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The effect of metformin and myoinositol on metabolic outcomes in women with polycystic ovary syndrome: role of body mass and adiponectin in a randomized controlled trial.
Soldat-Stanković, V, Popović-Pejičić, S, Stanković, S, Prtina, A, Malešević, G, Bjekić-Macut, J, Livadas, S, Ognjanović, S, Mastorakos, G, Micić, D, et al
Journal of endocrinological investigation. 2022;(3):583-595
Abstract
PURPOSE To compare the effects of insulin sensitizers metformin (MET) and myo-inositol (MI) on adiponectin levels and metabolic characteristics in women with polycystic ovary syndrome (PCOS) with respect to their body mass index (BMI). METHODS In this open label, parallel randomized clinical trial, 66 women with PCOS (33 normal-weight and 33 overweight/obese) were randomized to either MI (4 g/day) or MET (1500 mg/day) for a period of 6 months. Serum concentration of adiponectin, hormonal and metabolic laboratory outcomes and clinical assessment of BMI, body composition and Ferriman-Gallwey score (FG score) were evaluated before and after treatment. RESULTS After the 6-month intervention, comparison between MET and MI in time to treatment analysis showed no significant differences between the two treatments for all analyzed parameters. Only borderline significantly lower AUC glucose was found in the MET group in comparison to the MI group (p = 0.071). The main effect of treatment was shown for glucose concentration at 120 min OGTT (p = 0.032) and testosterone (p = 0.002). The main effect of time was shown for body mass (p = 0.004), waist circumference (p < 0.001), BMI (p = 0.003), body fat mass (p = 0.001), adiponectin (p = 0.020), fasting glucose (p = 0.001), testosterone (p = 0.015), SHBG (p = 0.013), 17OH progesterone (p = 0.008), LH (p = 0.004) and estradiol (p = 0.014). CONCLUSION Our study showed similar effects of MET and MI on BMI, body composition, hormonal profile, metabolism of glucose and insulin, and adiponectin level. The two insulin sensitizers, MET and MI, were useful in reducing BMI and improving body composition without significant differences between the two treatments in PCOS women. TRIAL REGISTRATION ISRCTN13199265. Trial registration date: 14.04.2021. (ISRCTN Registry), retrospectively registered.
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Metformin action over gut microbiota is related to weight and glycemic control in gestational diabetes mellitus: A randomized trial.
Molina-Vega, M, Picón-César, MJ, Gutiérrez-Repiso, C, Fernández-Valero, A, Lima-Rubio, F, González-Romero, S, Moreno-Indias, I, Tinahones, FJ
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112465
Abstract
BACKGROUND Metformin, which is known to produce profound changes in gut microbiota, is being increasingly used in gestational diabetes mellitus (GDM). The aim of this study was to elucidate the differences in gut microbiota composition and function in women with GDM treated with metformin compared to those treated with insulin. METHODS From May to December 2018, 58 women with GDM were randomized to receive insulin (INS; n = 28) or metformin (MET; n = 30) at the University Hospital Virgen de la Victoria, Málaga, Spain. Basal visits, with at least 1 follow-up visit and prepartum visit, were performed. At the basal and prepartum visits, blood and stool samples were collected. The gut microbiota profile was determined through 16S rRNA analysis. RESULTS Compared to INS, women on MET presented a lower mean postprandial glycemia and a lower increase in weight and body mass index (BMI). Firmicutes and Peptostreptococcaceae abundance declined, while Proteobacteria and Enterobacteriaceae abundance increased in the MET group. We found inverse correlations between changes in the abundance of Proteobacteria and mean postprandial glycemia (p = 0.023), as well as between Enterobacteriaceae and a rise in BMI and weight gain (p = 0.031 and p = 0.036, respectively). Regarding the metabolic profile of gut microbiota, predicted metabolic pathways related to propionate degradation and ubiquinol biosynthesis predominated in the MET group. CONCLUSION Metformin in GDM affects the composition and metabolic profile of gut microbiota. These changes could mediate, at least in part, its clinical effects. Studies designed to assess how these changes influence metabolic control during and after pregnancy are necessary.
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Characterising 18F-fluciclovine uptake in breast cancer through the use of dynamic PET/CT imaging.
Scott, NP, Teoh, EJ, Flight, H, Jones, BE, Niederer, J, Mustata, L, MacLean, GM, Roy, PG, Remoundos, DD, Snell, C, et al
British journal of cancer. 2022;(4):598-605
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Abstract
BACKGROUND 18F-fluciclovine is a synthetic amino acid positron emission tomography (PET) radiotracer that is approved for use in prostate cancer. In this clinical study, we characterised the kinetic model best describing the uptake of 18F-fluciclovine in breast cancer and assessed differences in tracer kinetics and static parameters for different breast cancer receptor subtypes and tumour grades. METHODS Thirty-nine patients with pathologically proven breast cancer underwent 20-min dynamic PET/computed tomography imaging following the administration of 18F-fluciclovine. Uptake into primary breast tumours was evaluated using one- and two-tissue reversible compartmental kinetic models and static parameters. RESULTS A reversible one-tissue compartment model was shown to best describe tracer uptake in breast cancer. No significant differences were seen in kinetic or static parameters for different tumour receptor subtypes or grades. Kinetic and static parameters showed a good correlation. CONCLUSIONS 18F-fluciclovine has potential in the imaging of primary breast cancer, but kinetic analysis may not have additional value over static measures of tracer uptake. CLINICAL TRIAL REGISTRATION NCT03036943.
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Effectiveness of carbohydrate counting and Dietary Approach to Stop Hypertension dietary intervention on managing Gestational Diabetes Mellitus among pregnant women who used metformin: A randomized controlled clinical trial.
Allehdan, S, Basha, A, Hyassat, D, Nabhan, M, Qasrawi, H, Tayyem, R
Clinical nutrition (Edinburgh, Scotland). 2022;(2):384-395
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is one of the most common complication of pregnancy that has significant impacts on both mother and her offspring health. The present study aimed to examine the effect of carbohydrate counting, carbohydrate counting combined with DASH, and control dietary interventions on glycemic control, and maternal and neonatal outcomes. METHODS A total of 75 pregnant women with GDM at 24th - 30th week of gestation were enrolled and randomized to follow one of the three diets: control or carbohydrate counting, or carbohydrate counting combined with Dietary Approach to Stop Hypertension (DASH). Only 70 of them completed the study until delivery. Fasting blood samples were taken at baseline and the end of the study to measure fasting blood glucose (FBG), fasting insulin, glycated hemoglobin (HbA1c), and fructosamine. Homeostatic model assessment-insulin resistance (HOMA-IR) score was calculated using HOMA2 calculator program. The participants recorded at least four blood glucose readings per day. Maternal and neonatal outcomes were collected from medical records. Dietary intake was assessed by three-day food records at the baseline and the end of the study. RESULTS Adherence to the three dietary interventions, resulted in decreased FBG levels significantly among all the participants (P < 0.05). Consumption of the carbohydrate counting combined with the DASH diet showed significant reduction in serum insulin levels and HOMA-IR score compared to carbohydrate counting group and control group. Means of fructosamine and HbA1c did not differ significantly among the three intervention diet groups. Overall mean of 1-h postprandial glucose (1 h PG) level was significantly lower in the carbohydrate counting combined with DASH group compared with that in the carbohydrate counting group and the control group (P < 0.001). The number of women who were required to commence insulin therapy after dietary intervention was significantly lower in carbohydrate counting group and carbohydrate counting combined with DASH group (P = 0.026). There were no significant differences in other maternal and neonatal outcomes among the three dietary intervention groups. CONCLUSIONS The carbohydrate counting and the carbohydrate counting combined with DASH dietary interventions resulted in beneficial effects on FBG and 1 h PG compared with the control diet. The three dietary interventions produced similar maternal and neonatal outcomes in women with GDM. TRIAL REGISTRATION This trial was registered on ClinicalTrials.gov under the identification code: NCT03244579. https://clinicaltrials.gov/ct2/show/NCT03244579.
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Effects of a Behavioral Weight Loss Intervention and Metformin Treatment on Serum Urate: Results from a Randomized Clinical Trial.
Hu, JR, Yeh, HC, Mueller, NT, Appel, LJ, Miller, ER, Maruthur, NM, Jerome, GJ, Chang, AR, Gelber, AC, Juraschek, SP
Nutrients. 2021;(8)
Abstract
Background: Lower body mass index (BMI) has been associated with lower serum urate (SU), but only in observational studies. We sought to determine the effects of behavioral weight loss and metformin treatment on SU in a randomized trial. Methods and Findings: The Survivorship Promotion In Reducing IGF-1 Trial (SPIRIT) was a parallel three-arm randomized controlled trial of overweight/obese adult cancer survivors without gout at a single center in Maryland, United States. Participants were randomized to: (1) coach-directed weight loss (behavioral telephonic coaching), (2) metformin (up to 2000 mg daily), or (3) self-directed weight loss (informational brochures; reference group). SU and BMI were assessed at baseline and at 3, 6, and 12 months post-randomization. The 121 participants had a mean ± standard deviation (SD) age of 60 ± 9 years, 79% were female, and 45% were Black. At baseline, BMI was 35 ± 5 kg/m2, and SU was 5.6 ± 1.3 mg/dL. Compared to the self-directed group, at 12 months, the coach-directed group reduced BMI by 0.9 kg/m2 (95% confidence interval (CI): -1.5, -0.4) and metformin reduced BMI by 0.6 kg/m2 (95% CI: -1.1, -0.1). However, compared to the self-directed group, the coach-directed group unexpectedly increased SU by 0.3 mg/dL (95% CI: 0.05, 0.6), and metformin non-significantly increased SU by 0.2 mg/dL (95% CI: -0.04, 0.5); these effects were attenuated when analyses included change in estimated glomerular filtration rate (eGFR). Conclusions: In this randomized trial of cancer survivors without gout, reductions in BMI either increased or did not change SU, potentially due to effects on eGFR. These results do not support a focus on BMI reduction for SU reduction; however, long-term studies are needed. ClinicalTrials.gov Registration: NCT02431676.
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Could the use of butyric acid have a positive effect on microbiota and treatment of type 2 diabetes?
Stachowska, E, Wiśniewska, M, Dzieżyc, A, Bohatyrewicz, A
European review for medical and pharmacological sciences. 2021;(13):4570-4578
Abstract
OBJECTIVE This review focuses on the role of butyrate as one of the key metabolites of gut microbiota. Butyrate along with other short-chain fatty acids, acetate and propionate, is one of the most important regulators of human metabolism. In this review, we discuss how changes in gut microbiota triggered by type 2 diabetes mellitus and its treatment (e.g., metformin) affect butyrate synthesis, how to increase butyrate production and whether there is robust evidence for the positive effects of sodium butyrate in the treatment of diabetes mellitus. MATERIALS AND METHODS Literature review was conducted by all authors. Studies published until 27/03/2020 were included. Search words were: ("butyric acid" OR "butyrate") AND ("type 2 diabetes "OR "T2DM"). The articles selected for the study were not chosen in a systematic manner, so the evidence may not be comprehensive. RESULTS Butyrate was found to effectively reduce inflammation and plays a prominent role in the function of the intestinal barrier. To date the use of sodium butyrate in the treatment of patients with T2DM is not very popular. Meanwhile, butyric acid can beneficially modulate intestinal functions, counteracting the negative effects of the disease as well as the drugs used to treat diabetes. CONCLUSIONS T2DM is a widespread chronic disease. Understanding role of microbiota in type 2 diabetes and the mechanisms connecting T2DM and alterations in gut microbiota could be the key to improved treatment of T2DM.
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Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19.
Lalau, JD, Al-Salameh, A, Hadjadj, S, Goronflot, T, Wiernsperger, N, Pichelin, M, Allix, I, Amadou, C, Bourron, O, Duriez, T, et al
Diabetes & metabolism. 2021;(5):101216
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AIMS: Metformin exerts anti-inflammatory and immunosuppressive effects. We addressed the impact of prior metformin use on prognosis in patients with type 2 diabetes hospitalised for COVID-19. METHODS CORONADO is a nationwide observational study that included patients with diabetes hospitalised for COVID-19 between March 10 and April 10, 2020 in 68 French centres. The primary outcome combined tracheal intubation and/or death within 7 days of admission. A Kaplan-Meier survival curve was reported for death up to day 28. The association between metformin use and outcomes was then estimated in a logistic regression analysis after applying a propensity score inverse probability of treatment weighting approach. RESULTS Among the 2449 patients included, 1496 were metformin users and 953 were not. Compared with non-users, metformin users were younger with a lower prevalence of diabetic complications, but had more severe features of COVID-19 on admission. The primary endpoint occurred in 28.0% of metformin users (vs 29.0% in non-users, P = 0.6134) on day 7 and in 32.6% (vs 38.7%, P = 0.0023) on day 28. The mortality rate was lower in metformin users on day 7 (8.2 vs 16.1%, P < 0.0001) and on day 28 (16.0 vs 28.6%, P < 0.0001). After propensity score weighting was applied, the odds ratios for primary outcome and death (OR [95%CI], metformin users vs non-users) were 0.838 [0.649-1.082] and 0.688 [0.470-1.007] on day 7, then 0.783 [0.615-0.996] and 0.710 [0.537-0.938] on day 28, respectively. CONCLUSION Metformin use appeared to be associated with a lower risk of death in patients with diabetes hospitalised for COVID-19.
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New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway.
Hsu, SK, Cheng, KC, Mgbeahuruike, MO, Lin, YH, Wu, CY, Wang, HD, Yen, CH, Chiu, CC, Sheu, SJ
International journal of molecular sciences. 2021;(17)
Abstract
Under metabolic stress conditions such as hypoxia and glucose deprivation, an increase in the AMP:ATP ratio activates the AMP-activated protein kinase (AMPK) pathway, resulting in the modulation of cellular metabolism. Metformin, which is widely prescribed for type 2 diabetes mellitus (T2DM) patients, regulates blood sugar by inhibiting hepatic gluconeogenesis and promoting insulin sensitivity to facilitate glucose uptake by cells. At the molecular level, the most well-known mechanism of metformin-mediated cytoprotection is AMPK pathway activation, which modulates metabolism and protects cells from degradation or pathogenic changes, such as those related to aging and diabetic retinopathy (DR). Recently, it has been revealed that metformin acts via AMPK- and non-AMPK-mediated pathways to exert effects beyond those related to diabetes treatment that might prevent aging and ameliorate DR. This review focuses on new insights into the anticancer effects of metformin and its potential modulation of several novel types of nonapoptotic cell death, including ferroptosis, pyroptosis, and necroptosis. In addition, the antimetastatic and immunosuppressive effects of metformin and its hypothesized mechanism are also discussed, highlighting promising cancer prevention strategies for the future.
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Metformin Treatment or PRODH/POX-Knock out Similarly Induces Apoptosis by Reprograming of Amino Acid Metabolism, TCA, Urea Cycle and Pentose Phosphate Pathway in MCF-7 Breast Cancer Cells.
Huynh, TYL, Oscilowska, I, Sáiz, J, Nizioł, M, Baszanowska, W, Barbas, C, Palka, J
Biomolecules. 2021;(12)
Abstract
It has been considered that proline dehydrogenase/proline oxidase (PRODH/POX) is involved in antineoplastic activity of metformin (MET). The aim of this study is identification of key metabolites of glycolysis, pentose phosphate pathway (PPP), tricarboxylic acids (TCA), urea cycles (UC) and some amino acids in MET-treated MCF-7 cells and PRODH/POX-knocked out MCF-7 (MCF-7crPOX) cells. MCF-7crPOX cells were generated by using CRISPR-Cas9. Targeted metabolomics was performed by LC-MS/MS/QqQ. Expression of pro-apoptotic proteins was evaluated by Western blot. In the absence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to similar inhibition of glycolysis (drastic increase in intracellular glucose and pyruvate) and increase in the utilization of phospho-enol-pyruvic acid, glucose-6-phosphate and some metabolites of TCA and UC, contributing to apoptosis. However, in the presence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to utilization of some studied metabolites (except glucose), facilitating pro-survival phenotype of MCF-7 cells in these conditions. It suggests that MET treatment or PRODH/POX-knock out induce similar metabolic effects (glucose starvation) and glycolysis is tightly linked to glutamine metabolism in MCF-7 breast cancer cells. The data provide insight into mechanism of anticancer activity of MET as an approach to further studies on experimental breast cancer therapy.
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The Effects of Vitamin D Supplementation on Metabolic and Oxidative Stress Markers in Patients With Type 2 Diabetes: A 6-Month Follow Up Randomized Controlled Study.
Cojic, M, Kocic, R, Klisic, A, Kocic, G
Frontiers in endocrinology. 2021;:610893
Abstract
Vitamin D deficiency could play an important role in the pathogenesis of type 2 diabetes mellitus (T2DM) as it may alter several crucial processes in the development of diabetes and its complications, such as pancreatic insulin secretion, peripheral insulin resistance, persistence of systemic "sterile" inflammation and immune activation. Vitamin D may also have an antioxidant effect through the inhibition of free radicals generation. The reported study was designed with eligible consecutively recruited patients with T2DM on standard metformin therapy (n=130), randomized in 1:1 ratio, considered to have undergone Vitamin D supplementation according to the guidelines proposed by the Endocrine Society, or to have continued with metformin only. The potential benefit was monitored through the influence on glycemia level, glycated haemoglobin (HbA1c), insulin resistance index (calculated as homeostatic model assessment; HOMA-IR), Castelli Risk Index I and Tryglicerides/Thiobarbituric acid-reactive substances (TG/TBARS) Index in a 6-month follow up period. Our study indicates that oral daily doses of vitamin D improve HbA1c levels over the 3-month and 6-month period, followed by a significant decrease in advanced oxidation protein products levels over the 3-month period when higher vitamin D doses are given. The effect of vitamin D on HOMA-IR index, malondialdehyde levels and TG/TBARS index was not statistically significant. Further investigation should consider defining the doses of vitamin D in patients with T2DM which may attenuate the oxidative stress risk, the risk of metabolic syndrome and the risk of related cardiovascular events.