Administration Of Metformin Research Articles

Metformin enhances endogenous neural stem cells proliferation, neuronal differentiation, and inhibits ferroptosis through activating AMPK pathway after spinal cord injury

BackgroundInadequate nerve regeneration and an inhibitory local microenvironment are major obstacles to the repair of spinal cord injury (SCI). The activation and differentiation fate regulation of endogenous neural stem cells (NSCs) represent one of the most promising repair approaches. Metformin has been extensively studied for its antioxidative, anti-inflammatory, anti-aging, and autophagy-regulating properties in central nervous system diseases. However, the effects of metformin on endogenous NSCs remains to be elucidated.MethodsThe proliferation and differentiation abilities of NSCs were evaluated using CCK-8 assay, EdU/Ki67 staining and immunofluorescence staining. Changes in the expression of key proteins related to ferroptosis in NSCs were detected using Western Blot and immunofluorescence staining. The levels of reactive oxygen species, glutathione and tissue iron were measured using corresponding assay kits. Changes in mitochondrial morphology and membrane potential were observed using transmission electron microscopy and JC-1 fluorescence probe. Locomotor function recovery after SCI in rats was assessed through BBB score, LSS score, CatWalk gait analysis, and electrophysiological testing. The expression of the AMPK pathway was examined using Western Blot.ResultsMetformin promoted the proliferation and neuronal differentiation of NSCs both in vitro and in vivo. Furthermore, a ferroptosis model of NSCs using erastin treatment was established in vitro, and metformin treatment could reverse the changes in the expression of key ferroptosis-related proteins, increase glutathione synthesis, reduce reactive oxygen species production and improve mitochondrial membrane potential and morphology. Moreover, metformin administration improved locomotor function recovery and histological outcomes following SCI in rats. Notably, all the above beneficial effects of metformin were completely abolished upon addition of compound C, a specific inhibitor of AMP-activated protein kinase (AMPK).ConclusionMetformin, driven by canonical AMPK-dependent regulation, promotes proliferation and neuronal differentiation of endogenous NSCs while inhibiting ferroptosis, thereby facilitating recovery of locomotor function following SCI. Our study further elucidates the protective mechanism of metformin in SCI, providing new mechanistic insights for its candidacy as a therapeutic agent for SCI.

The influence of metformin and empagliflozin administration on gut microbiota in individuals with type 2 diabetes mellitus and hypothyroidism

The influence of metformin and empagliflozin administration on gut microbiota in individuals with type 2 diabetes mellitus and hypothyroidism

Could the Propionic Acid Treatment in Combination with Metformin be Safe for the Small Intestine of Diabetic Rats?

Effects of propionic acid (PA) on the cellular and molecular processes in the small intestine under type 2 diabetes mellitus (T2DM)-induced endoplasmic reticulum (ER) stress remain incompletely studied. The aim of the study was to assess the state of unfolded protein response (UPR) system in the small intestine of diabetic rats and to explore PA's influence on metformin treatment. Male Wistar rats were divided into 1) control and 2) T2DM groups, and groups receiving (14 days, orally) 3) metformin (60 mg/kg), 4) PA (60 mg/kg), and 5) PA+metformin. Western blotting, RT-PCR, and transmission electron microscopy were performed. We found that T2DM induced elevation of ER intermembrane space and UPR overactivation based on increased GRP78, ATF6 and PERK levels in small intestine. Metformin treatment led to a further UPR activation. PA supplementation partially restored enterocytes functioning via normalization of ATF6 and PERK content, while IRE1 level reached the maximum value, compared to all groups. The most pronounced effect of adaptation to the T2DMinduced ER stress was observed after combined metformin and PA action. In particular, decreased ER intermembrane space in enterocytes was detected compared to separate metformin and PA administration, which was accompanied by restored GRP78, PERK and IRE1 levels. Our study proves the safety of additional therapy with propionic acid in combination with metformin for the functional state of small intestine. Due to its ability to modulate UPR signaling, PA may be considered a safe and perspective candidate for supportive therapy in T2DM, especially for neuroprotection.

Metformin administration during pregnancy tends to reduce the risk of gestational diabetes mellitus and improve pregnancy outcomes in previously infertile women with polycystic ovary syndrome who become pregnant.

Metformin reduces incidences of miscarriage and preterm delivery in polycystic ovary syndrome (PCOS) women, but its impact on gestational diabetes mellitus (GDM) is conflicting. Hence, this study set up selection criteria to include previously infertile women with PCOS but without pre-existing DM who became pregnant, aiming to minimize confounders and investigate the influence of metformin on GDM, miscarriage, and preterm delivery. This study included 195 previously infertile women with PCOS who became pregnant. They were divided into metformin (receiving metformin during pregnancy) and control (not receiving metformin) groups without intervention. Metformin group tended to have a lower incidence of GDM versus control group (13.3% versus 23.3%, P = 0.070). A logistic regression model adjusted for all baseline characteristics (demographics, infertile duration, and diabetes mellitus-related features) showed that metformin was associated with a decreased probability of GDM (odds ratio (OR): 0.426, P = 0.037). Metformin group showed a similar incidence of miscarriage (6.7% versus 11.1%, P = 0.273), but decreased incidences of preterm delivery (not statistically significant) (6.7% versus 13.3%, P = 0.091) and miscarriage or preterm delivery (13.3% versus 24.4%, P = 0.046) versus control group. A logistic regression model adjusted for all the aforementioned features revealed that metformin was related to a lower risk of miscarriage or preterm delivery (OR: 0.417, P = 0.040). Fetal outcomes, including birth weight (P = 0.245) and the incidence of 5min-Apgar score ≤ 7 (P = 0.702), were similar between groups. Metformin administration during pregnancy may reduce GDM, miscarriage, and preterm delivery risks without adverse effects on fetal outcomes in previously infertile women with PCOS.

Metformin administration in prevention of colorectal polyps in type 2 diabetes mellitus patients.

Colorectal polyps are frequently observed in patients with type 2 diabetes mellitus (DM), posing a significant risk for colorectal cancer. Metformin, a widely prescribed biguanidine drug for type 2 DM, has been suggested to have potential chemoprophylactic effects against various cancers. To explore the correlation between colorectal polyps and metformin use in type 2 DM patients. Type 2 DM patients were categorized into polyp and non-polyp groups. Following this, all patients were categorized into the type 2 DM-metformin, type 2 DM-non-metformin, and non-type 2 DM groups. Based on the baseline colonoscopy results, we performed pairwise comparisons of the incidence of colorectal polyps among the three groups. Additionally, we analyzed the relationship between colorectal polyps and the duration of metformin use and between the size and number of polyps and metformin use. Simultaneously, we focused on the specific pathological types of polyps and analyzed their relationship with metformin use. Finally, we compared the incidence of polyps between metformin and non-metformin groups according to the interval colonoscopy results. The rate of metformin use in patients with colorectal polyps was 0.502 times that of patients without colorectal polyps [odds ratio (OR) = 0.502, 95% confidence interval (CI): 0.365-0.689; P < 0.001]. The incidence of colorectal polyps did not differ significantly between the type 2 DM-metformin and non-type 2 DM groups (P > 0.05). Furthermore, the correlations between the duration of metformin use and the incidence of colorectal polyps and between the size and number of polyps and metformin use were not statistically significant (P > 0.05). Metformin use did not affect the incidence of colorectal polyps during interval colonoscopy (P > 0.05). Metformin use and colorectal polyp incidence in type 2 DM patients showed a negative correlation, independent of the hypoglycemic effect of metformin.

Effects of metformin on knee joint capsule fibrosis in a diabetic mouse model.

The antidiabetic agent metformin inhibits fibrosis in various organs. This study aims to elucidate the effects of hyperglycaemia and metformin on knee joint capsule fibrosis in mice. Eight-week-old wild-type (WT) and type 2 diabetic (db/db) mice were divided into four groups without or with metformin treatment (WT met(-/+), Db met(-/+)). Mice received daily intraperitoneal administration of metformin and were killed at 12 and 14 weeks of age. Fibrosis morphology and its related genes and proteins were evaluated. Fibroblasts were extracted from the capsules of 14-week-old mice, and the expression of fibrosis-related genes in response to glucose and metformin was evaluated in vitro. The expression of all fibrosis-related genes was higher in Db met(-) than in WT met(-) and was suppressed by metformin. Increased levels of fibrosis-related genes, posterior capsule thickness, and collagen density were observed in the capsules of db/db mice compared with those in WT mice; these effects were suppressed by metformin. Glucose addition increased fibrosis-related gene expression in both groups of mice in vitro. When glucose was added, metformin inhibited the expression of fibrosis-related genes other than cellular communication network factor 2 (Ccn2) in WT mouse cells. Hyperglycaemia promotes fibrosis in the mouse knee joint capsule, which is inhibited by metformin. These findings can help inform the development of novel strategies for treating knee joint capsule fibrosis.

Beneficial effect of metformin on tolerance to analgesic effects of sodium salicylate in male rats.

Tolerance to the analgesic effects of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) is a major concern for relieving pain. Thus, it is highly valuable to find new pharmacological strategies for prolonged therapeutic procedures. Biguanide-type drugs such as metformin (MET) are effective for neuroprotection and can be beneficial for addressing opioid tolerance in the treatment of chronic pain. It has been proposed that analgesic tolerance to NSAIDs is mediated by the endogenous opioid system. According to the cross-tolerance between NSAIDs, especially sodium salicylate (SS), and opiates, especially morphine, the objective of this study was to investigate whether MET administration can reduce tolerance to the anti-nociceptive effects of SS. Fifty-six male Wistar rats were used in this research (weight 200-250 g). For induction of tolerance, SS (300 mg/kg) was injected intraperitoneally for 7 days. During the examination period, animals received MET at doses of 50, 75, or 100 mg/kg for 7 days to evaluate the development of tolerance to the analgesic effect of SS. The hot plate test was used to evaluate the drugs' anti-nociceptive properties. Salicylate injection significantly increased hot plate latency as compared to the control group, but the total analgesic effect of co-treatment with SS + Met50 was stronger than the SS group. Furthermore, the effect of this combination undergoes less analgesic tolerance over time. It can be concluded that MET can reduce the analgesic tolerance that is induced by repeated intraperitoneal injections of SS in Wister rats.

The relationship between metformin administration and age-related macular degeneration; a systematic review and meta-analysis of observational studies

Introduction: Vision loss due to age-related macular degeneration (AMD) is a major and growing health issue. Given that no definitive treatment is available for AMD, this study aims to evaluate the association between metformin use and AMD risk using a systematic review and meta-analysis approach. Materials and Methods: In this study, databases including ProQuest, PubMed, Web of Science, Cochrane, and Google Scholar search engines were searched without time restriction until April 20, 2024, based on PRISMA statement guidelines. Data were analyzed using STATA 14 software at a significance level of P &lt; 0.05. Results: Overall, metformin administration reduced the risk of AMD (OR: 0.86, 95% CI: 0.80, 0.94). Concerning the dosage, a metformin dose of 1-270 g per 2 years (OR: 0.93, 95% CI: 0.90, 0.96) and 271-600 g per 2 years (OR: 0.91, 95% CI: 0.89, 0.94) mitigated the risk of AMD. Metformin use in women increased the risk of AMD (OR: 1.14, 95% CI: 1.09, 1.18). However, no significant relationship was noticed between metformin use and AMD risk in men (OR: 0.86, 95% CI: 0.73, 1.01). In addition, metformin was associated with a lower risk of AMD in case-control (OR: 0.93, 95% CI: 0.89, 0.97) and cohort (OR: 0.69, 95% CI: 0.51, 0.95) studies. Likewise, metformin use was associated with a lower risk of AMD in the age groups of 50-59 years (OR: 0.54, 95% CI: 0.50, 0.58) and 70-79 years (OR: 0.90, 95% CI: 0.84, 0.97). Conclusion: Metformin administration lowered the risk of AMD by 14%. Moreover, female gender was identified as a risk factor for AMD development. However, further studies are required on this subject to reach a definite conclusion. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (ID: CRD42024539904) and Research Registry (UIN: reviewregistry1824) website.

Twin neurological enigmas radiological and medical insight into a dual encounter with metformin induced encephalopathy

Metformin induced encephalopathy is an infrequent but critical neurological complication associated with metformin therapy. Lentiform fork sign, an infrequent radiological imaging (MRI), presents a distinctive image in basal ganglia pathology. It manifests as a V-shaped or fork-like hyperintensity in the globus pallidus and putamen regions. While it has been associated with various conditions like diabetic uremic encephalopathy, toxins like methanol and ethylene glycol, Neurodegenerative etiologies. Its occurrence following metformin administration remains rare because of contraindication of prescribing metformin in a hemodialysis patient due to its well-known side of lactic acidosis. This abstract aims to report and discuss two cases presenting the lentiform forks sign following metformin administration in patients undergoing hemodialysis due to end-stage renal disease. Symptomatic involvement of basal ganglia as metformin induced encephalopathy and resolution with clinical recovery following hemodialysis are rarely reported. We hereby report two such cases which shows symptomatic improvement clinically as well as radiologically following hemodialysis

Beneficial effect of lupeol and metformin in mouse model of intracerebroventricular streptozotocin induced dementia.

This study examines the effectiveness of lupeol and metformin in a mouse model of dementia generated by intracerebroventricular streptozotocin (i.c.v., STZ). Dementia was induced in Swiss mice with the i.c.v. administration of STZ at a dosage of 3mg/kg on the first and third day. The assessment of dementia involved an examination of the Morris Water Maze (MWM) performance, as well as a number of biochemical and histological studies. STZ treatment resulted in significant decrease in MWM performance; various biochemical alterations (increase in brain acetyl cholinesterase (AChE) activity, thiobarbituric acid reactive species (TBARS), nitrite/nitrate, and reduction in nuclear factor erythroid 2 related factor-2 (Nrf-2), reduced glutathione (GSH) levels) and neuroinflammation [increased myeloperoxidase (MPO) activity & neutrophil infiltration]. The administration of Lupeol (50mg/kg & 100mg/kg; p.o.) and Metformin (150mg/kg & 300mg/kg; p.o.) demonstrated a considerable reduction in the behavioral, biochemical, and histological alterations produced by STZ. Low dose combination of lupeol (50mg/kg; p.o.) and Metformin (150mg/kg; p.o.) produced more pronounced effect than that of high doses of either agent alone. It is concluded that Lupeol and Metformin has shown efficacy in dementia with possible synergism between the two and can be explored as potential therapeutic agents for managing dementia of Alzheimer's disease (AD) type.

Metformin Therapy for Acne Vulgaris: A Meta-Analysis.

Acne vulgaris is a common disease, which occurs in adolescents as well as adults and has a significant influence on the patient's quality of life (QoL) in every aspect. Due to resistance to standard therapies, it has become necessary to prospect for new treatment strategies. It is important to highlight that the diagnosis and treatment of the underlying cause of acne such as metabolic and hormonal disorders may significantly improve the effectiveness of acne treatment. The correlation between Insulin Resistance (IR) and acne has been proven. Both disorders share many common occurrence factors and activation pathways. Metformin, an antihyperglycemic agent, seems to be a possible therapy option, not only because of its insulin sensitizing ability but also via plenty of additional effects of this medicine. While the efficiency of metformin therapy in patients with acne and Polycystic Ovary Syndrome (PCOS) is well explored, it is still necessary to evaluate it in patients without any endocrinopathies. This meta-analysis aimed to estimate the effectiveness of oral metformin as a monotherapy in acne patients without PCOS or other endocrinopathies. Study selection was performed with included criteria such as no PCOS and other endocrinopathies diagnosed, oral administration of metformin, and metformin in monotherapy. Selected studies contained comparisons in the Global Acne Grading System (GAGS) before and after metformin therapy. Statistical analysis detected significant improvement in skin condition after treatment with metformin.

A phase II clinical trial of metformin combined with FOLFIRI plus bevacizumab as second-line therapy in patients with RAS-mutant metastatic colorectal cancer.

3534 Background: Metastatic colorectal cancer (mCRC) patients with RAS mutations are confronted with limited novel targeted therapy. We previously reported that KRAS mutation mediated MATE1 down-regulation sensitizes colorectal cancer cells to metformin. Based on our preclinical research, we designed a study to explore whether metformin combined with FOLFIRI plus bevacizumab would improve efficacy in RAS mutant mCRC. Methods: This single-arm, multicenter trial (ChiCTR2000037943) recruited patients with RAS mutant mCRC that had failed to first-line bevacizumab plus an oxaliplatin-based regimen of systemic therapies. Patients received metformin 1000mg PO twice daily on day 1-14, plus irinotecan 180 mg/m² IV, calcium folinate 400 mg/m² IV, fluorouracil 400 mg/m² IV, and a 46-h CIV of fluorouracil 2400 mg/m², and bevacizumab 5 mg/kg IV, repeated every 14 days. We used Simon's two-stage design. The primary endpoint was objective response rate (ORR). The secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: One hundred sixteen patients were recruited between July 2020 and March 2023. KRAS codon 12 mutations were present in 81 cases (69.8%), codon 13 mutations in 17 cases (14.7%), codon 61 mutations in 6 cases (5.2%), and codon 146 mutations in 3 cases (2.6%). For the 81 patients with KRAS codon 12 mutation, 42 were with G12D (51.9%), 21 with G12V (25.9%), 7 with G12A (8.6%), and 6 with G12C (7.4%) mutation. The ORR was 21.6% (25/116), and DCR was 76.7% (89/116). The median PFS was 8.0 months, and patients without liver metastasis had longer PFS than those with liver metastasis (9.5 months vs. 5.6 months, P &lt; 0.001). For the 45 patients without liver metastasis, the administration of metformin combined with FOLFIRI plus bevacizumab as second-line therapy resulted in significantly longer PFS than the first-line bevacizumab plus an oxaliplatin-based regimen (9.5 months vs. 7.9 months, P = 0.037). The median OS was not reached. The most common treatment-emergent adverse events (TEAEs) were neutropenia (73.7%), nausea (56.9%), anemia (54.3%) and diarrhea (49.1%). Grade 3 and above TEAEs occurred in 52 (44.8%) patients. No treatment-related mortality occurred. Conclusions: Metformin combined with FOLFIRI and bevacizumab had promising efficacy and tolerable toxicity in RAS mutant mCRC patients as second-line therapy. Further study in phase 3 trials is warranted. Clinical trial information: ChiCTR2000037943.

Harnessing Metformin's Immunomodulatory Effects on Immune Cells to Combat Breast Cancer.

Metformin, a medication known for its anti-glycemic properties, also demonstrates potent immune system activation. In our study, using a 4T1 breast cancer model in BALB/C WT mice, we examined metformin's impact on the functional phenotype of multiple immune cells, with a specific emphasis on natural killer T (NKT) cells due to their understudied role in this context. Metformin administration delayed the appearance and growth of carcinoma. Furthermore, metformin increased the percentage of IFN-γ+ NKT cells, and enhanced CD107a expression, as measured by MFI, while decreasing PD-1+, FoxP3+, and IL-10+ NKT cells in spleens of metformin-treated mice. In primary tumors, metformin increased the percentage of NKp46+ NKT cells and increased FasL expression, while lowering the percentages of FoxP3+, PD-1+, and IL-10-producing NKT cells and KLRG1 expression. Activation markers increased, and immunosuppressive markers declined in T cells from both the spleen and tumors. Furthermore, metformin decreased IL-10+ and FoxP3+ Tregs, along with Gr-1+ myeloid-derived suppressor cells (MDSCs) in spleens, and in tumor tissue, it decreased IL-10+ and FoxP3+ Tregs, Gr-1+, NF-κB+, and iNOS+ MDSCs, and iNOS+ dendritic cells (DCs), while increasing the DCs quantity. Additionally, increased expression levels of MIP1a, STAT4, and NFAT in splenocytes were found. These comprehensive findings illustrate metformin's broad immunomodulatory impact across a variety of immune cells, including stimulating NKT cells and T cells, while inhibiting Tregs and MDSCs. This dynamic modulation may potentiate its use in cancer immunotherapy, highlighting its potential to modulate the tumor microenvironment across a spectrum of immune cell types.

Biochemical investigation into the influence of telfairia occidentalis on hepatic oxidative stress markers and pro-inflammatory biomarkers induced by streptozotocin

In rat models of diabetes, this research examined the biochemical impact of Telfairia occidentalis (TO) on pro-inflammatory biomarkers and hepatic oxidative stress markers caused by streptozotocin (STZ). There were five experimental groups: G 1 (Normal control) received 0.5 ml of distilled water; G 2 through 5 received 10% fructose for 14 days, after which STZ was administered intraperitoneally once. After the diagnosis of diabetes was confirmed, rats in groups 3 (TO1), 4 (TO2), and 5 (MET) were given 200 mg/kg b.w. TO, 300 mg/kg b.w. TO, and 300 mg/kg b.w. Metformin, respectively, for 28 days. The findings show that STZ significantly (p&lt;0.05) increased malondialdehyde (MDA) levels in diabetic rats relative to the control group and significantly (p&lt;0.05) decreased the activities of liver antioxidant enzymes such as catalase (CAT), reduced glutathione (GSH), glutathione S-transferase (GST), glutathione peroxidase (GPx), and superoxide dismutase (SOD). On the other hand, administration of TO (200 mg/kg and 300 mg/kg) and Metformin (300 mg/kg) resulted in a significant (p&lt;0.05) increase in antioxidant enzyme activities and a significant (p&lt;0.05) decrease in MDA levels. Furthermore, the inflammatory biomarkers myeloperoxidase (MPO), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) as well as the apoptotic marker caspase-3 were significantly (p&lt;0.05) elevated upon STZ induction; however, these elevations were significantly (p&lt;0.05) attenuated upon TO administration, mirroring the effects of Metformin. In conclusion, Telfairia occidentalis significantly reduces the oxidative stress markers, inflammatory reactions brought on by STZ, and liver antioxidant status in diabetic rats. These results point to TO's possible therapeutic benefit in reducing diabetes-related liver problems via regulating oxidative and inflammatory pathways.

Evaluation of Systemic and Brain Pharmacokinetic Parameters for Repurposing Metformin Using Intravenous Bolus Administration.

Metformin's potential in treating ischemic stroke and neurodegenerative conditions is of growing interest. Yet, the absence of established systemic and brain pharmacokinetic (PK) parameters at relevant pre-clinical doses presents a significant knowledge gap. This study highlights these PK parameters and the importance of using pharmacologically relevant pre-clinical doses to study pharmacodynamics (PD) in stroke and related neurodegenerative diseases. An LC-MS/MS method to measure metformin levels in plasma, brain, and cerebrospinal fluid (CSF) was developed and validated. In vitro assays examined brain tissue binding and metabolic stability. Intravenous (IV) bolus administration of metformin to C57BL6 mice covered low to high dose range maintaining pharmacological relevance. Quantification of metformin in the brain was used to assess brain pharmacokinetic parameters, such as unidirectional blood-to-brain constant (Kin) and unbound brain-to-plasma ratio (Kp, uu, brain). Metformin exhibited no binding in the mouse plasma and brain and remained metabolically stable. It rapidly entered the brain, reaching detectable levels in as little as 5 minutes. A Kin value of 1.87 {plus minus} 0.27 µl/g/min was obtained. As the dose increased, Kp, uu, brain showed decreased value, implying saturation, but this did not affect an increase in absolute brain concentrations. Metformin was quantifiable in the CSF at 30 minutes but decreased over time, with concentrations lower than those in the brain across all doses. Our findings emphasize the importance of metformin dose selection based on pharmacokinetic parameters for pre-clinical pharmacological studies. We anticipate further investigations focusing on pharmacokinetics and pharmacodynamics (PKPD) in disease conditions, such as stroke. Significance Statement The study establishes crucial pharmacokinetic parameters of metformin for treating ischemic stroke and neurodegenerative diseases, addressing a significant knowledge gap. It further emphasizes the importance of selecting pharmacologically relevant pre-clinical doses. The findings highlight metformin's rapid brain entry, minimal binding, and metabolic stability. The necessity of considering pharmacokinetic parameters in pre-clinical studies provides a foundation for future investigations into metformin's efficacy for neurodegenerative disease (s).

Clinical evidence for the prognostic impact of metformin in cancer patients treated with immune checkpoint inhibitors

BackgroundPreclinical studies suggest that metformin might enhance the efficacy of immune checkpoint inhibitors (ICIs) and potentially influence the prognoses of cancer patients undergoing ICIs treatment. This study endeavors to assess the prognostic significance of metformin in cancer patients undergoing ICIs therapy, aiming to furnish evidence-based insights for clinical practice. MethodsA thorough literature search was conducted across electronic databases to encompass all potential records published before November 20th, 2023. A meta-analysis was executed utilizing Stata 17.0 to derive pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for both overall survival (OS) and progression-free survival (PFS). ResultsA total of 22 studies encompassing 9,011 patients met the inclusion criteria. Meta-analyses revealed a significant correlation between metformin use and poorer OS (HR, 1.13; 95 %CI, 1.04–1.23; P = 0.004) rather than PFS (HR, 1.04; 95 %CI, 0.96–1.14; P = 0.345) among cancer patients undergoing ICIs treatment. Subgroup analysis delineated that the concurrent administration of metformin and ICIs significantly associated with adverse prognoses in the European population (OS: HR, 1.23; 95 %CI, 1.10–1.39; P = 0.001; PFS: HR, 1.14; 95 %CI, 1.02–1.28; P = 0.024). ConclusionBased on current clinical evidence, concomitant metformin use does not appear to improve the prognostic outcomes for cancer patients undergoing ICIs therapy and may potentially correlate with inferior prognoses. Further studies are imperative to comprehensively elucidate the impact of metformin within the realm of ICIs therapy.

Long-term combination therapy with metformin and oxymetholone in a Fanconi anemia mouse model.

Fanconi anemia (FA) is a disease caused by defective deoxyribonucleic acid (DNA) repair that manifests as bone marrow failure, cancer predisposition, and developmental defects. We previously reported that monotherapy with either metformin (MET) or oxymetholone (OXM) improved peripheral blood (PB) counts and the number and functionality of bone marrow hematopoietic stem progenitor cells (HSPCs) number in Fancd2-/- mice. To evaluate whether the combination treatment of these drugs has a synergistic effect to prevent bone marrow failure in FA, we treated cohorts of Fancd2-/- mice and wildtype controls with either MET alone, OXM alone, MET+OXM, or placebo diet from age 3weeks to 18months. The OXM treated animals showed modest improvements in blood parameters including platelet count (p=.01) and hemoglobin levels (p<.05). In addition, the percentage of quiescent hematopoietic stem cell (HSC) (LSK [Lin-Sca+c-Kit+]) was significantly increased (p=.001) by long-term treatment with MET alone. The combination of metformin and oxymetholone did not result in a significant synergistic effect in any hematopoietic parameter. Gene expression analysis of liver tissue from these animals showed that some of the expression changes caused by Fancd2 deletion were partially normalized by metformin treatment. Importantly, no adverse effects of the individual or combination therapies were observed, despite the long-term administration. We conclude that androgen therapy is not a contraindication to concurrent metformin administration in clinical trials. HIGHLIGHTS: Long-term coadministration of metformin in combination with oxymetholone is well tolerated by Fancd2-/- mice. Hematopoietic stem cell quiescence in mutant mice was enhanced by treatment with metformin alone. Metformin treatment caused a partial normalization of gene expression in the livers of mutant mice.

Abstract PO1-05-11: Efficacy of metformin as adjunctive therapy in patients with de novo metastatic breast cancer: a retrospective cohort study

Abstract Background: Metformin, an oral biguanide used for the treatment of type-2 diabetes mellitus (DM), has been shown in a considerable number of studies to have an anti-tumorigenic impact against breast cancer cells through several mechanisms,thereby improving breast cancer outcomes. However, the impact of metformin treatment on survival outcomes in patients with non-diabetic breast cancer is still under debate, with very few data available regarding metformin administration in de novo metastatic breast cancer (dnMBC). This study was conducted to investigate and evaluate the impact on survival outcomes of patients with dnMBC treated with metformin as adjunctive therapy at our institutes. Methods: All dnMBC women who received chemotherapy-based systemic therapy or combined with metformin administered orally in our hospitals between March 2007 and November 2016 were enrolled in the study. Data were retrospectively extracted from the patients’case records. Data were analyzed according the clinicopathological features and treatment outcomes. All specimens were rechecked for the purpose of the research. Overall survival (OS), as the study endpoint, was defined as the time from pathologically confirmed diagnosis to all-cause death or end of the follow-up time.Kaplan-Meier estimate was used to calculate the survival rates.The difference between metformin and non-metformin groups was compared by the log-rank method.Cox regression analysis (uni-and multivariate analysis) was used to assess the effect of variables on survival outcomes.Analyses were performed by Stata 17 software for windows version. Results: A total of 252 women with dnMBC were included with an average age of 54.41±11.61 years. Among them, 97 patients (including 11 DM patients) received chemotherapy-based systemic therapy plus oral administration of metformin 850-1000mg twice daily (metformin group), and 155 patients received chemotherapy-based systemic therapy (non-metformin group). There was no significant difference in body mass index, age, N-stage, P53 index, ER/PR status, HER-2 expression and initial metastatic sites between metformin group and non-metformin group. But there were differences in T-stage and Ki67 index between the two groups (Table 1). The median follow-up was 70 months.The median OS was 24 months.The 3-year and 5-year OS rates for all patients were 29.8% (95% CI:24.2% to 35.4%) and 11.6% (95% CI:7.5% to 16.7%),respectively; Log-rank test showed that the metformin group had a significant advantage over the non-metformin group in OS rates(p=0.0002).The 3-year and 5-year OS rates in the metformin group were 42.3% (95% CI:32.4% to 51.8%) and 21.2% (95% CI:12.8% to 31.1%), respectively; the same rates for non-metformin group were 21.9% (95% CI: 15.8% to 28.7%) and 5.6% (95% CI: 2.4% to 11.1%), respectively. Results of proportional hazards model, after adjustment for T-stage and Ki67 index, depicted an independent prognostic value of metformin use with multivariate hazard ratio of 0.61 (95% CI: 0.45 to 0.81) for OS compared to non-metformin group (p=0.001).No survival advantage was found for DM patients (0.59;95% CI:0.29 to 1.22; p=0.159). Conclusions: Our data support a favorable outcome for survival associated with metformin use in dnMBC patients. However, the retrospective nature and small sample size of the current study are major limitations to reliable conclusions about metformin's potential to improve OS in patients. Therefore, prospective evidence from phase-3 randomized controlled trials on the feasibility of metformin use in dnMBC is required before its routine use can be recommended. Keywords: Metformin; De novo metastatic breast cancer; Adjunctive therapy; Survival outcomes Citation Format: Ren Chongxi, Sun Jianna, Kong Lingjun, Hongjun Yu. Efficacy of metformin as adjunctive therapy in patients with de novo metastatic breast cancer: a retrospective cohort study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-11.

Effects of Insulin and Metformin on Indomethacin-Induced Gastric Injury in Streptozotocin-Induced Diabetic and Non-Diabetic Rats

Diabetes is one of the major health issues globally. Diabetic gastropathy is a well-documented phenomenon. Current treatments for diabetes and its complications have proven to be unsatisfactory. Currently, standard insulin therapy alone is still not the best treatment for type 1 diabetes (T1D). Metformin, besides use in type 2 diabetes (T2D), might be considered for a treatment of T1D. This study analyzed the effects of insulin and metformin on the gastric injury caused by indomethacin in the streptozotocin (STZ)-induced diabetic (T1D) and control non-diabetic rats. STZ (60 mg/kg, i.p.) was administered once 2 weeks before indomethacin (IM, 35 mg/kg, s.c.) in rats. Control non-diabetic rats were injected with STZ vehicle. The development of diabetes was assessed by blood glucose levels, changes in the rats' body weight, and water consumption. Insulin (2 IU/kg, i.p.) and metformin (100 mg/kg, orally) were administered daily, separately to different groups of rats, starting from the 8th day after the administration of STZ, for 7 days. After the last administration of the drugs, the rats were fasted for 22 hours before IM administration. Four hours after IM administration, the rats were decapitated, the stomachs were removed to estimate the erosion area; the adrenal glands and thymus were removed to estimate their weight, and trunk blood was collected to test the corticosterone and glucose levels. During the first week after STZ administration characteristic signs of diabetes developed: increased blood glucose, increased water consumption, and slower body weight gain. A week after daily insulin administration (on the 14th day), the glucose level in diabetic rats was lower compared to the corresponding level on the 7th day (before insulin administration). At the same time, the glucose levels before (day 7) and after administration (day 14) of metformin did not differ significantly. The development of STZ-induced diabetes led to a pronounced worsening of the ulcerogenic effect of IM: the average area of erosions caused by IM was increased significantly compared to that in control non-diabetic rats. Administration of both insulin and metformin for 7 days prevented the ulcer-promoting effect of STZ. In addition, insulin, but not metformin, also had a gastroprotective effect in non-diabetic rats: it reduced the average area of IM-induced erosions. The development of STZ-induced diabetes was accompanied by the manifestation of signs of chronic stress: an increase in plasma corticosterone level, an increase in the relative weight of the adrenal glands, and a decrease in the relative weight of the thymus. Daily administration of insulin for 7 days, but not metformin, resulted in a decrease in corticosterone levels on day 14 in diabetic rats. In conclusion, both insulin and metformin effectively prevented the pronounced ulcer-promoting effect of STZ-induced diabetes on the gastric injury caused by indomethacin in rats. However, only insulin, but not metformin, also exerted gastroprotective effect against IM-induced injury in non-diabetic rats under our experimental conditions. Grant for the creation and development of the world-class scientific center "Pavlov Center “Integrative Physiology - to medicine, high-tech healthcare and technologies of stress resistance” and with financial support from the Ministry of Education and Science of the Russian Federation (No 075-15-2022-303 от 21.04.2022.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

HPLC-MS/MS Method for the Quantitative Determination of Metformin in Rat Plasma and Its Application to Comparative Bioavailability Assessment

Background: Metformin is a biguanide derivative utilized as a first-line treatment for type 2 diabetes for people over 60 years. However, it faces certain limitations due to its incomplete absorption, resulting in a 50-60% bioavailability. In addition to its blood glucose-lowering effect, the antiproliferative effect of metformin has been demonstrated in vitro. Therefore, it is necessary to consider alternative administration routes that can enhance the bioavailability of metformin, expanding its clinical use beyond its role as an antidiabetic agent. Objective: The aim of the study was to develop a reliable bioanalytical method for the quantitation of metformin in male Sprague-Dawley rat plasma and explore the promising alternative administration route for metformin use. Methods: A robust, high-performance liquid chromatography-tandem mass spectrometry method for the quantification of metformin in rat plasma was developed and validated according to the latest regulatory guidance for bioanalysis. Results: Based on the area under the curves obtained from the rat pharmacokinetic study, subcutaneous injection increased the systemic exposure of metformin by 1.79-fold compared to oral administration in rats. Conclusion: Subcutaneous administration of metformin enhances its bioavailability compared to oral administration, leading to increased antidiabetic effects and potential antitumor activity.