Metformin-induced Vitamin B12 Deficiency Research Articles

Metformin-induced vitamin b12 deficiency and its impact on neurological health

Metformin-induced vitamin b12 deficiency and its impact on neurological health

Bacteroides ovatus accelerates metformin-induced vitamin B12 deficiency in type 2 diabetes patients by accumulating cobalamin

Vitamin B12 (VB12) deficiency, which may lead to hematologic and neurologic symptoms, has been associated with metformin use, but the underlying mechanism is unclear. Here we report the B. ovatus as an effective VB12 catcher which was enriched in the type 2 diabetes patients suffered from VB12 deficiency after 3 to 6 months of metformin treatment. Colonization of B. ovatus increased the plasma levels of methylmalonic acid and homocysteine in high-fat diet (HFD)-fed mice treated with metformin, and compromised the efficacy of metformin against the HFD-induced metabolic disorders. Mechanistically, metformin increased the intracellular accumulation of VB12 in B. ovatus via btuB upregulation and promoted ATP production for energy-dependent translocation of VB12 transporters at the inner membrane, leading to an enhanced colonization of B. ovatus to compete for VB12 with hosts and subsequently an aggravated VB12 deficiency in the host. Our findings illustrate a previously unappreciated mechanism of metformin leads to host VB12 deficiency by acting directly on gut bacteria to increase their VB12 uptake and consumption, and suggest that inter-host-microbe competition for nutrients may broadly impact human health and drug safety.

Vitamin B12 Status in Long-Term Metformin Treated Type 2 Diabetes Mellitus Patients

Background: The association between long-term use of metformin and low vitamin B12 levels in patients with type 2 diabetes mellitus (T2DM) has been proven. However, the prevalence among metformin induced vitamin B12 deficiency in T2DM patients showed considerable variations among the studies. The potential of deficiency to cause new onset or worse preexisting peripheral neuropathy in T2DM patients has been investigated with conflicting results.The objective of this study is to determine the frequency of vitamin B12 deficiency among patients with T2DM patients on metformin therapy compared to those who are not taking metformin. Methods: This crosssectional analytical study was conducted at the Department of Medicine, in Sylhet M. A. G. Osmani Medical College &Hospital, Sylhet. Total 100 patients’ withT2DM were selected according to inclusion and exclusion criteria following informed written consent. They were divided into two groups; each groups contains 50 patients. Group-I included patients who were taking metformin for e”1 year and Group-II included patients who were not taking metformin for at least 1 year. Detailed history taking, proper clinical examinations and relevant investigations were done. After collection of all the required data, final analysis was carried out by using the SPSS version 22.0. Results: Among 100 patients of T2DM, mean age were 55.4±15.62 and 55.24±16.76 years, respectively among Group- I and Group-II. They were similar in terms of demographic profile. About 16.0% patients of group- I had vitamin B 12 deficiency and 6.0% had vitamin B 12 deficiency in Group-II. The mean serum Vitamin B 12 was 481.52±283.37 (pgm/mL) in group-I and 600.85±294.2 (pgm/mL) in group-II. The difference of serum Vitamin B 12 was statistically significant (p<0.041) between two groups. Reduced vitamin B 12 also found to be positively associated with duration of metformin intake (p<0.05) and presence of neuropathy (p<0.05). Conclusion: Metformin is significantly associated with decrease the level of vitamin B12. Bangladesh J Medicine 2022; 33: 43-48

Synergism between metformin and analgesics/vitamin B12 in a model of painful diabetic neuropathy

Metformin (a widely used antidiabetic drug) has demonstrated efficacy in models of painful diabetic neuropathy (PDN), as well as certain clinical efficacy in relieving/preventing PDN. This study aimed to determine the type of interaction between metformin and duloxetine/oxycodone/eslicarbazepine acetate [ESL]/vitamin B12 in relieving diabetic pain hypersensitivity. Antihyperalgesic efficacy was determined using a Von Frey apparatus in mice with streptozotocin-induced PDN. We examined metformin’s efficacy following oral (acute and prolonged 7-day treatment) and local (spinal and peripheral) application. The examined analgesics were administered in a single oral dose, whereas vitamin B12 was intraperitoneally administered for 7 days. In combination experiments, metformin (prolonged treatment) and analgesics/vitamin B12 were co-administered in fixed-dose fractions of their ED50 values and the type of interaction was determined using isobolographic analysis. Metformin produced dose-dependent antihyperalgesic effects in diabetic mice after oral (acute and prolonged 7-day treatment) and local spinal/peripheral application. Two-drug metformin combinations with analgesics/vitamin B12 also dose-dependently reduced mechanical hyperalgesia. The isobolographic analysis revealed that metformin synergises with analgesics/vitamin B12, with a 6–7 fold dose reduction of both drugs in the examined combinations. In conclusion, metformin reduces hyperalgesia in diabetic animals, most likely by acting at the spinal and peripheral level. Additionally, it synergizes with duloxetine/oxycodone/ESL/vitamin B12 in reducing hyperalgesia. Metformin co-treatment may increase analgesic efficacy and enable the use of lower (and potentially safer) analgesic doses for treating PDN. Combined metformin-vitamin B12 use may provide more effective pain relief and mitigate metformin-induced vitamin B12 deficiency.

Metformin-induced vitamin B12 deficiency can cause or worsen distal symmetrical, autonomic and cardiac neuropathy in the patient with diabetes.

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.

Long Term Use of Metformin and its Effect on Serum Vitamin B12 with its Oral Manifestations: A Review

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.

English

BACKGROUND Metformin is considered as a cornerstone in the treatment of diabetes and is the most frequently prescribed first line therapy for individuals with T2DM. Metformin use in type 2 diabetes mellitus has shown to cause vitamin B12 (B12) deficiency. Besides these, B12 deficiency related neuropathy may mimic and/or aggravate the underlying diabetic neuropathy. Furthermore, there have been lack of consensus regarding the universal routine screening of serum B12 levels among metformin users with T2DM, and similar studies from India are also limited. So, we wanted to study the relationship between metformin use and serum B12 in T2DM patients. METHODS The study included a total of 104 subjects of which 52 are T2DM affected individuals who are only on metformin therapy for at least 3 months, served as cases and 52 are newly diagnosed T2DM age and sex matched individuals yet to be medically treated, served as controls. Their blood samples were collected to estimate vitamin B12 and other parameters. RESULTS The median B12 levels in cases 213.5 pg/mL (IQR 136.25-301.0) were found to be significantly lower (P < 0.05) when compared to median levels of controls 240 pg/mL (IQR 214-303.25). B12 levels also showed a significant fall in their levels with increasing duration of T2DM. CONCLUSIONS Metformin induced vitamin B12 deficiency plays a major role in developing life risks in T2DM patients. Routine screening and supplementation of B12 may be required in T2DM patients KEYWORDS Metformin, Type 2 Diabetes Mellitus, Vitamin B12

Long-term metformin therapy and vitamin B12 deficiency: An association to bear in mind.

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.

Association of MTHFR (rs 1801133) gene polymorphism with biochemical markers of B12 deficiency in type 2 diabetes mellitus patients on metformin therapy

BackgroundLong-term administration of metformin in Type 2 Diabetes mellitus (T2DM), interferes with the absorption of vitamin B12 resulting in deficiency. Low levels of vitamin B12 are associated with cardiovascular morbidity and mortality in T2DM patients. Several genetic variants are associated with vitamin B12 deficiency; one among them is Methylene Tetrahydrofolate reductase (MTHFR). We analyzed MTHFR (rs180133) polymorphism and its association with metformin induced vitamin B12 deficiency in T2DM patients. MethodsThree hundred T2DM patients were included. For the study and they were screened for vitamin B12 deficiency markers – Methyl malonic acid (MMA), Homocysteine (Hcy) and high sensitive C reactive protein (hsCRP). Genetic variant was analyzed by ARMS-PCR method. Data was analyzed with various statistical tools like ROC, Odds ratio and Likelihood ratio. ResultsThere is significant reduction in folic acid and vitamin B12 in metformin users. HsCRP, Hcy and MMA are significantly increased with P < 0.001 in patients with metformin induced B12 deficiency. T allele in MTHFR (T allele ORs =2.1, TT genotype =3.6) showed risk of vitamin B12 deficiency in T2DM patients on metformin therapy. MTHFR gene polymorphism of TT genotype had a Likelihood ratio (LR) of 2.46 for folic acid, 2.77 for MMA and 3.38 for Hcy. ConclusionWe found an association between MTHFR rs180133, 677C > T and vitamin B12 status in T2DM patients on metformin therapy. Folic acid, MMA and Hcy were found to have high specificity in concordance with MTHFR which showed to be a good predictor for vitamin B12 deficiency in T2DM patients on metformin therapy.

Association of BHMT (rs 3733890) gene polymorphism with biochemical markers of B12 deficiency in T2DM patients on metformin therapy

Long term administration of metformin interferes with the absorption of vitamin B12 resulting in vitamin B12 deficiency.Among the various genetic variants that are associated vitamin B12 deficiency, we analyzed BHMT gene polymorphism and their association with metformin induced vitamin B12 deficiency in T2DM patients.A cross sectional study was done with 300 participants. Methyl malonic acid, homocysteine and high sensitive C reactive protein were analysed by Mass Spectrometry, Chemiluminescent analyser and Immunoturbidimetric method respectively. Genetic variants were analysed by ARMS-PCR method, Data was analyzed with various statistical tools like ROC, Odds ratio and Likelihood ratio. Significant reduction in folic acid and vitamin B12 in metformin users was found. High sensitive C reactive protein, homocysteine and methyl malonic acid are significantly increased in patients with metformin induced B12 deficiency. ‘A’ allele in BHMT (A allele OR =2.1, AA genotype =2.8) showed risk of vitamin B12 deficiency in T2DM patients on metformin therapy. BHMT gene polymorphism had LR of 2.65 for folic acid (AG genotype), 2.73 for MMA (AA genotype) and 2.63 for Homocysteine (AA genotype).We found an association between single nucleotide polymorphism of BHMT and diagnosis of vitamin B12 deficiency status in metformin users. Folic acid, MMA and homocysteine had high specificity in concordance with BHMT (rs3733890) polymorphism in predicting vitamin B12 deficiency. Early screening of SNP of BHMT in T2DM patients on metformin therapy will help us to identify group of people who are prone for vitamin B12 deficiency.

Profiling immuno-metabolic mediators of vitamin B12 deficiency among metformin-treated type 2 diabetic patients in Ghana.

The association between prolong metformin usage and B12 deficiency has been documented. However, the prevalence estimates of metformin-induced vitamin B12 deficiency showed substantial disparity among studies due to varied study definitions of vitamin B12 deficiency. Metformin blocks the calcium dependent absorption of the vitamin B12-Intrinsic Factor complex at the terminal ileum. Lack of intrinsic factor due to the presence of auto-antibodies to parietal cells (IFA) could lead to vitamin B12 deficiency and subsequently cause peripheral neuropathy. We investigated the prevalence of vitamin B12 deficiency using more sensitive, combined markers of vitamin B12 status (4cB12) and the immuno-biochemical mediators of vitamin B12 deficiency. In this observational study, 200 consecutive consenting metformin-treated T2DM patients, aged 35 and above, attending the diabetic clinic at KATH were recruited. Vitamin B12 deficiency was classified based on the Fedosov age-normalized wellness quotient. Anthropometric measurement was taken as well as blood samples for immunological and biochemical mediators. Peripheral neuropathy was assessed using the Michigan Neuropathy Screening Instrument (MNSI). Statistical analysis was performed using the R Language for Statistical Computing. Using the combined indicator (4cB12), the prevalence of metformin induced vitamin B12 deficiency was 40.5% whilst the prevalence of MNSI-Q and MNSI-PE diabetic neuropathy was 32.5% and 6.5% respectively. Participants with vitamin B12 deficiency had significantly higher levels of IFA, GPA, TNF-α, TC, LDL and albumin compared to those with normal vitamin B12 levels (p < 0.05). Correlation analysis revealed a statistically significant negative association between 4cB12 and the immunological markers [IFA (rs = -0.301, p<0.0001), GPA (rs = -0.244, p = 0.001), TNF-α (rs = -0.242, p = 0.001) and IL-6 (rs = -0.145, p = 0.041)]. Likewise, 4cB12 was negatively associated with TC (rs = -0.203, p = 0.004) and LDL (rs = -0.222, p = 0.002) but positively correlated with HDL (rs = 0.196, p = 0.005). Vitamin B12 deficiency and diabetic neuropathy are very high among metformin-treated T2DM patients and it is associated with increased GPA, IFA, TNF-α and cardiometabolic risk factors (higher LDL and TC and lower HDL). Upon verification of these findings in a prospective case-control study, it may be beneficial to include periodic measurement of Vitamin B12 using the more sensitive combined indicators (4cB 12) in the management of patients with T2DM treated with metformin in Ghana.

Evaluating the correlation between serum vitamin B12 levels and various haematologic indices among metformin-treated type 2 diabetic patients: A prospective analytical study

Background: Metformin-induced vitamin B12 deficiency state or metformin-induced hypocobalaminemia is gradually becoming an epidemic among diabetic patients on moderate-to-high doses of metformin or those diabetic patients on metformin for a long period of time. The potential effect of chronic metformin pharmacotherapy to cause vitamin B12 deficiency with abnormalities in haematologic indices and central/peripheral neuropathy has been widely reported. Long-term usage of metformin has been reported to be associated with intestinal malabsorption of vitamin B12 culminating in vitamin B12 deficiency with likely associated haematologic abnormalities (including macro-ovalocytic anaemia and immune dysfunctioning due to hypersegmentation of polymorphonuclear leukocytes), central/peripheral neuropathy and manifestation of biochemical derangements such as elevated homocysteine and methyl malonate levels. Aim: This study aimed to determine the correlation between serum vitamin B12 levels and various haematologic indices among metformin-treated type 2 diabetic patients in a clinical practice setting with the rational purpose of alleviating/preventing the associated derangements. Materials and Methods: This was a case-control, prospective, analytical, observational study of 200 adult participants (100 per group) attending the Endocrinology Out-patients Clinic of Irrua Specialist Teaching Hospital, Irrua, Edo State, Nigeria. For each participant, serum vitamin B12 level was determined using a vitamin B12 immunoassay technique, while the corresponding complete blood count was done using PCE-210N autohaematology analyser. Data were presented using tables and figures. Chi-square test was used to compare categorical variables, Student t-test was used in comparing means of continuous variables, while Pearson’s correlation study was done to determine the existence of any statistically significant correlation(s) between the serum vitamin B12 levels and various haematologic indices among the participants. Results: Approximately 41% versus 20% of the metformin-treated and metformin-naive diabetic patients, respectively, had frank vitamin B12 deficiency. There was a statistical difference between the total serum vitamin B12 levels in male and female diabetic patients with p = 0.048. Also, statistically significant differences existed with respect to mean corpuscular volume (MCV), mean corpuscular haemoglobin and total white blood cells count among the metformin-treated and metformin-naive diabetic patients. Furthermore, a statistically significant weak positive correlation existed between pack cell volume (PCV) and serum vitamin B12 level ( r = +0.148, p = 0.037), but a statistically significant weak negative correlation existed between MCV and serum vitamin B12 level ( r = −0.245, p = 0.0001). In addition, the test for associations between the serum vitamin B12 categorization status or metformin exposure status and the peripheral neuropathy components assessment revealed that there were statistically significant associations between the serum vitamin B12 categorization status or metformin exposure status versus pain sense ( p &lt; 0.0001 or &lt;0.001), vibration sense ( p &lt; 0.0001 or &lt;0.001) and light touch sense ( p &lt; 0.0001 or &lt;0.001) among the participants. Conclusion: In this study, statistically significant weak positive and weak negative correlations existed between serum vitamin B12 level versus PCV, and serum vitamin B12 level versus MCV, respectively. The peripheral neuropathy components assessment revealed that there were statistically significant associations between the serum vitamin B12 categorization status or metformin exposure status versus pain sense, vibration sense and light touch sense among the participants.

Discovering metformin-induced vitamin B12 deficiency in patients with type 2 diabetes in primary care.

Although metformin is the preferred initial pharmacological choice in type 2 diabetes, there is evidence that reveals a link between metformin use and vitamin B12 deficiency. The American Diabetes Association (ADA) has recently recommended periodic measurement of B12 levels for all patients on metformin. Medical record data collected for the preintervention period showed that only 5% (n = 23) of patients diagnosed with diabetes and on metformin had B12 levels checked at an internal medicine primary care practice. This was a quasi-experimental project of preintervention and postintervention design using a checklist containing important measures of diabetes control. The project sample population consisted of data of adults with type 2 diabetes aged 18 years and older who were prescribed metformin in the previous year at the primary care practice. The intervention focused on revising an existing diabetes measures checklist to include a prompt for an annual measurement of B12 levels. There was significant improvement in monitoring vitamin B12 levels and discovery of low vitamin B12 levels. These data show that the number of B12 levels checked increased from 23 during the preintervention to 155 during the intervention (p ≤ 0.0000). This project supports a conclusion that including a prompt to check B12 levels to an existing checklist increases B12 monitoring in this patient population. Results may encourage other providers to follow the ADA guidelines for monitoring vitamin B12 levels for patients taking metformin.

Assessment of Metformin Induced Vitamin-B12 Deficiency amongst Type-II Diabetic Patients Vis-À-Vis Evaluating the Quality of Life

Assessment of Metformin Induced Vitamin-B12 Deficiency amongst Type-II Diabetic Patients Vis-À-Vis Evaluating the Quality of Life

Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis.

Background:Metformin, a first line antihyperglycemic medication, is an AMPK activator and has been hypothesized to act as a geroprotective agent. Studies on its association with various classifications of age-related cognitive decline have shown mixed results with positive and negative findings.Objective:To synthesize the best available evidence on the association of metformin-use with risk, progression, and severity of dementia.Method:Eligible research investigated the effect of metformin on dementia, Alzheimer’s disease, or any measure of cognitive impairment compared to any control group who were not receiving metformin. The initial search resulted in 862 citations from which 14 studies (seven cohort, four cross-sectional, two RCTs, and one case control) were included.Results:Meta-analysis of three studies showed that cognitive impairment was significantly less prevalent in diabetic metformin (Odds ratio = 0.55, 95% CI 0.38 to 0.78), while six studies showed that dementia incidence was also significantly reduced (Hazard ratio = 0.76, 95% CI 0.39 to 0.88). Mini-Mental State Examination scores were not significantly affected by metformin-use, although both RCTs showed that metformin had a neuroprotective effect compared to placebo. Some studies found negative or neutral effects for metformin use by people with diabetes; the potential mechanism of metformin-induced vitamin B12 deficiency is discussed.Conclusions:Metformin should continue to be used as a first line therapy for diabetes in patients at risk of developing dementia or Alzheimer’s disease. The use of metformin by individuals without diabetes for the prevention of dementia is not supported by the available evidence.

Perspectives on Peripheral Neuropathy as a Consequence of Metformin-Induced Vitamin B12 Deficiency in T2DM.

Peripheral neuropathy (PN) is a primary complication of type 2 diabetes mellitus (T2DM) and a direct manifestation of vitamin B12 deficiency. Examining the effects of metformin use on PN status became imperative following clinical studies that showed the vitamin B12-lowering effect of the medication. The complexity of the topic and the inconsistency of the results warrant consideration of topic-specific perspectives for better understanding of the available evidence and more appropriate design of future studies.

Metformin and Vitamin B12 Deficiency: Where Do We Stand?

The association between metformin use and low vitamin B12 levels in type 2 diabetes mellitus patients is well-established. However, many aspects of the topic remain to be elucidated. There is still controversy on the current diagnostic approaches to vitamin B12 deficiency. It is now believed that measuring the serum levels of the vitamin may not reflect its metabolic status. Moreover, there were conflicting results from studies attempting to quantify and explore metformin-associated vitamin B12 deficiency and its clinical impacts. This article reviews the cellular functions of vitamin B12, the biomarkers utilized to define the vitamin deficiency and metformin-induced vitamin B12 deficiency with an emphasis on its prevalence and clinical impacts.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Vitamin B12 deficiency in metformin-treated type-2 diabetes patients, prevalence and association with peripheral neuropathy.

BackgroundThe association between long-term metformin use and low vitamin B12 levels has been proven. However, the prevalence estimates of metformin-induced vitamin B12 deficiency showed considerable variation among the studies. The potential of the deficiency to cause or worsen peripheral neuropathy in type-2 diabetes mellitus (T2DM) patients has been investigated with conflicting results. The aim of the study was to investigate: 1) the prevalence of vitamin B12 deficiency in T2DM patients on metformin; 2) the association between vitamin B12 and peripheral neuropathy; 3) and the risk factors for vitamin B12 deficiency in these patients.MethodsIn this cross-sectional study, consecutive metformin-treated T2DM patients attending diabetes clinics of two public hospitals in South Africa were approached for participation. Participation included measuring vitamin B12 levels and assessing peripheral neuropathy using Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire. The prevalence of vitamin B12 deficiency (defined by concentrations <150 pmol/L) was determined. Those with NTSS-6 scores >6 were considered to have peripheral neuropathy. The relationship between vitamin B12 and peripheral neuropathy was investigated when the two variables were in the binary and continuous forms. Multiple logistic regression was used to determine risk factors for vitamin B12 deficiency.ResultsAmong 121 participants, the prevalence of vitamin B12 deficiency was 28.1 %. There was no difference in presence of neuropathy between those with normal and deficient vitamin levels (36.8 % vs. 32.3 %, P = 0.209). Vitamin B12 levels and NTSS-6 scores were not correlated (Spearman’s rho =0.056, P = 0.54). HbA1c (mmol/mol) (OR = 0.97, 95 % CI: 0.95 to 0.99, P = 0.003) and black race (OR = 0.34, 95 % CI: 0.13 to 0.92, P = 0.033) were risk factors significantly associated with vitamin B12 deficiency. Metformin daily dose (gram) showed borderline significance (OR = 1.96, 95 % CI: 0.99 to 3.88, P = 0.053).ConclusionsClose to third of metformin-treated T2DM patients had vitamin B12 deficiency. The deficiency was not associated with peripheral neuropathy. Black race was a protective factor for vitamin B12 deficiency.

Is Metformin-Induced Vitamin B12 Deficiency Responsible for Cognitive Decline in Type 2 Diabetes?

Introduction:Diabetes mellitus has its deleterious effects on various aspects of cognition such as memory function, executive function, and information-processing speed. The present study aims to assess cognition in diabetes patients and also tries to find its association with Vitamin B12 deficiency induced by metformin.Materials and Methods:Thirty diabetics taking metformin and thirty nondiabetic controls were enrolled. Event-related potentials (ERPs) and serum Vitamin B12 levels were evaluated in them.Results:Vitamin B12 levels were found to be deficient, and latencies of waves P200 and P300 were prolonged in the diabetics as compared to the controls. The dose and duration of metformin had no association with the ERPs.Conclusions:Although the Vitamin B12 levels were deficient in diabetics on metformin, this is not the reason behind the cognitive impairment found in them.

Delayed auditory conduction in diabetes: is metformin-induced vitamin B12 deficiency responsible?

The present study aims to evaluate the functional integrity of the auditory pathway in patients with diabetes taking metformin. A further aim is to assess its association with vitamin B12 deficiency induced by metformin. Thirty diabetics taking metformin and 30 age-matched non-diabetic controls were enrolled. Stimulus-related potentials and vitamin B12 levels were evaluated in all the subjects. The diabetics showed deficient vitamin B12 levels and delayed wave III latency and III-V interpeak latency in the right ear and delayed Na and Pa wave latencies in the left ear compared with the controls. The dose and duration of metformin showed no association with the stimulusrelated potentials. Therefore, although vitamin B12 levels were deficient and auditory conduction impairment was present in the diabetics on metformin, this impairment cannot be attributed to the vitamin B12 deficiency.