Video
If I’m taking Metformin and B12 will the B12 even get absorbed? - The Nerve Doctors Background: Metformin may lead Digestive health supplements B 12 Merformin and neuropathy. Anv are no anf data on Jeuropathy prevalence of Metformin-related B 12 deficiency and Neuropathj in Fiber and colon health Arabian Beuropathy. Aims: Determine whether Metformin intake is associated with B 12 deficiency and whether B 12 deficiency is associated with diabetic peripheral neuropathy DPN and painful diabetic neuropathy. Results: Comparing Metformin to non-Metformin users there were no differences in B 12 levels, VPT, or DN4. Patients with B 12 deficiency had a comparable prevalence and severity of sensory neuropathy and painful neuropathy to patients without B 12 deficiency. Conclusion: Serum B 12 levels were comparable between Metformin and non-Metformin users with T2DM in Qatar.Metformin and neuropathy -
Here we have tested the hypothesis that metformin may protect against chemotherapy-induced neuropathic pain, dysesthesia and loss of IENFs in the hind paw of mice.
Our findings show that metformin is broadly effective in a preclinical mouse model suggesting that these findings may rapidly translate into transformative treatment strategies for the alleviation of these dose-limiting side effects. All behaviors were observed during the dark phase of the light cycle with red light.
treated with cisplatin Sigma-Aldrich, St. Louis MI daily at a dosage of 2. Control mice received an equivalent volume of saline. Metformin hydrochloride Sigma-Aldrich was freshly prepared in saline daily.
for seven consecutive days, beginning 24 h prior to the first dose of cisplatin of each cycle or 24 h before the start of the second cisplatin cycle. A separate group of mice was treated with paclitaxel i.
was given daily starting 24 h before the first dose of paclitaxel. On days when both cisplatin or paclitaxel and metformin were administered, metformin was given 30—60 min prior to cisplatin or paclitaxel.
Mechanical allodynia was measured as the hind paw withdrawal response to von Frey hair stimulation using the up-and-down method as we described previously [20]. Mice were placed in a plastic cage 10×10×13 cm 3 with a mesh floor for 30 min prior to testing. Subsequently, a series of von Frey hairs 0.
A trial began with the application of the 0. A positive response was defined as a clear paw withdrawal or shaking. Whenever a positive response occurred, the next lower hair was applied, and whenever a negative response occurred, the next higher hair was applied. To control for the possibility that behavioral changes are due to the motor impairment in cisplatin treated mice, motor function was assessed using the rotarod apparatus Med Associates INC, Georigia, VE.
Briefly, mice were placed individually on the rotating system and trained for three days at 16 rpm with three trials per day. Each trial lasted for three minutes; on the third day all mice completed the 3 minute training session.
In the actual motor function test, an accelerated rotarod assay 4—40 rpm over 5 min was evaluated for three trails and the latency to fall was recorded. For details see supporting information section File S2. In order to examine the effect of cisplatin on sensory function, we used a modification of the adhesive removal test [22].
Ocalo, FL was placed on the plantar surface of the hind paws. The animal performance in a testing cage 20×20×13 cm 3 was recorded in 15 min. The time until the mouse started to shake its paw or bring the paw to the mouth was recorded as a measure of the latency until the mouse noticed the presence of the adhesive patch on the paw.
For details see supporting information section File S1. For quantification of IENFs, 3×3 mm 2 biopsies were dissected from the central plantar surface of the hind paws.
The sections were blocked for 2 hrs at room temperature in 0. The blocking solution was removed and the sections were incubated with an antibody against the pan neuronal marker PGP9. Sections were washed in wash buffer and then three randomly chosen slices from each paw were quantified under a Leica fluorescence microscope.
The length of the epidermis within each field was measured using ImageJ. For details see supporting information section File S4. Representative images captured by using In Cell microscope are shown.
Data are expressed as mean ± SEM. Statistical analysis was carried out using repeated measure analysis of variance or dependent t test or one-way ANOVA followed by Bonferroni analysis.
Raw data are provided in the supporting information file S6. Mice were treated with two rounds of 5 daily i. injections with cisplatin with 5 days rest in between Figure 1a. Figure 1b demonstrates cisplatin induced persistent mechanical allodynia measured at 3 and 5 weeks after the 1 st cisplatin injection.
Co-administration of metformin treatment completely prevented cisplatin-induced mechanical allodynia Figure 1b. Metformin treatment alone did not have any effect on mechanical sensitivity Figure 1b. Treatment schedule; X: injection; O: no treatment.
as depicted in panel A. Mechanical allodynia was quantified with von Frey hairs using the up and down method. Effect of delayed metformin treatment on cisplatin-induced mechanical allodynia. as depicted in panel A and mechanical allodynia was monitored. daily from one day before until one day after paclitaxel and mechanical allodynia was measured.
Change in body weight after cisplatin and metformin treatment. To determine whether metformin treatment should be started together with cisplatin or can be delayed, we delayed metformin treatment until the 2 nd round of cisplatin treatment. The results in Figure 1c show that this delayed metformin treatment had no effect on mechanical allodynia.
These results strongly suggested that concomitant but not delayed treatment with metformin prevents cisplatin-induced mechanical allodynia. The beneficial effect of metformin was not limited to cisplatin-induced mechanical allodynia; also paclitaxel-induced mechanical allodynia was prevented by administration of metformin starting 24 hours prior to the first dose of paclitaxel Figure 1d.
Metformin treatment did not affect body weight when given alone and did not have any effect on the transient loss of bodyweight in mice treated with cisplatin Figure 1e or paclitaxel Data not shown. The effect of cisplatin on the time-to-respond to an adhesive patch on the hind paw was recorded as a novel indicator of chemotherapy-induced sensory deficit.
In cisplatin-treated mice the time-to-respond to the adhesive patch on the hind paw was significantly prolonged at 3 and 5 weeks after the 1 st cisplatin injection when compared to saline-treated mice Figure 2a.
Co-administration of metformin prevented the increase in latency to respond to the adhesive patch on the paw, whereas delayed treatment did not have any effect Figure 2a, c.
The time between the first response to the adhesive patch and subsequent removal of the patch was not affected by cisplatin treatment indicating normal motor function data not shown. In addition, cisplatin-treated mice showed normal performance on a rotarod indicating that the prolonged time-to-respond to the patch on the hind paw cannot be attributed to potential cisplatin-induced motor function deficits Figure 2d.
As a positive control, the data in Figure 2e show that the time-to-respond to the adhesive patch was also significantly increased in lidocaine-treated mice. Collectively, our findings support the notion that the increase in time-to-respond to the adhesive patch in cisplatin-treated mice is related to a sensory deficit, which is prevented by metformin treatment.
The time to respond to an adhesive patch on the hind paw was monitored. Effect of cisplatin treatment on rotarod performance. later, the time to respond to an adhesive patch on the hind paw was measured.
IENF loss had been reported in rat models of chemotherapy-induced neuropathy using cisplatin, oxaliplatin, taxol, paclitaxel and vincristine [13] , [14] , [23] , [24].
We analyzed the effect of metformin treatment on the IENF density in hind and fore paw of cisplatin treated mice at 5 weeks after the first cisplatin treatment. Saline-treated mice showed abundant distribution of nerve fibers entering the epidermis.
The IENF density was significantly decreased in response to cisplatin-treatment Figure 3a—b. Notably, metformin significantly protected against this cisplatin-induced IENF loss Figure 3c. There were no significant differences between metformin-treated cisplatin mice and saline- treated mice Figure 3d.
Paw biopsies obtained from the hind paw at 5 weeks after the start of treatment were stained for intraepidermal nerve fibers PGP9. White arrows indicate the intraepidermal nerve fibers stained by PGP9. D Quantification of intraepidermal nerve fiber density. The AMP kinase agonist metformin is an anti-diabetic drug that has been safely and widely used for the treatment of type 2 diabetes for decades.
This is the first study to show that metformin protects against cisplatin- and paclitaxel-induced mechanical allodynia in a mouse model. Additionally, this is the first study to demonstrate a loss of sensory sensitivity associated with CIPN in a mouse model. In search for an underlying mechanism, we show that metformin treatment protects against the loss of IENFs that occurs in response to cisplatin treatment.
Collectively, these findings indicate that metformin protects against cisplatin-induced peripheral neuropathy by reducing peripheral nerve damage. We propose that these findings represent the discovery of a safe preventive treatment for chemotherapy-induced neuropathy.
Because metformin is already widely used, rapid clinical translation of these findings should be possible. Metformin is the first-line treatment for type II diabetes because of its insulin sensitizing effects [25]. Individuals with obesity or polycystic ovary syndrome are also frequently treated with metformin.
In , over 61 million prescriptions for metformin were filed in the United States [26]. There is evidence that metformin treatment of diabetics reduces the risk of cancer in this population. In addition, preclinical and clinical studies indicate that metformin treatment may increase the efficacy of cancer treatment.
In a retrospective study in breast cancer patients with diabetes, patients treated with metformin had higher complete pathologic response rates to neoadjuvant therapy than diabetic patients treated with other antidiabetic drugs [27]. Similarly two retrospective cohort studies indicated that metformin treatment of diabetic patients with ovarian cancer may prolong disease specific and progression-free survival [28] , [29] , [30].
Preclinical data demonstrate that metformin inhibits cancer cell growth in vitro, enhances anti-tumor effects of chemotherapeutics in vitro, inhibits the inflammatory response associated with cancer and prolongs remission in response to chemotherapy in mouse xenograft models of cancer [31] , [32] , [33] , [34].
Collectively these findings have given rise to an increasing number of clinical trials aimed at examining the efficacy of metformin in cancer treatment.
The data we show here identify a potential additional beneficial effect of metformin in cancer treatment. Our finding that metformin protects against chemotherapy-induced peripheral neuropathy urges for inclusion of systematic assessment of neuropathy in trials with metformin in cancer patients.
Recent studies have shown that metformin alleviates pain amplification that occurs in response to peripheral nerve injury in mice and rats [4] , [18]. In these surgical models of neuropathic pain, it was shown that metformin reverses already existing mechanical allodynia.
We show here that metformin prevented development of cisplatin- and paclitaxel-induced mechanical allodynia only when treatment was started before start of the administration of these chemotherapeutics.
In contrast to what was observed in traumatic models of neuropathy, we did not observe any beneficial effect of metformin when treatment was started after the first round of cisplatin treatment, when mechanical allodynia had already developed.
This result is in contrast to previous observations in the spared nerve injury model in mice and spinal nerve ligation injury model in rats where metformin treatment after establishment of neuropathic allodynia effectively reversed this symptom of peripheral nerve injury.
While the reasons for this discrepancy between models are not presently clear, there are several possible reasons. First, chemotherapy-induced neuropathy is mechanistically distinct from trauma-induced neuropathy. A therapeutic benefit of AMPK activation in trauma-induced neuropathy is related to decreases in mTOR and MAPK signaling in injured nerves [5] , [35].
It is not currently known if these signaling pathways are altered in CIPN. On the other hand, CIPN involves clear changes in mitochondrial function that may be an important target for AMPK activation in CIPN [36]. If mitochondria are a relevant target for AMPK activation [37] in CIPN, it may not be possible to reverse this effect once established by the chemotherapeutic treatment.
Another possibility is that while the effects of metformin in trauma-induced neuropathy are AMPK-mediated this hypothesis is supported by similar findings with specific AMPK activating tool compounds , metformin effects in CIPN have a separate mechanism of action.
This can be tested with future experiments with AMPK activating tool compounds. One AMPK-independent possibility is metformin-mediated blockade of organic cation transporter 2 [38] which is required for oxaliplatin-induced CIPN [39].
While these mechanism-based studies are undoubtedly important, the aim of these studies was to assess metformin as a potential treatment for CIPN and our studies give a clear rationale for preventative clinical trials with this drug.
At present, knowledge about the mechanisms underlying chemotherapy-induced sensory deficits remains limited. Although the pain component of CIPN has received the most attention, sensory deficits are often longer lasting and thus debilitating for patients in daily life.
One of the aims of this study was to determine whether cisplatin treatment in mice leads to sensory impairment and to assess the effect of metformin on cisplatin-induced sensory impairment. To that end, we used the adhesive removal test, a sensitive method to evaluate both somatosensory and motor function in rats and mice [22].
In this test, an adhesive patch is placed on the plantar surface of the hind paw, and the latency to a behavioral response to the patch as well as latency to removal of the patch is assessed. The data show that the time to display a behavioral response to the adhesive patch placed on the paw is significantly prolonged in mice treated with cisplatin.
We also observed significant IENFs loss in mice treated with cisplatin. These findings are in line with earlier studies showing loss of IENFs in rats treated with chemotherapeutic agents such as paclitaxel [24] , vincristine [23] , oxaliplatin [13] and cisplatin [14].
In humans exposed to chemotherapy, damage to peripheral nerves in the extremities has also been reported [1]. Moreover, IENFs transmit sensations of tactile, cold, thermal and mechanical origin from the skin, and loss of IENFs has been shown to correspond to loss of these sensations in humans [40].
We show here that mice treated with cisplatin display sensory deficits and los of IENFs in the hind paws consistent with results using the adhesive tactile test. Co-administration of metformin prevented both sensory deficits and loss of IENFs in the paws. These results strongly suggest that the cisplatin-induced of loss of IENFs in the paw contributes to chemotherapy-induced sensory deficits.
The protective effect of metformin on loss of IENFs is consistent with earlier reported neuroprotective activity of metformin in models of brain damage. Moreover, in a model of peripheral nerve damage-induced neuropathy it has been shown that metformin increases the level of ApoE, a 34 kDa glycoprotein that is a major determinant of lipid transport and metabolism [18].
In addition, ApoE plays an important role in peripheral and central neuroregeneration and remyelination [18] , [41] , [42] , [43]. It remains to be determined whether metformin-induced increases in ApoE also contribute to the protective effect of metformin in our mouse model of chemotherapy-induced peripheral neuropathic pain.
It may seem contradictory that chemotherapy-induced decrease in IENF density is associated with decreased sensory function, but enhanced pain sensitivity. Electrophysiological and biochemical studies in cisplatin-treated rats show that sensitization of sensory neurons, increased spontaneous activity and prolonged after discharges in response to stimulation, plays a key role in pathological pain behaviors following platinum drugs [44].
In conclusion, this study is the first to demonstrate that metformin protects against chemotherapy-induced neuropathic pain and numbness in a mouse model. The beneficial effect of metformin is associated with a reduction in the loss of plantar IENFs. Whether these neuroprotective effects of metformin treatment in the mouse model of cisplatin-induced peripheral neuropathy are the direct cause of the protective effect of metformin treatment on pain and numbness need to be further investigated.
There are no FDA-approved drugs to treat CIPN. As a result of CIPN a significant subset of patients receives sub-optimal doses of anti-cancer treatment.
Moreover, CIPN markedly reduces quality of life both during and after completion of treatment. Because metformin has already been widely used, these findings strongly argue for an immediately available novel treatment to prevent chemotherapy-induced peripheral neuropathy in patients treated for cancer.
The ongoing studies on the usefulness of metformin as an add-on therapy in cancer treatment should include analysis of the potential beneficial effect of metformin on chemotherapy-induced neuropathy as an outcome measure.
We thank Dr. Dougherty, Department of Pain Medicine of MD Anderson Cancer Center for his help on IENF analysis. Jeannie Zhong from Baylor College of Medicine, Houston, TX for her kind support with image capture. Conceived and designed the experiments: QLMY AK KK XJH WZ TJP CC CJH.
Performed the experiments: QLMY KK XJH WZ. Analyzed the data: QLMY KK. Contributed to the writing of the manuscript: QLMY AK KK XJH WZ TJP CC CJH. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field.
Article Authors Metrics Comments Media Coverage Reader Comments Figures. Abstract Chemotherapy-induced peripheral neuropathy CIPN characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics.
McKemy, University of South California, United States of America Received: April 21, ; Accepted: May 27, ; Published: June 23, Copyright: © Mao-Ying et al. Von Frey test for mechanical allodynia Mechanical allodynia was measured as the hind paw withdrawal response to von Frey hair stimulation using the up-and-down method as we described previously [20].
Rotarod test for motor impairment To control for the possibility that behavioral changes are due to the motor impairment in cisplatin treated mice, motor function was assessed using the rotarod apparatus Med Associates INC, Georigia, VE.
Adhesive removal test for tactile hyposensitivity behavior In order to examine the effect of cisplatin on sensory function, we used a modification of the adhesive removal test [22]. Immunostaining for IENFs For quantification of IENFs, 3×3 mm 2 biopsies were dissected from the central plantar surface of the hind paws.
Statistical analysis Data are expressed as mean ± SEM. Results Effect of metformin on chemotherapy-induced neuropathic pain Mice were treated with two rounds of 5 daily i.
Download: PPT. Figure 1. Effect of metformin on cisplatin- or paclitaxel-induced mechanical allodynia in mice. Cisplatin-induced sensory deficits and metformin treatment The effect of cisplatin on the time-to-respond to an adhesive patch on the hind paw was recorded as a novel indicator of chemotherapy-induced sensory deficit.
Figure 2. Berchtold P, Bolli P, Arbenz U, Keiser G. Diabetologia — Tomkin GH, Hadden DR, Weaver JA, Montgomery DA. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J —7. PubMed Abstract CrossRef Full Text Google Scholar.
DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med —9. de Jager J, Kooy A, Lehert P, Wulffele MG, van der Kolk J, Bets D, et al.
Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B deficiency: randomised placebo controlled trial. BMJ c de Groot-Kamphuis DM, van Dijk PR, Groenier KH, Houweling ST, Bilo HJ, Kleefstra N.
Vitamin B12 deficiency and the lack of its consequences in type 2 diabetes patients using metformin. Neth J Med — PubMed Abstract Google Scholar. Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ, et al. Long-term metformin use and vitamin B12 deficiency in the diabetes prevention program outcomes study.
J Clin Endocrinol Metab — Kang D, Yun JS, Ko SH, Lim TS, Ahn YB, Park YM, et al. Higher prevalence of metformin-induced vitamin B12 deficiency in sulfonylurea combination compared with insulin combination in patients with type 2 diabetes: a cross-sectional study.
PLoS One 9:e Reinstatler L, Qi YP, Williamson RS, Garn JV, Oakley GP Jr. Association of biochemical B 1 2 deficiency with metformin therapy and vitamin B 1 2 supplements: the National Health and Nutrition Examination Survey, — Diabetes Care — Damiao CP, Rodrigues AO, Pinheiro MF, Cruz RAF, Cardoso GP, Taboada GF, et al.
Prevalence of vitamin B12 deficiency in type 2 diabetic patients using metformin: a cross-sectional study. Sao Paulo Med J —9. Khan A, Shafiq I, Hassan Shah M. Prevalence of vitamin B12 deficiency in patients with type II diabetes mellitus on metformin: a study from Khyber Pakhtunkhwa.
Cureus 9:e Chapman LE, Darling AL, Brown JE. Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: a systematic review and meta-analysis.
Diabetes Metab — Pop-Busui R, Boulton AJ, Feldman EL, Bril V, Freeman R, Malik RA, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Singh AK, Kumar A, Karmakar D, Jha RK. Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients.
J Postgrad Med —7. Roy RP, Ghosh K, Ghosh M, Acharyya A, Bhattacharya A, Pal M, et al. Study of vitamin B12 deficiency and peripheral neuropathy in metformin-treated early type 2 diabetes mellitus. Indian J Endocrinol Metab —7.
Russo GT, Giandalia A, Romeo EL, Scarcella C, Gambadoro N, Zingale R, et al. Diabetic neuropathy is not associated with homocysteine, folate, vitamin B12 levels, and MTHFR CT mutation in type 2 diabetic outpatients taking metformin. J Endocrinol Invest — Ahmed MA, Muntingh G, Rheeder P. Vitamin B12 deficiency in metformin-treated type-2 diabetes patients, prevalence and association with peripheral neuropathy.
BMC Pharmacol Toxicol Ma J, Yu H, Liu J, Chen Y, Wang Q, Xiang L. Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin. Eur J Pharmacol — Olt S, Oznas O. Investigation of the vitamin B12 deficiency with peripheral neuropathy in patients with type 2 diabetes mellitus treated using metformin.
North Clin Istanb —6. Al-Azayzih A, Al-Azzam SI, Alzoubi KH, Shawaqfeh M, Masadeh MM. Evaluation of drug-prescribing patterns based on the WHO prescribing indicators at outpatient clinics of five hospitals in Jordan: a cross-sectional study.
Int J Clin Pharmacol Ther — Wiles PG, Pearce SM, Rice PJ, Mitchell JM. Vibration perception threshold: influence of age, height, sex, and smoking, and calculation of accurate centile values.
Diabet Med — Harifi G, Ouilki I, El Bouchti I, Ouazar MA, Belkhou A, Younsi R, et al. Validity and reliability of the Arabic adapted version of the DN4 questionnaire Douleur Neuropathique 4 Questions for differential diagnosis of pain syndromes with a neuropathic or somatic component. Pain Pract — Validation of DN4 as a screening tool for neuropathic pain in painful diabetic polyneuropathy.
Unal-Cevik I, Sarioglu-Ay S, Evcik D. A comparison of the DN4 and LANSS questionnaires in the assessment of neuropathic pain: validity and reliability of the Turkish version of DN4. J Pain — Chen S, Lansdown A, Moat S, Ellis R, Goringe A, Dunstan F, et al.
An observational study of the effect of metformin on B12 status and peripheral neuropathy. Br J Diabetes Vasc Dis — Gupta K, Jain A, Rohatgi A. An observational study of vitamin b12 levels and peripheral neuropathy profile in patients of diabetes mellitus on metformin therapy.
Diabetes Metab Syndr —8. den Elzen WP, Groeneveld Y, de Ruijter W, Souverijn JH, le Cessie S, Assendelft WJ, et al. Long-term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther —7. Dharmarajan TS, Kanagala MR, Murakonda P, Lebelt AS, Norkus EP.
Do acid-lowering agents affect vitamin B12 status in older adults? J Am Med Dir Assoc —7. El-Khateeb M, Khader Y, Batieha A, Jaddou H, Hyassat D, Belbisi A, et al. Vitamin B12 deficiency in Jordan: a population-based study. Ann Nutr Metab —5.
Asiri YA, Al-Arifi MN. Polypharmacy and patterns in drug prescribing at a primary healthcare centre in the Riyadh region of Saudi Arabia. Int J Pharm Pract —8.
Malik RA, Aldinc E, Chan SP, Deerochanawong C, Hwu CM, Rosales RL, et al. Perceptions of painful diabetic peripheral neuropathy in South-East Asia: results from patient and physician surveys.
Adv Ther — Almuhannadi H, Ponirakis G, Khan A, Malik RA. Diabetic neuropathy and painful diabetic neuropathy: cinderella complications in South East Asia. J Pak Med Assoc —9. Petropoulos IN, Javed S, Azmi S, Khan A, Ponirakis G, Malik RA. Diabetic neuropathy and painful diabetic neuropathy in the Middle East and North Africa MENA region: much work needs to be done.
J Taibah Univ Med Sci — Google Scholar. American Diabetes A. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes Diabetes Care S73— Keywords: metformin, vitamin B12 deficiency, diabetic neuropathy, diabetic painful neuropathy, type 2 diabetes mellitus.
Citation: Elhadd T, Ponirakis G, Dabbous Z, Siddique M, Chinnaiyan S and Malik RA Metformin Use Is Not Associated With B 12 Deficiency or Neuropathy in Patients With Type 2 Diabetes Mellitus in Qatar.
doi: Received: 03 February ; Accepted: 02 May ; Published: 25 May Copyright: © Elhadd, Ponirakis, Dabbous, Siddique, Chinnaiyan and Malik.
This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. Malik, ram qatar-med. Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Top bar navigation.
About us About us. Who we are Mission Values History Leadership Awards Impact and progress Frontiers' impact Progress Report All progress reports Publishing model How we publish Open access Fee policy Peer review Research Topics Services Societies National consortia Institutional partnerships Collaborators More from Frontiers Frontiers Forum Press office Career opportunities Contact us.
Beuropathy Glucophage, Bristol-Myers Squibb is Wnd commonly utilized biguanide agent neurppathy the treatment of Refreshment Ideas for Events. Increasingly, it appears Fiber and colon health metformin may paradoxically increase Metformih risk of neuropathy Managing arthritic pain the patient with diabetes. Therefore, when you neuropwthy a patient with Mrtformin who is taking nejropathy, greater surveillance may be necessary for the presence of sensory, autonomic and motor neuropathy. Wile and colleagues noted that metformin increases homocysteine levels as well as methylmalonic acid levels, both contributing factors to neuropathy. In a recent issue of Diabetes Care, Palomba and co-workers also affirmed that metformin raises serum homocysteine levels with resultant endothelial dysfuction. The suggestion that metformin may act to raise homocysteine levels is not new as others have suggested that more than six months of exposure to metformin results in rising homocysteine levels.
Die Scham und die Schande!
Ich tue Abbitte, dass ich Sie unterbreche.