LC3 I in CLP and CLP + DMSO groups had no statistical significance，but Bax increased and Bcl-2 de- creased in CLP group (P＜0. 01) ．Compared with CLP group，the relative expression of Beclin-1 protein and LC3 II / LC3 I in Met group increased and p62 decreased (P＜0. 01) ，Bax decreased and Bcl-2 increased (P＜0. 01) . Compared with Met group，the relative protein expression of Beclin-1 and LC3 II / LC3 I in Met + 3-MA group de- creased and p62 increased (P＜0. 05) ，Bax increased and Bcl-2 decreased (P＜0. 05) ．Besides，the relative pro- tein expression of p-AMPK / AMPK in Met + CC group decreased (P＜0. 05) ．HE staining showed that there was no disorder in myocardial fibers in Sham group，and a large number of inflammatory cells infiltrated the myocardial fibers of CLP group in a clear disorder．The Met group showed vacuolar changes in the myocardium，while the Met + 3-MA group showed disordered arrangement of myocardial fibers and a small amount of inflammatory cell infiltra- tion．Under electron microscopy，the morphology of myocardial mitochondria in the Sham group was normal，while in the CLP group，the arrangement of mitochondrial cristae was disordered with vacuolar changes，and occasional autophagosomes were observed．Mitochondria in Met group showed slight swelling and a large number of autophago- somes．The mitochondria in the Met + 3-MA group showed significant swelling with a small amount of autophago- somes．@*Conclusion @#The protective effect of metformin on myocardial injury in septic mice can reduce cardiomyo- cyte apoptosis and improve mitochondrial damage by activating AMPK signaling pathway to induce autophagy.

Effects of dulaglutide combined with metformin on body metabolism, body fat composition and serum adipokines in obese patients with type 2 diabetes mellitus / 药学实践与服务

Objective To explore the clinical efficacy of dulaglutide combined with metformin in the treatment of obese patients with type 2 diabetes mellitus（T2DM）. Methods A total of 200 obese patients with T2DM who were treated in Shanghai Jiading District Anting Hospital from January 2021 to January 2023 were randomly divided into liraglutide group（n=100）and dulaglutide group（n= 100）. The liraglutide group was treated with liraglutide combined with metformin, and the dulaglutide group was treated with dulaglutide combined with metformin. Both groups were treated for 3 months. The body metabolic indexes [fasting blood glucose（FBG）, 2 h postprandial blood glucose（2 h PBG）, hemoglobin（HbA1 c）, total cholesterol（TC）, triglyceride（TG）], body fat composition [body fat rate, body mass index, subcutaneous fat rate of limbs, visceral fat index] and serum adipokines（adiponectin, neuropeptide Q（NPQ）, asprosin, irisin）levels were compared before treatment and 3 months after treatment. The clinical efficacy and adverse reactions of the two groups were observed. Results After 3 months of treatment, FBG, 2 h PBG, HbAlc, TC, TG, body fat rate, body mass index, subcutaneous fat rate of limbs, visceral fat index and asprosin in the two groups were lower than those before treatment, and those in the dulaglutide group were lower than those in the liraglutide group（P<0.05）. After 3 months of treatment, the levels of serum adiponectin, NPQ and irisin in the two groups were higher than those before treatment, and the increase in the dulaglutide group was greater than that in the liraglutide group（P<0.05）. The effective rate of dulaglutide group（98.00%）was higher than that of liraglutide group（91.00 %）（P<0.05）. There was no significant difference in the incidence of adverse reactions between the two groups（11.00%, 14.00%）（P>0.05）. Conclusion Dulaglutide combined with metformin could improve the metabolic status of obese T2 DM patients, regulate body fat composition and serum adipokines, with significant clinical efficacy and safety.

Applications and consideration for metformin in pregnancy / 中华围产医学杂志

Metformin is recognized for its dual action in lowering blood glucose levels and enhancing insulin sensitivity, positioning it as the primary oral drug for managing type 2 diabetes mellitus (T2DM). Despite its ability to cross the placenta and expose the fetus, extensive clinical application has not revealed significant adverse effects. Metformin finds widespread application during pregnancy in conditions such as obesity, polycystic ovary syndrome, T2DM, and gestational diabetes mellitus. This article aims to establish an evidence-based perspective on the impact of metformin administered during pregnancy on maternal and fetal outcomes, as well as the long-term health of offspring. Generally deemed safe and effective, metformin is viewed as a means to control hyperglycemia and manage gestational weight gain without conspicuous adverse effects on maternal and fetal pregnancy outcomes. However, metformin alone may not suffice for achieving glycemic control, necessitating the addition of insulin. Besides, the long-term offspring risks of metformin exposure are controversial, long-term follow-up study is urgent to bring certainty into this field. Thus, tight control over indications for metformin use during pregnancy is crucial to ensure optimal maternal and fetal health outcomes. Although not suggested as a first-line agent for glycemic control in pregnancy, it may be considered as an adjunctive option in cases of severe insulin resistance or in low-resource areas where access to insulin is challenging.

Metformin Inhibits ROS/TNF-alpha Axis-Mediated Chronic Kidney Disease Induced by TAA Independent of Leukocyte Infiltration in Association with the Inhibition of Kidney Injury Biomarkers / La Metformina Inhibe la Enfermedad Renal Crónica Mediada por el Eje ROS/TNF-alfa Inducida por TAA Independientemente de la Infiltración de Leucocitos en Asociación con la Inhibición de Biomarcadores de Lesión Renal

SUMMARY: The toxic effects of thioacetamide (TAA) and carbon tetrachloride on the human body are well recognized. In this study, we examined whether TAA intoxication can induce kidney leukocyte infiltration (measured as leukocyte common antigen CD45) associated with the augmentation of the reactive oxygen species (ROS)/tumor necrosis factor-alpha (TNF-α) axis, as well as biomarkers of kidney injury with and without metformin treatment. Rats were either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being sacrificed after 10 weeks (experimental group) or were pre-treated with metformin (200 mg/kg) daily for two weeks prior to TAA injections and continued receiving both agents until the end of the experiment, at week 10 (protective group). Using basic histology staining, immunohistochemistry methods, and blood chemistry analysis, we observed profound kidney tissue injury such as glomerular and tubular damage in the experimental group, which were substantially ameliorated by metformin. Metformin also significantly (p0.05) increase in kidney expression of CD45 positive immunostaining cells. In conclusion, we found that TAA induces kidney injury in association with the augmentation of ROS/TNF-α axis, independent of leukocyte infiltration, which is protected by metformin.

Son bien conocidosos los efectos tóxicos de la tioacetamida (TAA) y el tetracloruro de carbono en el cuerpo humano. En este estudio, examinamos si la intoxicación por TAA puede inducir la infiltración de leucocitos renales (medida como antígeno leucocitario común CD45) asociada con el aumento de las especies reactivas de oxígeno (ROS)/factor de necrosis tumoral-alfa (TNF-α), así como biomarcadores de daño renal con y sin tratamiento con metformina. A las ratas se les inyectó TAA (200 mg/kg; dos veces por semana durante 8 semanas) antes de sacrificarlas a las 10 semanas (grupo experimental) o se les pretrató con metformina (200 mg/kg) diariamente durante dos semanas antes de las inyecciones de TAA y continuaron recibiendo ambos agentes hasta el final del experimento, en la semana 10 (grupo protector). Usando tinción histológica básica, métodos de inmunohistoquímica y análisis químico de la sangre, observamos una lesión profunda del tejido renal, como daño glomerular y tubular en el grupo experimental, que mejoraron sustancialmente con la metformina. La metformina también inhibió significativamente (p0,05) en la expresión renal de células de inmunotinción positivas para CD45. En conclusión, encontramos que el TAA induce la lesión renal en asociación con el aumento del eje ROS/TNF-α, independientemente de la infiltración de leucocitos, que está protegida por metformina.

MALA: Acidosis láctica asociado al uso de metformina, una revisión a propósito de casos clínicos / MALA: Lactic acidosis associated with the use of metformin, review of clinical cases

La metformina es el fármaco preferido en el manejo inicial de la diabetes mellitus tipo 2 (DMT2). Aunque se recomienda su uso ampliamente, se debe tener precaución al prescribirla a poblaciones susceptibles a condiciones de riesgo de hipoperfusión sistémica, ya que puede provocar acumulación en el organismo y alteraciones metabólicas que desemboquen en acidosis láctica asociada a metformina, una complicación grave que a menudo es subdiagnosticada. Con el propósito de promover un mejor conocimiento sobre este tema, la presente revisión se centra en el análisis de la clínica, fisiopatología, diagnóstico y manejo de la acidosis láctica asociada a metformina, prestando especial atención al manejo mediante terapias de reemplazo renal. El análisis se basará en la experiencia de una serie de casos de acidosis láctica asociada a metformina atendidos en un centro clínico hospitalario en Chile.

Metformin is the preferred medication for the initial management of type 2 diabetes mellitus (T2DM). Although its use is widely recommended, caution should be exercised when prescribing it to populations susceptible to systemic hypoperfusion conditions, as it can lead to accumulation in the body and metabolic disturbances that may result in metformin-associated lactic acidosis. This severe complication is often underdiagnosed. To promote a better understanding of this topic, the present review focuses on the analysis of the clinical, pathophysiological, diagnostic, and management aspects of metformin-associated lactic acidosis, with particular attention to management through renal replacement therapies. The analysis will be based on the experience of a series of cases of metformin-associated lactic acidosis treated at a hospital clinical center in Chile.

Comparative evaluation of metformin & sitaformin in classic PCOS patients undergoing intracytoplasmic sperm injection: A randomized controlled pilot study

Background & objectives: Studies have shown that insulin resistance and hyperinsulinaemia play a major role in the pathogenesis of polycystic ovary syndrome (PCOS). Therefore, the use of insulin sensitizing drugs in the treatment of PCOS has attracted the attention of medicine and researchers. The aim of this study was to investigate the effects of sitaformin (sitagliptin/metformin) and metformin on the quality of oocyte and embryo in classic PCOS patients undergoing intracytoplasmic sperm injection (ICSI). Methods: Sixty patients of PCOS (25-35 yr) were randomly allocated into three groups (n=20, each group): a metformin-treated group (administered metformin 500 mg twice daily), a sitaformin-treated group (administered sitaformin 50/500 mg twice daily) and a placebo group. Participants in all the groups received the drug two months prior to the start of the ovulation cycle and treatment continued until the day of the oocyte aspiration. Results: Serum insulin and total testosterone levels decreaseed significantly after treatment in both the treatment groups as compared to the placebo (P<0.05). A significant decrease in the number of immature oocytes [MI + germinal vesicle (GV) stage] was observed in metformin and sitaformin groups as compared to the placebo. In addition, sitaformin group when compared to the metformin group showed a significant decrease in the number of immature oocytes (P<0.05). The number of mature and normal MII oocytes increased significantly in both the treatment groups compared to the placebo group (P<0.05). The number of mature and normal oocytes increased in sitaformin group in comparison to the metformin group, but the difference was not significant. There was a significant increase in the number of grade I embryos, fertilization and cleavage rates in the sitaformin group compared to the other groups (P<0.05). Interpretation & conclusions: This is the first study to compare the impact of sitaformin with metformin on oocyte and embryo quality in women with PCOS undergoing a gonadotropin-releasing hormone (GnRH) antagonist cycle. In conclusion, sitaformin can be more effective in decreasing immature oocytes and increasing the quality of embryos than the use of metformin.

Association of Metformin with Mortality in COVID-19 Patients: A Systematic Review and Meta-Analysis

Studies have demonstrated high prevalence of mortality in coronavirus disease (COVID-19) patients with type 2 diabetes mellitus; however, the effects of antidiabetic pharmacotherapy on COVID-19 complications need further exploration. The aim of the study was to explore the association of metformin use and mortality in COVID-19 patients. A literature search was conducted using the databases Medline (via PubMed) and Cochrane Central Register of Controlled Trials until February 09, 2021. Nine studies were included in the meta-analysis, including 12,684 COVID-19 patients. The meta-analysis suggested 37% lower risk of mortality in patients receiving metformin (risk ratio: 0.63; 95% confidence interval: 0.50–0.78; p?<?0.001). However, no significant difference in hospitalization days between the two groups (p?=?0.197) was observed. The analysis revealed significantly lower risk of having obesity (p?<?0.001), hypertension (p?<?0.001), heart failure (p?<?0.001), and cerebrovascular disease (p?=?0.015) in the group receiving metformin. The analysis also demonstrated significantly lower risk of using anticoagulants (p?=?0.015), diuretics (p?<?0.001), and antiplatelets (p?=?0.010) in patients receiving metformin. Our findings suggest that metformin use decreases mortality in COVID-19 patients. However, randomized studies demonstrating the consequences of metformin use are needed to understand the magnitude of the beneficial effects of metformin

Antiproliferative effects of 13α/ß-steroids on triple-negative MDA-MB-231 breast cancer cells: unraveling intracellular signaling without ERα

Abstract This study aimed to investigate the activities of novel 20(R)-3,20-dihydroxy-19-norpregn-1,3,5(10)-trienes (kuz7 and kuz8b) of natural 13ß- and epimeric 13α-series against triple-negative MDA-MB-231 breast cancer cells. High antiproliferative activity of synthesized compounds kuz8b and kuz7 against MDA-MB-231 triple-negative cancer cells was revealed. The steroid kuz7 of natural 13ß-configuration was more active against MDA-MB-231 cells than the 13α-steroid kuz8b. Cell cycle analysis revealed common patterns for the action of both tested compounds. The number of cells in the subG1 phase increased in a dose-dependent manner, indicating induction of apoptosis, which was also verified by PARP cleavage. In contrast, the number of cells in the G0/G1 phase decreases with increasing compound concentration. Steroid kuz7 at micromolar concentrations reduced the expression of GLUT1, a glucose transporter. High efficacy of the combination of kuz7 with biguanide metformin was shown, and synergistic effects on MDA-MB-231 cell growth and expression of the anti-apoptotic protein Bcl-2 were revealed. According to the obtained results, including the high activity of kuz7 against triple-negative cancer cells, the detected induction of apoptosis, and the decrease in GLUT1 expression, 13ß-steroid kuz7 is of interest for further preclinical studies both alone and in combination with the metabolic drug metformin

Development of metformin HCl granules using brown flaxseed mucilage as a retardant polymer: effects of polymer and drug ratio

Abstract Flaxseed (Linum usitatissimum L.) is the seed of a multipurpose plant of pharmaceutical interest, as its mucilage can be used as a natural matrix to develop extended-release dosage forms and potentially replace synthetic polymers. In this study, a 3² factorial design with two replicates of the central point was applied to optimize the development of extended-release granules of metformin HCl. The total fiber content of the mucilage as well as the friability and dissolution of the formulations were evaluated. The lyophilized mucilage presented a high total fiber content (42.63%), which suggests a high efficiency extraction process. Higher concentrations of the mucilage and metformin HCl yielded less friable granules. In addition, lower concentrations of metformin HCl and higher concentrations of the mucilage resulted in slower drug release during the dissolution assays. The release kinetics for most formulations were better represented by the Hixson-Crowell model, while formulations containing a higher concentration of the mucilage were represented by the Korsmeyer-Peppas model. Nonetheless, five formulations showed a longer release than the reference HPMC formulation. More desirable results were obtained with a higher concentration of the mucilage (13-18%) and a lower concentration of metformin (40%).

The effects of metformin, acetylsalicylic acid and ibuprofen on telomerase enzyme activity: inhibitory effect of ibuprofen

Abstract Telomerase enzyme is necessary for the elongation of telomeres while telomerase being critical for aging and cancer. Metformin, ibuprofen, and acetylsalicylic acid used in this research are drugs that millions of people already use and that many are likely to use in future. In this study, the effects of these drugs on telomerase activity of Mus musculus swiss albino mice in liver tissue were investigated and the telomerase activity was measured with a PCR-ELISA based kit. In the study a possible connection between telomerase enzyme activity and activities of antioxidant enzymes was also investigated by determining the activity of superoxide dismutase (SOD) and catalase enzymes. The data obtained show that metformin slightly decreased telomerase enzyme activity in low dose application; however, this change was not statistically significant. In ibuprofen application, there was a significant inhibitory effect when high doses were used; whereas, there was a slight inhibitory effect at low doses. In acetylsalicylic acid application, a slight activator effect was detected; it was not statistically significant, though. Metformin was observed to increase catalase and SOD activities in general while low and high doses of acetyl salicylic acid showed different effects. In addition, ibuprofen caused a statistically significant increase in liver SOD values. It is important to note that this study demonstrated a significant inhibitory effect of ibuprofen on telomerase enzyme activity in animal models..

Polineuropatia diabética assintomática induzida pelo uso crônico de metformina e correlação com vitamina B12 / Asymptomatic diabetic polyneuropathy induced by chronic metformin use and correlation with vitamin B12

Introdução: Diabetes Mellitus é doença metabólica, caracterizada pela deficiência absoluta ou relativa de insulina, que acomete cerca de 382 milhões de pessoas em todo mundo, tendo uma das complicações mais comuns a polineuropatia. A Metformina, medicamento amplamente utilizado como tratamento do Diabetes, foi descrita como responsável, em algumas literaturas, por causar ou agravar deficiência de vitamina B12, que está similarmente relacionada ao desenvolvimento de polineuropatia.Métodos: Nesse sentido, foi conduzido um estudo no município de Soledade ­ RS, com objetivo de verificar se essa relação é condizente com a realidade da localidade. Foram escolhidos 58 pacientes, dos quais 30 responderam questionários adaptados baseados na literatura e na Classificação de Neuropatia de Michigan (MNSS-Brasil), então colhidos 5 ml de sangue venoso da fossa antecubital, preparado soro do qual uma alíquota foi separada para determinação bioquímica da vitamina B12.Resultados: Analisando os resultados, a maioria dos pacientes analisados apresentou sintomas de polineuropatia, e 10% deste, deficiência vitamínica.Conclusão: nenhuma variável explicou a correlação do uso crônico da Metformina, dose e gênero com a deficiência da vitamina B12, o que indica que não há evidências fortes o suficiente que sustentem esse fato, de acordo com as particularidades da localidade analisada.

Introduction: Diabetes Mellitus is a metabolic disease, characterized by absolute or relative insulin deficiency, which affects about 382 million people, with polyneuropathy being one of the most common complications. Metformin, a drug widely used as a treatment for diabetes, has been described as responsible, in some literature, for causing or aggravating vitamin B12 deficiency, which is similarly related to the development of polyneuropathy.Methods: In this sense, a study was conducted in Soledade ­ RS, in order to verify whether this relationship is consistent with the reality of the locality. Fifty-eight patients were selected, of which 30 answered adapted questionnaires based on the literature and on the Michigan Neuropathy Classification (MNSS-Brazil), then 5 ml of venous blood was collected from the antecubital fossa, serum prepared from which an aliquot was separated for biochemical determination of the vitamin B12.Results: Analyzing the results, most of these patients presented symptoms of polyneuropathy and, 10% of them, vitamin deficiency.Conclusion: no variable explained the correlation of chronic use of Metformin, dose and gender with vitamin B12 deficiency, which indicates that there is not enough evidence to support this fact, according to the particularities of the analyzed locality.