Role of vildagliptin and its combination in type 2 diabetes mellitus management: a knowledge, attitude, and practice survey among Indian healthcare professionals

Background: Type 2 diabetes mellitus (T2DM) is a prevalent condition, with a significant burden in India, affecting approximately 74.2 million individuals. Vildagliptin, a selective dipeptidyl peptidase 4 (DPP-4) inhibitor, is approved globally for monotherapy and combination therapy. Recently, it became available as a generic product, which increased its accessibility to patients. This study aimed to assess the knowledge, attitude, and practice (KAP) regarding vildagliptin and its combination in T2DM management. Methods: A pan-India cross-sectional KAP survey was conducted from February 2022 to March 2023. The survey utilized a specially designed questionnaire focusing on various aspects of vildagliptin treatment. A total of 1,440 healthcare professionals (HCPs) with recognized qualifications and experience in diabetes management participated. Descriptive statistics were employed for data analysis. Results: HCPs reported initiating Vildagliptin monotherapy at an HbA1c 6.5-7.5%, while combination therapy with vildagliptin and metformin at HbA1c 7-8%. Vildagliptin was primarily preferred as an add-on to metformin. Inadequate HbA1c control with existing therapy emerged as the primary trigger for switching to vildagliptin and metformin combination. Treatment-na飗e T2DM patients with HbA1c 1.5% above target and those uncontrolled on metformin monotherapy or dual therapy were reported to benefit most from combination therapy. Combination therapy was reported to result in a glycemic reduction of 1.0-1.5%. HCPs perceived vildagliptin better than other DPP4 inhibitors due to its efficacy in reducing HbA1c and a lower risk of hypoglycemia. Conclusions: The KAP survey highlights the value Indian HCPs place on the effectiveness and tolerability of vildagliptin and their attitudes and practices in its use, highlighting its clinical utility in routine practice.

Expert opinion on the prescription practice of dual combination oral anti-diabetic drugs in type 2 diabetes mellitus management

Background: This study aimed to gather the clinicians� perspective regarding the use and prescription practice of dual combination oral anti-diabetic drugs (OADs) in type 2 diabetes mellitus (T2DM) management in Indian settings. Methods: A cross-sectional study was conducted by using a 29-item structured questionnaire covering factors considered, challenges, preferred indicators of glycemic control, continuous glucose monitoring (CGM) use, and strategies. Additionally, it explored clinicians' feedback and experiences with dual combination oral anti-diabetic drugs in T2DM management. Results: Seventy percent of clinicians observed improved adherence to dual combination therapy of OAD. The combination of dipeptidyl-peptidase 4 (DPP4) inhibitors and metformin was favored for early initiation and showed better tolerability within the first year according to 42% of clinicians. Approximately 63% of clinicians prefer vildagliptin + metformin for 40� year-old diabetics. The combination yields favorable outcomes: 21% in young, 14% in elderly, and 7% in long-standing diabetes cases. After 5 years, 37% of clinicians observed 40-50% of diabetics reaching an HbA1c goal of <7.0% with this combination. Clinicians choose glimepiride + metformin for treatment intensification based on its efficacy, cardiovascular (CV) safety, and fewer adverse events. These factors were collectively recognized by 66.54% of respondents. Conclusions: This study provided valuable insights into real-world clinical practices and preferences regarding dual combination therapy for diabetes management. Clinicians identified the fixed-dose combination of DPP4 inhibitors and metformin as the preferred choice and highlighted the effectiveness of glimepiride + metformin in overcoming treatment intensification challenges.

Effects of pentoxifylline and metformin combination therapy compared to metformin alone in infertile women with symptomatic endometrioma

Background: Endometriosis, a chronic inflammatory disease, significantly affects reproductive health and fertility in women. This study compares the efficacy of pentoxifylline plus metformin versus metformin alone in treating symptomatic endometrioma in infertile women.Methods: This randomized controlled trial was conducted at the department of reproductive endocrinology and infertility, BSMMU, Dhaka, from July 2022 to June 2023, involving 51 women. Participants were randomly allocated into two groups: pentoxifylline plus metformin (n=25) and metformin alone (n=26). Baseline and post-treatment evaluations included the size of endometrioma, pain scores using the visual analogue scale (VAS), and serum interleukin-6 (IL-6) levels. Data analysis focused on comparing treatment outcomes between the two groups.Result: At baseline, both groups were comparable in terms of sociodemographic characteristics, BMI, and type and duration of infertility. Post-treatment, the pentoxifylline plus metformin group showed significant reductions in endometrioma size (2.23±0.97 cm), VAS score (2.73±1.21), and IL-6 levels, all with p<0.001s. In contrast, the metformin alone group exhibited a significant reduction in endometrioma size (3.12±1.42 cm, p=0.003s) and VAS score (3.48±1.89, p<0.001s), but not in IL-6 levels (p=0.505ns). Pregnancy rates were 8.0% in the pentoxifylline plus metformin group and 3.85% in the metformin alone group (p=0.610ns). Side effects were minimal and comparable between the two groups.Conclusions: Pentoxifylline plus metformin demonstrated superior efficacy in reducing endometrioma size, pain scores, and IL-6 levels compared to metformin alone. However, no significant differences were observed in pregnancy rates or side effects. These findings indicate that the combination therapy could offer greater benefits in managing endometrioma size and pain, although further research is required to evaluate its impact on fertility outcomes in endometriosis patients.

Combining Therapy of Vildagliptin with Metformin Improves Glycemic Control than Using Metformin Alone in The Treatment of Type 2 Diabetes Mellitus

The purpose of the trial was to determine whether combination medication for type 2 diabetes mellitus offers better glycemic control than monotherapy. Subjects whose ages were more than 18 years and with glycated hemoglobin levels higher than 7.5% were enrolled. Among the 664 patients enrolled, 332 received monotherapy, while 332 were treated with combination therapy. The treatment groups received either vildagliptin + metformin combination therapy or metformin monotherapy. Vildagliptin, as an adjunct to metformin treatment, was to be evaluated for its safety and efficacy in reducing HbA1c levels from baseline. The study included individuals with a history of T2DM for 3 to 4 years who had been treated with either combination therapy or monotherapy for at least three months. Statistical analysis was done using SPSS software. As per the findings, it indicated that combination therapy led to a considerably greater reduction in glycated hemoglobin levels compared to monotherapy. Adverse events were also observed to vary significantly between the two treatment cohorts. Outcomes suggest that combination medication should be started earlier than monotherapy for superior glycemic control. Additionally, it was thought that the combo therapy had a positive safety profile.

Comparison of metformin and repaglinide monotherapy in the management of newly diagnosed diabetes mellitus type 2: a prospective study

Background: Diabetes Mellitus Type 2 (DMT2), which is characterized by the raised blood sugar level due to insulin resistance in body cells, has now become global epidemic. This study was aimed to compare the efficacy of metformin and repaglinide monotherapy in patients with newly diagnosed DMT2. Methods: This randomized comparative prospective study was performed in a tertiary care hospital of Lahore. 108 Patients’ enrollment was made via simple random sampling technique and a developed inclusion and exclusion criteria. Patients were divided into metformin and repaglinide groups via lottery method. Self-designed proforma was applied for data collection. Data analysis was done in SPSS version 25.0. Results: There was no significant difference in the means of pretreatment (p=0.08) and posttreatment (p=0.10) fasting blood sugar levels between two groups, while significant differences between the means of pretreatment and posttreatment fasting blood sugar levels within metformin group (p=0.02) and repaglinide group (p=0.01) were noted. Likewise, there was no significant difference in the means of pretreatment (p=0.07) HbA1C levels of two groups; however, significant difference was observed in the means of posttreatment (p=0.04) HbA1C of two groups. Moreover, significant differences were also seen between the means of pretreatment and posttreatment HbA1C levels in both metformin group (p=0.03) and repaglinide group (p=0.01). Conclusions: This study suggests that although both metformin and repaglinide are effective in the new-onset T2DM managementz; however, reduction in fasting blood sugar level and HbA1c was more in repaglinide group.

Potential effect of metformin and vildagliptin against isoniazid induced hepatotoxicity in Wistar albino rats

Background: Metformin and vildagliptin both are anti-diabetic agent and they play an important role in diabetic patients as they reduce blood glucose levels. Studies revealed that both metformin and vildagliptin has the ability to promote beta cell neogenesis and regeneration. So, our study was planned to explore the hepatoprotective potential of metformin and vildagliptin in Wistar albino rats exposed to isoniazid (INH) induced hepatotoxicity. Methods: Wistar albino rats weighing 150-180 g were obtained from Mass Biotech, Chengalpattu, Tamil Nadu. The animals were divided into 6 groups (n=6) and further treated orally against INH-induced hepatotoxicity except normal control group. group 1: normal control, group 2: INH, group 3: metformin+INH, group 4: vildagliptin+INH, group 5: metformin amd vildagliptin+INH, group 6: silymarin. Results: In the present study, INH was administered for 21 days to induce liver damage to rats except normal group. Each group was treated with metformin, vildagliptin, (metformin+vildagliptin) combination and silymarin half an hour before INH challenge. On the 22nd day the blood samples were collected to estimate the AST and ALT levels. Immediately after blood collection the animals were sacrificed, the livers were removed and kept in 10% formalin for histopathological examination. Conclusions: The study found that metformin, vildagliptin, and their combination showed hepatoprotective activity against INH-induced hepatotoxicity. The combination of metformin+vildagliptin was the most effective. Metformin reduces oxidative stress, while vildagliptin balances pro-oxidant and anti-oxidant levels, contributing to their hepatoprotective effects. This suggests their potential usefulness in drug-induced hepatotoxicity.

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.

Influence of SLC22A1 gene polymorphisms on gastrointestinal adverse effects with metformin therapy in South Indian type 2 diabetes mellitus patients

Background: Metformin, a first-line agent in Type 2 diabetes mellitus, causes gastrointestinal adverse effects in 20-30% of patients, leading to discontinuation in 5-10% of them. Organic cation transporter 1 (OCT1) encoded by SLC22A1, transports metformin from the enterocytes into the bloodstream. Reduced function OCT1 variants could lead to increased luminal concentration of metformin leading to gastrointestinal adverse effects. Two single nucleotide polymorphisms in the SLC22A1 gene were studied in this cross-sectional study with cases and controls. Objective was to determine the association between genetic polymorphisms rs628031 (1222A>G) and rs622342 (1386C>A) in SLC22A1 gene and gastrointestinal adverse effects to metformin therapy in South Indian type 2 diabetes mellitus patients. Methods: The study was conducted in JIPMER, Puducherry, India in T2DM patients (n=300) of South Indian origin, who were categorized into case (N=100) and control (N=200) groups, based on their gastrointestinal tolerance to metformin. DNA was extracted from the patients using whole blood by phenol-chloroform method and genotyping was done using real-time PCR. Results: Minor allele frequency of rs628031 (A allele) and rs622342 (C allele) were 33.8% and 26.5% respectively. Genotype frequencies did not differ significantly between the case and control groups (rs628031, p=0.45, rs622342, p=0.28). Female gender (AOR 3.77; 95% CI 2.07, 6.85; p<0.001) and proton pump inhibitor usage (AOR 7.66; 95% CI 3.01, 19.47; p<0.001) had higher association with metformin intolerance. Conclusions: No significant association was found between the genotypes of single nucleotide polymorphisms (rs628031 and rs622342) in the SLC22A1 gene and gastrointestinal adverse effects to metformin therapy in South Indian type 2 diabetes mellitus patients.

Combination of purple sweet potato (Ipomoea batatas L.) leaf extract with metformin on blood glucose and total cholesterol levels of albino rats induced by high-fat diet and streptozotocin

Background: Diabetes mellitus is a metabolic disease characterized by hyperglycemia due to impaired insulin secretion, often accompanied by hypercholesterolemia. Metformin is a first-line antihyperglycemic drug that is often combined with other antihyperglycemic drugs. Purple sweet potato leaves have been widely studied to reduce glucose and cholesterol levels. Methods: This study was an experimental study using rats induced with a high-fat diet and streptozotocin, which were divided into 8 treatment groups, namely groups given CMC Na 0.5%, Metformin 45 mg/kg BW, Purple Sweet Potato Leaf Extract (SPLE) 200 mg/kg BW, SPLE 400 mg/kg BW, SPLE 800 mg/kg BW, SPLE 200 mg/kg BW with metformin 45 mg/kg BW, SPLE 400 mg/kg BW with metformin 45 mg/kg BW, and SPLE 800 mg/kg BW with metformin 45 mg/kg BW. Results: After treatment for 28 days with SPLE doses of 200 mg, 400 mg, and 800 mg/kg BW, both single doses and combinations with metformin showed a decrease in fasting blood glucose levels and total cholesterol, which were statistically significantly different (p<0.05) between treatment groups using the one-way ANOVA. The combination of SPLE 800 mg/kg BW with metformin normalized blood glucose levels of 93.50±4.93 mg/dl. Conclusion: The combination of purple sweet potato leaf extract with metformin is more effective in reducing blood glucose and total cholesterol levels compared to the single administration of metformin and SPLE.

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.

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.

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.

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.

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.

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.

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.