Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Reviews
Year : 2022 | Month : March | Volume : 16 | Issue : 3 | Page : ZE01 - ZE06 Full Version

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


Published: March 1, 2022 | DOI: https://doi.org/10.7860/JCDR/2022/53256.16055
CJ Sanjay, Karthikeya Patil, D Nagabhushana, Romali Panda, VG Mahima

1. Reader, Department of Oral Medicine and Radiology, JSS Dental College and Hospital, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India. 2. Professor and Head, Department of Oral Medicine and Radiology, JSS Dental College and Hospital, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India. 3. Reader, Department of Oral Medicine and Radiology, JSS Dental College and Hospital, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India. 4. Postgraduate Student, Department of Oral Medicine and Radiology, JSS Dental College and Hospital, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India. 5. Professor, Department of Oral Medicine and Radiology, JSS Dental College and Hospital, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India.

Correspondence Address :
Dr. Karthikeya Patil,
Professor and Head, Department of Oral Medicine and Radiology, JSS Dental College
and Hospital, JSS Academy of Higher Education and Research
Mysuru-570015, Karnataka, India.
E-mail: dr.karthikeyapatil@jssuni.edu.in

Abstract

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 B12 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 revolves 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.

Keywords

Antihyperglycaemics, Cobalamin, Oro-mucosal lesions, Type 2 diabetes mellitus

Diabetes Mellitus (DM) is the commonest non communicable diseases in this era of development and globalisation. According to World Health Organisation (WHO) (1), the prevalence rate of Diabetes in India is 8.7% in the age group of 20-70 years. Diabetes affected 8.5 percent of persons aged 18 and above in 2014. Diabetes was the direct cause of 1.5 million fatalities in 2019, with 48 percent of all diabetes-related deaths occurring before the age of 70 years (2). Diabetes caused a 5% rise in premature mortality rates (death before the age of 70 years) between 2000 and 2016. Diabetes-related premature mortality declined in high-income nations from 2000 to 2010, but then surged from 2010 to 2016. Diabetes-related premature mortality increased in lower-middle-income nations over both eras. In contrast, between 2000 and 2016, the global risk of dying from any of the four major non communicable illnesses (cardiovascular diseases, cancer, chronic respiratory diseases, or diabetes) between the ages of 30 and 70 fell by 18% (2). The rising prevalence of diabetes amongst all other non communicable diseases in India is multifactorial, some of which constitute rapid urbanisation, sedentary sluggish lifestyle, unbalanced diet, usage of tobacco and alcohol consumption, obesity, lack of exercise etc. The Diabetes Research Centre in Madras conducted several investigations on the risk factors that contribute to T2DM in Indian population (3).

Previously DM was classified based on age at onset and therapy employed (4),(5). The American Diabetes Association (4),(5) has revised the classification because each type could possibly have patients younger or older age group and the revised classification is based on the pathophysiology of DM and not the basis of treatment (5). (Table/Fig 1) shows the revised classification of T2DM (4),(5).

Non insulin hypoglycaemic therapies (non insulin hypoglycaemic agents) which are routinely used to treat hyperglycaemia in people with Type 2 Diabetes namely Biguanides (metformin), Sulfonylureas, Thiazolidinediones (e.g., pioglitazone), Alpha-glucosidase inhibitors (e.g., acarbose), Meglitinides (e.g., nateglinide), Dipeptidyl Peptidase (DDP)-4 inhibitors (gliptins), Glucagon-like peptide-1 agonists (exenatide, liraglutide), Amylin analogues (Pramlintide), Bile acid sequestrants (colesevelam) and Dopamine agonists (bromocriptine) (6),(7),(8).

The most widely recommended drug for T2DM patients is Metformin (1,1-dimethylbiguanide). It has a proven therapeutic effectiveness, has an excellent safety profile, is low-cost, and is suggested as the first-line oral medication in T2DM in combination with lifestyle changes (9).

METFORMIN IN THE MANAGEMENT OF T2DM

Galega officinalis (also known as goat’s rue) is a traditional herbal medication in Europe that was discovered to be high in guanidine, which was proved to reduce blood glucose in 1918. In 1920s and 1930s, Metformin and other guanidine derivatives were used to treat diabetes, but they were phased out owing to toxicity and greater insulin availability. In the 1940s, Metformin was rediscovered while looking for antimalarial drugs, and was found to be effective for the treatment of influenza and also lowering blood glucose (10).

It does this by lowering hepatic glucose synthesis and intestinal glucose absorption. Metformin is an outstanding therapeutic option with a highly favourable risk-to-benefit ratio that was first licenced by the Food and Drug Administration in 1994 and commercialised in 1995. To reduce Gastrointestinal (GI) side-effects, start with the lowest effective dose (500 mg twice daily orally) and gradually increase dosage (11). The first-line for management of T2DM is Metformin (12),(13). Since, its approval in the United Kingdom in 1958 and the United States in 1995, metformin has become one of the most extensively used medications in the treatment of T2DM, with dosages ranging from 500-2,500 mg/day (14). According to the American Diabetes Association/European Association for the Study of Diabetes guidelines, it is the first-line oral therapy medication for people with T2DM (15). Metformin improves glycaemic control in people with T2DM by improving insulin sensitivity in the liver and other tissues. The major consequence is a reduction in hepatic glucose synthesis and an increase in glucose excretion in the skeletal muscles (16). Metformin improves insulin suppression of endogenous hepatic glucose synthesis and clearance in the fasting state, but not insulin-mediated glucose absorption in peripheral tissues, according to a systematic review of in-vivo investigations in humans. Metformin works in the liver (17),(18),(19),(20),(21), small intestines (22),(23),(24), and skeletal muscles (25),(26) to assist glycaemic control. (Table/Fig 2) Shows the mechanism of action of metformin at different sites to improve glycaemic control and lower plasma glucose (17),(18),(19),(20),(21),(22),(23),(24),(25),(26).

Berchtold P et al., reported vitamin B12 malabsorption in patients treated with metformin for as little as three months in 1969 (14). Based on a cross-sectional study, Tomkin GH et al., suggested annual serum B12 testing for all patients on long-term metformin medication as early as 1971 (15). Since then, cross-sectional, retrospective, and longitudinal observational studies (27),(28) as well as case reports (29),(30) have revealed that long-term metformin use and vitamin B12 deficiency are linked (31),(32). However, there have been few prospective placebo-controlled trials to determine the risk of vitamin B12 deficiency in metformin-treated individuals, and none specifically in prediabetic persons. The majority of randomised trials on this topic have been modest or short-term (six months) and have mostly involved patients with type 2 diabetes (33). (Table/Fig 3) shows the previous studies about Metformin Induced Cobalamin Deficiency (MICD) and the prevalence according to those studies (14),(15),(28),(29),(30),(34),(35),(36).

VITAMIN B12 SERUM DEFICIENCY AND ITS IMPLICATIONS

Vitamin B12, also known as cobalamin, is a water-soluble vitamin that is essential for Deoxyribonucleic Acid synthesis, proper haemopoiesis, and neurological function. As a result, the clinical picture of vitamin B12 insufficiency is dominated by haematological and neurocognitive impairment (37). Dietary vitamin B12 binds to the R-protein secreted by the salivary glands after it is released. Proteolytic breakdown of the vitamin B12-IF (intrinsic factor) complex is extremely difficult. The complex binds to specific receptors on the mucosa of the terminal ileum, a place where it can be found (37),(38). Vitamin B12, as a co-factor, facilitates the conversion of methyl malonyl coenzyme A (CoA) to succinyl-CoA in another important enzymatic route; resulting in an increase in serum methylmalonic acid (MMA). Following this, the neuronal membranes’ fatty acid production is disrupted (39). Vitamin B12 is also required for the production of monoamines, or neurotransmitters, such as serotonin and dopamine (40). Vitamin B12 deficiency interferes with this production. Because of its cellular and vasculotoxic effects, hyperhomocysteinemia has been linked to an increased risk of cardiovascular events (41),(42),(43). For absorption, vitamin B12 forms a compound with the cubulin (endocytic) receptor in the ileum. The ileal cell surface ordinarily takes this B-12 endocytic receptor complex via a calcium-dependent mechanism. Metformin binds to the B12-cubulin complex and gives it a positive charge, altering membrane potential and competitively repelling divalent calcium ions, limiting calcium-dependent uptake and resulting in B12 malabsorption, for which calcium supplementation has been used to treat some patients with metformin-induced B12 insufficiency (44),(45).

Diagnosis of Metformin Induced Vitamin B12 Deficiency in T2DM

There are currently no published guidelines advocating for routine vitamin B12 deficiency screening in T2DM patients. However, it is clinically reasonable to screen for vitamin B12 deficiency in type 2 diabetic patients prior to starting metformin and then annually in elderly patients with a history of long-term metformin use (≥3-4 years), high-dose metformin use (≥2 g/day), and clinically worsening diabetic distal polyneuropathy in the presence or absence of the discussed haematological abnormalities (46).

The method for detecting vitamin B12 insufficiency in diabetic patients and the general public is comparable. The preliminary screening step for vitamin B12 deficiency should be the measurement of serum vitamin B12 concentrations. Concentrations of less than 200 pg/mL are usually indicative of deficiency in vitamin B12 while values are >400 pg/mL ensure that there is no vitamin B12 deficiency (47). In type 2 diabetes, patients with borderline serum vitamin B12 concentrations of 200-400 pg/mL and modest haematological symptoms, measuring serum MMA or homocysteine concentrations is a more sensitive and specific technique for screening. Serum homocysteine and MMA values of 5-15 mol/L and 0.28 mol/L, respectively, are considered normal (46),(48). Despite the fact that the medical literature is unclear about who should be monitored for MICD and how often, we believe that MICD should be suspected in all metformin-treated diabetic patients who have one or more of the following findings in their medical history, clinical signs, or laboratory studies:

• On a peripheral blood smear, oval macrocytic red blood cells ((Mean Corpuscular Volume (MCV) >100 fL) with or without anaemia. One of the characteristics of (cobalamin and folate insufficiency is an increase in red blood cell MCV (macrocytosis), while other reasons are also acquired (i.e., alcoholism, liver disease, hypothyroidism, myelodysplastic syndromes, drugs, etc.,) (46),(48).
• On a peripheral blood smear, the presence of hypersegmented neutrophils (i.e., >5% of neutrophils with five lobes or 1% of neutrophils with 6 lobes) (48).
• An unknown cause of pancytopenia (a combination of anaemia, thrombocytopenia, and neutropenia).
• Unexplained neuropsychiatric symptoms, including dementia or weakness, sensory ataxia, and paresthesias, or clinically exacerbated established diabetic peripheral neuropathy (49),(50).
• Elderly diabetic patients with long-term (≥3-4 years) high-dose (≥2 g per day) metformin use, especially if complicated by peripheral neuropathy, with or without haematological manifestations of cobalamine deficiency, and with or without everyday utilisation acid-suppressive drugs (as H2-receptor antagonists, antacids, proton pump inhibitors) (51)

SYSTEMIC MANIFESTATIONS OF VITAMIN B12 DEFICIENCY

(Table/Fig 4) shows different systemic manifestations of Vitamin B12 deficiency (46),(52),(53),(54),(55),(57),(58).

ORAL MANIFESTATIONS OF VITAMIN B12 SERUM DEFICIENCY

As aforementioned, vitamin B12 deficiency has an impact on oral health, and the following are some of the oral signs recorded in the literature such as glossopyrosis, glossitis, and glossodynia cause a beefy red tongue that appears smooth and shiny. Hunters’ glossitis or Moeller’s glossitis, which is related to pellagra’s “Bald tongue of sand with”, Recurrent Aphthous Stomatitis (RAS), Haemorrhagic gingiva, ulcerative gingivitis, gingival manifestations of Vitamin B12 deficiency, oral mucosa epithelial dysplasia, oral paraesthesia, and delayed wound healing and burning mouth syndrome (58),(59),(60),[61].

Vitamin B12 Deficiency and Glossitis

Atrophic glossitis is caused by a vitamin B12 deficiency and manifests as a bright red, smooth, painful, and burning tongue (59),(60),[61]. Kim J et al., compared clinical aspects of vitamin B12 insufficiency patients with a medical history of gastrectomy to those without a history of gastrectomy in research including twenty-two individuals [62]. The most common symptom was depapillation of the tongue. They concluded that individuals with glossodynia, especially those with normal oral mucosa and/or no history of gastrectomy, should be evaluated for Vitamin B12 deficiency [62].

A case of a 61-year-old lady with a six month history of a persistent burning sensation on the tongue was described by Stoopler ET and Kuperstein AS in 2013 [63]. Glossitis was identified after clinical examination revealed depapillation of the tongue. Laboratory tests revealed macrocytic anaemia and low vitamin B12 levels, prompting the patient to have a vitamin B12 injection; which completely resolved her symptoms. They recommended that glossitis might be the only symptom, and that the oral physician should handle the situation properly [63].

In 2009, Pontes HA et al., reported on a 41-year-old female patient who followed a rigorous vegetarian diet [64]. On clinical examination, the tongue’s dorsal and lateral margins exhibited pale mucosa, atrophic glossitis, and numerous erythematous patches and substantial B12 deficiency was discovered during a haematological investigation. Although history and clinical examination assisted in the diagnosis of megaloblastic anaemia, the authors advised to be keen about oral manifestations [64].

In 2009, Graells J et al., described four cases of oral linear lesions caused by vitamin B12 deficiency that were devoid of neurologic signs and anaemia [65]. They proposed that glossitis with linear lesions might be an early clinical symptom, and that serum levels should be checked even if anaemia is not present [65].

Hunter’s Glossitis and Vitamin B12 Deficiency

Hunter’s glossitis is a well-known oral symptom of B12 deficiency that begins as diffuse bright red areas (“beefy red”) and proceeds to atrophic glossitis. The dorsal and ventral surfaces, as well as the tongue’s edge, are the most common sites for lesions. The mucosa of the palatal, buccal, and labial mucosa can also be damaged, with lesions showing as linear, band-like, or irregular erythema [64]. As reported by Pontes HA et al., Graells J et al., in 2009 and Flores IL et al., the dorsal and ventral surfaces, as well as the tongue’s margin, are the most common sites for lesions [64],[65],[66]. The mucosa of the palatal, buccal, and labial mucosa can also be damaged, with lesions showing as linear, band-like, or irregular erythema.

Recurrent Aphthous Stomatitis (RAS) and Vitamin B12 Deficiency

Vitamin B12 is a co-enzyme that helps in glucose metabolism, protein synthesis, and haematopoiesis. Changes in the oral mucosa, such as stomatitis and glossitis, have recently been reported to represent the sole early oral indication of vitamin B12 insufficiency. It’s unknown what function vitamin B12 deficiency has in the aetiology of RAS. RAS cell-mediated immunity is thought to be reduced in people with RAS, and alterations in the oral epithelium of the tongue and buccal mucosa have been seen. These alterations resemble those found in the bone marrow and blood as a result of aberrant DNA synthesis [67],[68],[69].

The efficacy of daily dose in the therapy of people with RAS was investigated by Liu HL et al., in research published in 2013 [67]. The findings revealed a substantial improvement in RAS in the study group when compared to the control groups, indicating that supplementary medicines may be effective in both short and long-term RAS management.

In 2011, Qazi JA; conducted research on 65 RAS patients to validate the therapeutic benefits of Vitamin B12 in RAS patients [68]. Regardless of blood vitamin B12 levels, the number, length, and size of ulcers were reduced in the group treated with vitamin B12 1000mcg compared to the other group treated with 500 mcg. Regardless of their blood Vitamin B12 levels, the authors recommended that Vitamin B12 1000 mcg taken sublingually is a safe and effective therapy.

In 2010, Kozlak ST et al., conducted a study on the effects of dietary vitamin consumption in RAS patients [69]. The authors concluded that the existence of a deficit permits the development of an underlying inclination to ulceration, and that dietary intake may prevent instances of ulceration breakout in RAS patients.

Vitamin B12 Deficiency and Oral Premalignant Disorders and Malignancies

Several studies have found a link between low systemic levels of vitamin B12 and/or folate and an increased risk of cancer in oral epithelial tissues in those who are at risk [70]. Gorgulu O et al., conducted a study on 60 people in 2010 to investigate the role of serum homocysteine, folate, and vitamin B12 levels in the pathogenesis of Laryngeal Squamous Cell Cancer (LSCC) by measuring serum levels, and found that these levels are linked to metabolic changes in cellular metabolism, which lead to carcinogenesis [71]. In 68 Oral Submucous Fibrosis (OSMF) patients, Wang YP et al., looked at gastric parietal cell antibody positivity, serum iron, vitamin B12, and folic acid deficits [72]. However, the cause of lower serum levels of Vitamin B12 in OSMF patients remains unknown [72].

Vitamin B12 Deficiency and Oral Lichen Planus (OLP)

In a study conducted by Chen HM et al., the relationship between iron, folic acid, and vitamin B12 deficiency and homocysteine level was assessed in 352 OLP subjects, and it was found that OLP patients had a higher frequency of haemoglobin, iron, or vitamin B12 deficiency, as well as abnormally elevated blood homocysteine level than control participants [73].

MANAGEMENT OF VITAMIN B12 DEFICIENCY

Patients in the United Kingdom are currently treated with injectable cobalamin according to the following guidelines, regardless of the underlying cause [74]. Hydroxocobalamin 1 mg on alternate days for two weeks is the standard prescription for people with no neurological damage, followed by three-monthly injections of hydroxocobalamin 1 mg [74]. If patients have pernicious anaemia, patients should follow this regimen for the rest of life. If the deficiency is caused by something else, treatment should be continued until the haematological indices improve significantly. If the patient has significant neurological symptoms, is present, or the diagnosis is unclear, he or she should be sent to secondary care. If there is a suspicion of malabsorption, gastric cancer, or celiac disease, patient should see a gastroenterologist. Treatment of underlying problems, such as antibiotics for bacterial overgrowth [75] and the discontinuation of offending medicines, can often be beneficial [74],[75]. The discovery of an alternative IF-independent mechanism for vitamin B12 absorption 60 years ago resulted in the finding that big enough doses, in the range of 100-100,000 g (even though only 1% of the cyanocobalamin was absorbed), were sufficient to meet the daily need [76].

In two separate trials, Andrès E et al., proved the efficacy of oral cobalamin in alleviating both biochemical and clinical signs of vitamin B12 insufficiency [76],[77]. Furthermore, in both groups, a similar proportion of participants showed improvement in neurological symptoms such as bilateral paraesthesia and ataxia (22 percent in the oral arm vs 27 percent in the intramuscular arm). Castelli MC et al., used a similar design to get similar results when they gave 1,000 g orally per day [78].

METFORMIN AND CANCER RISK

Metformin preferentially destroys cancer stem cells and inhibits tumour growth, according to Hirsch HA et al., [79]. Metformin was also found to have a synergistic effect with chemotherapeutic medicines in nude mice, reducing tumour bulk and prolonging remission. When compared to other antidiabetic medicines, meta-analyses of metformin and cancer risk in diabetic patients found that metformin users had a one-third lower total cancer risk and cancer mortality [79],[80]. The results of trials comparing metformin to placebo or normal treatment, as well as trials lasting more than a year, did not favour metformin. The confidence intervals, on the other hand, were broad, and there was a lot of clinical heterogeneity between the studies when it came to the comparators. In addition, there was insufficient data to investigate particular cancer outcomes. Another significant drawback was the little follow-up time (average 4.1 years). Metformin’s favourable effect on cancer risk was observed in most observational studies when the medicine was administered for more than five years [80],[81].

Conclusion

Analysis of serum Vitamin B12 in T2DM patients treated with metformin to rule out vitamin B12 deficiency in metformin-induced cobalamin deficiency is highly essential to ensure general wellbeing to rule out all neuro-psychiatric ailments to oral manifestations. Few studies conclude any inter relationship between the above two factors and derive the results about the metformin induced vitamin B12 deficiency. To test the idea that metformin has an anticancer impact, long-term randomised clinical trials particularly designed to establish metformin’s influence on cancer risk are much needed. The risk factors discovered have relevance for metformin-treated patients’ screening and preventative methods for their general euphoria.

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DOI and Others

DOI: 10.7860/JCDR/2022/53256.16055

Date of Submission: Nov 10, 2021
Date of Peer Review: Dec 23, 2021
Date of Acceptance: Jan 06, 2022
Date of Publishing: Mar 01, 2022

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? NA
• Was informed consent obtained from the subjects involved in the study? NA
• For any images presented appropriate consent has been obtained from the subjects. NA

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