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Long-Term Use of Metformin and Vitamin B12 Deficiency in Diabetes
Abstract
This extensive review delves into the complex relationship between prolonged use of metformin and the possible emergence of vitamin B12 deficiency (VB12D) in diabetic patients. Metformin, a pivotal element in diabetes management, is constantly linked with decreased absorption of vitamin B12, prompting concerns about the enduring consequences of this interaction. The review systematically amalgamates current evidence, elucidating the prevalence, mechanisms, and clinical ramifications of VB12D induced by consistent consumption of metformin. Exploring the different pathways through which metformin might disrupt the absorption of Vitamin B12, the review encompasses interference with the calcium-dependent membrane activity and alterations of the microbiota present in the gut. A meticulous analysis of experimental studies and human trials is undertaken, accentuating the prevalence of variable VB12D among individuals on long-duration treatment of metformin across diverse populations and age groups. Clinical indications of cobalamin deficiency, spanning haematological abnormalities to neurological complications, are systematically examined. Furthermore, the review delves into the potential implications of cobalamin deficiency associated with metformin on diabetes-related complications and overall patient health. This review offers a comprehensive overview of the intricate interplay between the use of metformin and deficiency of vitamin B12 in diabetic patients, emphasizing the importance that lies in routine monitoring, early detection, and personalized interventions to optimize the long-period safety and efficiency of metformin in the treatment of diabetes. It also proposes future research directions to refine clinical guidelines and enhance the understanding regarding the correlation between diabetes, metformin, and vitamin B12.
... Studies demonstrate that NETs trigger NLRP3 inflammasome in macrophages and enhance IL-1β related inflammation [6]. This inflammatory environment is significant in Diabetic Foot Ulcer (DFU) where NETosis is augmented and high levels of histone H3 (citrullinated), elastase, and other pro-inflammatory molecules are expressed compared to nondiabetic control patients [7][8][9]. Diabetic patients have a high level of glucose in their bloodstream, which in turn increases the rate of histone citrullination and promotes NET release, possibly increasing tissue injury in wounds [10]. It has been established that Staphylococcus aureus increases NET production in diabetic patients as compared to non-diabetic patients. ...
... Hashem et al. found in a prospective clinical study that metformin use was associated with exacerbated DPN, especially within the first 6 months of treatment and more prominently in high-dose groups [9]. Hussain et al. [23] further explored this phenomenon, suggesting that metformin may lead to vitamin B12 (cobalamin) deficiency by interfering with calcium-dependent membrane activity and altering gut microbiota. Vitamin B12 deficiency can subsequently cause progressive demyelination, peripheral neuropathy, and hematological abnormalities. ...
Objective: Given the important role of metformin in diabetes treatment and the uncertainty regarding its relationship with diabetic neuropathy, this study aims to assess the causal relationship between metformin and diabetic neuropathy using Mendelian randomization.
Methods: Instrumental variables were derived from publicly available genome-wide association study datasets. Two study cohorts were assigned: a training cohort (exposure ID: ukb-a-159) and a testing cohort (ID: ukb-b-14609), with the outcome ID being finn-b-DM_NEUROPATHY for both. The primary analysis used inverse variance weighting (IVW) for Mendelian randomization, supplemented by weighted median (WMed), weighted mode (WM), simple mode (SM), and MR Egger regression (MER). To test for heterogeneity, pleiotropy, and publication bias, we conducted leave-one-out sensitivity analyses, MR Egger regression, and further assessed with funnel plots.
Results: Mendelian randomization analysis showed a significant positive causal relationship between metformin and diabetic neuropathy in both the training set (IVW: logOR 14.73, 95% CI [9.60, 19.86], p=1.78E-08) and the testing set (IVW: logOR 15.83, 95% CI [11.10, 20.56], p=5.54E-11). The WMed, WM, SM, and MER models all consistently supported this conclusion, with no evidence of pleiotropy or heterogeneity, indicating robust results.
Conclusion: From an epidemiological perspective, this study reveals a significant positive correlation between metformin use and diabetic neuropathy through Mendelian randomization analysis. This finding not only provides new insights into the field of diabetes treatment but also suggests that the use of metformin may be associated with the potential side effect of increased risk of diabetic neuropathy.
... Diet emerges as a central determinant influencing the diversity of the gut microbiome, and numerous studies have scrutinized the intricate relationship between dietary patterns and the composition of the gut microbiota [43]. For instance, an investigation involving a substantial cohort of asymptomatic Chinese adults unveiled that a general dietary pattern characterized by diminished refined grain consumption exhibited a correlation with heightened abundances of the genus Anaerostipes, along with a specific species within it. ...
Depression is a prevalent mood disorder with significant public health implications. Despite extensive research, its precise causes remain inadequately understood. Recently, interest has surged in the role of the gut microbiome and its metabolites in the pathophysiology of depression. This review aims to provide a comprehensive overview of the relationship between gut microbiota, its metabolites, and depression while exploring potential mechanisms influencing the efficacy of antidepressant medications. A narrative review methodology was employed, synthesizing recent studies utilizing a multi-omics approach. We examined alterations in gut microbiome composition and metabolite production in individuals diagnosed with depression, discussing the technical tools and methods commonly applied in this research area. The findings indicate that individuals with depression show significant alterations in gut microbiome composition, notably an imbalance in Firmicutes, Bacteroidetes, and Actinobacteria. Changes in metabolite production, including short-chain fatty acids, tryptophan, and bile acids, were also observed. Moreover, the review highlights that antidepressant medications may exert their therapeutic effects by modulating gut microbiota and its metabolites. This review emphasizes the intricate interplay between gut microbiota, its metabolites, and depression, revealing critical insights into the mechanisms underlying antidepressant efficacy. We recommend that future research focus on elucidating these interactions to develop innovative therapeutic strategies, potentially transforming the management of depression through microbiota-targeted approaches.
Cubebin, a dibenzyl butyrolactone lignan belonging to several distinct families, including Aristolochiaceae, Myristicaceae, Piperaceae, and Rutaceae, and possesses several pharmacological activities, including analgesic, anti-inflammatory, antioxidant, and vasodilatory. The current study aimed to evaluate the effect of cubebin on streptozotocin (STZ)-evoked diabetic nephropathy (DN). DN is a well-identified complication of diabetes mellitus (DM) characterized by renal hypertrophy that progressively declines kidney function. Wistar rats were randomly divided into groups- normal, STZ control (65 mg/kg/body weight), and STZ + cubebin (10 and 20 mg/kg). Biochemical parameters such as glucose levels, kidney parameters, lipid profile, oxidative stress, endogenous antioxidant markers, inflammatory cytokines and histopathology were performed. Molecular docking [(PDB ID: TNF-α (7JRA), NF-κB (1SVC), TGF-β1 (3TZM)] and dynamic simulation (MDS) were also performed with the selected target. STZ-induced DN was changes in these parameters. In contrast, DN + cubebin at 10 and 20 mg/kg doses improved the biochemical parameters and histological changes. Furthermore, molecular docking and simulation studies showed a binding affinity with negative binding energy with TNF-α (7jra, − 11.342 kcal/mol), TGF-β1 (3tzm, − 9.162 kcal/mol) and NF-κB (1svc, − 6.665 kcal/mol). The results of MDS provided insight into the mechanisms that associate proteins TNF-α, NF-κB, and TGF-β1 in conformational dynamics upon binding to cubebin. In conclusion, these findings exhibit a potential effect of cubebin in STZ-evoked DN rats.
Background
Drug-induced hepatotoxicity, particularly from ethanol and acetaminophen (APAP), is a pressing global health challenge. This damage arises from oxidative stress and inflammation, manifesting as elevated liver enzymes and structural liver alterations. Resveratrol and silymarin, recognized for their antioxidant and anti-inflammatory properties, offer potential hepatoprotective benefits.
Methods
This study investigated the hepatoprotective efficacy of resveratrol and silymarin, alone and in combination, in a rat model of ethanol- and APAP-induced liver injury. Thirty Wistar rats were divided into five groups: control, ethanol-APAP, ethanol-APAP-resveratrol, ethanol-APAP-silymarin, and ethanol-APAP-resveratrol-silymarin. Treatments were administered orally for 10 days. Serum ALT and AST levels were assessed, and liver tissues underwent histological evaluation.
Results
Ethanol and APAP administration significantly elevated ALT and AST levels, alongside severe liver structural disruptions. Treatment with resveratrol or silymarin alone normalized enzyme levels and improved liver histology. Notably, the combined resveratrol-silymarin treatment exhibited greater reductions in ALT and AST levels and superior restoration of liver architecture compared to either treatment alone, indicating a synergistic hepatoprotective effect.
Conclusions
Resveratrol and silymarin effectively counteract ethanol- and APAP-induced hepatotoxicity by mitigating oxidative stress and inflammation. Their combined use demonstrates a synergistic benefit, as evidenced by enhanced biochemical and histological improvements. These findings support the potential therapeutic role of these natural agents in managing drug-induced liver injury.
Diabetic gastroparesis (DGP) delays gastric emptying in diabetes patients, notably impacting those with type 1 and long-standing type 2 diabetes. Symptoms include early satiety, fullness, appetite loss, bloating, abdominal pain, and vomiting, arising from slow stomach-to-intestine food movement. DGP’s unpredictable nature complicates diagnosis and blood glucose management, leading to severe complications like dehydration, malnutrition, and bezoar formation. Understanding DGP’s mechanisms is crucial for effective management. Vagal dysfunction, disturbances in the interstitial cells of Cajal, reduced neural nitric oxide synthase, and increased oxidative stress contribute to the complex pathophysiology. Accurate diagnosis demands a comprehensive approach, utilizing tools like gastric scintigraphy and the Gastric Emptying Breath Test. Considering the complex relationship between DGP and glycemia, managing blood glucose levels becomes paramount. Nutritional interventions, tailored to each patient, address malnutrition risks, emphasizing smaller, more frequent meals and liquid consistency. DGP’s complex nature necessitates collaborative efforts for enhanced diagnostic strategies, improved pathophysiological understanding, and compassionate management approaches. This comprehensive approach offers hope for a future where individuals with DGP can experience improved well-being and quality of life.
Introduction:The potential influence of micronutrient status on obesity should be considered. Nevertheless, previous research examining the relationship between serum vitamin B12 levels and obesity has yielded inconclusive results. The objective of this study was to investigate the associations between serum vitamin B12 levels and obesity and diabetes mellitus (DM) in a population consisting of persons aged 18 years and older.
Methods: A retrospective case-control research was undertaken on a sample of 1024 individuals aged 18 years and older who were admitted to a tertiary healthcare facility (Recep Tayyip Erdoğan University Education and Research Hospital, Rize) for either overweight-related issues or routine check-ups. The primary objective of this study was to assess the B12 levels of these individuals. The researcher recorded the body mass index (BMI) and history of DM for all subjects.
Results: The study comprised a total of 1024 participants, consisting of 834 females and 190 males. The levels of vitamin B12 in women were found to be 308±113 pg/mL, while in men, the levels were 304±125 pg/mL. The results of the statistical analysis indicate that there is no statistically significant disparity in vitamin B12 levels between males and females (p=0.748). There was a statistically significant positive correlation seen between age and B12 levels; however, the magnitude of this connection was found to be minor (p=0.000, R2=0.017). The study findings revealed that out of the 1,024 individuals evaluated, 179 individuals exhibited B12 levels below 200, while 845 individuals displayed vitamin B12 levels above 200. The study findings indicated that there was no statistically significant distinction observed in the occurrence of obesity and DM in relation to vitamin B12 deficiency (p = 0.938, p = 0.08, respectively).
Conclusion: The results of this study offer empirical support for the notion that there is no significant difference in vitamin B12 levels between individuals afflicted with obesity and diabetes and those unaffected by these conditions. Interestingly, it was shown that serum B12 levels exhibited a modest increase with advancing age.
In this overview, the latest achievements in dietary origins, absorption mechanism, bioavailability assay, health advantages, cutting-edge encapsulation techniques, fortification approaches, and innovative highly sensitive sensor-based detection methods of vitamin B12 (VB12) were addressed. The cobalt-centered vitamin B is mainly found in animal products, posing challenges for strict vegetarians and vegans. Its bioavailability is highly influenced by intrinsic factor, absorption in the ileum, and liver reabsorption. VB12 mainly contributes to blood cell synthesis, cognitive function, and cardiovascular health, and potentially reduces anemia and optic neuropathy. Microencapsulation techniques improve the stability and controlled release of VB12. Co-microencapsulation of VB12 with other vitamins and bioactive compounds enhances bioavailability and controlled release, providing versatile initiatives for improving bio-functionality. Nanotechnology, including nanovesicles, nanoemulsions, and nanoparticles can enhance the delivery, stability, and bioavailability of VB12 in diverse applications, ranging from antimicrobial agents to skincare and oral insulin delivery. Staple food fortification with encapsulated and free VB12 emerges as a prominent strategy to combat deficiency and promote nutritional value. Biosensing technologies, such as electrochemical and optical biosensors, offer rapid, portable, and sensitive VB12 assessment. Carbon dot-based fluorescent nanosensors, nanocluster-based fluorescent probes, and electrochemical sensors show promise for precise detection, especially in pharmaceutical and biomedical applications.
Background
Several studies documented that metformin use contributes to vitamin B12 deficiency in patients with type 2 diabetes mellitus (T2DM). However, there has been a lack of data assessing this issue in Jordan.
Aims
Assess the vitamin B12 serum levels, frequency of vitamin B12 deficiency, and related factors among Jordanian patients with T2DM patients treated with metformin.
Methods
a total of 447 subjects attending a primary health care center were included in this cross-sectional study consisting of T2DM patients who use metformin and a control group of non-diabetics. Serum B12 levels were evaluated and B12 deficiency was defined as serum B12 levels ≤ 200 pmol/L. Associations of B12 serum levels or B12 deficiency with other factors like gender, age, and duration of T2DM were analyzed.
Results
There was no significant difference in serum B12 levels nor the frequency of vitamin B12 deficiency between T2DM metformin-treated patients and control groups. Among metformin-treated patients there was no difference relating to age, type 2 diabetes mellitus duration, proton pump inhibitors use, and metformin use (duration, dose) between patients with or without B12 deficiency.
Conclusion
The prevalence of vitamin B12 deficiency among T2DM patients on metformin treatment in this study was high (48.9%). However, the treatment with metformin and the dose of metformin use was not associated with vitamin B12 deficiency.
Metformin is a widely used and effective medication in type 2 diabetes (T2DM) as well as in polycystic ovary syndrome (PCOS). Single nucleotide polymorphisms (SNPs) contribute to the occurrence of metformin side effects. The aim of the present study was to identify intronic genetic variants modifying the occurrence of metformin side effects and to replicate them in individuals with T2DM and in women with PCOS. We performed Next Generation Sequencing (Illumina Next Seq) of 115 SNPs in a discovery cohort of 120 metformin users and conducted a systematic literature review. Selected SNPs were analysed in two independent cohorts of individuals with either T2DM or PCOS, using 5′-3′exonucleaseassay. A total of 14 SNPs in the organic cation transporters (OCTs) showed associations with side effects in an unadjusted binary logistic regression model, with eight SNPs remaining significantly associated after appropriate adjustment in the discovery cohort. Five SNPs were confirmed in a combined analysis of both replication cohorts but showed different association patterns in subgroup analyses. In an unweighted polygenic risk score (PRS), the risk for metformin side effects increased with the number of risk alleles. Intronic SNPs in the OCT cluster contribute to the development of metformin side effects in individuals with T2DM and in women with PCOS and are therefore of interest for personalized therapy options.
Inflammation is an essential immune response that helps fight infections and heal tissues. However, chronic inflammation has been linked to several diseases, including cancer, autoimmune disorders, cardiovascular diseases, and neurological disorders. This has increased interest in finding natural substances that can modulate the immune system inflammatory signaling pathways to prevent or treat these diseases. Luteolin is a flavonoid found in many fruits, vegetables, and herbs. It has been shown to have anti‐inflammatory effects by altering signaling pathways in immune cells. This review article discusses the current research on luteolin's role as a natural immune system modulator of inflammatory signaling mechanisms, such as its effects on nuclear factor‐kappa B, mitogen‐activated protein kinases, Janus kinase/signal transducer and activator of transcription, and inflammasome signaling processes. The safety profile of luteolin and its potential therapeutic uses in conditions linked to inflammation are also discussed. Overall, the data point to Luteolin's intriguing potential as a natural regulator of immune system inflammatory signaling processes. More research is needed to fully understand its mechanisms of action and possible therapeutic applications.
Secondary diabetes is a rare condition, often overlooked, underdiagnosed, or mistaken for type 1 or type 2 diabetes. So, in patients suffering from CP presenting with DKA, it is important to consider secondary diabetes for planning effective long-term management. CT scans and MRIs play an important role in the diagnosis of the small subset of the population affected with secondary diabetes which should be considered. The limitation of this study is the lack of islet antibodies or c-peptide measurements
The number of people living with chronic kidney disease (CKD) is growing as our global population continues to expand. With aging, diabetes, and cardiovascular disease being major harbingers of kidney disease, the number of people diagnosed with diabetic kidney disease (DKD) has grown concurrently. Poor clinical outcomes in DKD could be influenced by an array of factors—inadequate glycemic control, obesity, metabolic acidosis, anemia, cellular senescence, infection and inflammation, cognitive impairment, reduced physical exercise threshold, and, importantly, malnutrition contributing to protein-energy wasting, sarcopenia, and frailty. Amongst the various causes of malnutrition in DKD, the metabolic mechanisms of vitamin B (B1 (Thiamine), B2 (Riboflavin), B3 (Niacin/Nicotinamide), B5 (Pantothenic Acid), B6 (Pyridoxine), B8 (Biotin), B9 (Folate), and B12 (Cobalamin)) deficiency and its clinical impact has garnered greater scientific interest over the past decade. There remains extensive debate on the biochemical intricacies of vitamin B metabolic pathways and how their deficiencies may affect the development of CKD, diabetes, and subsequently DKD, and vice-versa. Our article provides a review of updated evidence on the biochemical and physiological properties of the vitamin B sub-forms in normal states, and how vitamin B deficiency and defects in their metabolic pathways may influence CKD/DKD pathophysiology, and in reverse how CKD/DKD progression may affect vitamin B metabolism. We hope our article increases awareness of vitamin B deficiency in DKD and the complex physiological associations that exist between vitamin B deficiency, diabetes, and CKD. Further research efforts are needed going forward to address the knowledge gaps on this topic.
The International Society of Pediatric and Adolescent Diabetes (ISPAD) recommends metformin (MET) use for metabolic disturbances and hyperglycemia, either in combination with insulin therapy or alone. A caveat of MET therapy has been suggested to be biochemical vitamin B12 deficiency, as seen mainly in studies conducted in adults. In the present case–control study, children and adolescents of different weight status tiers on MET therapy for a median of 17 months formed the cases group (n = 23) and were compared with their peers not taking MET (n = 46). Anthropometry, dietary intake, and blood assays were recorded for both groups. MET group members were older, heavier, and taller compared with the controls, although BMI z-scores did not differ. In parallel, blood phosphorus and alkaline phosphatase (ALP) concentrations were lower in the MET group, whereas MCV, Δ4-androstenedione, and DHEA-S were higher. No differences were observed in the HOMA-IR, SHBG, hemoglobin, HbA1c, vitamin B12, or serum 25(OH)D3 concentrations between groups. Among those on MET, 17.4% exhibited vitamin B12 deficiency, whereas none of the controls had low vitamin B12 concentrations. Participants on MET therapy consumed less energy concerning their requirements, less vitamin B12, more carbohydrates (as a percentage of the energy intake), and fewer fats (including saturated and trans fats) compared with their peers not on MET. None of the children received oral nutrient supplements with vitamin B12. The results suggest that, in children and adolescents on MET therapy, the dietary intake of vitamin B12 is suboptimal, with the median coverage reaching 54% of the age- and sex-specific recommended daily allowance. This low dietary intake, paired with MET, may act synergistically in reducing the circulating vitamin B12 concentrations. Thus, caution is required when prescribing MET in children and adolescents, and replacement is warranted.
Mental health services continue to experience rising demand that exceeds capacity. The COVID-19 pandemic exacerbated this crisis, with access to services being reduced. Although video consultations (VCs) are a solution, usage in UK community mental healthcare settings remains limited. This study aims to investigate psychiatrists’ and general practitioners’ (GPs) perceptions of the benefits and challenges of VC for the diagnosis and follow-up of general adult mental health patients in the community during the COVID-19 pandemic. Semi-structured interviews in NHS community mental healthcare settings were conducted. Psychiatrists (n = 11) and GPs (n = 12) were recruited through purposive sampling. An explorative qualitative approach was employed. Data were analysed using thematic analysis. Four key themes were identified: (1) patient access to VC, (2) suitability of VC for mental health consultations, (3) information gathering with VC and (4) clinician satisfaction with VC. This study provides valuable insights into the experiences of psychiatrists and GPs working in the UK during the COVID-19 pandemic. To facilitate a digital-first future for the NHS, greater investment in remote technologies is required, particularly in the context of growing mental healthcare demand. Though face-to-face consultations remain the gold standard, VC provides an efficient way of communicating with patients, particularly those with less severe forms of mental illness.
Metformin is the most often prescribed drug for people with type 2 diabetes (T2D). More than 120 million patients with T2D use metformin worldwide. However, monotherapy fails to achieve glycemic control in a third of the treated patients. Genetics contribute to some of the inter-individual variations in glycemic response to metformin. Numerous pharmacogenetic studies have demonstrated that variations in genes related to pharmacokinetics and pharmacodynamics of metformin's encoding transporters are mainly associated with metformin response.
The goal of this review is to evaluate the current state of metformin pharmacogenetics and metabolomics research, discuss the clinical and scientific issues that need to be resolved in order to increase our knowledge of patient response variability to metformin, and how to improve patient outcomes. Metformin's hydrophilic nature and absorption as well as its action mechanism and effectiveness on T2D initiation are discussed. The impacts of variations associated with various genes are analysed to identify and evaluate the effect of genetic polymorphisms on the therapeutic activity of metformin. The metabolic pattern of T2D and metformin is also indicated. This is to emphasise that studies of pharmacogenetics and metabolomics could expand our knowledge of metformin response in T2D.
Objectives: The objective of this study was to estimate the occurrence of Vitamin B12 deficiency in patients with type 2 diabetes mellitus treated with metformin, and the clinical and biochemical profile of vitamin B12 deficiency in them. Materials and Methods: This was a cross sectional study. Type 2 Diabetics over the age of 18 years were recruited for the study. Patients were divided into two groups - one groupof 62 patients who were on metformin for more than 6 months and the other group of 62 patients who were on other oral hypoglycemic agents or insulin. Patients were interviewed using a questionnaire. Relevant blood investigations were done. Results: The mean (+SD) age of study population was 57 (±9.8) years with an age range of 35 to 79 years. There was high prevalence of vitamin B12 deficiency in patients with type 2 diabetic mellitus treated with metformin (22.6%)(p-value<0.001). This study showed a statistically significant inverse relationship between duration of metformin use and vitamin B12 levels (p-value 0.01). There was a statistically significant correlation between the dose of metformin and vitamin B12 deficiency – the higher the dose, the lower the average vitamin B12 level (p-value 0.02). The study revealed significantly increased neuropathic symptoms in Type 2 Diabetic patients on metformin with B12 deficiency than with normal B12 levels (p-value<0.001). Conclusions: This study demonstrated a high prevalence of vitamin B12 deficiency in patients with type 2 diabetic patients treated with metformin (22.6%). Hencethe measurement of vitamin B12 should become an essential part of the annual review in all patients with type 2 diabetic patients on metformin therapy. The study revealed significantly increased neuropathic symptoms in Type 2 Diabetic patients on metformin with B12 deficiency than with normal B12 levels.
The current meta-analysis aims to explore the effect of metformin use on vitamin B12 deficiency in patients with type 2 diabetes mellitus (T2DM) and the factors associated with it. This meta-analysis followed the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines and the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. We searched PubMed and EMBASE from January 1, 2010, to October 31, 2022, to collect the studies that reported the effect of metformin on the deficiency of vitamin B12 in patients with T2DM and the factors associated with it. A total of 17 studies were included in the current meta-analysis. Among all the included studies, 13 were cross-sectional studies, 3 were retrospective cohorts, and one was a case-control study. The pooled rate of deficiency of vitamin B12 in patients receiving metformin (23.16%) was significantly higher compared to patients who were not on metformin (17.4%) (OR: 2.95, 95% CI: 2.18-4.00, p-value: 0.001). Factors significantly associated with vitamin B12 deficiency in patients with T2DM and receiving metformin include the duration of metformin use and a greater dose of metformin. In conclusion, our meta-analysis found that the prevalence of vitamin B12 deficiency is greater in patients receiving metformin compared to patients who did not receive metformin. Given the importance of vitamin B12 in nutrition, metformin-induced B12 decrease may be harmful to patients with T2DM. Supplemental vitamin B12 may be advantageous for those on metformin.
Background and aims
Metformin-treated type 2 diabetes mellitus (T2DM) patients are at higher risk of vitamin B12 deficiency and more severe neuropathy symptoms. There is still no guideline suggesting vitamin B12 supplementation for this population. This study aimed to analyze the efficacy of vitamin B12 supplementation in this population.
Method
Studies reporting the efficacy of vitamin B12 supplementation in metformin-treated T2DM patients were systematically searched in PubMed, Cochrane, EBSCOHost, and Scopus following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Additional relevant studies were searched manually through citations. Study quality and risk of bias were assessed using suitable tools.
Results
Seven clinical trials with a total of 506 participants were included. Using the Cochrane's Risk of Bias 2 tools for clinical trials, 4 studies were assessed to have high risk of bias and 3 studies had low risk of bias. There were 5 studies that measured changes in serum vitamin B12 level, all of which reported a statistically significant increase after supplementation. Significant reductions in homocysteine after supplementation were found in 2 studies. Its effect on neuropathy symptoms was still unclear, with 2 studies reporting a significant improvement and 1 study reporting no significant effect.
Conclusions
The results of this systematic review support the implementation of vitamin B12 supplementation for metformin-treated T2DM to prevent or treat vitamin B12 deficiency and neuropathy. More high-quality clinical studies are required to generate quantitative analysis and to encourage supplementation in available guidelines.
Objectives: To assess knowledge and practice of physicians regarding Vitamin B12 Screening among Type 2 diabetes mellitus (T2DM) and assess knowledge of physicians about recent American diabetic association (ADA) guidelines updates. Methods: A cross sectional study was conducted at Primary Health Care (PHC) centers in Buraidah, Qassim from January to April 2022. Data was collected using a structured questionnaire which was based on ADA guidelines among all physicians of PHCs. Statistical package for social sciences (SPSS) version 23.0 was used for analysis. Frequencies and percentages were calculated for categorical variables and means with standard deviations were calculated for continuous variables. Results: About 135 (72.2%) physicians would test T2DM patients who are on metformin for Vitamin B12, and only 65 (34.8) would test them annually. Early signs of Diabetic peripheral neuropathy (DPN) are pain, burning sensation, tangling sensation, numbness and loss of protective sensation (LOPS). Only 23 (12.3%) of them knew the all five symptoms. Forty-five (45.5%) of participants would not treat DPN with B12 supplementation. Only (57.2%) order Vit B12 testing for DM2 who are on metformin, and (49.2%), (29.4%) would order them if the patient has neuropathy and on annual basis respectively. Majority of physicians (70.6%) give Vit B12 supplements as treatment of DPN. Conclusions: There is poor knowledge and practices related to B12 deficiency among primary care physicians. This calls for training and educating primary care physicians regarding B12 deficiency screening, neuropathy and their management. There is also need for providing sufficient resources in order to ensure B12 screening in high risk diabetic patients.
Biguanides are a family of antidiabetic drugs with documented anticancer properties in preclinical and clinical settings. Despite intensive investigation, how they exert their therapeutic effects is still debated. Many studies support the hypothesis that biguanides inhibit mitochondrial complex I, inducing energy stress and activating compensatory responses mediated by energy sensors. However, a major concern related to this "complex" model is that the therapeutic concentrations of biguanides found in the blood and tissues are much lower than the doses required to inhibit complex I, suggesting the involvement of additional mechanisms. This comprehensive review illustrates the current knowledge of pharmacokinetics, receptors, sensors, intracellular alterations, and the mechanism of action of biguanides in diabetes and cancer. The conditions of usage and variables affecting the response to these drugs, the effect on the immune system and microbiota, as well as the results from the most relevant clinical trials in cancer are also discussed.
Background:
Diabetes is a global pandemic, especially in Arab countries.
Aim:
The goal of this study was to review the published studies that were conducted to determine the relationship between metformin treatment for type 2 diabetes mellitus (T2DM) and vitamin B12 deficiency and to identify possible complications in this relationship.
Methods:
I searched for all relevant studies published in English before 2020 on the PubMed and Web of Knowledge databases using the following terms: "metformin", "vitamin B12", "neuropathy", "diabetes mellitus", and Middle Eastern countries.
Results:
Eleven studies were included in this review which indicated an association between taking metformin and B12 deficiency in patients with T2DM in Arab countries. This B12 deficiency was found to be negatively associated with the dose and duration of metformin therapy. The physician's knowledge of current ADA recommendations regarding supplementation with and screening of the B12 level for T2DM patients on metformin was also found to have an effect.
Conclusion:
Metformin therapy is associated with B12 deficiency among people with T2DM in Arabic countries. Thus, diabetes must be managed in compliance with current guidelines and recommendations, and B12 levels must be routinely monitored, particularly in those who have been long-term takers of metformin, to ensure the suitable management of diabetes and its complications.
Metformin blocks the absorption of vitamin B12 through a mechanism that has not been established but could be because of interference with the calcium‐dependent binding of the intrinsic factor vitamin B12 complex to the cubam receptor in the terminal ileum. The subsequent deficiency of vitamin B12 may cause or accelerate distal symmetrical and autonomic neuropathy in the patient with diabetes. Several observational studies and meta‐analyses have reported a significant association between metformin utilization and vitamin B12 deficiency. Prospective studies have shown that not only do metformin utilizers have lower vitamin B12 levels but they also have higher frequencies of distal symmetrical polyneuropathy and autonomic neuropathy (including cardiac denervation, which is associated with increased incidences of cardiac arrhythmias, cardiac events and mortality). Therefore, periodic monitoring of vitamin B12 is recommended in all patients who utilize metformin, particularly if metformin has been used for over 5 years at which stage hepatic stores of vitamin B12 would probably be depleted. Factors that accelerate the loss of hepatic vitamin B12 stores are proton pump inhibitors, bariatric surgery, being elderly and having an increased turnover of red blood cells. If serum vitamin B12 levels are borderline, measurement of methylmalonic acid and homocysteine levels can detect vitamin B12 deficiency at its earliest stage. Therapies include prophylactic calcium and vitamin B12 supplements, metformin withdrawal, replenishing vitamin B12 stores with intramuscular or oral vitamin B12 therapy and regular monitoring of vitamin B12 levels and vitamin B12 supplements if metformin continues to be utilized. With adequate vitamin B12 replacement, while symptoms of neuropathy may or may not improve, objective findings of neuropathy stabilize but do not improve.
Introduction
Type 2 diabetes mellitus (DM) is a prevalent global health problem and is on a constant rise, especially in middle- and low-income countries. Vitamin B12 malabsorption is one of the reported side effects of metformin. Our study aims to assess the correlation of B12 deficiency in type 2 diabetics using metformin for their treatment.
Methods
This case-control study was conducted in a tertiary care hospital in Pakistan from February 2021 to December 2021. Patients (n=100) with a documented diagnosis of type 2 DM on metformin monotherapy for a minimum of six months were enrolled via consecutive convenient non-probability sampling. Another 100 patients without a history of diabetes were included in the study as a control group for comparison.
Results
Serum vitamin B-12 levels were higher in the non-diabetic participants as compared to the diabetic group (301.71 ± 72.12 vs. 189.25 ± 31.22; p-value: <0.0001). Hypovitaminosis was more significant in the diabetic group (p-value: 0.0000). Serum vitamin B12 levels were found to be declining with the increasing duration of metformin use (p-value: <0.0001).
Conclusion
Our study found a significant effect of vitamin B12 deficiency in metformin-treated patients. Therefore, it is prudent to recognize B12 deficiency as a potential side effect of long-term use of metformin. A periodic screening of B12 in such patients and subsequent supplementation of vitamin B12 is an effective and safe means of prevention of development or worsening of peripheral nerve damage and other clinical manifestations.
Metformin is the most frequently prescribed first line therapy for Type 2 Diabetes Mellitus (T2DM) and it is one of the fewer antihyperglycaemics associated with improvements in the morbidity and mortality of cardiovascular disease associated with T2DM. Although there are major beneficial effects but it is shown to have disadvantages with long-term use of metformin. Recent studies have shown that metformin induces malabsorption of Vitamin B12, which may increase the risk of developing Vitamin B 12 deficiency. Vitamin B12 is one of the integral nutritional components that affect the oral health with individuals with decreased levels exhibit various oral manifestations such as glossitis, glossodynia, recurrent ulcers, angular cheilitis, dysgeusia, lingual paraesthesia, burning sensations and pruritis. Most of the vitamin B12 deficiencies are associated with malabsorption syndrome, gastrectomy cases, and elderly people. The prevalence of oral manifestations with regard to metformin induced Vitamin B12 has to be considered as new paradigm in routine diagnosis and investigations. This review likewise centers around the mechanism involved in metformin induced vitamin B12 deficiency and possible implications in the diagnosis and management of oro-mucosal lesions associated with such deficiency.
Metformin is the leading drug for treating type 2 diabetics, but the mechanism of action of metformin, despite some suggested mechanisms such as the activation of the AMP-kinase, is largely unknown. Among its many positive effects are the reduction of blood glucose levels, the inhibition of cyclic AMP synthesis, gluconeogenesis and an increase in sensitivity to insulin. Recent studies have described the natural antagonist of cyclic AMP, prostaglandylinositol cyclic phosphate. Synthesis of cyclic PIP is stimulated in all organs by hormones such as insulin and also by drugs such as metformin. Its primary action is to trigger the dephosphorylation of proteins/enzymes, phosphorylated on serine/threonine residues. Cyclic PIP triggers many of the regulations requested by insulin. The parallels between the beneficial effects of metformin and the regulations triggered by cyclic PIP suggest that the mechanism of action of this key drug may well be explained by its stimulation of the synthesis of cyclic PIP.
Diabetes is considered the most common non-communicable disease, coupled with high blood pressure and lipids. Thus, decreasing carbohydrate, sugar, fat and sodium (4Ds) are target behaviors for patients with diabetes to reduce the chance of long-term complications. This two-group, quasi-experimental research was designed mainly to assess the effects of a 4Ds program on dietary behaviors and blood sugar control of patients with type 2 diabetes in Pathumthani Province. Seventy patients were recruited from the sub-district health promotion hospital (HPH) of Muang District. The experimental group attended the program activities based on Bandura’s social learning theory for 12 weeks. Pre- and post-test data were collected using a structured interview questionnaire. T-test was applied to test the program effectiveness. Findings affirmed the effectiveness of the 4Ds program. Because the experimental group gained more knowledge and had higher self-efficacy to manage blood sugar control behaviors, better perceived outcome expectations in modifying the behaviors and significantly less carbohydrate, sugar, fat and sodium consumption than the comparison group was observed (p<0.001). Their average fasting blood sugar (FBS) decreased to the desired controllable level. The average FBS of the comparison group slightly decreased. The FBS of the experimental group was significantly decreased than the comparison group (p<0.001). In designing an intervention, health officers may use self-efficacy as a starting point of the program features and the knowledge required should be relevant to the designed behavioral targets
Background
Metformin is the most-used drug in type 2 diabetes mellitus (T2DM) management, but it may lower B12 status as a use consequence. However, few studies in Saudi Arabia have assessed this risk.
Aim
This study aimed to estimate the prevalence of vitamin B12 deficiency in metformin-treated type 2 diabetic patients and its association with drug duration and dose with relation to B12 dietary intake.
Method
A cross sectional study was conducted with 206 patients with type 2 diabetic patients using metformin for 6 months or more and attending the diabetic clinics at Al-Noor Specialist Hospital in Holy Makkah. Serum B12 levels were estimated, and biochemical B12 deficiency was defined as serum levels <243 nmol/L. Demographic, medical history, dietary assessment for B12 intake, and data on metformin use were collected using an online survey. Statistical package for the social sciences (SPSS) version 25 was used for statistical analysis.
Results
Vitamin B12 deficiency occurred in 17.5% of the patients using metformin. Significant differences existed according to diabetes duration (p = 0.002) between patients showing deficiencies and normal ranges of vitamin B12. No significant differences were found according to metformin dose, duration, and vitamin B12 intake.
Conclusion
The prevalence of B12 deficiency in patients with type 2 diabetic patients using metformin was 17.5%. The risk of this relationship might increase with longer metformin use and is influenced by the occurrence and duration of diabetes.
We aimed to determine the prognostic association between cardiac autonomic neuropathy (CAN) and cardiovascular disease events (CVE) and mortality in type 1 and type 2 diabetes through a systematic review and meta-analysis. This systematic review and meta-analysis was registered with PROSPERO (CRD42020216305) and was conducted with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodological criteria. CAN was defined on the basis of 1 (early/possible CAN) or ≥2 (definite CAN) positive autonomic function tests as per the Toronto Consensus guidelines. Studies included those with prospective CVE or mortality data. Methodological variables/risk of bias were assessed using ROBINS-I (Risk Of Bias In Non-randomized Studies - of Interventions) and RoB-2 (Risk-Of-Bias tool for randomized trials) appraisal tools. Electronic database searches yielded 18 467 articles; 84 articles were screened full-text, 26 articles fulfilled the inclusion criteria for quantitative synthesis. Sixteen studies from patients with (n=2875) and without (n=11 722) CAN demonstrated a pooled relative risk (RR) of 3.16 (95%CI 2.42 to 4.13; p<0.0001) of future CVE in favour of CAN. Nineteen studies provided all-cause mortality data from patients with (n=3679) and without (n=12 420) CAN, with a pooled RR of 3.17 (95%CI 2.11 to 4.78; p<0.0001) in favour of CAN. The risk of both future CVE and mortality was higher in type 1 compared with type 2 diabetes and with a definite CAN (vs possible CAN) diagnosis. Three studies were considered to have risk of serious bias. This study confirms the significant association between CAN and CVE and all-cause mortality. The implementation of population-based CAN screening will identify a subgroup with disproportionately higher cardiovascular and mortality risk that will allow for earlier targeted intervention.
Objectives:
This study aimed to demonstrate the effectiveness of early medication treatment and metformin use for cancer prevention in type 2 diabetes patients.
Methods:
A population-based cohort data was used from the Korean National Health Insurance Service-National Sample Cohort database (KNHIS-NSC) for 2002-2013. Patient-specific medication prescription status was defined by the landmark-time (LMT; a fixed-time after cohort entry), considering both pre- and post-LMT prescription drugs to control methodological biases in observational study. LMT was set to 2 years. Logistic regression analysis with multivariable adjustment was conducted to analyze the cancer incidence by patient-specific medication prescription status.
Results:
Only 33.36% of the subjects were prescribed medication early (before LMT) with compliance. Cancer incidence with early prescription and compliance was 25% lower (OR=0.75, 95% CI=0.67-0.84) than those without, and as an early prescribing medication, metformin monotherapy and metformin combination therapy had a 34% (OR=0.66, 95% CI=0.51-0.83) and 25% (OR=0.75, 95% CI=0.64-0.88) lower cancer risk than non-users, respectively. Patients who were prescribed late (after LMT) but did not comply with the prescription had a 24% (OR=1.24, 95% CI=0.97-1.58) higher cancer incidence than non-users. Among patients started monotherapy early and unchanged through the entire follow-up, those who started on metformin had a 37% (OR=0.63, 95% CI=0.41-0.99) lower risk of cancer than non-metformin.
Conclusion:
Doctors must prescribe antidiabetic medication early, and the patient must comply with the prescribed medication regardless of the time of prescription to prevent cancer in diabetic patients. Metformin monotherapy or combination is recommended as early prescription.
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 groups. Using electronic health records from 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. 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 overall, 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 25 kg/m ² there was a protective effect for DPP-I, warranting further investigation. 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.
Objective:
To compare the safety and efficacy of glimepiride and vildagliptin as add-on therapy to metformin in newly diagnosed patients with type 2 diabetes mellitus (T2DM).
Methods:
This 24-week, prospective, comparative, observational study was conducted among newly diagnosed patients with T2DM. The primary endpoint was a change in fasting plasma glucose (FPG), postpradinal glucose (PPG), and HbA1c from the baseline to week 24. The key secondary endpoints were monitoring treatment-emergent adverse events such as hypoglycemia, overall gastrointestinal symptoms and weight gain, and electrocardiogram (ECG) findings.
Results:
A total of 100 eligible patients were divided into two groups: group A (n = 50) received vildagliptin plus metformin and group B (n = 50) received glimepiride plus metformin. The mean age of the patients was 49.98 years and 52.12 years in group A and group B, respectively. Electrocardiographic findings were within normal limits in all the patients from group A, whereas 47 patients from group B showed normal ECG findings. A significant decrease in HbA1c, fasting and post-prandial plasma glucose was observed with group A and group B from the baseline to week-24. However, at week-24, reduction in HbA1c and blood glucose parameters were comparable between the groups. Safety outcomes did not show any events of hypoglycemia with vildagliptin. Mild hypoglycemia was reported with glimepiride in five patients.
Conclusion:
Vildagliptin-metformin appeared to be equally effective to glimepiride-metformin in reducing HbA1c level and blood glucose parameters, however, resulted in better adverse event profiles with lower risks of hypoglycemia.
The increasing prevalence of diabetes and its complications, such as cardiovascular and kidney disease, remains a huge burden globally. Identification of biomarkers for the screening, diagnosis, and prognosis of diabetes and its complications and better understanding of the molecular pathways involved in the development and progression of diabetes can facilitate individualized prevention and treatment. With the advancement of analytical techniques, metabolomics can identify and quantify multiple biomarkers simultaneously in a high-throughput manner. Providing information on underlying metabolic pathways, metabolomics can further identify mechanisms of diabetes and its progression. The application of metabolomics in epidemiological studies have identified novel biomarkers for type 2 diabetes (T2D) and its complications, such as branched-chain amino acids, metabolites of phenylalanine, metabolites involved in energy metabolism, and lipid metabolism. Metabolomics have also been applied to explore the potential pathways modulated by medications. Investigating diabetes using a systems biology approach by integrating metabolomics with other omics data, such as genetics, transcriptomics, proteomics, and clinical data can present a comprehensive metabolic network and facilitate causal inference. In this regard, metabolomics can deepen the molecular understanding, help identify potential therapeutic targets, and improve the prevention and management of T2D and its complications. The current review focused on metabolomic biomarkers for kidney and cardiovascular disease in T2D identified from epidemiological studies, and will also provide a brief overview on metabolomic investigations for T2D.
Background: Diabetes Mellitus is one of the most encountered disease in our out patient department and metformin is the first drug of choice to treat Diabetes mellitus. As metformin is one of the cheapest drug, many patients use these drug for long period of time with consultation and without consultations with doctors. Patients under long term metformin use are not aware of Vitamin B12 deficiency and its associated signs and symptoms. In Nepal due to poverty, lack of education and awareness on diabetes mellitus we doctors find much difficult to explain patients on the consequences of diseases. So I decided to do this study which could be much easier to explain patients on effect of metformin of vitamin B12 levels and the consequences life style modifications and supplement of Vitamin B12 to the patients. Methods: This is a Cross-Sectional Study done in the patients with Type 2 diabetes were selected based on inclusion and exclusion criteria. Basic biochemical investigation were sent the lab of the National academy of medical science. Serum B12 assay were done. Vitamin B12 deficiency is defined as values <150pg/ml. Association between vitamin B12 deficiency with duration of metformin therapy, duration of diabetes, with age, sex were done. Results: The mean vitamin B12 level is low as the duration of metformin treatment increases. The sex, age relation with development of vitamin B12 deficiency was not significant. In my study out of 210 patients 107 patients were having severe vitamin B12 deficiency level and 63 patients had a borderline Vitamin B12 deficiency level which shows that the deficiency increases as per longer use of metformin, which shows prevalence of 50.95%. Conclusions: Vitamin B12 deficiency occurs in type 2 diabetes mellitus patients treated with long term metformin. The duration of metformin therapy significantly affects the development of vitamin B12 deficiency. As a treating physician we always need to explain our patients about the side effect of metformin and regular follow up and investigations must be done to early diagnosis of vitamin B12 deficiency to improve the quality of life.
To date, metformin remains the first-line oral glucose-lowering drug used for the treatment of type 2 diabetes thanks to its well-established long-term safety and efficacy profile. Indeed, metformin is the most widely used oral insulin-sensitizing agent, being prescribed to more than 100 million people worldwide, including patients with prediabetes, insulin resistance, and polycystic ovary syndrome. However, over the last decades several observational studies and meta-analyses have reported a significant association between long-term metformin therapy and an increased prevalence of vitamin B12 deficiency. Of note, evidence suggests that long-term and high-dose metformin therapy impairs vitamin B12 status. Vitamin B12 (also referred to as cobalamin) is a water-soluble vitamin that is mainly obtained from animal-sourced foods. At the cellular level, vitamin B12 acts as a cofactor for enzymes that play a critical role in DNA synthesis and neuroprotection. Thus, vitamin B12 deficiency can lead to a number of clinical consequences that include hematologic abnormalities (e.g., megaloblastic anemia and formation of hypersegmented neutrophils), progressive axonal demyelination and peripheral neuropathy. Nevertheless, no definite guidelines are currently available for vitamin B12 deficiency screening in patients on metformin therapy, and vitamin B12 deficiency remains frequently unrecognized in such individuals. Therefore, in this "field of vision" article we propose a list of criteria for a cost-effective vitamin B12 deficiency screening in metformin-treated patients, which could serve as a practical guide for identifying individuals at high risk for this condition. Moreover, we discuss additional relevant topics related to this field, including: (1) The lack of consensus about the exact definition of vitamin B12 deficiency; (2) The definition of reliable biomarkers of vitamin B12 status; (3) Causes of vitamin B12 deficiency other than metformin therapy that should be identified promptly in metformin-treated patients for a proper differential diagnosis; and (4) Potential pathophysiological mechanisms underlying metformin-induced vitamin B12 deficiency. Finally, we briefly review basic concepts related to vitamin B12 supplementation for the treatment of vitamin B12 deficiency, particularly when this condition is induced by metformin.
Vitamin B12 deficiency in early childhood is an important cause of neurodevelopmental delay and regression. Most of these cases occur in exclusively breast-fed infants of deficient mothers. Symptoms and signs of vitamin B12 deficiency appear between the ages of 2 to 12 months and include vomiting, lethargy, failure to thrive, hypotonia, and arrest or regression of developmental skills. Approximately one half of this cases exhibit abnormal movements, variously described as tremors, twitches, chorea, or myoclonus. Urinary concentrations of methylmalonic acid and homocysteine are characteristically elevated in vitamin B12 deficiency. Hyperglycinuria is sometimes present. The early diagnosis and treatment of vitamin B12 deficiency is crucial for significant neurological impairment and long-term prognosis. Treatment with vitamin B12 corrects these metabolic abnormalities very rapidly (within a few days). Vitamin B12 supplementation of pregnant women may prevent neurological and neuroradiological findings of the infants. Because of the importance of vitamin B12 in the development of the foetal and neonatal brain, vegetarian and vegan mothers should be aware of the severe and not fully-reversible damages caused by insufficient nutritional intake of vitamin B12 during pregnancy and lactation. Therefore, efforts should be directed to prevent its deficiency in pregnant and breastfeeding women on vegan diets and their infants. It is also important to take the nutritional history of both infants and their mothers for the early prevention and treatment. Here an interesting case of vitamin B12 deficiency in a 10-month-old boy presented with psychomotor regression, hypotonia and lethargy.
Background: Metformin, a commonly used antidiabetic medication, is available in both an immediate-release (IR) formulation and a long-acting formulation (metformin extended-release; XR).
Objective: We performed a systematic review to compare the effectiveness, safety, and patient compliance and satisfaction between the metformin IR and XR formulations.
Method: We searched for randomized control trials (RCTs) and observational studies comparing the effectiveness, safety, or patient compliance and satisfaction of metformin XR with metformin IR using the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases. Following report screening, data collection, and risk of bias assessment, we separately pooled data from RCTs and observational studies using the Grading of Recommendation Assessment, Development, and Evaluation approach to rate the quality of evidence.
Result: We included five RCTs, comprising a total of 1,662 patients, and one observational study, comprising 10,909 patients. In the meta-analyses, no differences were identified in outcomes of effectiveness and safety between the two forms of metformin (including change in HbA1c: mean difference (MD), 0.04%, 95% confidence interval [CI], −0.05–0.13%, fasting blood glucose: MD, −0.03 mmol/L, 95% CI, −0.22–0.15 mmol/L, postprandial blood glucose: MD, 0.50 mmol/L, 95% CI, −0.71–1.72 mmol/L, adverse events of abdominal pain: relative risk (RR), 1.15, 95% CI, 0.57–2.33, all-cause death (RR, 3.02, 95% CI 0.12–73.85), any adverse events (RR, 1.14, 95% CI 0.97–1.34), any adverse events leading to treatment discontinuation: RR, 1.51, 95% CI, 0.82–2.8, any gastrointestinal adverse events: RR, 1.09, 95% CI, 0.93–1.29, diarrhea: RR, 0.82, 95% CI, 0.53–1.27, flatulence: RR, 0.43, 95% CI, 0.15–1.23, nausea: RR, 0.97, 95% CI, 0.64–1.47, severe adverse events: RR, 0.64, 95% CI, 0.28–1.42, and vomiting: RR, 1.46, 95% CI, 0.6–3.56). Data from both the RCTs and the observational study indicate mildly superior patient compliance with metformin XR use compared with metformin IR use; this result was attributable to the preference for once-daily administration with metformin XR.
Conclusion: Our systematic review indicates that metformin XR and IR formulations have similar effectiveness and safety, but that metformin XR is associated with improved compliance to treatment.
Vitamin B12 plays a very important role in human body and its deficiency can be detrimental to the production of red blood cells, anemia, memory loss, low immunity to infection, and permanent and severe damage in the nervous system and brain. In the present work, vitamin B12 sensing has been accomplished using two Electrochemiluminescence (ECL) platforms, one with Bipolar Electrode (BPE), while the second one Single Electrode (SE). The electrodes were fabricated on polyimide (PI) substrate by creating optimized Laser-Induced Graphene (LIG). With optimized speed and power of CO2 Laser, non-conducting portion of PI gets converted into conducting zone (electrodes) for ECL imaging. A 3D-printed miniaturized portable system was developed to detect and monitor the ECL signals. Android smartphone was effectively used to provide dual functions such as to drive the DC to DC buck-boost converter and to capture the ECL images. The sensing of vitamin B12 was accomplished in the linear range 0.5–700 nM and 0.5–1000 nM with a limit of detection (LOD) 0.107 nM (R2 = 0.98, n = 3) and 0.094 nM (R2 = 0.977, n = 3), respectively, for BPE and SE-based ECL platforms correspondingly. Therefore, proposed ECL platforms can be selectively used in various domains such as point of care testing (POCT) and biomedical applications.
Aim:
To investigate the effect of normalizing vitamin B12 (B12) levels with oral B12 (methylcobalamin) 1000 μg/day for one year in patients with diabetic neuropathy (DN).
Patients and methods:
In this prospective, double-blind, placebo-controlled trial, 90 patients with type 2 diabetes on metformin for at least four years and both peripheral and autonomic DN were randomized to an active treatment group (n = 44) receiving B12 and a control group (n = 46) receiving a placebo. All patients had B12 levels less than 400 pmol/L. Subjects underwent measurements of sural nerve conduction velocity (SNCV), sural nerve action potential (amplitude) (SNAP), and vibration perception threshold (VPT), and they performed cardiovascular autonomic reflex tests (CARTs: mean circular resultant (MCR), Valsalva test, postural index, and orthostatic hypotension). Sudomotor function was assessed with the SUDOSCAN that measures electrochemical skin conductance in hands and feet (ESCH and ESCF, respectively). We also used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE, respectively) and questionnaires to evaluate quality of life (QoL) and level of pain (pain score).
Results:
B12 levels increased from 232.0 ± 71.8 at baseline to 776.7 ± 242.3 pmol/L at follow-up, p < 0.0001, in the active group but not in the control group. VPT, MNSIQ, QoL, pain score, SNCV, SNAP, and ESCF significantly improved in the active group (p < 0.001, p = 0.002, p < 0.0001, p < 0.000, p < 0.0001, p < 0.0001, and p = 0.014, respectively), whereas CARTS and MNSIE improved but not significantly. MCR, MNSIQ, SNCV, SNAP, and pain score significantly deteriorated in the control group (p = 0.025, p = 0.017, p = 0.045, p < 0.0001, and p < 0.0001, respectively).
Conclusions:
The treatment of patients with DN with 1 mg of oral methylcobalamin for twelve months increased plasma B12 levels and improved all neurophysiological parameters, sudomotor function, pain score, and QoL, but it did not improve CARTS and MNSIE.
Diabetic Foot Ulcer (DFU) is a severe complication of diabetes causing an economic burden and affecting millions of patients worldwide. Treatment of DFU has gained an attention of biomedical engineering as the traditional methods were having various challenges to overcome which, 3D Scaffolds (Nanofibers) have emerged as potential candidates. Nanofibrous scaffolds are a promising approach as they can mimic extracellular matrix,
rejuvenate the skin, and promote the wound healing. This review focuses on the delivery strategies of nanofibers, including their fabrication techniques and different polymers utilized in reparation along with their merits and demerits. Furthermore, the applications of nanofibers and recent patents that got approved have been discussed. Overall, this review attempts to highlight the potential of nanofibers in diabetic foot ulcer treatment and the need for further research and development to optimize their use in clinical settings.
Introduction:
Teleconsultation gained popularity to provide safe medical care during the pandemic. However, literature on the sustainability of teleconsultation service at primary care beyond pandemic situations is scarce. This study aimed to determine the use of teleconsultation services for non-communicable disease (NCD) follow-up and explore the benefits and challenges of the service implementation during and beyond COVID-19 pandemic in Malaysia.
Materials and methods:
An exploratory qualitative study was conducted using videoconferencing. Fourteen medical officers working in public primary healthcare clinics from various regions of Malaysia were chosen using purposive sampling process, and participants underwent a total of seven paired in-depth interview (IDI) sessions. IDIs were video recorded, transcribed and subjected to interpretive thematic analysis.
Results:
The two main themes which emerged were the benefits and challenges of NCD teleconsultation service. Various categories relating to benefits of teleconsultation for NCD care are as follows: (1) Improved efficiency for patient care delivery (improved effectiveness, convenient, improved safety, better disease monitoring, patient empowerment) and (2) Benefits for Health Care Providers (improved healthcare and service delivery). Main challenges identified were as follows: (1) Challenges for Delivery of Care (Patients' adaptation in using teleconsultation service, Patients abusing the system, Poor digital literacy, No proper disease monitoring record), (2) Challenges for Health Care Providers (Lack of dedicated team and training, Higher workload and time-consuming) and (3) Challenges for Health Care System (Institutional policy, legal and regulatory weakness, Medical record documentation and prescription updates).
Conclusion:
Optimisation of NCD patient healthcare delivery via teleconsultation is beneficial during and after pandemic. Targeted improvements to address current challenges are crucial to optimise its use beyond the pandemic period in the Malaysian public healthcare system.
Objectives: To determine the prevalence of vitamin B12 deficiency in a Tunisian population with type 2 diabetes (T2D) on metformin treatment for more than three years and to identify its risk factors. Methods: This is a cross-sectional study conducted on 257 patients with T2D treated with metformin for at least three years. Patients were divided into two groups according to their vitamin B12 status. Low vitamin B12 was defined as ≤ 203 pg/mL. Results: The mean age of the patients was 59.8 ± 7.9 years. The mean duration of metformin use was 10.2 ± 5.2 years. The mean vitamin B12 level was 294.9 ± 156.4 pg/mL. The prevalence of vitamin B12 deficiency was 28.4%. Male gender, HbA1c < 7% and hyperhomocysteinemia were significantly associated with vitamin B12 deficiency (respectively p = 0.02, p < 0.001, p < 0.001). Homocysteine level was negatively correlated with vitamin B12 level (r = -0.2, p = 0.001). Dose and duration of metformin treatment, peripheral neuropathy and anemia were not associated with vitamin B12 deficiency. On multivariate analysis, HbA1c < 7% and hyperhomocysteinemia were independently associated with vitamin B12 deficiency (respectively OR = 3.2, 95%CI = [1.6-6.3] and OR = 2.3, 95%CI = [1.2-4.2]). Discussion: The prevalence of vitamin B12 deficiency in patients with T2D on metformin treatment was high. Hyperhomocysteinemia is associated with vitamin B12 deficiency suggesting that the deficit occurs at the tissue level.
Background:
Choline, folate, and vitamin B12 are required for growth and development, but there is limited information on the intakes and relationships to biomarkers of status in children.
Objectives:
The objective of this study was to determine the choline and B-vitamin intakes and relationship to biomarkers of status in children.
Methods:
A cross-sectional study was conducted in children (n = 285, aged 5-6 y) recruited from Metro Vancouver, Canada. Dietary information was collected by using 3 24-h recalls. Nutrient intakes were estimated by using the Canadian Nutrient File and United States Department of Agriculture database for choline. Supplement information was collected by using questionnaires. Plasma biomarkers were quantified by using mass spectrometry and commercial immunoassays, and relationships to dietary and supplement intake were determined by using linear models.
Results:
Daily dietary intakes of choline, folate, and vitamin B12 were [mean (SD)] 249 (94.3) mg, 330 (120) DFE μg, and 3.60 (1.54) μg, respectively. Top food sources of choline and vitamin B12 were dairy, meats, and eggs (63%-84%) and for folate, were grains, fruits, and vegetables (67%). More than half of the children (60%) were consuming a supplement containing B-vitamins, but not choline. Only 40% of children met the choline adequate intake (AI) recommendation for North America (≥250 mg/d); 82% met the European AI (≥170 mg/d). Less than 3% of children had inadequate folate and vitamin B12 total intakes. Some children (5%) had total folic acid intakes above the North American tolerable upper intake level (UL; >400 μg/d); 10% had intakes above the European UL (>300 μg/d). Dietary choline intake was positively associated with plasma dimethylglycine, and total vitamin B12 intake was positively associated with plasma B12 (adjusted models; P < 0.001).
Conclusions:
These findings suggest that many children are not meeting the dietary choline recommendations, and some children may have excessive folic acid intakes. The impact of imbalanced one-carbon nutrient intakes during this active period of growth and development requires further investigation.
Introduction
: Brain Insulin-resistance plays a critical role in pathogenesis of Alzheimer's disease (AD). Current study explored the therapeutic mechanism of metformin (insulin sensitizer) and its solid-lipid nanoformulation (SLN) in rat-model of AD. In our study, SLN was prepared using microemulsion method. AD was induced with ICV-Aβ whereas the control-group (sham) received ICV-NS. Treatment arms included, disease-control (no treatment), Metformin (50mg/kg, 100mg/kg and 150mg/kg), SLN-metformin 50mg/kg and memantine 1.8mg/kg (positive-control). Animals were tested for cognitive performance (EPM, MWM) after 21 days of therapy and sacrificed. Aβ (1-42), hyperphosphorylated tau, pAKTser473, GSK-3β, p-ERK (ELISA), metformin level(HPLC), neuronal injury score(H&E), Bcl2 and Bax(IHC) was evaluated in isolated brain. In our study, metformin-SLN were of spherical shape (size<200 nm) with 94.08% entrapment efficiency. Metformin was detectable in brain. Compared to sham, the disease-control group showed significantly higher (p≤0.05) memory impairment(MWM and EPM), hyperphosphorylated tau, Aβ(1-42), neuronal-injury, Bax and lower Bcl-2 expression. Treatment with metformin and nanoformulation significantly reverse these parameters. AKT-ERK-GSK3β-Hyperphosphorylated tau pathway was found to be involved in the protective efficacy of metformin. To conclude, both metformin and its SLN were found to be effective as therapeutic agents in AD which act through the AKT-ERK-GSK3β-Hyperphosphorylated tau pathway. We need population based studies to confirm the same.
The coronavirus disease 2019 (COVID-19) is an infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that produces respiratory symptoms and has serious consequences for people's cardiovascular systems (CVS). It is a severe issue and a major task not only for health care experts but also for governments to contain this pandemic. SARS-CoV-2 is the seventh member of the human coronavirus family to be implicated in this zoonotic outbreak. COVID-19's CV interactions are comparable to those of SARS-CoV, Middle East respiratory syndrome (MERS-CoV), and influenza. Those who have COVID-19 and underlying cardiovascular diseases (CVDs) are at a higher risk of serious illness and mortality, and disease has been linked to several direct and indirect CV consequences. COVID-19 causes CVDs such as arrhythmias, cardiac arrest, cardiogenic shock, myocarditis, stress-cardiomyopathy, and acute myocardial damage (AMD) as a consequence of acute coronary syndrome. The provision of CV care may expose health care professionals to risk as they become hosts or vectors of viral transmission. It binds to the angiotensin-converting enzyme receptor, causing constitutional and pulmonary signs in the beginning, and then as the infection advances, it affects other organs such as the gastrointestinal tract, CVS, neurological system, and so on. COVID-19 mortality is increased by underlying CVDs comorbidities.
Background:
Type 2 diabetes mellitus is one of the most globally common chronic diseases. Metformin is the most popular prescribed medication for the treatment of diabetes. Studies suggest that metformin is associated with vitamin B12 deficiency, which may impart adverse health complications.
Objective:
This review screens the literatures to clarify the effect of metformin on vitamin B12 deficiency among type 2 diabetes mellitus patients.
Methods:
Google Scholar, PubMed, Research Gate, and Semantic Scholar were searched for the association between metformin intake and vitamin B12 deficiency in type 2 diabetes mellitus patients using relevant key words and their combinations. Selected studies were those conducted on patients taking metformin with no vitamin B12 supplement. Nineteen studies (fifteen observational studies and four randomized controlled trials) met the inclusion criteria. These studies were assessed for design, setting, study population, and overall quality.
Results:
There is a positive correlation between metformin intake and vitamin B12 deficiency. This has been accompanied by increased homocysteine and decreased folate levels. Despite the refuting the findings, most studies showed that higher doses of metformin were strongly associated with lower vitamin B12 levels, while the duration of treatment was not.
Conclusion:
Regular measurement of vitamin B12 levels during long-term metformin treatment is recommended. A clear policy should be in place to illuminate the importance of this screening in preventing vitamin B12 deficiency complications. Taking therapeutic supplements or injections of vitamin B12 along with vitamin B12 rich diet may decrease the incidence of its deficiency in diabetic patients taking metformin.
Background/aim:
There have been no studies to date examining the effect of metformin treatment on vitamin B12 status in children and adolescents. In this prospective study, the effects of metformin on blood vitamin B12, serum methylmalonic acid (MMA), homocysteine and holo-transcobalamin-II (holo-TC-II) levels were assessed in pediatric age group.
Materials and methods:
This prospective study was conducted at the Pediatric Endocrinology and Adolescent Department between January 2017 and March 2019. Metabolic syndrome and polycystic ovary syndrome diagnosed patients with insulin resistance and/or impaired glucose tolerance, patients with type 2 diabetes mellitus (DM) treated with metformin were enrolled in study. Blood vitamin B12, MMA, homocysteine, holo-TC-II levels and hemogram values were evaluated.
Results:
Twenty-four patients were enrolled in study. Among these, 15 (62.5%) were female. The mean age of patients was 13.7±2.3 (10-19) years. Sixteen patients were diagnosed with metabolic syndrome and 8 patients were type 2 DM. At 6-month follow-up of all patients, there was no statistically significant difference in terms of vitamin B12, homocysteine, MMA and holo-TC-II levels. A 0.6% decline in vitamin B12 levels were revealed. At 12-month follow-up of 11 patients (45.8%) (6 Type 2 DM, 5 metabolic syndrome), no statistically significant difference was determined in vitamin B12, homocysteine, MMA and holo-TC-II levels. There were 6% decline in vitamin B12 levels and 10.9% increase in homocysteine levels, 5.4% decrease was detected in holo-TC-II level.
Conclusion:
Although no significant changes in the serum vitamin B12, homocysteine, MMA or holo-TC-II levels with metformin therapy were detected, long-term prospective studies with high-dose metformin treatment in pediatric population are needed to confirm our results.
In this review of megaloblastic anemia (MA), an overview of vitamin B12 and folate body requirements, biochemical pathways, and laboratory testing strategies will be provided. However, the focus of this review is the classic and unique features of MA in blood and bone marrow. Acquired MA is a benign disorder for many, but can be detrimental for some. The clinical presentation can vary considerably, and the spectrum of symptoms and signs is diverse and quite broad. Prompt recognition and therapy are critical to prevent potential irreversible damage and clinical sequelae, especially in patients with vitamin B12 deficiency. A delay in diagnosis of vitamin B12 deficiency can result in significant neurologic sequelae that may not fully resolve with treatment, including in neonates and young infants. The blood and bone marrow features in MA can closely mimic thrombocytopenic purpura, myelodysplasia, and other myeloid neoplasms. Both pancytopenia and normal MCV at presentation are common in MA and raise unique challenges for the diagnostician. Partially treated MA is also a significant diagnostic “trap”. MA is highly responsive to treatment, and patients tend to improve rapidly upon treatment initiation. However, the broad range of clinical and hematologic features makes the rapid, successful diagnosis of MA a unique challenge for the hematopathologist. Even in the era of state-of-the-art laboratory testing, a high suspicion is required.
The incidence of diabetes mellitus is rapidly increasing, and this condition often results in significant metabolic disease and severe complications. Nurses have a crucial role in monitoring, educating and supporting people with diabetes, as well as their families and significant others. This article provides an overview of the main types and common symptoms of diabetes, its acute and long-term complications and its management. It also outlines the nurse's role in diabetes care, which frequently includes assessing and empowering patients.
Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes an initiative designed to increase vitamin B12 screening in patients with type 2 diabetes on long-term metformin therapy at a free clinic in the southeastern United States.
Introduction
The emergence of COVID-19 and its ensuing restrictions on in-person healthcare has resulted in a sudden shift towards the utilization of telemedicine. The purpose of this study is to assess patient satisfaction and patient-reported outcome measures (PROMs) for individuals who underwent follow-up for shoulder surgery using telemedicine compared to those who received traditional in-person clinic follow-up.
Methods
Patients who underwent either rotator cuff repair or total shoulder arthroplasty during a designated pre-COVID-19 (traditional clinic follow-up) or peri-COVID-19 (telemedicine follow-up) span of time were identified. PROMs including the American Shoulder and Elbow Surgeons standardized assessment form, the three-level version of the EQ-5D form, the 12-Item Short Form survey, and a modified version of a published telemedicine survey were administered to participants six months post-operatively via phone call.
Results
Sixty patients agreed to participate. There was no significant difference between the pre-COVID-19 and peri-COVID-19 groups in patient satisfaction with their follow-up visit ( p = 0.289), nor was there a significant difference in PROMs between the two groups. In total, 83.33% of the telemedicine group and 70.37% of the in-person clinic group preferred traditional in-person follow-up over telemedicine.
Discussion
In a cohort of patients who underwent telemedicine follow-up for shoulder surgery during the COVID-19 pandemic, there was no difference in patient satisfaction and PROMs compared to traditional in-person clinic follow-up. This study indicates that while the majority of participants preferred face-to-face visits, patients were relatively satisfied with their care and had similar functional outcome scores in both groups, despite the large disruption in healthcare logistics caused by COVID-19.