Browsing by Subject "metformin"

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  • Chan, Juliana C. N.; Paldanius, Päivi M.; Mathieu, Chantal; Stumvoll, Michael; Matthews, David R.; Del Prato, Stefano (2021)
    We analysed glycaemic durability (sustained glycaemic control) with early combination therapy (metformin plus vildagliptin) versus metformin monotherapy, among patients with type 2 diabetes diagnosed before (young-onset [YOD]) and after (late-onset [LOD]) the age of 40 years, enrolled in the VERIFY trial. The primary endpoint was time to initial treatment failure (TF), defined as HbA1c of 7.0% or higher at two consecutive scheduled visits after randomization. The time to secondary TF was assessed when both groups were receiving and failing on the combination. A total of 186 (9.3%) patients had YOD and 1815 (90.7%) had LOD with a mean age difference of 20.4 years. Compared with metformin monotherapy, early combination reduced the risk of time to initial TF for both YOD (48%,P<.0006) and LOD (46%,P<.0001). With early combination, risk for time to secondary TF was reduced by 48% (P<.0035) in YOD and 24% (P<.0009) in LOD. Both treatment approaches were well tolerated with no unexpected safety concerns. In treatment-naive patients with YOD (HbA1c 6.5%-7.5%), an early combination strategy improved attainment of the glycaemic target with durability and delayed treatment escalation compared with initial metformin monotherapy.
  • Ji, Linong; Chan, Juliana C. N.; Yu, Miao; Yoon, Kun Ho; Kim, Sin Gon; Choi, Sung Hee; Huang, Chien-Ning; Te Tu, Shih; Wang, Chih-Yuan; Paldanius, Päivi Maria; Sheu, Wayne H. H. (2021)
    Type 2 diabetes (T2D) in the East Asian population is characterized by phenotypes such as low body mass index, an index of beta-cell dysfunction, and higher percentage of body fat, an index of insulin resistance. These phenotypes/pathologies may predispose people to early onset of diabetes with increased risk of stroke and renal disease. Less than 50% of patients with T2D in East Asia achieve glycaemic targets recommended by national or regional guidelines, which may be attributable to knowledge and/or implementation gaps. Herein, we review the latest evidence with special reference to East Asian patients with T2D and present arguments for the need to use early combination therapy to intensify glycaemic control. This strategy is supported by the 5-year worldwide VERIFY study, which reported better glycaemic durability in newly diagnosed patients with T2D with a mean HbA1c of 6.9% treated with early combination therapy of vildagliptin plus metformin versus those treated with initial metformin monotherapy followed by addition of vildagliptin only with worsening glycaemic control. This paradigm shift of early intensified treatment is now recommended by the American Diabetes Association and the European Association for the Study of Diabetes. In order to translate these evidence to practice, increased awareness and strengthening of the healthcare system are needed to diagnose and manage patients with T2D early for combination therapy.
  • Matthews, David R.; Del Prato, Stefano; Mohan, Viswanathan; Mathieu, Chantal; Vencio, Sergio; Chan, Juliana C. N.; Stumvoll, Michael; Paldanius, Päivi M. (2020)
  • Calza, Giulio; Nyberg, Elisabeth; Mäkinen, Matias; Soliymani, Rabah; Cascone, Annunziata; Lindholm, Dan; Barborini, Emanuele; Baumann, Marc; Lalowski, Maciej; Eriksson, Ove (2018)
    Metformin is the first line drug for type 2 diabetes but its molecular mechanisms remain unclear. Here, we have studied the acute effect of a therapeutically relevant intrahepatic concentration of metformin on glucose production from lactate. We selected the perfused rat liver as experimental system since it enables the complete control of drug dosage. We used MALDI (matrix-assisted laser desorption/ionization) mass spectrometry imaging to estimate the concentration of metformin in the livers and we measured the concentration of glucose in the effluent medium under basal conditions and following lactate addition. MALDI mass spectra of thin-sections of freeze-clamped rat liver perfused with metformin showed a peak at 130.16 m/z which was unambiguously assigned to metformin. The mass spectrometric detection limit was at a tissue concentration of about 250 nM, and uptake of metformin from the perfusion medium to the liver occurred with a K-m of 0.44 mM. Metformin was evenly distributed in the liver irrespective of its concentration in the perfusion medium and the duration of a perfusion. At a parenchymal concentration of 30 mu M, metformin did not induce any significant suppression of the basal or lactate-induced glucose release from the liver. These results show that matrix-assisted laser desorption/ionization mass spectrometry imaging can be applied to estimate the tissue concentration and distribution of metformin in a therapeutically relevant micromolar concentration range. Our findings challenge the view that metformin causes an inhibition of glucose release from the liver by an acute inhibition of mitochondrial glycerol 3-phosphate dehydrogenase (EC
  • Khatun, Masuma; Urpilainen, Elina; Ahtikoski, Anne; Arffman, Riikka K.; Pasanen, Annukka; Puistola, Ulla; Tapanainen, Juha S.; Andersson, Leif C.; Butzow, Ralf; Loukovaara, Mikko; Piltonen, Terhi T. (2021)
    Stanniocalcin-1 (STC-1) is a glycoprotein hormone involved in diverse biological processes, including regulation of calcium phosphate homeostasis, cell proliferation, apoptosis, inflammation, oxidative stress responses, and cancer development. The role of STC-1 in endometrial cancer (EC) is yet to be elucidated. In this study, we investigated the protein expression pattern of STC-1 in a tissue microarray (TMA) cohort of hysterectomy specimens from 832 patients with EC. We then evaluated the prognostic value of STC-1 expression regarding the clinicopathologic features and patients survival over a period of 140 months. Our results revealed that in EC tissue samples, STC-1 is mainly localized in the endometrial epithelium, although some expression was also observed in the stroma. Decreased STC-1 expression was associated with factors relating to a worse prognosis, such as grade 3 endometrioid tumors (p = 0.030), deep myometrial invasion (p = 0.003), lymphovascular space invasion (p = 0.050), and large tumor size (p = 0.001). Moreover, STC-1 expression was decreased in tumors obtained from obese women (p = 0.014) and in women with diabetes mellitus type 2 (DMT2; p = 0.001). Interestingly, the data also showed an association between DNA mismatch repair (MMR) deficiency and weak STC-1 expression, specifically in the endometrial epithelium (p = 0.048). No association was observed between STC-1 expression and disease-specific survival. As STC-1 expression was particularly low in cases with obesity and DMT2 in the TMA cohort, we also evaluated the correlation between metformin use and STC-1 expression in an additional EC cohort that only included women with DMT2 (n = 111). The analysis showed no difference in STC-1 expression in either the epithelium or the stroma in women undergoing metformin therapy compared to metformin non-users. Overall, our data may suggest a favorable role for STC-1 in EC behavior; however, further studies are required to elucidate the detailed mechanism and possible applications to cancer treatment.
  • Seppälä, Laura K.; Vettenranta, Kim; Pitkäniemi, Janne; Hirvonen, Elli; Leinonen, Maarit K.; Madanat-Harjuoja, Laura-Maria (2020)
    An association between maternal diabetes, its medication and childhood cancer has not been previously explored in a registry-based setting. With a case-control design, we aimed to explore whether maternal diabetes is associated with an increased risk of childhood cancer in the offspring. Combining data from population-based registries, we analyzed a total of 2,029 cases, i.e. persons with childhood cancer diagnosed under the age of 20?years between years 1996-2014 and a total of 10,103 matched population controls. The mothers of the cases/controls and their diagnoses of diabetes (DM) before/during pregnancy as well as their insulin/metformin prescriptions during pregnancy were identified. Conditional logistic regression modelling was used to analyze the risk of childhood cancer. The OR for childhood cancer among those exposed to any maternal diabetes was 1.32 (95% CI 1.14-1.54) compared to the offspring of the non-diabetic mothers. The effect of maternal diabetes on the risk of childhood cancer remained elevated even after adjusting for maternal age, parity and smoking. Our data suggest that maternal diabetes medication may reduce the risk for childhood cancer (adjusted OR 0.83, 95% CI 0.36-1.94), especially in gestational diabetes (adjusted OR 0.26, 95% CI 0.05-1.25), compared to the diabetic mothers without medication. The risk of childhood leukemia was significantly higher among children exposed to any maternal diabetes (OR 1.36, CI 1.04-1.77) compared to the unexposed. Maternal diabetes appears to be associated with an increased risk of childhood cancer in the offspring. The possible risk-reducing effect of an exposure to diabetes medication on offspring cancer risk warrants further investigation. This article is protected by copyright. All rights reserved.
  • Oh, Sehyun; Cho, Youngup; Chang, Minsun; Park, Sunghyouk; Kwon, Hyuk Nam (2021)
    The biguanide drug metformin has been widely used for the treatment of type 2 diabetes, and there is evidence supporting the anticancer effect of metformin despite some controversy. Here, we report the growth inhibitory activity of metformin in the breast cancer (MCF-7) cells, both in vitro and in vivo, and the associated metabolic changes. In particular, a decrease in a well-known oncometabolite 2-hydroxyglutarate (2-HG) was discovered by a metabolomics approach. The decrease in 2-HG by metformin was accompanied by the reduction in histone methylation, consistent with the known tumorigenic mechanism of 2-HG. The relevance of 2-HG inhibition in breast cancer was also supported by a higher level of 2-HG in human breast cancer tissues. Genetic knockdown of PHGDH identified the PHGDH pathway as the producer of 2-HG in the MCF-7 cells that do not carry isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) mutations, the conventional producer of 2-HG. We also showed that metformin's inhibitory effect on the PHGDH-2HG axis may occur through the regulation of the AMPK-MYC pathway. Overall, our results provide an explanation for the coherent pathway from complex I inhibition to epigenetic changes for metformin's anticancer effect.
  • Lingaiah, Shilpa; Morin-Papunen, Laure; Risteli, Juha; Tapanainen, Juha S. (2019)
    Objective: To study the effects of metformin treatment on bone turnover in women with polycystic ovary syndrome (PCOS), as measured by serum concentrations of bone turnover markers. Design: Post hoc study of a previously conducted prospective multicenter, placebo-controlled, randomized study. Setting: University clinic. Patient(s): The study cohort consisted of 74 non-obese women (body mass index <27 kg/m(2)) and 44 obese women (body mass index >= 27 kg/m(2)) diagnosed with PCOS, with a mean age of 27.6 +/- 4.0 (SD) years. Intervention(s): Randomization to receive metformin or placebo for 3 months. Main Outcome Measure(s): Serum levels of bone formation marker procollagen type I amino-terminal propeptide (PINP) and bone resorption marker carboxy-terminal cross-linking telopeptide of type I collagen (CTX) at baseline and after metformin/placebo treatment. Result(s): Serum levels of PINP and CTX were similar between the metformin and placebo groups at baseline in the whole study population. Obese women, when compared with non-obese, had lower baseline levels of PINP and CTX. Levels of PINP and CTX were significantly reduced in the whole study population, as well as in both non-obese and obese women after 3 months of metformin treatment, whereas no significant changes were observed in the placebo group. Conclusion(s): Metformin treatment, when compared with placebo, was associated with reduced bone turnover, as suggested by reductions in markers of bone formation and resorption, leading to slower bone remodeling in premenopausal women with PCOS. ((C) 2019 by American Society for Reproductive Medicine.)
  • Savelius, Mariel (Helsingin yliopisto, 2020)
    Breast cancer remains as the leading cause of cancer deaths among women. Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes and lacks targetable receptors, consequently, cannot be treated with current hormone of anti-HER2 targeting therapies. Thus, there is a need for discovering novel and well-tolerated therapies. MYC is a proto-oncogene and a transcription factor, that is frequently amplified and overexpressed in breast cancers. MYC is involved in many cellular processes promoting cell proliferation, however, overexpression of MYC can also sensitize cells to replicative stress and apoptotic cell death. In our previous studies we have shown that pharmacological activation of AMPK, a cellular energy sensor, synergises with Bcl-2 family inhibitors, such as navitoclax and venetoclax, and activates MYC-dependent apoptosis in breast cancer cell lines, transgenic mouse models of MYC-dependent mammary tumorigenesis and in MYC-high patient-derived explant cultures (PDECs). In subsequent study we observed, that indirect AMPK activator metformin alone inhibited tumor growth in vivo, but did not induce apoptosis in mouse tumors or in PDECs. Metformin, a type II diabetes mellitus drug, has shown anti-cancer effects in some population studies and is under investigation for a cancer therapies, however the whole mechanism of action in cancer is still not well-known. To elucidate metformin’s effects on MYC overexpressing triple-negative breast cancer cells, I will present, that metformin has anti-proliferative effects and show that long term metformin treatment induces senescence biomarkers in MYC-high TNBC breast cancer cell lines. To study metformin's short and long-term anti-proliferative activity, cell proliferation during and after drug treatment was investigated, which showed, that metformin’s effects do not seem to persist long after drug withdrawal. In conclusion, the key observation of this thesis was, that metformin does inhibit the proliferation of MYC overexpressing cancer cells and presents a senescence phenotype that possibly can be exploited to find new targeted therapies for triple-negative breast cancer patients.
  • Lehtonen, Sanna (2020)
    Metformin is the most commonly prescribed drug for treating type 2 diabetes mellitus (T2D). Its mechanisms of action have been under extensive investigation, revealing that it has multiple cellular targets, either direct or indirect ones, via which it regulates numerous cellular pathways. Diabetic kidney disease (DKD), the serious complication of T2D, develops in up to 50% of the individuals with T2D. Various mechanisms contribute to the development of DKD, including hyperglycaemia, dyslipidemia, oxidative stress, chronic low-grade inflammation, altered autophagic activity and insulin resistance, among others. Metformin has been shown to affect these pathways, and thus, it could slow down or prevent the progression of DKD. Despite several animal studies demonstrating the renoprotective effects of metformin, there is no concrete evidence in clinical settings. This review summarizes the renoprotective effects of metformin in experimental settings. Special emphasis is on the effects of metformin on podocytes, the glomerular epithelial cells that are central in maintaining the glomerular ultrafiltration function.
  • Ciparyte, Auguste (Helsingin yliopisto, 2020)
    Diabetic ovarian cancer patients who take metformin as part of their anti-diabetic medication generally respond better to DNA-damaging cancer treatment. The molecular mechanisms of the anti-cancer effects of metformin are currently being investigated, but they remain poorly elucidated. Not much is understood about the metformin effect on DNA damage in ovarian cancer cells, where it is of particular importance. When chemotherapy-induced double-stranded DNA breaks are unrepaired, cells reach a point when they cannot tolerate the accumulated DNA damage and die. However, some ovarian cancer cells efficiently employ DNA repair mechanisms, the most prominent being homologous recombination (HR), to overcome DNA damage. Efficient HR causes chemoresistance. An important question is whether metformin has the ability to induce the HR-deficient state in cancer cells, thereby sensitizing them to treatment. This study did not examine HR directly, but it assessed HR indirectly by observing the effect of metformin on recovery from DNA damage in two ovarian cancer cell lines: OVCAR4 (HR-proficient) and Kuramochi (HR-deficient). Additionally, this study evaluated the metformin effect on cell proliferation and apoptosis. OVCAR4 and Kuramochi cells were exposed to varying metformin concentrations (0,5 mM, 5 mM, 10 mM, 15 mM, 20 mM and 25 mM) and for varying durations (24 hours and 48 hours). This study also tested how metformin pretreatment affected the cells’ ability to repair externally (ionizing irradiation) induced DNA damage. The cells were imaged with a high-content imaging system, and percentages of nuclei that were positive for markers for different cellular processes (i.e., DNA damage, proliferation, and apoptosis) were calculated. The study found that only high metformin concentrations, such as 20 mM were able to increase DNA damage and reduce cell proliferation in HR-proficient OVCAR4 cells, both non-irradiated and irradiated. The HR-deficient Kuramochi cell line was generally more sensitive to metformin, particularly with regards to DNA damage, which increased using metformin concentrations < 20 mM. However, 20 mM concentration resulted in the most significant effects. Similarly, only high metformin concentration (25 mM) increased apoptosis, although data were obtained only for a limited number of Kuramochi cells. More experiments on apoptosis would be beneficial. Also, more extensive experiments for the irradiation part are needed to validate these preliminary findings, as well as examining whether high metformin concentrations (> 20 mM) affect specifically the HR-mediated DNA repair pathway.
  • Id, Linda (Helsingin yliopisto, 2022)
    Breast cancer is the most common cancer in the world and among women the most cancer deaths causing cancer. MYC is a proto-oncogene, which becomes oncogenic when its expression is deregulated in cancer. MYC is commonly overexpressed in human tumours and this alteration is associated with aggressive cancer phenotype. Furthermore, alterations in the MYC network have been found in the great majority of breast cancers. MYC promotes mitochondrial apoptosis causing a cancer vulnerability, however, in cancer cells the apoptosis is often prevented by antiapoptotic BCL-2 family members. In this study, cell viability and cell death analysis of treated triple-negative breast cancer cell lines together with dendritic cell activation experiments were conducted. This study aimed to find the most potent BCL-2 family antagonist (BH3 mimetic) to combine with metformin to overcome the antiapoptotic BCL-2 family proteins inhibition of MYC-induced apoptosis. In addition, this study determined whether the combinations could induce immunogenic cell death to further intensify cancer cell killing through anti-tumour immunity. In this study, BH3 mimetics combined with metformin were found to induce cell death and reduce cell viability in TNBC cell lines. In addition, metformin and BH3 mimetics were found to activate dendritic cells directly and through immunogenic cell death of cancer cells. However, no MYC-dependent cell death or immunogenic cell death were observed, and this study was unable to indicate the most potent BH3 mimetic to combine with metformin.
  • Mäkinen, Matias (Helsingin yliopisto, 2017)
    Målet för detta forskningsprojekt var att utveckla en metod med vars hjälp det är möjligt att detektera farmakologiska substanser i levervävnad med hjälp av masspektrometrisk bildtagning, så kallad MALDI-MSI. I litteraturen finns beskrivet tillämpningar av MALDI-MSI med vars hjälp det detekterats till exempel lipider i vävnader eller såsom i denna studie farmkologiska substanser. Arbetet bestod av två delmoment. I den första delen isolerades hepatocyter ur råttlever genom att perfusera kollagenas via portvenen. Hepatocyternas funktion analyserades genom att mäta deras metaboliska aktivitet med en analysator som mäter cellernas syrekonsumtion. Med analysen kunde visas att cellernas som isolerats var livsdugliga och där med sker upptagningen av substanser i hepatocyterna på ett fysiologiskt sätt. I den andra delen perfuserades levern på levande råttor genom portvenen med olika farmakologiska substanser. Levern togs tillvara och skars i tunna fryssnitt som sedan analyserades med MALDI-MSI. Kärlstrukturerna i fryssnitten färgades för att kunna urskilja ifall substanserna var belägna inne i själva i vävnaden eller i blodkärlen, ett bevis på metodens spatiala urskiljningsförmåga. Huvudfokus sattes på detektion av metformin i levervävnad eftersom de kliniska tillämpningsmöjligheterna ansågs vara störst för denna substans, då den nyligen börjats användas vid behandling av cancer. I framtiden är det möjligt att metforminets koncentration i tumörvävnaden kan bestämmas med hjälp av metoden och där med få mera detaljerad information om den optimala behandlingsdosen. Utöver att endast identifiera metformin kunde även dess distribution och koncentration i levervävnaden bestämmas med hjälp av den utvecklade metoden. Nu har metoden endast prövats med perfuserade vävnadssnitt, nästa steg skulle vara att mäta koncentrationen efter systemisk behandling.
  • Boussios, Stergios; Mikropoulos, Christos; Samartzis, Eleftherios; Karihtala, Peeter; Moschetta, Michele; Sheriff, Matin; Karathanasi, Afroditi; Sadauskaite, Agne; Rassy, Elie; Pavlidis, Nicholas (2020)
    Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women. Two-thirds of patients present at advanced stage at diagnosis, and the estimated 5 year survival rate is 20-40%. This heterogeneous group of malignancies has distinguishable etiology and molecular biology. Initially, single-gene sequencing was performed to identify germline DNA variations associated with EOC. However, hereditary EOC syndrome can be explained by germline pathogenic variants (gPVs) in several genes. In this regard, next-generation sequencing (NGS) changed clinical diagnostic testing, allowing assessment of multiple genes simultaneously in a faster and cheaper manner than sequential single gene analysis. As we move into the era of personalized medicine, there is evidence that poly (ADP-ribose) polymerase (PARP) inhibitors exploit homologous recombination (HR) deficiency, especially in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers. Furthermore, extensive preclinical data supported the development of aurora kinase (AURK) inhibitors in specific tumor types, including EOC. Their efficacy may be optimized in combination with chemotherapeutic or other molecular agents. The efficacy of metformin in ovarian cancer prevention is under investigation. Certain mutations, such as ARID1A mutations, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which are specific in ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC), may offer additional therapeutic targets in these clinical entities. Malignant ovarian germ cell tumors (MOGCTs) are rare and randomized trials are extremely challenging for the improvement of the existing management and development of novel strategies. This review attempts to offer an overview of the main aspects of ovarian cancer, catapulted from the molecular mechanisms to therapeutic considerations.