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Periodontitis is an oral chronic inflammatory disease. Inhibiting tissue destruction and promoting tissue regeneration are important means for the treatment of periodontitis. Metformin not only has hypoglycemic effect but also has anti-inflammatory effect. Metformin has been shown to inhibit oxidative stress and activate autophagy through AMPK/mTOR pathway. High mobility group box 1 (HMGB1) has been implicated in the pathogenesis of many inflammatory diseases including periodontitis, it can participate in the induction of oxidative stress. HMGB1 is an autophagy regulator under oxidative stress, which can activate mTOR pathway. However, it is not clear whether metformin is related to HMGB1 and its mechanism in the process of periodontitis. Cell viability and expression of inflammatory cytokines were clarified by Cell Counting Kit-8, real-time PCR and enzyme-linked immunosorbent assay. Western blot and immunofluorescence were conducted to determine HMGB1 intracellular localization and expression of autophagy-associated proteins in vitro. Experimental periodontitis mice model was induced by administering a ligature. Immunohistochemistry was performed to detect the expression and localization of HMGB1 in vivo. The results of CCK-8, real-time PCR, enzyme-linked immunosorbent assay, Western blot and immunofluorescence showed lipopolysaccharide (LPS) treatment inhibited cell viability, and increased HMGB1 expression at a dose-independent manner. Metformin can reduce the effect of LPS. It also improves autophagy pathway inhibited by LPS and down-regulates mTOR expression. In addition, metformin attenuated alveolar bone resorption induced by ligation. This study provides new evidence for that metformin is a potential drug for the treatment of periodontitis and HMGB1 may be a potential target for periodontal intervention.

Clozapine is an atypical antipsychotic used in refractory schizophrenia, also efficient in alleviating dyskinesia in Parkinson’s disease. Despite its potency, this drug is associated with severe metabolic side effects, including increased risk for diabetes. We report the case of a 45-year-old overweight woman with Parkinson’s disease who presented with rapid-onset hyperglycaemia within 2 months after starting clozapine for refractory dyskinaesia. She had a history of gestational diabetes. At presentation, her blood glucose level was 505 mg/dL and glycated haemoglobin 12.4%, with no catabolic symptoms. Clozapine was suspended and metformin was started, but adequate glycaemic control was achieved only with insulin therapy, along with exenatide and empagliflozin afterwards. We assume that clozapine acted as a trigger for rapid deterioration of glycaemic control through direct pathophysiological mechanisms, rather than an indirect slowly evolving weight gain-related metabolic syndrome pathway. Clinicians should be aware of this complication, enabling timely diagnosis and proper treatment.

Background: The Diabetes Health Plan (DHP), a value-based insurance plan that reduces cost sharing, was previously shown to modestly increase employer-level medication adherence. However, it is unclear whether the DHP has a larger impact on individual-level medication adherence among lower- or higher-income beneficiaries. Methods: An employer-level propensity score match was done to identify suitable control employers, followed by individual-level propensity score weighting. These weights were applied to difference-in-difference (DID) models examining 1) the effect of the DHP and 2) the effect of income on changes in adherence to metformin, statins, and ACE/ARBs. The weights were then applied to a differences-in-differences-in-differences (DDD) model to estimate the differential impact of DHP status on changes in adherence by income group. This is a retrospective, quasi-experimental study.Results: There were no significant differences in changes to adherence for any medications between beneficiaries enrolled in the DHP versus standard plans. However, changes in adherence were higher for all medications among those in the highest income strata (>$75,000) versus those in the lowest income strata (Conclusion: We did not find significant associations between the DHP and changes in individual-level medication adherence, even for low-income beneficiaries. New strategies to improve consumer engagement may be needed in order to translate value-based insurance designs into changes in patient behavior.

Background: According to available research, there have been no head-to-head studies comparing the effect of glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors on cardiovascular outcomes among patients with type 2 diabetes not reaching glycemic goal with metformin. Methods: Relevant studies were identified through electronic searches of PubMed and EMBASE published up to January 15, 2020. Efficacy outcomes of interest included the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, its individual components, all-cause death, and hospitalization for heart failure (HF). Safety outcomes included all suggested side effects of both agents previously reported. Results: Eleven studies, including 94,727 patients were used for the analysis. The risk of composite end point was significantly lower in both groups compared to the control group (hazard ratio [HR], 0.88, 95% confidence interval [CI] 0.85–0.92, p < 0.001). The risk of hospitalization for HF was significantly lower in both groups but the magnitude of the effect was more pronounced in the SGLT-2 inhibitors group (HR 0.68, 95% CI 0.60–0.76, p < 0.001) than the GLP-1 agonists group (HR 0.92, 95% CI 0.84–0.99, p = 0.03). Patients treated with GLP-1 agonists discontinued trial medications more frequently compared to conventionally treated patients because of serious side effects. Conclusions: Both GLP-1 agonists and SGLT-2 inhibitors showed comparable cardiovascular outcomes in patients with type 2 diabetes. However, the SGLT-2 inhibitors were associated with more pronounced reduction of hospitalization for HF and lower risk of treatment discontinuation than GLP-1 agonists.

BACKGROUND Since the turn of the century, the prevalence of diabetes mellitus in Australia has increased, primarily due to rising rates of type 2 diabetes. Simultaneously, the landscape of diabetes medications has evolved significantly. The change in prescribing trends and public spending on diabetes medications within Australia during this period are not well defined. AIMS We sought to establish the frequency and cost of dispensed diabetes medications in the Australian public healthcare system between 2003 and 2019. METHODS We performed a longitudinal nationwide observational study using data obtained from the Pharmaceutical Benefits Scheme (PBS) and Medicare Benefits Schedule websites, which contain information on frequency and spending of diabetes medications dispensed in Australia. RESULTS The total number of PBS-subsidised prescriptions dispensed for diabetes increased from 5,218,690 in 2003 to 12,188,568 in 2019, and spending increased from $117,241,031 to $598,904,983. Of the non-insulin agents, metformin was consistently the most frequently dispensed agent, with a rapid growth in metformin combination tablets. Dispensation of sulphonylureas and thiazolidinediones have declined, with a simultaneous increase in DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists. CONCLUSIONS Our data show a large growth in the use of diabetes medications between 2003 and 2019. The rapid growth in dispensing of drugs with proven cardiovascular and renal benefits reflect the evolving approach of diabetes treatment, from a historical approach targeting glycaemic control alone, to a modern individualised approach targeting specific co-morbidities. This article is protected by copyright. All rights reserved.

Background: Melanoma, also known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin but may rarely occur in the mouth, intestines or, eye. This study aims to examine the expression of the mammalian target of rapamycin (mTOR)/70S6K signaling pathway in melanoma cancer. Methods: The B16F10 cell line treated with dacarbazine IC50 and different concentrations of metformin (0.5, 2, and 8 mM) for 24 hr and mTOR and 70S6k proteins expression were examined by western blotting. Cell viability was measured by MTT assay. Results: Western blot analysis showed that after different concentrations of metformin and dacarbazine treatments, the mTOR and 70S6K protein expression significantly (P Conclusion: Metformin-induced repression of mTOR/70S6k axis activity disrupts B16F10 growth. Thus, we believe that combination therapy may be a suitable potential therapeutic target for melanoma cancer.

Background. The safety and efficacy of combination tablets of metformin plus sulfonylurea or plus dipeptidyl peptidase-4 inhibitors have not been studied previously. This study aimed to compare the efficacy and safety of Gliconorm versus Sitavia plus among patients with type 2 diabetes mellitus who fast Ramadan. Methods. This was an open-label study conducted from 1 May 2018 till 1 July 2018. People with type 2 diabetes mellitus who were drug-naive or on metformin only, with HbA1c < 10 % were included. The participants were divided into two groups. The first group was given Gliconorm (glibenclamide 5 mg + metformin 1000 mg), while the second group was given Sitavia plus (sitagliptin 50 mg + metformin 1000 mg) imme-diately after Iftar. Glycated hemoglobin (HbA1c) was measured before and after Ramadan. Several home recordings of blood glucose were collected. In addition, patients were asked to report any hypoglycemic or severe hyperglycemic episodes. Results. A total of 34 participants (18 women) (19 in the first group and 15 in the second group) were involved the study. The mean age was 49.6 ± 9.3 years. HbA1c reduced from 8.7 % (72 mmol/mol) to 7.6 % (60 mmol/mol) and from 8.7% (72 mmol/mol) to 7.7 % (61 mmol/mol) in the first and second group, respectively (p < 0.0001). Only one patient in the first group experienced one episode of hypoglycemia and hyperglycemia. Conclusion. Both medications seem to be safe and effective during Ramadan fasting.

Although Helicobacter pylori infection is the most important causative factor for gastric cancer (GC), H. pylori eradication alone does not completely eliminate the GC risk. In addition to H. pylori eradication, other risk factors for GC should be identified and targeted. Diabetes mellitus (DM) confers a 20% increased risk of GC, which could be mediated via several biological mechanisms including the stimulation of cell proliferation via hyperinsulinemia and increased insulingrowth factor production, the promotion of angiogenesis, and DNA damage. With a current global prevalence of 9.3% and a predicted rise to 10.2% by 2030, DM could contribute substantially to the burden of GC cases worldwide. Emerging evidence showed that metformin possesses chemopreventive effects via both direct (e.g., adenosine monophosphate-activated protein kinase activation and subsequent inhibition of the mammalian target of rapamycin pathway) and indirect (e.g., modulation of the interaction between tumor cells and their microenvironment and gut microbiota) pathways. A recent meta-analysis of observational studies showed that metformin use was associated with 24% lower GC risk. However, many available observational studies related to metformin effects suffered from biases including the failure to adjust for the H. pylori infection status and serial glycemic control and time-related biases. Future prospective studies addressing these pitfalls are needed.

Background To investigate the causality between metformin and gut microbiome in the treatment of type 2 diabetes (T2D). Methods This study was conducted on individuals with newly diagnosed and treatment-naive T2D. We used 16s rRNA sequencing to understand the effect of metformin on the composition and diversity of the gut microbiota. We also compared the differences in relative abundances of gut microbiome at the genus level in treatment-naive T2D patients before and after metformin treatment for 2 months and used Spearman rank correlation coefficient analysis of genus abundance in relation to blood glucose and related factors. Results Metformin significantly reduced blood glucose and levels of the related factors in treatment-naive individuals with T2D after 2 months of treatment. 16s rRNA sequencing showed that metformin treatment altered the composition and diversity of the gut microbiome. Differences in relative abundances at the genus level among groups revealed that Megamonas and Klebsiella in T2D groups were significantly higher compared with those in the control group. Treatment with metformin caused a significant reduction in the abundances of Megamonas and Klebsiella. Spearman rank correlation coefficient analysis showed a significant positive correlation between Megamonas and blood glucose, HbA1c, GSP, and ALT. In Klebsiella, a significant positive correlation between HbA1c and ALT was found. Conclusions Metformin reduces blood glucose in T2D by interaction with different gut bacteria, possibly Megamonas and Klebsiella pneumoniae.

SIGNIFICANCE: Metformin has been proposed as a treatment for systemic lupus erythematosus (SLE). The primary target of metformin, the electron transport chain complex I in the mitochondria, is associated with redox homeostasis in immune cells, which plays a critical role in the pathogenesis of autoimmune diseases. This review addresses the evidence and knowledge gaps on whether a beneficial effect of metformin in lupus may be due to a restoration of a balanced redox state. RECENT ADVANCES: Clinical trials in SLE patients with mild-to-moderate disease activity and preclinical studies in mice have provided encouraging results for metformin. The mechanism by which this therapeutic effect was achieved is largely unknown. Metformin regulates redox homeostasis in a context-specific manner. Multiple cell types contribute to SLE, with evidence of increased mitochondrial oxidative stress in T cells and neutrophils. CRITICAL ISSUES: The major knowledge gaps are whether the efficacy of metformin is linked to a restored redox homeostasis in the immune system, and if it does, in which cell types it occurs? We also need to know which patients may have a better response to metformin, and whether it corresponds to a specific mechanism? Finally, the identification of biomarkers to predict treatment outcomes would be of great value. FUTURE DIRECTIONS: Mechanistic studies must address the context-dependent pharmacological effects of metformin. Multiple cell types as well as a complex disease etiology should be considered. These studies must integrate the rapid advances made in understanding how metabolic programs direct the effector functions of immune cells. Antioxid. Redox Signal. 36, 462–479.

Background: Observational studies suggest an anti-neoplastic effect associated with statins, metformin, dipeptidyl peptidase-4 inhibitors (DPP4i), while sulfonylureas may have a neutral or detrimental effect. The aim of this study was to determine the impact of these medications in patients with myelodysplastic syndromes (MDS). Methods: A prospective Canadian national registry containing disease and patient-related characteristics enrolled patients with MDS between January 1, 2006 and December 31, 2019. The Ontario subset of the registry was linked to population-based health system administrative databases. The primary outcome was the impact of statin/oral hypoglycemic medication exposure on overall survival (OS). Cumulative medication exposure (in months) was evaluated from 1-year prior to registry enrollment to date of death or end of follow-up (March 31, 2020) as a time-varying covariate. Cox regression analysis controlling for comorbid disease burden (Aggregated Diagnosis Groups; ADG) and sociodemographic factors (age, sex, rurality, income quintile) examined the relationship between medication exposure and OS. Our secondary outcome was leukemia-free survival (LFS), in which cause-specific hazard model was used to evaluate the association between medication exposure and LFS, taking death as the competing event. Results: In total, 533 patients aged >66 years were included (395 lower-risk IPSS, 130 higher-risk IPSS). The median age was 76.0 years (IQR 72.0-81.0), 65.1% were male and 9% had secondary MDS. The mean follow-up was 2.6 years (SD+ 2.4). Starting one year prior to registry enrollment and until the end of follow-up, 49.3% used a statin, 18.9% used metformin, 9.0% used a sulfonylurea and 6.4% used a DPP4i. On univariate analysis, we identified an improved OS in the lower-risk IPSS group using DPP4i (HR 0.98, 95% CI 0.95-1.00, p=0.05), while there was no significant difference in the higher-risk IPSS group for users of DPP4i (HR 1.03, 95% CI 0.99-1.07, p=0.21). In both lower and higher-risk IPSS groups, there was no difference in mortality for statins (HR 1.00, CI 1.00-1.01, p=0.93), metformin (HR 1.00, CI 0.99-1.01, p=0.81) and sulfonylureas (HR 1.00, CI 0.99-1.02, p=0.43). Increased age (p There was no association between exposure to the studied medications and LFS in the lower-risk group: metformin (HR 0.99, 95% CI 0.96-1.02, p=0.32), sulfonylureas (HR 0.99, 95% CI 0.94-1.04, p=0.57) and statins (HR 0.99, 95% CI 0.98-1.01, p=0.41). The impact of DPP4i exposure on LFS could not be assessed in lower risk disease due to infrequent events. There was also no association in the higher-risk IPSS group: DPP4i (HR 1.06, 95% CI 1.00-1.12, p=0.05), metformin (HR 1.02, CI 0.98-1.05, p=0.34), sulfonylureas (HR 1.04, 1.00-1.08, p=0.07) and statins (HR 1.02, 1.00-1.04, p=0.12). On multivariable analysis in the lower-risk IPSS group, no associations were identified between the use of medications of interest and all-cause mortality: DPP4i (HR 0.98, 95% CI 0.95-1.00, p=0.06), metformin (HR 1.00, 95% CI 0.99-1.01, p=0.99), sulfonylurea (HR 1.00, 95% CI 0.99-1.02, p=0.65) and statins (HR 1.00, 95% CI 0.99-1.00, p=0.56). In those with known cause of death, the main cause of death amongst DPP4i users was infection (35.7%) followed by acute myeloid leukemia (AML) (21.4%) and cardiac disease (14.3%), while the main cause of death in patients not on DPP4i was progressive MDS (23.2%) followed by AML (22.5%) and infections (22.1%). Conclusions: DPP4i may confer a survival benefit in lower-risk but not higher-risk MDS that cannot be explained by a reduction in cardiovascular deaths. Metformin, sulfonylureas and statins showed no impact on OS and LFS in lower and higher-risk groups. Improved bone marrow function through exosome inhibition and increased granulocyte-macrophage colony stimulating activity is the suggested mechanism for the potential survival benefit with DPP4i in lower-risk IPSS patients. This represents the first study evaluating the impact of oral hypoglycemic mediations and statins in a large cohort of patients with MDS. Further prospective studies are required to further evaluate the effects of DPP4i in MDS. Disclosures Leber: AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Khalaf: Pfizer: Honoraria; Novartis: Honoraria; Paladin: Honoraria. Sabloff: TaiHo: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Yee: Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Research Funding; Janssen: Research Funding; Jazz: Research Funding; MedImmune: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Tolero: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding. Buckstein: Celgene: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; TAIHO: Research Funding; Otsuka: Research Funding.

Background Consensus lacks regarding the association between diabetes mellitus (DM) and the prognosis of patients with non-Hodgkin lymphoma (NHL). We aimed to systematically evaluate the above association, as well as the potential influence of metformin use in a meta-analysis of cohort studies. Materials and Methods Cohort studies investigating the association between DM and survival outcomes of patients with NHL were included by search of electronic databases that included PubMed, Embase, and Web of Science. A random-effects model was adopted to combine the results. Results Eight cohort studies including 8652 patients with NHL were analyzed. Compared to non-DM patients with NHL, DM was associated with poor overall survival (OS, hazard ratio [HR] = 1.49, 95% confidence interval [CI]: 1.18-1.89, P .10). Conclusions DM is associated with poor survival outcomes in patients with B-cell NHL, which is consistent in patients with DLBCL. Concurrent metformin use in DM patients with NHL may be associated with improved survival outcomes.

The placenta is a highly metabolically active organ fulfilling the bioenergetic and biosynthetic needs to support its own rapid growth and that of the fetus. Placental metabolic dysfunction is a common occurrence in preeclampsia although its causal relationship to the pathophysiology is unclear. At the outset, this may simply be seen as an "engine out of fuel." However, placental metabolism plays a vital role beyond energy production and is linked to physiological and developmental processes. In this review, we discuss the metabolic basis for placental dysfunction and propose that the alterations in energy metabolism may explain many of the placental phenotypes of preeclampsia such as reduced placental and fetal growth, redox imbalance, oxidative stress, altered epigenetic and gene expression profiles, and the functional consequences of these aberrations. We propose that placental metabolic reprogramming reflects the dynamic physiological state allowing the tissue to adapt to developmental changes and respond to preeclampsia stress, whereas the inability to reprogram placental metabolism may result in severe preeclampsia phenotypes. Finally, we discuss common tested and novel therapeutic strategies for treating placental dysfunction in preeclampsia and their impact on placental energy metabolism as possible explanations into their potential benefits or harm.

Background:Oxandrolone is a synthetic testosterone analogue that is widely used among bodybuilders and athletes. However, oxandrolone causes male infertility. Recently, it was found that metformin reduces the risk of infertility associated with diabetes mellitus.Aim:This study aimed to investigate the protective effects of metformin against oxandrolone-induced infertility in male rats.Methods:Rats continuously received one of four treatments (n=7) over 14 days: control DMSO administration, oxandrolone administration, metformin administration, or co-administration of oxandrolone and metformin. Doses were equivalent to those used for human treatment. Subsequently, testicular and blood samples were collected for morphological, biochemical, and histological examination. In addition, gene expression of the testosterone synthesizing enzyme CYP11A1 was analyzed in the testes using RT-PCR.Results:Oxandrolone administration induced male infertility by significantly reducing relative weights of testes by 48%, sperm count by 82%, and serum testosterone levels by 96% (ANOVA, P value < 0.05). In addition, histological examination determined that oxandrolone caused spermatogenic arrest which was associated with 2-fold downregulation of testicular CYP11A1 gene expression. However, co-administration of metformin with oxandrolone significantly ameliorated toxicological alterations induced by oxandrolone exposure (ANOVA, P value < 0.05).Conclusion:Metformin administration protected against oxandrolone-induced infertility in male rats. Further clinical studies are needed to confirm the protective effect of metformin against oxandrolone-induced infertility among athletes.

Advanced age is the main risk factor for the manifestation of late onset neurodegenerative diseases. Metformin, an anti-diabetic drug, was shown to extend longevity and to ameliorate the activity of recognized aging hallmarks. Here, we compared the clinical, pathological and biochemical effects of Metformin to those of Nano-PSO (GranagardTM), a brain targeted anti-oxidant shown by us to delay disease advance in transgenic mice mimicking for genetic Creutzfeldt Jacob disease (CJD) linked to the E200KPrP mutation. We demonstrate that both Metformin and Nano-PSO reduced aging hallmarks activities such as activated AMPK, the main energy sensor of cells as well as Nrf2 and COX IV1, regulators of oxidation and mitochondrial activity. Both compounds reduced inflammation and increased stem cells production, however did not decrease PrPSc accumulation. As opposed to Nano-PSO, Metformin neither delayed clinical disease advance in these mice nor reduced the accumulation of sulfated glycosaminoglycans, a pathological feature of prion disease. We conclude that elevation of anti-aging markers may not be sufficient to delay the fatal advance of genetic CJD.

Background Skeletal muscle atrophy is a severe condition that involves loss of muscle mass and quality. Drug intake can also cause muscle atrophy. Biguanide metformin is the first‐line and most widely prescribed anti‐diabetic drug for patients with type 2 diabetes. The molecular mechanism of metformin in muscle is unclear. Methods Myostatin expression was investigated at the protein and transcript levels after metformin administration. To investigate the pathways associated with myostatin signalling, we used real‐time polymerase chain reaction, immunoblotting, luciferase assay, chromatin immunoprecipitation assay, co‐immunoprecipitation, immunofluorescence, primary culture, and confocal microscopy. Serum analysis, physical performance, and immunohistochemistry were performed using our in vivo model. Results Metformin induced the expression of myostatin, a key molecule that regulates muscle volume and triggers the phosphorylation of AMPK. AMPK alpha2 knockdown in the background of metformin treatment reduced the myostatin expression of C2C12 myotubes (−49.86 ± 12.03%, P 3.12‐fold ± 0.13, P 3.3‐fold, P

Formation of reactive oxygen species has been linked to the development of diabetes complications. Treatment with metformin has been associated with a lower risk of developing diabetes complications, including when used in combination with insulin. Metformin inhibits Complex 1 in isolated mitochondria and thereby decreases the formation of reactive oxygen species. Thus, we post-hoc investigated the effect of metformin in combination with different insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes. Four hundred and fifteen individuals with type 2 diabetes were randomized (1:1) to blinded treatment with metformin (1,000 mg twice daily) versus placebo and to (1:1:1) open-label biphasic insulin, basal-bolus insulin, or basal insulin therapy in a 2 × 3 factorial design. RNA and DNA oxidation were determined at baseline and after 18 months measured as urinary excretions of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), respectively. Urinary excretion of 8-oxoGuo changed by +7.1% (95% CI: 0.5% to 14.0%, P = 0.03) following metformin versus placebo, whereas changes in 8-oxodG were comparable between intervention groups. Biphasic insulin decreased urinary excretion of 8-oxoGuo (within-group: −9.6% (95% CI: −14.4% to −4.4%)) more than basal-bolus insulin (within-group: 5.2% (95% CI: −0.5% to 11.2%)), P = 0.0002 between groups, and basal insulin (within-group: 3.7% (95% CI: −2.0% to 9.7%)), P = 0.0007 between groups. Urinary excretion of 8-oxodG decreased more in the biphasic insulin group (within-group: −9.9% (95% CI: −14.4% to −5.2%)) than basal-bolus insulin (within group effect: −1.2% (95% CI: −6.1% to 3.9%)), P = 0.01 between groups, whereas no difference was observed compared with basal insulin. In conclusion, eighteen months of metformin treatment in addition to different insulin regimens increased RNA oxidation, but not DNA oxidation. Biphasic insulin decreased both RNA and DNA oxidation compared with other insulin regimens.

Background and Objectives : Non-alcoholic fatty liver disease (NAFLD) is associated with inflammation and subsequent increase in cardiovascular risk. Because of its widespread presence and distribution, invasive diagnostic procedures (i.e., liver biopsy) are reserved for a limited number of subjects. With liver ultrasound, Fatty liver index (FLI) and fibrosis-4 (FIB-4) scores non-invasively assess liver steatosis and fibrosis. We aimed to evaluate the changes in inflammatory markers and FLI/FIB-4 scores in non-obese metformin-treated type 2 diabetes patients (T2DM) with NAFLD. Methods: All subjects underwent abdominal ultrasound aiming for NAFLD stratification (grade 1 to 3 according to its severity). Metabolic parameters (morning glycaemia, HbA1C, lipids, liver function tests) and serum inflammatory markers (C-reactive protein, ferritin, and nitric oxide), and FLI/FIB-4 are calculated. Results: FLI score and ultrasound NAFLD grades correlated (p Conclusion: This pilot study suggests that the serum inflammatory markers at the average normal values point to the sufficiency of metformin-single therapy in inflammation control in non-obese T2DM patients with NAFLD.

Metformin is the first-line oral antidiabetic drug that shows multiple pleiotropic effects of anti-inflamation, anti-cancer, anti-aging, anti-microbia, anti-atherosclerosis, and immune modulation. Metformin's effects on men's related health are reviewed here, focusing on reproductive health under subtitles of erectile dysfunction (ED), steroidogenesis and spermatogenesis; and on prostate-related health under subtitles of prostate specific antigen (PSA), prostatitis, benign prostate hyperplasia (BPH), and prostate cancer (PCa). Updated literature suggests a potential role of metformin on arteriogenic ED but controversial and contradictory effects (either protective or harmful) on testicular functions of testosterone synthesis and spermatogenesis. With regards to prostate-related health, metformin use may be associated with lower levels of PSA in humans, but its clinical implications require more research. Although there is a lack of research on metform's effect on prostatitis, it may have potential benefits through its anti-microbial and anti-inflammatory properties. Metformin may reduce the risk of BPH by inhibiting the insulin-like growth factor 1 pathway and some but not all studies suggest a protective role of metformin on the risk of PCa. Many clinical trials are being conducted to investigate the use of metformin as an adjuvant therapy for PCa but results currently available are not conclusive. While some trials suggest a benefit in reducing the metastasis and recurrence of PCa, others do not show any benefit. More research works are warranted to illuminate the potential usefulness of metformin in the promotion of men's health.

Metformin treatment improved ADPKD disease severity in a relevant, slowly progressive ADPKD mouse model that recapitulates a PKD-associated PKD1 mutation. Relative to controls, metformin reduced kidney weight/body weight, cystic index and BUN levels, while improving GFR, blood pressure and anemia. Metformin also reduced key inflammatory and injury markers, along with cell proliferation markers. These findings suggest several beneficial effects of metformin in this ADPKD mouse model, which may help inform new ADPKD therapies in patients.

Sodium-glucose cotransporter 2 inhibitors have been shown to reduce cardiovascular events but are currently not used as the first-line therapy. This study was conducted to evaluate the cost-effectiveness of first-line empagliflozin plus metformin versus metformin monotherapy among Australians with type 2 diabetes mellitus (T2DM) and existing cardiovascular disease (CVD).A Markov model with 1-year cycles and a 5-year time horizon was constructed to simulate the occurrence of recurrent cardiovascular events among Australians aged 50 to 84 years with T2DM and CVD. Efficacy results were derived from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose trial. Costs and utilities were drawn from published sources. The evaluation adopted both health care and societal perspectives, with the latter ascribing the Australian government's "value of statistical life year" (A$213 000) to each year lived by a person. Future outcomes were discounted at 5% annually. Sensitivity analyses were conducted to enhance the robustness of conclusions.Compared with metformin monotherapy, first-line empagliflozin plus metformin reduced overall cardiovascular events by 0.82% and overall deaths by 7.72% over 5 years. There were 0.2 years of life saved per person and 0.16 quality-adjusted life years gained, at a net health care cost of A$4408. These equated to incremental cost-effectiveness ratios of A$22 076 per year of life saved and A$28 244 per quality-adjusted life year gained. The gains in the value of statistical life year equated to A$42 530 per person, meaning that from a societal perspective, the intervention was cost-saving.First-line empagliflozin plus metformin may represent a cost-effective strategy for the management of T2DM and CVD in Australia.

BACKGROUND AND AIMS: This study assesses the influence of demographic, lifestyle, and medication in the association between CRP and mortality in a national sample of adults with diabetes. METHODS AND RESULTS: Cross-sectional study of data from 1999-2010 National Health and Nutrition Examination Survey (unweighted n= 3,952; Weighted n= 19,064,710). Individuals were categorized as having diabetes if told by a provider they had diabetes, were taking insulin or other diabetes medications, or had a glycosylated hemoglobin A1c (HbA1c) ≥ 6.5%. CRP was classified into four categories: normal (1.0 mg/dL). Higher risk for mortality was associated with a very high-risk of CRP (HR=1.88 (95% CI: 1.27 - 2.78), being a current (HR=1.49 (95% CI: 1.10 - 2.01) or former (HR=1.34 (95% CI: 1.03 – 1.73) smoker, and taking insulin (HR=1.60 (95% CI: 1.25 – 2.05), taking anti-hypertensives (HR=1.50 (95% CI: 1.22 – 1.85), and having comorbidities such as cancer (HR=1.32 (95% CI: 1.05 – 1.66) and hepatitis infection (HR=1.76 (95% CI: 1.07 – 2.91), while taking Metformin (HR=0.62 (95% CI: 0.50 – 0.76) had a lower risk of mortality. CONCLUSION: In this sample of adults with diabetes, demographic, lifestyle, and medication factors influenced the association between CRP and mortality. Interventions should focus on these factors to reduce mortality in adults with diabetes.

Background: Obesity-induced inflammation facilitates depression and premenstrual tension syndrome. Hypoxia is a common feature of inflammation. Hypoxia inducible factors adapt cells to low oxygen tension and inflammation. Objectives: We aimed to see how obesity, along with Amiloride, Hydrochlorothiazide, Metformin, calorie restriction, and walking exercise, affected psychosomatic characteristics of premenstrual tension syndrome, during a six-month period.Patients and methods: A prior ethical committee approval and informed patients’ consent were taken. This study was performed in Tanta University, Egypt from May 2019 to December 2019. This study aims at evaluating the effects of obesity-induced inflammatory mediators on psychosomatic effects in women having premenstrual tension syndrome. Effects of combined therapy using (Metformin, Amiloride. Hydrochloride/ Hydrochlorthiazide, caloric restriction, half an hour of walking exercise per day, and Vitazinc capsules) treatment was compared to the same combined therapy including Royal vitamin G treatment (instead of Vitazinc) on alleviating psychosomatic manifestations of premenstrual tension syndrome. Sixty obese women having premenstrual tension syndrome were categorized into younger age group (18-39 years) and older age (40-48 years) versus a non-obese age-matched control group. Body mass index in addition to serum tumour necrosis factor-α (TNF- α), hypoxia-inducible factor-1α (HIF-1α) and receptor activator of nuclear factor- kappa-Β ligand (RANKL) were assessed. Related psychosomatic manifestations of premenstrual tension syndrome (edema, anxiety, and fatigue) were also assessed. Results: Obesity significantly increased serum TNF-α (p < 0.01), HIF-1 α (p < 0.01) and RANKL (p < 0.01). Obesity-induced biochemical effects were higher in older obese women than younger ones. Obesity significantly exaggerated the severity of investigated psychosomatic manifestations (p < 0.001). Both combined therapies (including either Vitazinc or Royal vitamin G) significantly and dramatically decreased the percentage of cases having psychosomatic manifestations (p < 0.001) that was closely related to the decreased serum biochemical parameters. Conclusion: Combined therapy containing Royal vitamin G significantly improved serum biochemical parameters and psychosomatic manifestations better than combined therapy containing Vitazinc.

Aim: Study aims to assess amylase, lipase of patients with Type 2 diabetes under different types of treatments. Materials & methods: Patients’ treatment modalities including insulin, metformin, pioglitazone, sodium-glucose co-transporter-2 inhibitors, insulin secretagogues, dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists were compared. Results: There was no difference in amylase and lipase levels between dipeptidyl peptidase-4 inhibitor users and non-users (p = 0.2, p = 0.3, respectively) and glucagon like peptide-1 analog users and non-users (p = 0.1, p = 0.7, respectively). Patients who use insulin secretagogues had significantly higher amylase, lipase (77.2 ± 39.8 vs 69.5 ± 33.0, p = 0.038 and 47.2 ± 33.2 vs 39.6 ± 26.8, p = 0.01, respectively) and patients on basal insulin had lower amylase levels (69.9 ± 37.7 vs 77.2 ± 33.7, p = 0.014). Conclusion: Incretin-based therapies showed no difference in amylase and lipase levels whereas there was increase with secretagogues and decrease with basal insulin.

Metformin is an important class of oral hypoglycemic agents for type 2 diabetes via inhibiting gluconeogenesis in liver and increasing the sensitivity of receptor to insulin. It also displayed a wide range of therapeutic effects towards many other diseases, including different kinds of cancers, bone disorders, inflammation and even aging and the microbial infections. Despite its widespread clinical applications, administration of metformin in clinic is still restricted due to the relative low bioavailability, short half-life and side effects. To overcome these limitations, various types of nanoparticulate drug delivery systems, including proteins, polymers and inorganic nanoparticles for loading and delivering metformin have been reported. In this review, nanoparticles-based drug delivery systems for delivering metformin were summarized in the first part. The biomedical applications of these nanoparticles-based drug delivery systems were introduced in the following section. Finally, combination therapy based on drug delivery systems for metformin are also discussed. We trust this review article will attract great interest for the scientists from chemistry, materials, biological and medical fields.

Purpose: Although metformin and sildenafil can protect various organs against ischemia/reperfusion (I/R) injuries, their effects and mechanisms of action in bladder I/R injuries remain unknown. This study investigated the effects and mechanisms of action of metformin and sildenafil against bladder I/R insults in rats.Methods: One hundred male Sprague-Dawley rats were randomly divided into 5 groups, each of which contained 20 rats: a sham-operated group, a bladder I/R group, and bladder I/R groups treated with metformin, sildenafil, or both agents. Ischemia was induced by clamping the bilateral common iliac arteries with atraumatic vascular clamps for 2 hours, followed by reperfusion for 7 days. During this period, rats were injected once daily with 4-mg/kg metformin and/or 1-mg/kg sildenafil.Results: I/R injuries induced increased malondialdehyde levels and myeloperoxidase activity and decreased superoxide dismutase activity. These changes were attenuated by treatment with metformin and/or sildenafil. The I/R group had significantly higher Jun N-terminal kinase, p38 mitogen-activated protein kinase (MAPK), Bax, caspase-3, and nuclear factor-kappa B (NF-κB) levels, and lower extracellular signal-regulated kinase, and Bcl-2 levels in the bladder than the sham-operated group; these changes were significantly ameliorated by metformin and/or sildenafil treatment. No differences in the levels of these markers were observed between rats coadministered metformin and sildenafil and those treated with either agent alone.Conclusions: Metformin and sildenafil protected the rat bladder against I/R injuries. This effect may have been due to the inhibition of reactive oxygen species production through MAPK, Bax, and Bcl-2 activation, and the restoration of inflammation through NF-κB inhibition. However, the combination of metformin and sildenafil was not more effective than either agent alone.

Background Metformin has recently been shown not to increase the risk of lactic acidosis in patients with chronic kidney disease (CKD). Thus, the criteria for metformin use in this population has expanded. However, the relationship between metformin use and clinical outcomes in CKD remains controversial. Methods This study considered data from 97,713 diabetes patients with an estimated glomerular filtration rate of

Background: Intracerebral hemorrhage (ICH) is a major cause of death and disability globally. As a type of secondary injury after ICH, treatment for cell death can promote the recovery of neurological function. Methods: Among all the cell death, neuronal necroptosis has recently been demonstrated of significance in the pathogenesis of ICH. However, the administration of drugs against necroptosis has many limitations. Results: In the present study, we found that metformin, a first-line medication for the treatment of type 2 diabetes, can effectively inhibit neuronal necroptosis after ICH by activating the AMPK related pathway, thereby significantly improving neurological function scores and reducing brain edema. Conclusion: These results will provide a new perspective for future research in necroptosis.

BACKGROUND AND AIMS In patients with nonalcoholic fatty liver disease (NAFLD), those with type 2 diabetes (DM) have a high risk of progression to hepatocellular carcinoma (HCC). However, the determinants of HCC risk in these patients remain unclear. APPROACH AND RESULTS We assembled a retrospective cohort of patients with NAFLD and DM diagnosed at 130 facilities in the Veterans Administration between 1/1/2004 and 12/31/2008. We followed patients from the date of NAFLD diagnosis to HCC, death or 12/31/2018. We used landmark Cox proportional hazards models to determine the effects of anti-DM medications (metformin, insulin, sulfonylureas) and glycemic control (% of follow up time with HbA1c < 7%) on the risk of HCC, while adjusting for demographics and other metabolic traits (hypertension, obesity, dyslipidemia). We identified 85,963 patients with NAFLD and DM. In total, 524 patients developed HCC during a mean of 10.3 years of follow up. Most common treatments were metformin monotherapy (19.7%), metformin-sulfonylureas (19.6%), insulin (9.3%), and sulfonylureas monotherapy (13.6%). Compared to no medication, metformin was associated with 20% lower risk of HCC (HR 0.80, 95% CI 0.93-0.98). Insulin had no effect on HCC risk (HR 1.02, 95% CI 0.85-1.22, p=0.85). Insulin in combination with other oral medications was associated with a 1.6-1.7-fold higher risk of HCC. Adequate glycemic control was associated with a 31% lower risk of HCC (HR 0.69, 95% CI 0.62-0.78). CONCLUSIONS In this large cohort of patients with NAFLD and DM, use of metformin was associated with a reduced risk of HCC while use of combination therapy was associated with increased risk. Glycemic control can serve as a biomarker for HCC risk stratification in patients with NAFLD and diabetes.

Introduction. Recently, many studies have been devoted to the study of type 2 diabetes mellitus (DM2) worldwide. In most countries of the world, the increase in the prevalence of DM2 among children and adolescents is accompanied by an increase in childhood obesity. The presence of obesity or overweight in children can complicate the diagnosis of various types of DM. Detection and treatment of DM2 is extremely important for the society due to the wide range of severe diabetes complications.The aim of this work was to analyze the frequency of DM2 according to the Register of patients with DM, and to determine the state of glycemic control in children with DM2. Materials and methods. An analysis of glycemic control in children with DM2 who received various treatment regimens: with diet and lifestyle modifications, or with additional oral hypoglycemic agents (metformin monotherapy, or combination with insulin therapy). The glycemic control was assessed by measurement of glycated hemoglobin (HbA1c) level. Results. According to the data Register in Ukraine, the prevalence of DM among children has a tendency to rise — from 8.6 per 10 thousand children in 2005, to 13.14 — in 2019 year. The prevalence of DM2 in 2019 was 0.47 % of all cases of DM, and its prevalence contained 0.062 per 10 thousand children under 19 years of age with significant differences in the frequency of its diagnosis in different regions of Ukraine. We analyzed the state of glycemic control in children with DM2 aged from 9 up to 19 years old (Me 16.2 [15.5; 18.0]), with a disease duration 0.5—12 years (Me 4.5 [1.0] ; 7.5]). The age of diagnosis of DM2 was 2-17 years old (Me 11.7 [8.5; 15.0]), and 91.3 % of patients had obesity. Diet and lifestyle modifications were used in 34.8 % of patients, metformin monotherapy in 52.2 %, and metformin and insulin combination therapy in 13 % of patients. HbA1c values ​​ranged from 5.0 to 11.4 % (Me 7.2 % [5,8; 8,0]). The proportion of children who had ideal or optimal glycemic control (HbA1c 7.0—7.5 %) was 52.2 %, suboptimal (HbA1c 7.6—9.0 %) — 39.1 %, high-risk glycemic control (HbA1c> 9.1 %) — 8.7 % of children. The most unsatisfactory HbA1c levels ​​were registered in children who received metformin in combination with insulin (Me 10.6 % [10,15; 11,4]). Chronic complications of DM2 have not been reported.Conclusions. We found a low prevalence of DM2 among the pediatric population in Ukraine, more likely due to the low quality of its detection among children diagnosed with DM, as well as among children among high risk groups. Most children with DM 2 were obese. The majority of patients with DM2 (52.2 %) received metformin monotherapy, more than a third did not receive oral hypoglycemic agents. In most children with DM2 (52,2 %), the state of glycemic control corresponded to the optimal (

Метою дослідження було вивчення впливу препарату метформін на рівень деяких гормонів жирової тканини та медіаторів генералізованого неспецифічного запалення при цукровому діабеті 2-го типу. Обстежено 38 пацієнтів з уперше виявленим цукровим діабетом 2-го типу перед початком і після 12 місяців цукрознижувальної монотерапії Глюкофажем. Отримані результати свідчать, що нормалізація показників вуглеводного обміну, зниження маси тіла пацієнтів на тлі проведеного лікування спричинено не лише прямим впливом метформіну на поліпшення поглинання глюкози периферичними тканинами, а і його здатністю модулювати секрецію адипоцитокінів.

З метою вивчення впливу цукрознижувальної терапії за допомогою комбінації глімепіриду й метформіну SR упродовж 12 тижнів на показники вуглеводного й ліпідного обміну, динаміку рівня адипокінів у плазмі крові та показники жорсткості артеріальної стінки великих артерій (аорти та її гілок) спостерігали 30 пацієнтів (з них 18 — жінки) з цукровим діабетом 2-го типу віком 60,10 ± 1,08 року із серед-ньою тривалістю основного захворювання 5,7 ± 0,9 року. Результати. Порівняно з початковими значеннями відзначено покращення показників вуглеводного обміну. Так, рівень HbA1c знизився на 1,7 % (р < 0,001), глікемії натще — на 22 % (р < 0,001), постпрандіальної глікемії — на 44 % (р < 0,001). Крім того, на тлі терапії спостерігалося покращення ліпідного обміну: зниження загального холестерину на 13,2 % (р < 0,01), холестерину ліпопротеїнів низької щільності — на 19,3 % (р < 0,01), тригліцеридів — на 30,6 % (р < 0,05). Спостерігалися зміни рівня адипокінів у плазмі крові: зниження рівня адипонектину з 5,98 ± 0,52 мг/мл до 4,45 ± 0,29 мг/мл (р < 0,01), а також тенденція до збільшення рівня лептину в плазмі крові з 14,6 ± 2,3 нг/мл до 18,12 ± 2,90 нг/мл (р > 0,05). Зміни швидкості пульсової хвилі в аорті та аортального індексу аугментації були статистично незначущими (р > 0,05). Зміни антропометричних показників (ваги, індексу маси тіла, окружності талії і стегон), а також загальної кількості жирової тканини, визначеної методом імпедансометрії, були статистично незначущими (р > 0,05).Висновки. Комбінована цукрознижувальна терапія глімепіридом і метформіном SR упродовж 12 тижнів призвела до статистично значущого покращення вуглеводного та ліпідного обміну, не впливала на антропометричні показники й загальну кількість жирової тканини, запобігала прогресуванню артеріосклерозу великих судин за даними показників жорсткості артеріальної стінки.

Комбинация метформина (МФ) (2 г в сутки) и пиоглитазона (ПГ) (30 мг в сутки) у 57 больных ишемической болезнью сердца (ИБС) и сахарным диабетом 2-го типа (СД-2) снижает показатели хронического воспаления (ХВ) низкой интенсивности: уровень фактора некроза опухоли альфа в крови — в 5 раз через 6 месяцев, интерлейкина-6 — в четыре раза соответственно по сравнению с исходным уровнем. Эта комбинация является безопасной, оказывает позитивный клинический эффект в отношении ИБС и более эффективно нормализует уровень гликированного гемоглобина у больных по сравнению с комбинацией МФ и препарата сульфонилмочевины. Поскольку ХВ является фактором, инициирующим развитие атеросклероза, ИБС, артериальной гипертензии и СД-2, комбинацию МФ и ПГ следует считать эффективным и безопасным средством профилактики и лечения этих заболеваний, что подтверждается анализом современной научной литературы.

Метформін — препарат першої лінії для лікування цукрового діабету (ЦД) 2-го типу, застосування якого зменшує прогресування порушень вуглеводного обміну і сприяє зниженню показників летальності. Прогресуючий перебіг ЦД 2-го типу призводить до того, що пацієнтам, початкова терапія яких включала лише метформін, зрештою потрібне покрокове додавання інших цукрознижувальних препаратів для досягнення і підтримання глікемічного контролю. В огляді літератури аналізуються різні підходи до покрокової індивідуальної інтенсифікації терапії ЦД 2-го типу. Найбільш популярною і вивченою комбінацією, спрямованою на обидва дефекти, що визначають розвиток метаболічних порушень при ЦД 2-го типу (відносний дефіцит інсуліну та інсулінорезистентність), залишається комбінація метформіну з препаратами сульфонілсечовини. Глімепірид має унікальне поєднання інсуліносекретогенних («ощадлива» стимуляція) та інсуліносенситайзерних властивостей при нейтральному ефекті на масу тіла і низькому ризику гіпоглікемій. Тому глімепірид на сьогодні є кращим вибором у хворих на ЦД 2-го типу за наявності кардіоваскулярного ризику порівняно з іншими сульфонілсечовинними препаратами.

У статті наведені результати дослідження впливу інгібіторів α-глюкозидази на масу тіла та основні показники вуглеводного обміну. Автори відзначають позитивний ефект препаратів цієї групи на всі компоненти метаболічного синдрому, безпеку для організму, відсутність серйозних протипоказань і низький рівень розвитку гіпоглікемій. Воглібоз як представник групи інгібіторів α-глюкозидази може ефективно використовуватися в комбінації з метформіном, а також у поєднанні з інсулінотерапією.

Обзор посвящен обоснованию перспективности применения комбинированной терапии сахарного диабета 2-го типа пероральными антигипергликемическими препаратами с различным механизмом действия (метформин + производные сульфонилмочевины) и инсулином. Второй пероральный препарат целесообразно добавлять, когда средние дозы первого препарата не обеспечивают полной эффективности; при этом, поскольку дозы антигипергликемических неинсулиновых препаратов обычно не увеличивают до максимальных, побочные эффекты уменьшаются. Кроме того, сочетание гетерогенных антидиабетических эффектов в пределах и за пределами гликемического контроля, характерных для комбинации бигуанида (метформин), производного сульфонилмочевины (глимепирид) и инсулина, таких как снижение гипоадипонектинемии, дислипидемии, оксидативного стресса, воспаления, дисфункции сосудистых эндотелиальных клеток, устранение «гипергликемической памяти», сохранение феномена ишемического прекондиционирования, повышение выживаемости панкреатических β-клеток и др., предоставляет дополнительные преимущества в лечении сахарного диабета 2-го типа, а также в профилактике и терапии сердечно-сосудистых осложнений.

To investigate the protective effects of metformin on the diabetic mice with cognitive impairment induced by the combination of streptozotocin (STZ) and isoflurane anesthesia. The isoflurane-anesthetized cognitive impairment model mice were established and then observed via behavioral tests and histopathological examination. Then these model mice were randomly assigned to three groups, which received the PBS, low and high doses of metformin, respectively. The body weight, food and water consumption of model mice were measured every other day. The mechanisms of metformin on ameliorating the cognitive dysfunction were further investigated by histomorphological, biochemical and Western blot analysis. After 14-days treatment of metformin, the diabetic symptoms in STZ-induced diabetic mice were significantly alleviated. Metformin could restore the isoflurane- and STZ-induced hippocampal tissue damage, cognitive and memory impairment in exposed space via improving the oxidative stress, upregulating the contents of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in the hippocampus tissues of diabetic mice. Furthermore, chronic treatment of metformin significantly down-regulated the expression of AGEs, RAGE, pNF-κB, iNOS, and COX-2. In conclusion, metformin can improve the isoflurane- and STZ-induced cognitive impairment in diabetic mice via improving oxidative stress and inhibiting the AGEs/RAGE/NF-κB signaling pathway.

Background: DPP-4 inhibitors (DPP-4i) and sulphonylureas remain the most widely prescribed add-on treatments after metformin. However, there is limited evidence from clinical practice comparing major adverse cardiovascular events (MACE) in patients prescribed these treatments, particularly among those without prior history of MACE and from vulnerable population.Methods: Using electronic health records from the UK primary care, we undertook a retrospective cohort study with people diagnosed type-2 diabetes mellitus, comparing incidence of MACE (myocardial infarction, stroke, major cardiovascular surgery, unstable angina) and all-cause mortality among those prescribed DPP-4i versus sulphonylureas as add-on to metformin. We stratified analysis by history of MACE, age, social deprivation and comorbidities and adjusted for HbA1c, weight, smoking-status, comorbidities and medications.Results: We identified 17,570 patients prescribed sulphonylureas and 6,267 prescribed DPP-4i between 2008-2017. Of these, 16.3% had pre-existing MACE. Primary incidence of MACE was similar in patients prescribed DPP-4i and sulphonylureas (10.3 vs 8.5 events per 1000 person-years; adjusted Hazard Ratio (adjHR): 0.94; 95%CI 0.80–1.14). For those with pre-existing MACE, rates for recurrence were higher, but similar between the two groups (21.8 vs 17.2 events per 1000 person-years; adjHR: 0.93; 95%CI 0.69–1.24). For those aged over 75 and with BMI less than 25kg/m2 there was a protective effect for DPP-I, warranting further investigation.Conclusions: Patients initiating a DPP-4i had similar risk of cardiovascular outcomes to those initiating a sulphonylurea. This indicates the choice should be based on safety and cost, not cardiovascular prognosis, when deciding between a DPP-4i or sulphonylurea as add-on to metformin.

Efforts to determine whether metformin can increase the effectiveness of neoadjuvant chemoradiotherapy in rectal cancer have increased in recent years. However, retrospective studies have yielded inconclusive results. Objectives The aim of this study was to compare oncological outcomes and survival after neoadjuvant chemoradiotherapy in patients with rectal cancer taking metformin versus in those not taking metformin. Methods This study analyzed 423 consecutive patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy and curative surgery between January 2010 and May 2020; of these, 59 were taking metformin and 364 were not taking metformin. Results Patients taking metformin had a lower proportion of tumor regression (6.8% versus 22.0%, P = 0.012) as well as a lower proportion of patients achieving a pathological complete response (6.8% versus 20.6%, P = 0.011). In the multivariate analysis, independent predictors of pathologic complete response were not taking metformin (OR: 5.26, 95% CI: 1.12-24.85, P= 0.035) and cT2 stage (OR: 3.49, 95% CI: 1.10-11.07, P= 0.034); the interval was also an independent predictor of tumor regression (OR: 1.78, 95% CI: 1.06-2.96, P= 0.028). No differences were observed in survival between groups. Conclusion Metformin was not associated with better tumor responses or survival after neoadjuvant treatment.

The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. Here, we show GP73, a Golgi protein upregulated in livers from patients with a variety of liver diseases, exhibits Rab GTPase-activating protein (GAP) activity regulating ApoB export. Upon regular-diet feeding, liver-GP73-high mice display non-obese NAFLD phenotype, characterized by reduced body weight, intrahepatic lipid accumulation, and gradual insulin resistance development, none of which can be recapitulated in liver-GAP inactive GP73-high mice. Common and specific gene expression signatures associated with GP73-induced non-obese NAFLD and high-fat diet (HFD)-induced obese NAFLD are revealed. Notably, metformin inactivates the GAP activity of GP73 and alleviates GP73-induced non-obese NAFLD. GP73 is pathologically elevated in NAFLD individuals without obesity, and GP73 blockade improves whole-body metabolism in non-obese NAFLD mouse model. These findings reveal a pathophysiological role of GP73 in triggering non-obese NAFLD and may offer an opportunity for clinical intervention., Dysregulation of lipid metabolism and transport contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here the authors identify GP73 as a TBC-domain Rab GTPase-activating protein that regulates very low-density lipoprotein export and promotes NAFLD development in mice.

Background: Two distinct subtypes of treatment-resistant schizophrenia (TRS) have been recently reported, including early-treatment resistance (E-TR) as the dominant subtype and late-treatment resistance (L-TR). However, the response rate to clozapine, incidence of clozapine-induced prediabetes/diabetes, and effects of metformin at preventing clozapine-induced prediabetes/diabetes in patients with schizophrenia E-TR subtype need investigating. To assess clozapine-induced metformin-resistant prediabetes/diabetes and its correlation with clinical efficacy in schizophrenia E-TR subtype. Methods: This prospective cohort study enrolled 230 patients with schizophrenia E-TR subtype from Tianjin Kangtai Hospital between January 2015 and December 2020.The patients were treated with adequate doses of clozapine for 16 weeks, during which patients with prediabetes/diabetes were assigned to receive add-on metformin. Incidence of clozapine-induced prediabetes/diabetes and metformin-resistant prediabetes/diabetes and the efficacy of clozapine as assessed by the Positive and Negative Syndrome Scale (PANSS) score. Findings: Clozapine-induced prediabetes/diabetes occurred in 176 patients (170 prediabetes and 6 diabetes), with 76.52% incidence. The blood sugar of 43 (24.43%) patients was controlled with metformin. Despite add-on metformin, 47.06% (74/170) of patients with clozapine-induced prediabetes progressed to diabetes. In total, the incidence of clozapine-induced metformin-resistant prediabetes/diabetes was 75.57% (133/176). On completion of 16-week clozapine treatment, 16.52% (38/230) patients showed clinical improvement with PANSS scores of ≥50% declining. Furthermore, clozapine-induced prediabetes/diabetes was significantly correlated with the poor clinical efficacy of clozapine for schizophrenia E-TR subtype. In comparison with patients that did not have clozapine-induced prediabetes/diabetes, clinical efficacy was significantly lower in patients with clozapine-induced prediabetes/diabetes. Of note, the lowest clinical efficacy detected in patients with clozapine-induced diabetes [odds ratio (OR) of 0.18; 95% confidence interval (CI), 0.07–0.44]. Interpretation: The incidence of clozapine-induced metformin-resistant prediabetes/diabetes was considerably high in the schizophrenia E-TR subtype. Clozapine-induced metformin-resistant prediabetes/diabetes represents an independent risk factor that adversely affects the clinical efficacy of clozapine for the schizophrenia E-TR subtype. This study provided new evidence for re-evaluating the use of clozapine for TRS, especially E-TR subtype, and the use of metformin for the glycemic control of clozapine-induced prediabetes/diabetes. Funding: This study was supported by the National Natural Science Foundation of China (81871052 and 81571319). Declaration of Interests: All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and there is no conflict of interest to disclose. Ethics Approval Statement: The study protocol was reviewed and approved by the Ethic Committee of Tianjin Kangtai Hospital (Tianjin, China).

Background: Is insulin initiation linked to increasing body mass index (BMI) in all patients with type-2-diabetes (T2D)? To determine distinct longitudinal patterns of BMI change over time. Materials and Methods: 5057 patients with T2D (55% males, median BMI [IQR]: 30.0 [26.9-33.3] kg/m2) aged ≥40 years at diabetes diagnosis and with ≥2 years of follow-up after insulin initiation irrespective of previous or concurrent use of metformin/dipeptidyl peptidase-4-inhibitor from the multicenter prospective diabetes registry DPV were studied. To identify subgroups following a similar pattern of BMI change after insulin initiation, longitudinal group-based trajectory modeling was applied. Multinomial logistic regression was then used to analyze covariates associated with group membership. Results: Three heterogeneous groups with either relevant BMI increase (delta-BMI: +4.0 kg/m2 after 2 years; 12% of patients); slight BMI increase (+0.4 kg/m2; 80%); or BMI decrease (-3.2 kg/m2; 8%) were identified. Patients with older age [OR (95% CI): 1.37 (1.11-1.69)] and obesity [2.05 (1.65-2.55)] before insulin start were more often in the BMI decreasing group, and less often in the BMI increasing class [0.80 (0.67-0.95); 0.82 (0.69-0.98)]. A worse HbA1c both at insulin start and during follow-up [1.90 (1.60-2.26); 1.17 (1.07-1.27)], a higher insulin dose [1.67 (1.33-2.10)], and severe hypoglycemic events [2.38 (1.60-3.53)] after insulin initiation were all linked with higher odds of belonging to the BMI increasing trajectory. Conclusions: Patient heterogeneity with respect to weight gain after initiation of insulin therapy in adult T2D was detected by an objective computer algorithm. Older people with obesity should not defer from insulin use due to fear of weight gain.

Objectives To assess the cost-effectiveness and cost utility of sitagliptin/metformin for the treatment of type 2 diabetes mellitus compared to those of glibenclamide/metformin in a semiprivate hospital and to compare the cost-effectiveness and cost utility of sitagliptin/metformin in a semiprivate hospital to those in the public health system (PHS) of Ecuador in 2019. Methods A cost-effectiveness study considering the probability of cardiovascular death as the outcome and quality-adjusted life-year as a measure of utility, estimating direct medical costs in US dollars by a model case from the perspective of the third payer. The results will be presented as an incremental cost-effectiveness ratio. One-way and 2-way sensitivity analyses with tornado diagrams were performed. Results Direct medical costs were lower at the hospital than from the PHS in Ecuador. Considering the drugs metformin/sitagliptin, the total cost was $35.69 less in the hospital ($880.38) than from the comparator ($916.07). The highest percentage of direct medical costs corresponded to drugs (between 63.94% and 84.65%). An ICER of –$19 131.61 was obtained at the Hospital Un Canto a la Vida and –$1621.85 at PHS. In addition, the cost per quality-adjusted life-year earned was $611.11. Sensitivity analysis showed that the probability of drug use and the relative risk of cardiovascular death associated with such prescription were parameters that most affected the model. Conclusions The combination therapy metformin/sitagliptin compared to metformin/glibenclamide was shown not to be cost-effective in the Hospital Un Canto a la Vida, and highly cost-effective in the PHS.

Metformin, a commonly used, well-tolerated treatment for type 2 diabetes, is being deployed in clinical trials to ameliorate aging in older non-diabetic humans. Concerningly, some experiments in model organisms have suggested that metformin use at old ages shortens lifespan and is toxic to mitochondria. The demonstrated safety of metformin therapy in humans and the conflicting data from model organisms compelled us to test the hypothesis that metformin treatment would be toxic to older rats. To define an effective dose in 30-month-old hybrid rats, we evaluated two doses of metformin (0.1%, 0.75% of the diet) and treated the rats for four months. Body mass decreased at the 0.75% dose. Neither dose affected mortality between 30- and 34-months of age. We assessed mitochondrial integrity by measuring mitochondrial DNA copy number and deletion mutation frequency, and mitochondrial respiration in skeletal muscle and the heart. In skeletal muscle, we observed no effect of metformin on quadriceps mass, mtDNA copy number, or deletion frequency. In the heart, metformin-treated rats had higher mtDNA copy number, lower cardiac mass, with no change in mtDNA deletion frequency. Metformin treatment resulted in lower mitochondrial Complex I-dependent respiration in the heart. We found that, in old rats, metformin did not compromise mitochondrial DNA integrity, did not affect mortality, and may have cardiac benefits. These data provide some reassurance that a metformin intervention in aged mammals is not toxic at appropriate doses.

Metformin is an oral hypoglycemic drug widely used in the management of type 2 diabetes mellitus. We have recently demonstrated that metformin exhibits activity in models of nociceptive and neuropathic pain. However, little is known about its effects in experimental models of inflammation and inflammatory pain. Thus, the present study aimed to evaluate the activity of metformin in experimental models of inflammation and inflammatory pain in mice, as well as the underlying mechanisms. Previous (1 h) per os (p.o.) administration of metformin (250, 500 or 1000 mg/kg) inhibited the mechanical allodynia and paw edema induced by intraplantar (i.pl.) injection of carrageenan (600 μg) and also the pleurisy induced by this stimulus (200 μg, intrapleural). In the model of mechanical allodynia and paw edema induced by carrageenan, metformin also exhibited activity when administered after (1 h) the inflammatory stimulus. Metformin (1000 mg/kg) reduced the production of tumor necrosis factor-α induced by i.pl. injection of carrageenan. Metformin antiallodynic effect was not affected by previous administration of naltrexone (5 or 10 mg/kg, intraperitoneal) or cyproheptadine (5 or 10 mg/kg, p.o). However, this effect was abolished by previous administration of glibenclamide (20 or 40 mg/kg, p.o). In conclusion, the results demonstrate the activity of metformin in models of inflammation and inflammatory pain. In addition, the results indicate that the activity of metformin may be mediated by activation of ATP-sensitive potassium channels and reduction of production of inflammatory mediators. Altogether, these results stimulate the conduction of studies aiming to evaluate whether metformin may be repositioned in the treatment of patients with painful and inflammatory disorders.

We assessed the glycaemic durability with early combination (EC; vildagliptin+metformin [MET], n=22) versus MET monotherapy (n=17), among newly-diagnosed type 2 diabetes mellitus (T2DM) enrolled (between 2012 and 2014) in the VERIFY study from Korea (n=39). Primary endpoint was time to initial treatment failure (TF) (glycosylated hemoglobin [HbA1c] ≥7.0% at two consecutive scheduled visits after randomization [end of period 1]). Time to second TF was assessed when both groups were receiving and failing on the combination (end of period 2). With EC the risk of initial TF significantly reduced by 78% compared to MET (n=3 [15%] vs. n=10 [58.7%], P=0.0228). No secondary TF occurred in EC group versus five patients (29.4%) in MET. Patients receiving EC treatment achieved consistently lower HbA1c levels. Both treatment approaches were well tolerated with no hypoglycaemic events. In Korean patients with newly diagnosed T2DM, EC treatment significantly and consistently improved the long-term glycaemic durability as compared with MET.

Introduction Although metformin is recommended as a first-line treatment for patients with type 2 diabetes (T2D) in Western countries, no specific treatment is recommended in Japan, and various agents are used. Metformin has long been used at low doses in Japan, and information regarding its effect at the maximum maintenance dose is lacking. Here, we compared the efficacy and safety of metformin at 1500 mg/day with those of the other oral anti-diabetic drugs (OADs) approved in Japan. Methods Randomized controlled trials comparing a change in hemoglobin A1c (HbA1c) from baseline at 12 weeks or later (ΔHbA1c) among OADs (including placebo) as a first-line treatment in adult patients with T2D were selected by systematic review with comprehensive searching of CENTRAL, MEDLINE, Ichushi Web, and EMBASE and manual searching of clinical trial registries. The ΔHbA1c and incidence of hypoglycemia were compared among OAD treatments using Bayesian network meta-analysis (NMA). The relative risk (RR) of the incidence of hypoglycemia was determined relative to that of placebo. Results Forty-six randomized controlled trials were identified in the systematic review, and 37 studies, comprising 38 different types of treatments, including placebos, were selected for the NMA of ΔHbA1c. Compared with metformin 1500 mg/day, 20 OAD treatments were significantly less effective in reducing HbA1c from baseline (differences from metformin 1500 mg/day: 0.40–0.96%). Two treatments (glimepiride 2 mg/day and pioglitazone 45 mg/day) showed greater mean reductions in HbA1c from baseline than metformin 1500 mg/day (− 0.38% and − 0.03%), although these differences were not significant. Regarding the incidence of hypoglycemia, only pioglitazone 30 mg/day among 31 treatments showed a lower RR (

The safety windows and toxicity of clinically available known drugs allow drug repurposing to be a popular treatment strategy for several diseases, including cancers. Several common drugs, e.g., metformin, statin, and aspirin are on clinical trials for repurposing in oncology treatment. Most of repurposed drugs, however, cannot be used as single agents and some do not exert any clinically significant effects. The limitations and possible biases from observational studies and preclinical models to repurpose these drugs are debatable. In this article, the limitations and probability of using metformin, one of the most repurposed drugs for cancer treatment and in oncological practice, are discussed.

OBJECTIVE Our objective was to evaluate the pharmacokinetics and bioequivalence of test and reference (JANUMET®) formulations of sitagliptin phosphate/metformin hydrochloride tablets at a single dose of 50 mg/850 mg. METHODS The study was a randomized, open-label, two-period, double-crossover trial. Volunteers under fasting (n = 24) and fed (n = 24) conditions were given a single oral dose of test or reference formulations of sitagliptin phosphate/metformin hydrochloride tablets 50 mg/850 mg. We used the liquid chromatography tandem mass spectrometry method to determine the concentrations of sitagliptin and metformin in the plasma of subjects. Pharmacokinetic metrics were calculated using the WinNonlin 7.0 program, and bioequivalence was evaluated using SAS 9.4. RESULTS Under the fasting condition, the 90% confidence intervals (CIs) of geometric mean ratio for maximum plasma drug concentration (Cmax), area under the plasma concentration-time curve from time zero to time t (AUC0-t), and AUC from time zero to infinity (AUC0-∞) of sitagliptin between the test and reference groups were 101.70-120.62%, 99.81-105.61%, and 100.27-106.12%, respectively; for metformin, they were 90.39-111.48%, 94.76-109.12%, and 95.76-110.38%, respectively. Under the fed condition, they were 102.12-117.31%, 100.80-107.81%, and 100.82-107.78%, respectively, for sitagliptin and 95.53-105.22%, 92.76-103.07%, and 93.40-104.14%, respectively, for metformin. Both were generally well-tolerated. CONCLUSION The two formulations of sitagliptin phosphate/metformin hydrochloride tablets were bioequivalent under fasting and fed conditions in healthy Chinese subjects.