Metformin Treatment Research Articles

Reproductive outcomes in female mice offspring due to maternal metformin treatment.

Metformin has shown beneficial effects on reproduction in women. However, its use during pregnancy remains controversial, as metformin can cross the placenta. Most studies have focused on the metabolic impact on the offspring of treated mothers, with limited information regarding its reproductive effects. The aim of this study was to evaluate potential alterations in ovarian function and fertility in female offspring of mothers treated with metformin during pregnancy and lactation. C57BL/6 female mice were treated with metformin four weeks before mating, and the treatment was maintained during gestation and lactation. Seven weeks after weaning, metabolic parameters as well as ovarian and reproductive function of the offspring were analyzed. The offspring of treated mothers were lighter at birth and, in adulthood, they had more gonadal adipose tissue with no alterations in body weight. No changes in glucose metabolism were observed. Their follicular development was modified, with more early antral and atretic follicles and less primary and late antral follicles. Anti-Müllerian hormone expression and ovarian angiogenesis were increased. The estrous cycle, hormonal production and fertility were not affected by metformin exposure, however, the F2 generation showed higher body weight at birth. Metformin can induce fetal programming in animals exposed to it during development, impacting metabolism and ovarian functionality in adulthood. Under physiological conditions, these alterations do not result in reduced fertility or endocrine disruptions. Our data warrant studies in women to make informed decisions regarding metformin administration during critical developmental periods in clinical settings.

P-63 PREVENTION OF POSSIBLE ABORTIONS IN PREGNANT WOMEN WITH REFETOFF SYNDROME USING METFORMIN AND THUS ACHIEVING A HEALTHY BIRTH

Abstract Introduction Refetoff syndrome (RS) is an autosomal dominantly inherited rare disease (1/40,000), characterized by thyroid hormone resistance (THR) mostly caused by Thyroid Hormone Receptor Beta (THR-B) gene defect. In the pregnancy period of female RS patients, the probability of live birth may decrease to 15%. It has been reported in the literature that metformin has effects on the thyroid hormone metabolism. Two female patients with RS being followed up in our center had pregnancy period that resulted in healthy deliveries with the use of metformin. This observation led us to question that metformin treatment may have positive effects in pregnancy of these patients by unknown mechanism of THR. We could not find any case reports or studies in the literature about the pregnancy periods in patients with RS, so we wanted to share our follow-up experience. Clinical Case Patient A and B were siblings with genetically proven THR-B mutation (figure 1). Patient A was on metformin treatment for insulin resistance before pregnancy. Her previous two pregnancies resulted in miscarriage following metformin discontinuation in pregnancy. In her third pregnancy under our follow-up, metformin treatment was continued. She completed the pregnancy without any problem and gave birth to healthy twins. Patient B, sister of Patient A, had two pregnancies. She used metformin in both pregnancies because of the favorable outcome in her sister. There were no problems in her pregnancies. The use of metformin has been shown to decrease TSH levels in patients with prediabetes and diabetes. The studies emphasize that metformin leads to a decrease in TSH values in individuals with subclinical or overt hypothyroidism, but this effect is not seen in healthy euthyroid patients. There are also reports that the effect of metformin leads to a decrease in thyroid hormone levels as well as thyroid gland and nodule size. In the literature search, we could only find a case report about metformin use in RS. In the report, metformin was started in a 28-year-old male RS patient due to a diabetic picture that developed over time. THR improved after metformin, but after a while metformin was discontinued due to dyspeptic complaints. Following the cessation of metformin THR became severe again. Although the exact mechanism of the thyroid suppressive effects of metformin is not clearly known, it is hypothesized that metformin, a compound that can cross the blood-brain barrier, increases the number and affinity of thyroid hormone receptors in the pituitary and hypothalamus, causes an increase in central dopaminergic activity, and as a result increases the pituitary feedback effect of peripheral thyroid hormones. Conclusion The incidence of healthy births in patients with RS is low. When we combine the limited literature data with our experience, we suggest that metformin treatment may contribute positively to a healthier pregnancy outcome in patients with RS.Figure 1:The pedigree of the family with Refetoff syndrome Table 1:Summary of pregnancies Table 2:Blood and genetic results of patients and* The records of two patients with Refetoff syndrome who were followed up in our center were obtained from the electronic health records.

Modulation of placental angiogenesis by metformin in a rat model of gestational diabetes.

Gestational diabetes mellitus (GDM) significantly disrupts placental structure and function, leading to complications such as intrauterine growth restriction (IUGR) and preeclampsia. This study aimed to investigate the effects of GDM on placental histology, angiogenesis, and oxidative stress, as well as evaluate metformin's protective role in mitigating these changes. A total of 60 pregnant Sprague-Dawley rats were divided into four groups: control, metformin-treated, GDM, and GDM with metformin. GDM was induced using streptozotocin (STZ) at 40mg/kg, and metformin was administered at 200mg/kg from gestational day (GD) 4 to GD17. Blood glucose and insulin levels were assessed, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was calculated. Placentae were weighed and subjected to histological, immunohistochemical, and molecular analyses, focusing on key angiogenesis markers (VEGF, VEGFR, CD31, KLF2) and oxidative stress indicators (MDA, eNOS). GDM increased placental weight, angiogenesis (elevated VEGF, VEGFR, CD31), and oxidative stress (elevated MDA, eNOS). Histopathological changes included villous edema, membrane rupture, and hemosiderin deposition. Metformin treatment reduced placental weight; normalized VEGF, KLF2, and PlGF expression; and improved placental architecture. Additionally, oxidative stress was significantly reduced in metformin-treated GDM rats. In conclusion, GDM induces placental abnormalities, promoting excessive angiogenesis and oxidative stress, potentially leading to IUGR and other complications. Metformin showed protective effects by reducing placental overgrowth and restoring vascular and oxidative balance. These findings suggest that metformin may play a therapeutic role in improving placental health in GDM pregnancies, warranting further investigation into its long-term effects on fetal development and maternal health.

Mangiferin protects mesenchymal stem cells against DNA damage and cellular aging via SIRT1 activation.

The protective effects of mangiferin (MAG) against etoposide- and high glucose (HG)-induced DNA damage and aging were investigated in human bone marrow-mesenchymal stem cells (hBM-MSCs). Etoposide, a topoisomerase II inhibitor, was used to induce double-strand breaks (DSBs) in hBM-MSCs, resulting in increased genotoxicity, elevated levels of the DNA damage sensor ATM and CDKN1A, and decreased levels of the aging markers H3 and H4. MAG activated AMPK and SIRT1, thus protecting against DSB-induced damage. Following long-term exposure to HG, MAG significantly mitigated DNA damage and delayed cellular aging, as evidenced by the preservation of H3, H4, LMNB1, and SIRT1 mRNA levels and reduction in γ-H2AX foci and DSBs. Furthermore, MAG improved genome stability, as indicated by decreased LINE1 expression and increased levels of the heterochromatin marker TRIM28, thereby maintaining H3K9me3 levels. MAG and metformin treatment enhanced cell proliferation, reduced senescence-associated β-galactosidase staining, and lowered the levels of the senescence-associated secretory phenotype factors IL-1A, IL-1B, IL-6, IL-8, CCL2, and CCL20 and senescence marker CDKN1A, CDKN2A and p53. MAG may reduce DNA damage and delay aging in hBM-MSCs under HG conditions, highlighting their potential as therapeutic agents for aging-related diseases.

Lactobacillus rhamnosus GG Combined with Metformin Alleviates Alcohol-Induced Liver Inflammation in Mice by Maintaining the Intestinal Barrier and Regulating Treg/Th1 Cells.

Disturbances of the intestinal barrier enabling bacterial translocation exacerbate alcoholic liver disease (ALD). Lactobacillus rhamnosus GG (LGG) has been shown to exert beneficial effects in gut dysbiosis and chronic liver disease. The current study assessed the combined effects of LGG and metformin, which play roles in anti-inflammatory and immunoregulatory processes, in alcohol-induced liver disease mice. A diet comprising 5% alcohol for 4 weeks was employed to develop an alcohol-induced liver injury model. Mice were orally administered LGG, metformin, or their combination on alternate days. Tight junction (TJ) proteins, gut microbiome composition, inflammatory cytokines, Jun N-terminal kinase (JNK), and p38 signals were assessed. When compared with treatment with LGG or metformin alone, combined LGG and metformin treatment substantially lowered the symptoms of inflammation, steatosis, and elevated liver enzymes caused by alcohol administration. Combination treatment significantly improved intestinal microecology, evidenced by the recovery of intestinal flora, TJ proteins, and intestinal villi. Combination treatment reduced hepatic inflammation by blocking p38 and JNK phosphorylation. The combination of LGG and metformin corrected immune-response dysregulation and improved ALD by enhancing the intestinal microbiome, restoring mucosal barrier integrity, modulating immune function, and decreasing liver injury. These results provide information for the development of intestinal microbiota-based preventive and therapeutic agents against ALD.

Imeglimin, unlike metformin, does not perturb differentiation of human induced pluripotent stem cells towards pancreatic β-like cells and rather enhances gain in β cell identity gene sets.

Metformin treatment for hyperglycemia in pregnancy (HIP) beneficially improves maternal glucose metabolism and reduces perinatal complications. However, metformin could impede pancreatic β cell development via impaired mitochondrial function. A new anti-diabetes drug imeglimin, developed based on metformin, improves mitochondrial function. Here we examine the effect of imeglimin on β cell differentiation using human induced pluripotent stem cell (iPSC)-derived pancreatic islet-like spheroid (SC-islet) models. Human iPSCs are differentiated into SC-islets by three-dimensional culture with and without imeglimin or metformin. Differentiation efficiencies of SC-islets were analyzed by flow cytometry, immunostaining, quantitative PCR, and insulin secretion assay. RNA sequencing and oxygen consumption rate were obtained for further characterization of SC-islets. SC-islets were cultured with proinflammatory cytokines, in part mimicking the uterus environment in HIP. Metformin perturbed SC-islet differentiation while imeglimin did not alter it. Furthermore, imeglimin enhanced the gene expressions of β cell lineage markers. Maintenance of mitochondrial function and optimization of TGF-β and Wnt signaling were considered potential mechanisms for augmented β cell maturation by imeglimin. In the presence of proinflammatory cytokines, imeglimin ameliorated β cell differentiation impaired by cytokines and metformin. Imeglimin does not perturb differentiation of SC-islet cells and rather enhances gain in β cell identity gene sets in contrast to metformin. This may lead to the improvement of in vitro β cell differentiation protocols.

Metformin-induced mitophagy suppresses auditory hair cell apoptosis via AMPK pathway.

Hearing loss is a pervasive issue affecting numerous individuals, and its etiology and categorization are multifaceted. Among these, sensorineural hearing loss (SNHL) emerges as the most prevalent variant among these. The primary causative factor underlying SNHL resides in the depletion of auditory hair cells within the cochlea, yet the pursuit of efficacious therapeutic interventions remains an ongoing challenge. Previous investigations have illuminated the role of mitochondrial dysfunction in precipitating cellular apoptosis, and mitophagy has emerged as a promising mechanism to ameliorate such dysfunction. Additionally, it has been noted that metformin possesses the specific ability to induce mitophagy. Herein, our objective is to explore the protective effects of metformin-induced mitophagy against apoptosis in auditory hair cells (HEI-OC1 cells) and explore its potential mechanisms. Our results revealed that metformin effectively triggered mitophagy in HEI-OC1 cells. Moreover, metformin treatment showed the ability to prevent tert-butyl hydroperoxide (TBHP) induced mitochondrial dysfunction and intrinsic apoptotic pathways. Mechanistically, we discovered that metformin activates AMP-activated protein kinase (AMPK) signaling in HEI-OC1 cells stimulated by TBHP, thereby triggering mitophagy. Overall, our results suggest that metformin may represent a promising and innovative therapeutic strategy for mitigating the onset of hearing loss.

Microbial succinate promotes the response to metformin by upregulating secretory immunoglobulin a in intestinal immunity

ABSTRACT Metformin is the first-line pharmacotherapy for type 2 diabetes mellitus; however, many patients respond poorly to this drug in clinical practice. The potential involvement of microbiota-mediated intestinal immunity and related signals in metformin responsiveness has not been previously investigated. In this study, we successfully constructed a humanized mouse model by fecal transplantation of the gut microbiota from clinical metformin-treated – responders and non-responders, and reproduced the difference in clinical phenotypes of responsiveness to metformin. The abundance of Bacteroides thetaiotaomicron, considered a representative differential bacterium of metformin responsiveness, and the level of secretory immunoglobulin A (SIgA) in intestinal immunity increased significantly in responder recipient mice following metformin treatment. In contrast, no significant alterations in B. thetaiotaomicron and SIgA were observed in non-responder recipient mice. The study of IgA˗/˗ mice confirmed that downregulated expression or deficiency of SIgA resulted in non-response to metformin, meaning that metformin was unable to improve dysfunctional glucose metabolism and reduce intestinal and adipose tissue inflammation, ultimately leading to systemic insulin resistance. Furthermore, supplementation with succinate, a microbial product of B. thetaiotaomicron, potentially reversed the non-response to metformin by inducing the production of SIgA. In conclusion, we demonstrated that upregulated SIgA, which could be regulated by succinate, was functionally involved in metformin response through its influence on immune cell-mediated inflammation and insulin resistance. Conversely, an inability to regulate SIgA may result in a lack of response to metformin.

Mitigating the Impact of High-Fat Diet: The Role of Metformin and Exercise Interventions in Alleviating Autism-Like Behaviors and Insulin Resistance in Mice

Mitigating the Impact of High-Fat Diet: The Role of Metformin and Exercise Interventions in Alleviating Autism-Like Behaviors and Insulin Resistance in Mice

Efficacy of metformin and verteporfin treatment alone or in combination in a murine head and neck cancer xenograft model.

Despite treatment advances, head and neck squamous cell carcinoma (HNSCC) still poses a significant global health challenge. Combination therapies have emerged as more effective strategies than traditional chemotherapy in clinical practice by improving tumor response rates and patient survival while minimizing treatment-related toxicity. This study investigates the anticancer effects of metformin and verteporfin (Yes-associated protein 1 [YAP1] inhibitor) alone or in combination in HNSCC using vitro and in vivo approaches. Quantitative RT-PCR analysis of HNSCC cell lines reveals upregulation of YAP1 and related genes in the Hippo signaling pathway. Cell viability assays demonstrate a beneficial synergistic effect between metformin and verteporfin in inhibiting HNSCC tumor growth. In male BALB/cAJcl-nu/nu mice harboring HNSCC tumor xenografts, intraperitoneal administration of metformin and verteporfin enhances the inhibitory effect on tumor growth and suppresses YAP1 nuclear translocation when compared to vehicle or monotherapies. Furthermore, combination of these drugs reduces tumor cell proliferation (marked by Ki-67) and inhibits phosphoS6 ribosomal protein, as observed through immunofluorescent and immunohistochemical (IHC) analyses. The in vivo study underscores the therapeutic potential of the dual targeting approach with metformin and verteporfin in treating HNSCC, with minimal toxicity.

Aerobic exercise and metformin attenuate the cognitive impairment in an experimental model of type 2 diabetes mellitus: focus on neuroinflammation and adult hippocampal neurogenesis.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that increases the prevalence of cognitive impairment in the geriatric population. Aerobic exercise is an excellent non-pharmacological therapeutic strategy to prevent Alzheimer's disease, the most common form of dementia. The exact molecular mechanism of aerobic exercise (Exe) as an intervention to counter cognitive decline is far from clear. Metformin is a first-line agent against T2DM with neuroprotective properties. The present study assessed the role of treadmill exercise in combination with a low dose of metformin (Met; 70mg/kg) in cognitive impairment and its associated molecular mechanism in T2DM rats. The experimental model of T2DM-associated cognitive decline was created by administration of a high-fat diet (HFD) with a low dose of streptozotocin (STZ; 35mg/kg). Neurobehavioral assessments were performed to evaluate spatial recognition and fear-conditioned memory across the groups: control, HFD + STZ, HFD + STZ + Exe, and HFD + STZ + Exe + Met. In addition, we performed immunohistochemistry and western blotting on the rat hippocampal tissue from the above groups for protein expression studies. T2DM rats showed a significant cognitive decline compared to the control group, which improved in the long-term exercise and metformin co-administered animals. The level of neuroinflammation was significantly elevated in the hippocampal tissue of T2DM rats compared to the control and lowered after exercise and metformin treatment. T2DM reduced mature neurons and neurogenesis while increasing astrogliosis and microgliosis, ameliorated by exercise and metformin treatment. Moreover, T2DM impaired hippocampal neurogenesis by reducing the canonical Wnt/β-catenin pathway, which got upregulated in exercise and metformin-co-administered rats. Long-term aerobic exercise with metformin treatment ameliorated neuroinflammation and promoted adult hippocampal neurogenesis via upregulating the canonical Wnt/β-catenin pathway in T2DM rats.

The Impact of Diabetes Mellitus and Metformin Use on Outcomes After Endovascular Aneurysm Repair.

Objective: To study the influence of diabetes mellitus (DM) and metformin treatment on aneurysm sac remodeling after endovascular aneurysm repair (EVAR). Methods: A retrospective single-center cohort analysis was conducted on consecutive patients who underwent elective EVAR for an infrarenal abdominal aortic aneurysm (AAA) between January 2011 and December 2021. Differences between study groups were analyzed and Kaplan-Meier analysis were employed to describe overall and reintervention-free survival. Cox regression analysis was performed to identify predictors of sac shrinkage. Results: A total of 529 patients were included: 74 (14.0%) had DM and metformin treatment, 26 (4.9%) had DM without metformin treatment, and 429 (81.1%) did not have DM. At one-year follow-up, diabetic patients showed significantly less sac shrinkage compared to non-diabetic patients (40.0% vs. 52.0%; p = 0.038), with a trend toward more stable sac behavior in diabetic patients (52% vs. 42%; p = 0.055). At last follow-up, sac shrinkage was significantly less in diabetic patients on metformin treatment compared to non-diabetics (48.6% vs. 59.9%; p = 0.047). No differences in sac shrinkage were observed between diabetics with and without metformin treatment. The presence of endoleak was significantly higher in groups showing stable sac behavior and growth. Through nine-year follow-up, overall survival was significantly less in diabetic patients compared to non-diabetic ones (23.5% vs. 37.5%; p < 0.001). Conclusions: This study showed a negative impact of diabetes mellitus and metformin treatment on sac shrinkage following EVAR. The presence of any type of endoleak was associated with reduced sac shrinkage at both time points. Overall survival was significantly lower in diabetic patients compared to non-diabetic patients.

Regulation of macrophage polarization by metformin through inhibition of TLR4/NF-κB pathway to improve pre-eclampsia.

Pre-eclampsia (PE) is a pregnancy complication featuring hypertension and proteinuria. Metformin exerts clinically preventive effects on PE with an unspecified mechanism. Placental tissues from PE patients and normal pregnant (NP) women were collected. Twenty-four pregnant mice were divided into control, PE (40μg/kg lipopolysaccharides (LPS)-induced modeling), aspirin, and metformin groups. After acquisition of bone marrow-derived macrophages (BMDM) and THP-1cells, cells were categorized into control, LPS (100ng/mL), metformin, and metformin+toll-like receptor 4 (TLR4) agonist RS 09 groups. Inflammatory factors and macrophage polarization were detected by ELISA, flow cytometry, immunofluorescence, immunohistochemistry, and qRT-PCR methods. TLR4/Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway protein expression was examined using Western blot. Both PE patients and PE-like mice enhanced inducible nitric oxide synthase (iNOS), TLR4, p-NF-κB/NF-κB, and p-inhibitor of NF-κB (IκBα)/IκBα expression, and lower arginase 1 (Arg-1) expression. Moreover, metformin treatment in PE-like mice increased fetal number and weight and reduced hypertension, proteinuria, insulin resistance, tumor necrosis factor-α (TNF-α), IL-6, IL-1β, chemokine ligand 4 (CCL4), C-X-C motif chemokine ligand 2 (CXCL2) expression and M1 macrophage polarization, with similar inhibition to aspirin. In LPS-induced cells, metformin had the same effects mentioned above. Decreased TLR4, p-NF-κB/NF-κB, and p-IκBα/IκBα protein expression was caused by metformin both in vivo and in vitro. In vitro, RS 09 intervention inhibited anti-inflammatory and pro-M2 polarizing effects of metformin, activating TLR4/NF-κB pathway. Metformin may ameliorate PE by promoting M2 macrophage polarization through up-regulating TLR4/NF-κB pathway, laying theoretical basis for metformin clinical application in PE.

Metformin's impact on asprosin and FBN1 expression: Potential mechanisms beyond insulin sensitivity in type 2 diabetes in rats.

Asprosin, a novel adipokine released under fasting conditions, may play a significant role in the pathophysiology of type 2 diabetes mellitus (T2DM). The objective of this study is to investigate the effects of metformin on serum asprosin levels and FBN1 gene expression in white adipose tissue in male rats. Thirty-two male Wistar rats were randomly and equally divided into four groups (n=8): 1. Control Group (CON): Received standard food; 2. Non-Diabetic Metformin Group (CON+MET): Received standard food and were treated with metformin (400mg/kg/day) for four weeks; 3. Diabetic Group (DM): Induced with T2DM; and 4. Diabetic Metformin Group (DM+MET): Induced with T2DM and treated with metformin (400mg/kg/day) for four weeks. Finally, serum asprosin levels, lipid profiles, fasting glucose, and insulin concentrations were measured. The expression level of the FBN1 gene in white adipose tissue was quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Serum asprosin levels were significantly higher in the DM group compared to both the CON and CON+MET groups (P<0.0001). However, serum asprosin levels were significantly lower in the DM+MET group than in the DM group (P=0.0003). Additionally, the FBN1 gene expression level in white adipose tissue was significantly higher in the DM group compared to the CON group (P=0.0053), while FBN1 gene expression was significantly lower in the DM+MET group than in the DM group (P<0.0001). Furthermore, lipid profile, insulin resistance, and fasting blood sugar improved in the CON+MET and DM+MET groups compared to the CON and DM groups, respectively. Our findings in diabetic male rats reveal that metformin treatment significantly downregulates FBN1 gene expression and reduces serum asprosin levels, suggesting a potential mechanism for its therapeutic benefits beyond improving insulin sensitivity.

Anti-diabetic agents and the risks of dementia in patients with type 2 diabetes: a systematic review and network meta-analysis of observational studies and randomized controlled trials.

To evaluate the association between anti-diabetic agents and the risks of dementia in patients with type 2 diabetes (T2D). Literature retrieval was conducted in PubMed, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov between January 1995 and October 2024. Observational studies and randomized controlled trials (RCTs) in patients with T2D, which intercompared anti-diabetic agents or compared them with placebo, and reported the incidence of dementia were included. Conventional and network meta-analyses of these studies were implemented. Results were exhibited as the odds ratio (OR) or risk ratio (RR) with 95% confidence interval (CI). A total of 41 observational studies (3,307,483 participants) and 23 RCTs (155,443 participants) were included. In the network meta-analysis of observational studies, compared with non-users, sodium glucose cotransporter-2 inhibitor (SGLT-2i) (OR = 0.56, 95%CI, 0.45 to 0.69), glucagon-like peptide-1 receptor agonist (GLP-1RA) (OR = 0.58, 95%CI, 0.46 to 0.73), thiazolidinedione (TZD) (OR = 0.68, 95%CI, 0.57 to 0.81) and metformin (OR = 0.89, 95%CI, 0.80 to 0.99) treatments were all associated with reduced risk of dementia in patients with T2D. The surface under the cumulative ranking curve (SUCRA) evaluation conferred a rank order as SGLT-2i > GLP-1RA > TZD > dipeptidyl peptidase-4 inhibitor (DPP-4i) > metformin > α-glucosidase inhibitor (AGI) > glucokinase activator (GKA) > sulfonylureas > glinides > insulin in terms of the cognitive benefits. Meanwhile, compared with non-users, SGLT-2i (OR = 0.43, 95%CI, 0.30 to 0.62), GLP-1RA (OR = 0.54, 95%CI, 0.30 to 0.96) and DPP-4i (OR = 0.73, 95%CI, 0.57 to 0.93) were associated with a reduced risk of Alzheimer's disease while a lower risk of vascular dementia was observed in patients receiving SGLT-2i (OR = 0.42, 95%CI, 0.22 to 0.80) and TZD (OR = 0.52, 95%CI, 0.36 to 0.75) treatment. In the network meta-analysis of RCTs, the risks of dementia were comparable among anti-diabetic agents and placebo. Compared with non-users, SGLT-2i, GLP-1RA, TZD and metformin were associated with the reduced risk of dementia in patients with T2D. SGLT-2i, and GLP-1RA may serve as the optimal choice to improve the cognitive prognosis in patients with T2D.

Changes in Prolactin and Insulin Resistance in PCOS Patients Undergoing Metformin Treatment: A Retrospective Study

Background: Prolactin levels have been shown to influence metabolic outcomes, including insulin resistance. Metformin is known to be beneficial in polycystic ovary syndrome (PCOS) patients. PCOS women might react differently to metformin treatment depending on their baseline prolactin levels. Methods: In this retrospective study, the homeostasis model assessment for insulin resistance (HOMA-IR), prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), the LH:FSH ratio, and total testosterone and sex hormone-binding globulin (SHBG) were measured in 75 obese/overweight women with PCOS and insulin resistance before initiation of metformin treatment and after 6–8 months. Results: At baseline, HOMA-IR was inversely correlated to SHBG (r = −0.408; p &lt; 0.001) and prolactin (r = −0.402; p &lt; 0.001). After 6–8 months of metformin treatment, the LH:FSH ratio and the HOMA-IR declined significantly (p &lt; 0.05). A significant positive correlation could be shown between basal prolactin and the difference in the HOMA-IR (r = 0.233; p = 0.044). Women with lower baseline prolactin (≤14.9 ng/mL) revealed a sharper decline in HOMA-IR (−0.8, IQR −1.0; −0.5 vs. −0.6, IQR −0.8; −0.3; p = 0.049) as well as an increase in prolactin at follow-up (1.6 ng/mL, IQR −0.2;3.8 vs. −1.3, IQR −4.6;3.2; p = 0.003) compared to patients with a baseline prolactin &gt; 14.9 ng/mL. Conclusions: In overweight/obese, insulin-resistant PCOS women, lower baseline prolactin levels are associated with higher baseline HOMA-IR levels as well as with a better response to metformin treatment. More data are necessary to prove these observations in larger populations.

Effect of Metformin on Meibomian Gland Epithelial Cells: Implications in Aging and Diabetic Dry Eye Disease.

Metformin, a commonly prescribed medication for managing diabetes, has garnered increasing interest as a potential therapeutic option for combating cancer and aging. The current study investigated the effects of metformin treatment on human meibomian gland epithelial cells (hMGECs) at morphological, molecular, and electron microscopy levels. HMGECs were stimulated in vitro with 1 mM, 5 mM, and 10 mM metformin for 24, 48, and 72 h. The assessed outcomes were cell proliferation assays, lipid production, ultrastructural changes, levels of IGF-1, Nrf2, HO-1, apoptosis-inducing factor 1 (AIF1) at the protein level, and the expression of oxidative stress factors (matrix metallopeptidase 9, activating transcription factor 3, CYBB, or NADPH oxidase 2, xanthine dehydrogenase). Morphological studies showed increased lipid production, the differentiation of hMGECs after stimulation with metformin, and the differentiation effects of undifferentiated hMGECs. Proliferation tests showed a reduction in cell proliferation with increasing concentrations over time. AIF1 apoptosis levels were not significantly regulated, but morphologically, the dying cells at a higher concentration of 5-10 mM showed a rupture and permeabilization of the plasma membrane, a swelling of the cytoplasm, and vacuolization after more than 48 h. The IGF-1 ELISA showed an irregular expression, which mostly decreased over time. Only at 72 h and 10 mM did we have a significant increase. Mitochondrial metabolic markers such as Nrf2 significantly increased over time, while HO-1 decreased partially. The RT-PCR showed a significant increase in MMP9, CYBB, XDH, and ATF with increasing time and metformin concentrations, indicating cell stress. Our results using a cell line suggest that metformin affects the cellular physiology of meibomian gland epithelial cells and induces cell stress in a dose- and duration-dependent manner, causing changes in their morphology and ultrastructure.

Investigating predictive factors in treatment response with metformin in patients with gestational diabetes mellitus: a cross-sectional analytical-descriptive study.

As the utilization of metformin for gestational diabetes mellitus (GDM) treatment continues to rise, a substantial segment of these patients will ultimately necessitate insulin during their therapeutic journey. Hence, assessing patients' clinical and laboratory attributes becomes invaluable in determining their likelihood of responding favorably to metformin medication. This discernment aids in selecting an optimal management approach, wherein the patients most likely to benefit significantly from metformin are identified, while alternative therapies like insulin are considered for individuals with a lower probability of treatment response. This was a cross-sectional analytical-descriptive study of individuals with GDM. Initially, the subject's laboratory results and demographic information were submitted. Following that, metformin was administered to all subjects along with counseling on maintaining a healthy diet and lifestyle. Following a 4-week interval, the patients were reassessed and divided into two groups based on their response to metformin medication and then analyzed. 807 people participated in this study, of which 329 people (40.8%) responded to treatment and the failure rate of metformin treatment was 59.2%. This research revealed that the predictive factors of response to metformin medication were, respectively, the amount of 1-hour oral glucose tolerance test (OGTT) (OR = 62.66), 2-hour postprandial plasma glucose (OR = 54.04), 2-hour OGTT (OR = 17.37), followed by the history of abortion (OR = 14.88), the number of pregnancies (gravida 3 and more) (OR = 5.06) and history of infertility (OR = 2.6). The current study's findings indicated that to enhance GDM care, metformin prescriptions should be prescribed to patients depending on their clinical characteristics and laboratory results.

Metformin Treatment With or Without Mediterranean Diet for the Prevention of Age-Related Diseases in People With Metabolic Syndrome: The MeMeMe Randomized Trial.

The Metformin and Dietary Restriction to Prevent Age-Related Morbid Events in People With Metabolic Syndrome (MeMeMe) trial tested whether 1,700 mg/day metformin (MET) with or without a Mediterranean diet (MedDiet) intervention could reduce the cumulative incidence of major noncommunicable diseases in people with metabolic syndrome. A total of 1,442 participants were randomly assigned to one of four interventions: 1) MET (1,700 mg/day) plus MedDiet intervention (MET+MedDiet); 2) placebo plus MedDiet intervention; 3) MET (1,700 mg/day) alone; and 4) placebo alone. Participants were followed up for 3 years on average. The primary outcome was the cumulative incidence of major noncommunicable diseases (including type 2 diabetes, cardiovascular diseases, and cancer). Secondary outcomes were the incidence of type 2 diabetes and the changing prevalence of metabolic syndrome. The crude incidence of the major noncommunicable diseases was 6.7 cases per 100 person-years in the MET+MedDiet group, 6.9 in the MET alone group, 13.3 in the placebo plus MedDiet group, and 11.3 in the placebo group. The differences were fully explained by the reduction of type 2 diabetes, which was 80% and 92% lower in the MET and MET+MedDiet groups, respectively, compared with placebo. The use of 1,700 mg/day MET is effective to prevent diabetes in people selected on the basis of metabolic syndrome.

Assessment of hypoxia and its dynamic evolution in glioblastoma via qBOLD MRI: a comparative study with metformin treatment

BackgroundTo investigate the accuracy of quantitative blood oxygen level-dependent (qBOLD) magnetic resonance imaging (MRI) in identifying hypoxia within glioblastoma and explore dynamic changes in oxygenation status of glioblastoma with and without metformin administration.MethodsThree healthy and seven C6-bearing rats underwent 7-T qBOLD MRI. Oxygen extraction fraction (OEF) and cerebral metabolism rate of O2 (CMRO2) were calculated from qBOLD data. Tumor tissues were stained using hypoxia-inducible factor-1α (HIF-1α) and pimonidazole. The correlation between the hypoxia markers and corresponding qBOLD-based parameters was analyzed. Six C6-bearing rats were divided into metformin-treated and control groups for a longitudinal study of qBOLD imaging changes, with scans conducted on the 12th, 15th, and 18th day post-tumor implantation.ResultsIn healthy rats, gray matter showed higher values than white matter in T2, T2*, cerebral blood volume (CBV), and cerebral blood flow (CBF), whereas OEF was lower. Glioblastoma tissues exhibited elevated T2, T2*, CBV, and CBF but decreased OEF and CMRO2 relative to normal-appearing white matter. No significant correlation was found between staining scores from HIF-1α and pimonidazole. T2* and T2 values were negatively correlated with pimonidazole scores in tumor regions. As the tumor progressed, OEF values increased with intra-tissue variations, whereas CMRO2 decreased. Metformin delayed the reduction of T2 and T2* values, with significant differences in OEF and CMRO2 values compared to controls on day 18.ConclusionT2* and T2 values were significantly associated with the hypoxia status in glioma. Metformin could potentially mitigate the progression of hypoxia in glioblastoma, which can be tracked by qBOLD parameters.Relevance statementThis study demonstrates the potential of qBOLD parameters in assessing glioma dynamic oxygen metabolism and the efficacy of metformin as an anti-hypoxic agent, providing insights into improving glioblastoma treatment strategies.Key PointsThe study investigated qBOLD imaging’s accuracy in identifying hypoxia status within glioblastoma.qBOLD effectively assesses hypoxia and its dynamic evolution in glioblastoma.qBOLD parameters assist in identifying a suitable patient demographic for metformin treatment.Graphical