Current type 2 diabetes guidelines: Individualized treatment and how to make the most of metformin.

Evidence-based guidelines provide the premise for the delivery of quality care to preserve health and prevent disabilities and premature death. The systematic gathering of observational, mechanistic and experimental data contributes to the hierarchy of evidence used to guide clinical practice. In the field of diabetes, metformin was discovered more than 100 years ago, and with 60 years of clinical use, it has stood the test of time regarding its value in the prevention and management of type 2 diabetes. Although some guidelines have challenged the role of metformin as the first-line glucose-lowering drug, it is important to point out that the cardiovascular-renal protective effects of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists were gathered from patients with type 2 diabetes, the majority of whom were treated with metformin. Most national, regional and international guidelines recommend metformin as a foundation therapy with emphasis on avoidance of therapeutic inertia and early attainment of multiple treatment goals. Moreover, real-world evidence has confirmed the glucose-lowering and cardiovascular-renal benefits of metformin accompanied by an extremely low risk of lactic acidosis. In patients with type 2 diabetes and advanced chronic kidney disease (estimated glomerular filtration rate 15-30 mL/min/1.73m2), metformin discontinuation was associated with an increased risk of cardiovascular-renal events compared with metformin persistence. Meanwhile, it is understood that microbiota, nutrients and metformin can interact through the gut-brain-kidney axis to modulate homeostasis of bioactive molecules, systemic inflammation and energy metabolism. While these biological changes contribute to the multisystem effects of metformin, they may also explain the gastrointestinal side effects and vitamin B12 deficiency associated with metformin intolerance. By understanding the interactions between metformin, foods and microbiota, healthcare professionals are in a better position to optimize the use of metformin and mitigate potential side effects. The United Kingdom Prospective Diabetes Study and the Da Qing Diabetes Prevention Program commenced 40 years ago provided the first evidence that type 2 diabetes is preventable and treatable. To drive real-world impact from this evidence, payors, practitioners and planners need to co-design and implement an integrated, data-driven, metformin-based programme to detect people with undiagnosed diabetes and prediabetes (intermediate hyperglycaemia), notably impaired glucose tolerance, for early intervention. The systematic data collection will create real-world evidence to bring out the best of metformin and make healthcare sustainable, affordable and accessible.

Metformin modifies plasma microbial-derived extracellular vesicles in polycystic ovary syndrome with insulin resistance.

INTRODUCTION: This study investigated changes in plasma microbial-derived extracellular vesicles (EVs) in patients with polycystic ovary syndrome and insulin resistance (PCOS-IR) before and after metformin treatment, and aimed to identify bacterial taxa within EVs that were biologically and statistically significant for diagnosis and treatment. METHODS: The case-control study was conducted at Xiamen Chang Gung Hospital, Hua Qiao University. Plasma samples were collected from five PCOS-IR patients of childbearing age before and after 3 months of metformin treatment, and the samples were sequenced. The diversity and taxonomic composition of different microbial communities were analyzed through full-length 16 S glycosomal RNA gene sequencing. RESULTS: After metformin treatment, fasting plasma glucose levels and IR degree of PCOS-IR patients were significantly improved. The 16 S analysis of plasma EVs from metformin-treated patients showed higher microbial diversity. There were significant differences in EVs derived from some environmental bacteria before and after metformin treatment. Notably, Streptococcus salivarius was more abundant in the metformin-treated group, suggesting it may be a potential probiotic. DISCUSSION: The study demonstrated changes in the microbial composition of plasma EVs before and after metformin treatment. The findings may offer new insights into the pathogenesis of PCOS-IR and provide new avenues for research.

Bridging the gap: exploring the causal relationship between metformin and tumors.

Objective: Numerous studies have reported that metformin can reduce the risk of tumor development. However, some of the results of these studies are conflicting, necessitating a more reliable evaluation. Methods: We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) of tumors to explore the causal relationship between metformin and tumors. Two cohorts of patients taking metformin were obtained from the UK Biobank. Complete phenotype data of the tumors were obtained from FinnGen_R10. We elucidated the causal relationship using a two-sample Mendelian randomization (MR) analysis. More importantly, we conducted a meta-analysis to ensure relatively unbiased results. In the MR analysis, we used the inverse-variance weighted (IVW) method as the main outcome indicator. Subsequently, two cohorts were integrated for the meta-analysis. Finally, we investigated the mechanisms through mediational MR analysis. Results: MR analysis revealed that metformin might have a causal relationship with 13 tumor-associated phenotypes in the training cohort. Four phenotypes were validated in the testing cohort. In the training and testing cohorts, metformin exhibited a protective effect against brain meningiomas and malignant neoplasms of the breast (HER-positive), oral cavity, tonsils, and the base of the tongue. Intriguingly, after integrating the results of the two cohorts for the meta-analysis, 12 results were statistically significant. Mediational MR analysis suggested that the effects of metformin on brain meningiomas may be weakened by the presence of the family Oxalobacteraceae. Conclusion: Metformin exhibits potential preventive and therapeutic effects on four types of tumors: brain meningioma, malignant neoplasms of the breast (HER-positive), oral cavity and tonsils, and the base of the tongue. Large randomized controlled trials are required to confirm these findings.

Preadmission metformin use increased the incidence of hyperlactatemia at admission and 30-day in-hospital mortality among T2D patients with heart disease at high risk of hypoxia.

BACKGROUND: Surprisingly, despite the high prevalence of metformin use in type 2 diabetes (T2D) patients with heart disease, limited safety data is available regarding metformin use in patients with acute and critical heart disease. METHODS: In this single-center retrospective study, patients admitted to the cardiology department for heart failure (HF) or acute coronary syndrome (ACS) between December 2013 and December 2021 and who underwent arterial blood gas analysis at admission with an estimated glomerular clearance rate of ≥45 ml/min/1.73 m2 were identified. The incidences of hyperlactatemia, acidosis, and 30-day in-hospital mortality were compared between preadmission metformin users and nonusers. RESULTS: Of 526 admissions, 193/193 metformin users/nonusers were selected in a propensity score-matched model. Metformin users had greater lactate levels (2.55 ±â€¯2.07 mmol/L vs. 2.00 ±â€¯1.80 mmol/L P < 0.01), a greater incidence of hyperlactatemia [odds ratio (OR) = 2.55; 95% confidence interval (CI), 1.63-3.98; P < 0.01] and acidosis (OR = 1.78; 95% CI, 1.00-3.16; P < 0.05) at admission and a greater incidence of in-hospital mortality (OR = 3.83; 95% CI, 1.05-13.94; P < 0.05), especially those with HF/acute myocardial infarction, elderly age, or without preadmission insulin use. CONCLUSIONS: Our results suggest that, compared to metformin nonusers, preadmission use of metformin may be associated with a greater incidence of hyperlactatemia and acidosis at admission and greater 30-day in-hospital mortality among T2D patients with HF or ACS at high risk of hypoxia, particularly those without preadmission insulin use. The safety of metformin in this population needs to be confirmed in prospective controlled trials.

Metformin beyond type 2 diabetes: Emerging and potential new indications.

Metformin is best known as a foundational therapy for type 2 diabetes but is also used in other contexts in clinical medicine with a number of emerging and potential indications. Many of its beneficial effects may be mediated by modest effects on weight loss and insulin sensitivity, but it has multiple other known mechanisms of action. Current clinical uses beyond type 2 diabetes include: polycystic ovarian syndrome; diabetes in pregnancy/gestational diabetes; prevention of type 2 diabetes in prediabetes; and adjunct therapy in type 1 diabetes. As metformin has been in clinical use for almost 70 years, much of the underpinning evidence for its use in these conditions is, by definition, based on trials conducted before the advent of contemporary evidence-based medicine. As a result, some of the above-established uses are 'off-label' in many regulatory territories and their use varies accordingly in different countries. Going forward, several current 'repurposing' investigational uses of metformin are also being investigated: prevention of cancer (including in Li Fraumeni syndrome), renal protection, Alzheimer's disease, metabolic dysfunction-associated steatotic liver disease and promotion of healthy ageing. Despite the longevity of metformin and its important current roles beyond type 2 diabetes in clinical medicine, it has further potential and much research is ongoing.

Effectiveness of dual combination therapy of acarbose plus metformin and acarbose plus myo-inositol in ameliorating the metabolic and endocrinologic complications of polycystic ovary syndrome - A randomized controlled trial.

INTRODUCTION: PCOS, beyond being characterized by reproductive disturbances, is a complicated rapid expanding metabolic and endocrinologic disorder of the recent times. Nearly 70% PCOS women show resistance to insulin. AIM: The aim of the study is to determine and compare the effectiveness of acarbose plus metformin and acarbose plus myo-inositol combination therapy in alleviating the metabolic and endocrinologic complications of PCOS. MATERIALS AND METHODS: An open labelled RCT was conducted on 168 PCOS women attending the gynaecology clinic at SRM MCH & RC, Chengalpattu and the trial was registered in CTRI (No. CTRI/2022/04/041877). Group A (n = 56) received metformin 500 mg/TID alone; group B (n = 54) received (acarbose 25 mg/TID for 4 weeks then 50 mg/TID for other 20 weeks) along with metformin 500 mg/TID and group C (n = 54) received (acarbose 25 mg/TID for 4 weeks then 50 mg/TID for other 20 weeks) along with myoinositol 1000 mg/BD. All parameters were measured at baseline and at the end of 6 months. RESULTS: Significant reduction of LH, LH: FSH, TT, HOMA-IR was observed in all the groups. FSH increased only in metformin group. Increase in serum progesterone and reduction in FI, TGL, LDL were significant only in acarbose plus myo-inositol group. SHBG and HDL increased significantly only in acarbose plus metformin group. No changes in BMI, TC and VLDL were observed in any group. CONCLUSION: Therefore, decrease in FI, HOMA-IR, TGL, LDL seen in acarbose plus myo-inositol group indirectly contributes to cardio-metabolic safety in PCOS. Similarly, a significant increase in SHBG levels with acarbose plus metformin group shows correction of the excess androgen and restoration of ovulation.

Metformin use and survival in people with ovarian cancer: A population-based cohort study from British Columbia, Canada.

OBJECTIVES: There is an active debate regarding whether metformin use improves survival in people with ovarian cancer. We examined this issue using methods designed to avoid immortal time bias-as bias that occurs when participants in a study cannot experience the outcome for a certain portion of the study time. METHODS: We used time-dependent analyses to study the association between metformin use for all 4,951 patients diagnosed with ovarian cancer in 1997 through 2018 in the province of British Columbia, Canada. Cox proportional hazards models were run to estimate the association between metformin and survival in the full cohort of ovarian cancer patients and among a cohort restricted to patients with diabetes. RESULTS: Metformin use was associated with a 17 % better ovarian cancer survival in the full cohort (adjusted hazard ratio (aHR) = 0.83 (95 %CI 0.67, 1.02)), and a 16 % better ovarian cancer survival for serous cancers patient's cohort (aHR = 0.84 (95 %CI 0.66, 1.07)), although both were not significant. However, a statistically significant protective effect was observed when restricting to the diabetic cohort (aHR = 0.71 (95 %CI 0.54-0.91)), which was also seen among serous cancers (aHR = 0.73 (95 %CI 0.54-0.98)). CONCLUSION: Metformin use was associated with improved ovarian cancer survival. The lack of statistical significance in the full cohort may reflect that diabetes is associated with reduced cancer survival, and thus diabetes itself may offset the benefit of metformin when examining the full cohort. Future research should examine metformin use among non-diabetic ovarian cancer patients.

Metformin as a therapeutic agent for obesity-associated immune dysfunction.

Obesity is associated with impaired immune function, characterized by inflammation, and leading to poor response to infection, impaired vaccine response, increased susceptibility to autoimmune disease, and increased risk of cancer and cancer mortality. Worse, there is evidence that weight loss alone may be insufficient to reverse the immune dysfunction caused by obesity. It is therefore critically important to identify alternative therapeutic approaches to decrease the negative effects of obesity-associated inflammation. Here, we will review evidence that the antidiabetic drug metformin may be considered as a therapeutic agent for obesity-associated immune dysfunction. Metformin has immune-modulatory effects, stimulating or suppressing the immune response in both a cell-specific and disease-specific manner. Although the mechanism of action of metformin on the immune system remains to be fully elucidated, there is strong evidence that metformin enters select immune cells and disrupts electron transport, leading to both AMPK-dependent and AMPK-independent effects on immune cell differentiation and cytokine production. These effects of metformin on immune cells have been shown to improve immune responses to infection, autoimmunity, and cancer.

Survival and Vision Restoration Following Severe Metformin-associated Metabolic Acidosis With Transient Blindness: A Case Report and Review of the Literature.

Metformin-associated lactic acidosis (MALA) is a life-threatening condition that may occur as a side effect of biguanides. This condition has a mortality rate of approximately 55 % depending on the severity. Typical symptoms include abdominal pain, nausea, vomiting, and diarrhea, but may also manifest with severe symptoms such as blindness, distributive shock, and renal failure requiring ICU level care. We present the case of a female in her early 70s who arrived at the emergency department with altered mental status and new-onset blindness, later diagnosed with severe acidosis (pH 6.607). She was intubated for hemodynamic instability and continuous renal replacement therapy (CRRT) was started to address her acid-base status. Her metformin concentration was found to be exceptionally high at 34 mcg/ml, significantly surpassing the normal range of 1-2 mcg/ml. Fortunately, the patient survived and was subsequently transferred to the medical floors in stable condition. Physicians should perform medication review and consider "MALA" as a potential etiology of severe acidosis when forming a differential diagnosis.

Causal prior-embedded physics-informed neural networks and a case study on metformin transport in porous media.

This study introduces a novel approach to transport modelling by integrating experimentally derived causal priors into neural networks. We illustrate this paradigm using a case study of metformin, a ubiquitous pharmaceutical emerging pollutant, and its transport behaviour in sandy media. Specifically, data from metformin's sandy column transport experiment was used to estimate unobservable parameters through a physics-based model Hydrus-1D, followed by a data augmentation to produce a more comprehensive dataset. A causal graph incorporating key variables was constructed, aiding in identifying impactful variables and estimating their causal dynamics or "causal prior." The causal priors extracted from the augmented dataset included underexplored system parameters such as the type-1 sorption fraction F, first-order reaction rate coefficient α, and transport system scale. Their moderate impact on the transport process has been quantitatively evaluated (normalized causal effect 0.0423, -0.1447 and -0.0351, respectively) with adequate confounders considered for the first time. The prior was later embedded into multilayer neural networks via two methods: causal weight initialization and causal prior regularization. Based on the results from AutoML hyperparameter tuning experiments, using two embedding methods simultaneously emerged as a more advantageous practice since our proposed causal weight initialization technique can enhance model stability, particularly when used in conjunction with causal prior regularization. amongst those experiments utilizing both techniques, the R-squared values peaked at 0.881. This study demonstrates a balanced approach between expert knowledge and data-driven methods, providing enhanced interpretability in black-box models such as neural networks for environmental modelling.

Metformin monotherapy versus predominantly older non-metformin antidiabetic medications for cerebrovascular risk in early type 2 diabetes management.

AIM: Choosing the initial treatment for type 2 diabetes (T2D) is pivotal, requiring consideration of solid clinical evidence and patient characteristics. Despite metformin's historical preference, its efficacy in preventing cerebrovascular events lacked empirical validation. This study aimed to evaluate the associations between first-line monotherapy (metformin or non-metformin antidiabetic medications) and cerebrovascular complications in patients with T2D without diabetic complications. METHODS: We analysed 9090 patients with T2D without complications who were prescribed either metformin or non-metformin medications as initial therapy. Propensity score matching ensured group comparability. Cox regression analyses, stratified by initial metformin use, assessed cerebrovascular disease risk, adjusting for multiple covariates and using competing risk analysis. Metformin exposure was measured using cumulative defined daily doses. RESULTS: Metformin users had a significantly lower crude incidence of cerebrovascular diseases compared with non-users (p < .0001). Adjusted hazard ratios (aHRs) consistently showed an association between metformin use and a lower risk of overall cerebrovascular diseases (aHRs: 0.67-0.69) and severe events (aHRs: 0.67-0.69). The association with reduced risk of mild cerebrovascular diseases was significant across all models (aHRs: 0.73-0.74). Higher cumulative defined daily doses of metformin correlated with reduced cerebrovascular risk (incidence rate ratio: 0.62-0.94, p < .0001), indicating a dose-dependent effect. CONCLUSION: Metformin monotherapy is associated with a reduced risk of cerebrovascular diseases in early-stage T2D, highlighting its dose-dependent efficacy. However, the observed benefits might also be influenced by baseline differences and the increased risks associated with other medications, such as sulphonylureas. These findings emphasize the need for personalized diabetes management, particularly in mitigating cerebrovascular risk in early T2D stages.

Effect of metformin on gut microbiota imbalance in patients with T2DM, and the value of probiotic supplementation.

PURPOSE: To investigate the effect of metformin on gut microbiota imbalance in patients with type 2 diabetes mellitus (T2DM), and the value of probiotic supplementation. METHODS: A total of 84 newly diagnosed T2DM patients were randomly divided into probiotics group, metformin group, and control group, with 28 patients in each group. The blood glucose control, islet function, gut microbiota, and inflammatory factors were compared between three groups. RESULTS: After 3 months of treatment, fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2-h PG), and glycosylated hemoglobin A1c (HbA1c) were evidently decreased in both probiotics and metformin groups (P < 0.05) and were lower than that in the control group prior to treatment. Besides, FPG, 2-h PG, and HbA1c were lower in the metformin group than that in the control group. FPG, 2-h PG, and HbA1c were further lower in the probiotic group than in the metformin group (P < 0.05). Fasting insulin (FINS) and islet ß cell (HOMA-ß) -function were dramatically increased in the same group (P < 0.05), while insulin-resistant islet ß cells (HOMA-IR) were significantly lower in the same group (P < 0.05); FINS and HOMA-ß were significantly higher, while HOMA-IR was significantly lower (P < 0.05) in both groups than in the control group prior to treatment. HOMA-IR was also lower in the probiotic group than in the metformin group after treatment (P < 0.05); the number of lactobacilli and bifidobacteria increased (P < 0.05) in both probiotic and metformin groups than in the control group prior to treatment, and the number of Enterobacteriaceae and Enterococcus was lower in the control group prior to treatment (P < 0.05). In addition, the number of lactobacilli and bifidobacteria was higher and the number of enterobacteria and enterococci was lower in the probiotic group than that in the metformin group after treatment, and the differences were statistically significant (P < 0.05). Lipopolysaccharide (LPS), interleukin 6 (IL-6), and C-reactive protein (CRP) levels were lower in both probiotic and metformin groups (P < 0.05). The serum LPS, IL-6, and CRP levels were lower in both probiotic and metformin groups, compared to the control group prior to the treatment (P < 0.05). CONCLUSION: Metformin while treating T2DM assists in improving the imbalance of gut microbiota.

Metformin induces tumor immunogenic cell death in ovarian cancer by activating AMPK pathway.

Inducing immunogenic cell death (ICD) process may be an important antitumor strategy in ovarian cancer (OC). Metformin (Met) has been shown to have antitumor effects in OC, but whether it mediates the ICD to inhibit OC process is unclear. Human OC cell lines (SKOV3 and A2780) were treated with Met. Dendritic cell (DC) and CD8+T cells were isolated from the peripheral blood mononuclear cells of volunteers. Cell counting kit 8 assay was used to measure cell viability, and immunofluorescence staining was performed to detect the percentages of membrane and intracellular calreticulin (CRT). CRT level, DC maturation and effector cell activation were evaluated by flow cytometry. The levels of IL-10 and IFN-γ, as well as the releasements of HMGB1 and ATP, were detected using corresponding kits. The protein levels of heat shock protein 70/90 (HSP70/90) and AMPKα were tested by western blot analysis, and the mRNA levels of CD80, CD86, IL-10, and IFN-γ were measured by quantitative real-time PCR. Colony formation assay was utilized for assessing cell cytotoxicity. Mice transplanted tumor model was constructed to assess the effect of Met on OC tumor growth, and immunohistochemistry staining was used to analyze CD80+ and CD86+ cells in mice tumor tissues. Our data showed that Met inhibited OC cell viability and induced CRT exposure. Besides, Met could promote the release of HMGB1 and ATP, as well as induce DC maturation. In vivo experiments suggested that Met restrained OC tumor growth via activating antitumor immune response. Moreover, Met activated AMPK pathway, and silenced AMPK pathway reversed the promoting effect of Met on CRT exposure and the releasements of HMGB1 and ATP in OC cells. In conclusion, Met induced ICD-mediated immune destruction in OC via activating AMPK pathway, indicating that Met might be used in the immunotherapy of OC.

Metformin is associated with reduced risk of mortality and morbidity in burn patients compared to insulin.

PURPOSE: The standard of care for burned patients experiencing hyperglycemia associated with the hypermetabolic response is insulin therapy. Insulin treatment predisposes burn patients to hypoglycemia, which increases morbidity and mortality. Metformin has been suggested as an alternative to insulin therapy for glycemic control in burn patients given its safety profile, but further research is warranted. This study investigated whether metformin use in burn patients is associated with improved glycemic control and morbidity/mortality outcomes compared to insulin use alone. MATERIALS AND METHODS: Using the TriNetX database, we conducted a retrospective study of burned patients who were administered insulin, metformin, or both within one week of injury. Demographic, comorbidity, and burn severity information were collected. Patients were categorized by treatment type, propensity score-matched, and compared for the following outcomes within 3 months: hyperglycemia, hypoglycemia, sepsis, lactic acidosis, and death. Statistical significance was set a priori at p ≤ 0.05. RESULTS: The insulin cohort was at increased risk for all outcomes (all p < 0.0001) compared to the metformin cohort, and an increased risk for sepsis, lactic acidosis, and death (all p ≤ 0.0002) compared to the insulin/metformin combination cohort. When compared to the metformin cohort, the combination cohort was at increased risk for all outcomes (all p ≤ 0.0107) except death. CONCLUSIONS: Treatment with metformin after burn is associated with a reduced risk of morbidity and mortality compared to insulin. The combination of insulin and metformin is no more effective in reducing the risk of hyperglycemia and hypoglycemia than insulin alone but is less effective than metformin alone.

Advances in metformin-delivery systems for diabetes and obesity management.

Metformin is a medication that is commonly prescribed to manage type 2 diabetes. It has been used for more than 60 years and is highly effective in lowering blood glucose levels. Recent studies indicate that metformin may have additional medical benefits beyond treating diabetes, revealing its potential therapeutic uses. Oral medication is commonly used to administer metformin because of its convenience and cost-effectiveness. However, there are challenges in optimizing its effectiveness. Gastrointestinal side effects and limitations in bioavailability have led to the underutilization of metformin. Innovative drug-delivery systems such as fast-dissolving tablets, micro/nanoparticle formulations, hydrogel and microneedles have been explored to optimize metformin therapy. These strategies enhance metformin dosage, targeting, bioavailability and stability, and provide personalized treatment options for improved glucose homeostasis, antiobesity and metabolic health benefits. Developing new delivery systems for metformin shows potential for improving therapeutic outcomes, broadening its applications beyond diabetes management and addressing unmet medical needs in various clinical settings. However, it is important to improve drug-delivery systems, addressing issues such as complexity, cost, biocompatibility, stability during storage and transportation, loading capacity, required technologies and biomaterials, targeting precision and regulatory approval. Addressing these limitations is crucial for effective, safe and accessible drug delivery in clinical practice. In this review, recent advances in the development and application of metformin-delivery systems for diabetes and obesity are discussed.

Association of Genetic Polymorphism rs 77630697(Gly64Asp) of Multidrug and Toxin Extrusion -1 with glycemic response to metformin in patients with Type 2 Diabetes Mellitus.

Objective: To determine the relationship between Gly64Asp (rs77630697) polymorphism of multidrug and toxin extrusion-1 (MATE-1) and therapeutic response of metformin in Type-2 diabetic patients. Methods: A longitudinal study was conducted at Riphah International Hospital, Islamabad from June 2020 to December 2021. Type-2 diabetic patients (n=200) on metformin monotherapy fulfilling the inclusion criteria were enrolled and followed up till three months. Based on change in HbA1c, they were divided into responders and non-responders. DNA was extracted and genotyping was done by TETRA ARMS PCR. Data was entered and association was analyzed by SPSS 22. Results: Out of 200 participants, 104 were categorized as responders and 96 as non-responders. The genotype and allelic distribution of rs77630697 was significantly different between responders and non-responders. The variant genotype (GG) was most prevalent among the study population and among responders. After follow up of three months, difference in glycemic response was found to be statistically significant (p < 0.05) among three genotypes (GG, GA and AA). The decline in HbA1c was highest in GG genotype with almost two-fold reduction in comparison with GA and AA. Carriers of allele A were significantly associated with impaired response to metformin. Conclusion: The variable therapeutic response to metformin in the responders and non-responders may be contributed to rs77630697 isoform variation of MATE-1.

Dataset for analysis of metabolic pathways and their reversibility associated with anti-proliferative effect of metformin in liver cancer cells.

Despite epidemiological indications, utility of metformin in liver cancer remains debated and the understanding of the mechanism underlying its anti-cancer effects remains incomplete. Particularly, whether it operates via similar mechanism under glucose-sufficient and glucose- deficient environments or whether these effects are reversible remains unexplored. This metabolomic dataset was collected from liver cancer (HepG2) cells treated with metformin or placebo over a period of 3 h to 48 h as well as from cells recovering after metformin withdrawal. Cells were exposed to placebo or 2.5 mM metformin with or without glucose (5 mM) supplementation. The cells were harvested at 3, 6, 12, 24, and 48 h post-treatment. Cells were also harvested after 24 h of treatment under one of these conditions followed by reversal of glucose and/or metformin exposure status for 48 h. Metabolites from six biological replicates of each experimental group were extracted using chilled monophasic metabolite extraction solvent (Water: Acetonitrile: Isopropanol= 2:3:3) containing homovanillic acid as an internal standard. Samples were derivatized using MOX reagent followed by MSTFA. Untargeted metabolomic profiling of derivatized samples were performed using an Agilent 7890B gas chromatograph coupled to a 5977B single quadrupole mass spectrometer. Analytes were injected through a splitless liner and separated on a HP-5MS ultra-inert column using ultrapure helium as the carrier gas. Peak alignment, annotation, and integration were done using Agilent MassHunter Quantitative analysis software. Multivariate analysis was performed using MetaboAnalyst 5.0. These experiments were performed to unravel the longitudinal evolution of cellular metabolome in response to metformin treatment, its glucose dependence, as well as to examine the reversibility of these changes. The dataset can help to identify glucose-independent pathways involved in anti-cancer effect of metformin. The dataset can be used to design experiments to develop novel therapeutic combinations synergistically acting with metformin to cripple the metabolic fitness of cancer cells. It can also help to develop experiments to test the effect of metformin withdrawal in liver cancer.

Metformin improves cognitive dysfunction through SIRT1/NLRP3 pathway-mediated neuroinflammation in db/db mice.

Diabetes mellitus (DM), an important public health problem, aggravates the global economic burden. Diabetic encephalopathy (DE) is a serious complication of DM in the central nervous system. Metformin has been proven to improve DE. However, the mechanism is still unclear. In this study, the db/db mice, a common model used for DE, were employed to explore and study the neuroprotective effect of metformin and related mechanisms. Behavioral tests indicated that metformin (100 or 200 mg/kg/day) could significantly improve the learning and memory abilities of db/db mice. The outcomes from the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) demonstrate that metformin effectively modulates glucose and insulin signaling pathways in db/db mice. The results of body weight and blood lipid panel (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) show that metformin promotes the level of lipid metabolism in db/db mice. Furthermore, data from oxidative stress assays, which measured levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase, suggest that metformin suppresses oxidative stress-induced brain damage in db/db mice. In addition, western blot, Nissl staining, and immunofluorescence results showed that metformin increased the expressions of nerve growth factor and postsynaptic density 95 and repaired neuronal structural damage. For the mechanism study, metformin activated SIRT1 and inhibited the expression of NLRP3 inflammasome (NLRP3, ASC, caspase-1, IL-1ß, and IL-18) and inflammatory cytokines (TNFα and IL-6). In conclusion, metformin could ameliorate cognitive dysfunction through the SIRT1/NLRP3 pathway, which might be a promising mechanism for DE treatment.

Exploring the link between metformin use and adhesive capsulitis of the shoulder: a retrospective cohort study in Taiwan.

The risk of adhesive capsulitis of shoulder in diabetic patients taking metformin has not been evaluated. We aimed for evaluating the relative risk of adhesive capsulitis of shoulder in diabetic patients taking metformin at the level of the whole country population. We conducted a retrospective cohort study using a national health insurance database in Taiwan from 2000 to2015. We used International Classification of Diseases, Ninth Revision, to categorise the medical condition for study group and comparison group. We used Cox proportional hazard regression analyses to determined adjusted hazard ratios (aHRs) of adhesive capsulitis of shoulder between study and comparison group after adjusting for sex, age, and comorbidities.Among 30,412 diabetic patients using metformin, 3020 patients were diagnosis with adhesive capsulitis of shoulder during follow up. Of the 121,648 patients without the use of metformin, 11,375 patients developed adhesive capsulitis of shoulder. Adhesive capsulitis of shoulder risk was elevated in patients taking metformin than in non-metformin group (adjusted hazard ratio [HR] 1.179, 95% confidence interval [95% CI] 1.022 to 1.268; p = 0.039). Risk of adhesive capsulitis of shoulder among the diabetic patients taking metformin was higher than those did not taking metformin.