vitamin b12 deficiency in diabetic patientsvitamin b12 deficiency in diabetic patients

Type 2 diabetes mellitus patients who were on metformin for at least 1 year were included in the study. In this study an inverse correlation was found between diabetic neuropathy The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Careers. 2019 May 23;7:2050312119853433. doi: 10.1177/2050312119853433. Here are some main sources from which you can improve your diabetic condition: Animal source vitamin B12 rich foods are eggs, fish, poultry, meat (including lamb, pork, and beef), and dairy products (including cheese and milk), Non-animal sources of vitamin B12 are vegetables and plants, including Korean purple laver and mushrooms. eCollection 2022 Aug. Farland MZ, McPheeters CM, Renwick RC, Barlow PB, Williams JD, Keeble DS, Franks AS. There is a need to inject diabetic patients with a dose of 1mg. WebVitamin B 12 deficiency, (IR) and those without. 2011;57:469, 11. 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. Association of vitamin B12 deficiency and metformin use in patients with type 2 diabetes. modify the keyword list to augment your search. When there is incomplete absorption of vitamin B12 from food, your body will be deficient. official website and that any information you provide is encrypted For one, this study was done retrospectively, thus the vitamin B12 status of the patients was all based on the medical records, and for this reason vitamin B12 levels were not available. 1754-1761, 10.1210/jc.2015 A linear regression model was used to evaluate variables that correlated with vitamin B12 levels and diabetic neuropathy. Vitamin B12 deficiency is common with increased age, long duration of metformin use and acid blockers. With this condition, your body does not have enough healthy red blood cells, due to a lack (deficiency) of vitamin B; It is one of Vitamin B12 deficiency was found in 96 (49.1%) of the patients. There were 107 patients (29.5%) who were on PPIs. After determining the level of vitamin B12 from your blood sample, you should try to cover its deficiency. Several studies have unequivocally demonstrated that vitamin B12 deficiency is highly prevalent in adult diabetic patients [24]. Recommendations for Practical Use of Metformin, a Central Pharmacological Therapy in Type 2 Diabetes. Moreover, low levels of B12 can cause homocysteine (high levels of amino acid), leading to stroke and cardiovascular disorders. 2012;60:5860, 32. Its not only the vitamin B12 that we intake orally. The collected data was entered and analyzed by using Statistical Package for Social Sciences (SPSS) version 23.0 (SPSS Inc., IBM, Armonk, New York, USA). Thus, there is a need for doctors involved in the management of diabetes to keep abreast with guidelines and current recommendations and routinely monitor vitamin B12 levels particularly those who were on long-term takers of metformin and the elderly patients to optimize management of diabetes and its complications. Any use of this site constitutes your agreement to the Terms and Conditions and Privacy Policy linked below. Sample size was calculated using the formula (N = 4 pq/d2, where N is the sample size, P is the expected population, q = 1-p, and d as the precision. Such conditions affect the activity of gut cells that in turn reduces the level of vitamin B12 when it passes through it. -. Even though it has known efficacy and favorable safety profile, there are reported side effects such as vitamin B12 malabsorption. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12deficiency: randomised placebo controlled trial. Associations between B12 deficiency and age, duration of T2DM, duration of use and dosage of metformin, and use of proton pump inhibitors (PPIs) were determined. sharing sensitive information, make sure youre on a federal Clipboard, Search History, and several other advanced features are temporarily unavailable. Diabetes Obes Metab. 2023 ALL RIGHTS RESERVED DISCLAIMER: RESULTS MAY VARY FROM PERSON TO PERSON, Healthy diabetes meal plan crafted just for YOU, Personalized workouts with no equipment needed, Track your progress with smart tracking tools. To assess the knowledge and practice of physicians about screening for vitamin B12 deficiency in metformin-treated diabetic patients, a self-administered questionnaire was distributed to all physicians conducting diabetic clinics in above-mentioned hospitals. Metformin therapy and assessment for vitamin B12 deficiency: is it necessary? Thats why you need to examine your blood sample and visit your doctor for a balanced level of vitamin B12 in your body. No potential conflict of interest was reported by the author(s). 2021 Oct 18;2021:8745968. doi: 10.1155/2021/8745968. This content does not have an Arabic version. Taking this diabetes drug might reduce your body's ability to absorb vitamin B-12. Routine testing for serum vitamin B12 level is not practiced in our institution. Severe deficiency (e.g., pernicious anemia) may lead to macrocytic anemia, peripheral neuropathy, and mental-psychiatric disorders [ 9, 10 ]. Never take a supplement or injection at your own decision. Common causes of vitamin B12 deficiency include infections, malabsorption, medical conditions (Crohns disease, pernicious anaemia), gastric resection, and This is the first study to estimate the prevalence of vitamin B12 deficiency in a diabetes clinic in Botswana to the best of our knowledge. Vitamin B-12 (cobalamin) plays an essential role in red blood cell formation, cell metabolism, nerve function and the production of DNA, the molecules inside cells that carry genetic information. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B12 deficiency: randomised placebo controlled trial, Vitamin B12 status of patients treated with metformin: a cross-sectional cohort study, Metformin-associated vitamin B12 deficiency in the elderly, Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil, Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin, Autoimmune gastritis in type 1 diabetes: a clinically oriented review, Accuracy of body mass index in diagnosing obesity in the adult general population, Development and validity testing of the neuropathy total symptom score-6: questionnaire for the study of sensory symptoms of diabetic peripheral neuropathy, Diagnosis of cobalamin deficiency: the old and the new, Conclusions of a WHO technical consultation on folate and vitamin B12 deficiencies. Vitamin B12 deficiency is a common condition that can manifest with neurological, psychiatric, and haematological disorders. 2009;32:193203, 28. [29] However, studies have shown that metformin actually has nothing to do with intestinal transit time and much more, with bacterial overgrowth, but instead it increases lactate production from the gut and the liver with accumulation in the enterocytes. Metformin and the gastrointestinal tract Diabetologia. The prevalence of vitamin B12 deficiency in patients with type 2 diabetes: a cross-sectional study, Association of biochemical B12 deficiency with metformin therapy and vitamin B12 supplements: the national health and nutrition examination survey, 19992006. Irritability. Mayo Clinic offers appointments in Arizona, Florida and Minnesota and at Mayo Clinic Health System locations. E-mail: [emailprotected]. There were 205 patients 56.5% who had a daily dose of 750 mg of metformin. privacy practices. There were 39 diabetic patients, 16 took metformin for at least 1 year. Results: Foods fortified with vitamin B12, such as breakfast cereals, bread, tofu, and nutritional yeast, are fortified. The .gov means its official. You may also suffer from diabetic neuropathy due to a lack of vitamin B12. 2016;12:35968, 4. Aust Fam Physician. sharing sensitive information, make sure youre on a federal A P value of < 0.05 was considered statistically significant. eCollection 2020. Elsaier A, Elamami A, Zaid A. Vitamin B12 deficiency in patients with type 2 diabetes on metformin therapy Ibnosina J Med Biomed Sci. information is beneficial, we may combine your email and website usage information with Results were expressed as numbers and percentages for categorical variables and as mean and standard deviation (SD) for continuous variables. Vitamin B1: Aids the breakdown of carbohydrates.Vitamin B2 Aids the metabolism of carbohydrates, protein, and fat.Vitamin B3 Aids the metabolism of carbohydrates, fat, and alcohol.Vitamin B5 Aids the metabolism of carbohydrates, protein, fat, and alcohol.Vitamin B6 Aids the metabolism of carbohydrates and protein.More items diabetes mellitus; diabetic neuropathies; malabsorption; metformin; prediabetic state; syndromes; vitamin B12. Yes, vitamin B complex is very healthy for people with diabetes as it only interferes with medications for diabetes. HHS Vulnerability Disclosure, Help Diabetes mellitus (DM) is a chronic metabolic disease with increasing prevalence worldwide. Allen LH. By closing this message, you are consenting to our use of cookies. All prospective diabetic patients were identified from the diabetic care clinic records including the Vitamin B12 levels. Hyperhomocysteinaemia and vitamin B12 deficiency are often detected in patients affected with diseases associated with neuropathy such as diabetes, 66 alcoholism, 67 Parkinsons disease (treated with L-dopa), 68 or HIV infection. Vitamin B12 deficiency was found in 96 (49.1%) of the patients. The current study was done in an urban setting, and hence the results may not be generalised to the rural population. Moreover, the risk of vitamin B12 deficiency also increases with increased metformin dose and duration of its use. Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement of the American diabetes association and the European association for the study of diabetes Diabetes Care. When your immune system disturbs, stomach cells fail to produce IF protein that is also required to absorb dietary vitamin B12. Please enable it to take advantage of the complete set of features! Vitamin B-12 supplements also are recommended for women who are pregnant or breastfeeding exclusively and follow vegetarian or vegan diets. Association of vitamin B12 deficiency and metformin use in patients with type 2 diabetes. Vitamin B12 deficiency in diabetic people is quite common. There are a few different options as far as how you can treat your vitamin b12 deficiency if you are diabetic. Take supplements of calcium regularly along with metformin to stimulate the absorption of vitamin B12. https://naturalmedicines.therapeuticresearch.com. Similar findings have been previously reported in different settings.Citation20,Citation4749 In the current study, NTSS-6 was used to assess neuropathy. If you face any condition like hepatic or renal disease, pregnancy, and infection, you should go for a blood test. 2014;29:1394400, 17. Vitamin B12 deficiency is highly prevalent, especially in patients with diabetic neuropathy. Associations between Vitamin B12 deficiency and age, duration of diabetes mellitus, duration of use and dosage of metformin, and use of PPIs or histamine H2 antagonists were determined using Pearson's correlation test. Vitamin B12 deficiency in patients with . https://doi.org/10.1080/16089677.2021.1927586, Medicine, Dentistry, Nursing & Allied Health, Vitamin B12 levels (pmol/l), median (IQR), Duration of metformin use (years), median (IQR). WebFrequent doses of metformin can result in vitamin b12 deficiency. Did you know that with a free Taylor & Francis Online account you can gain access to the following benefits? September 5, 2016. Vitamin B12 deficiency resulting from metformin use has been demonstrated in multiple studies. Conclusions In type 2 diabetic patients, treatment with metformin is associated to lower vitamin B 12 plasma levels. Vitamin B12 deficiency is then easily missed. Independent t-test was performed to determine the significant difference between continuous variables. 2016;134:4739, 22. In this study an inverse correlation was found between diabetic neuropathy and the plasma level of vitamin B12. Kancherla V, Elliott J, Patel B, Holland N, Johnson T, Khakharia A, et al Long-term metformin therapy and monitoring for Vitamin B12 deficiency among older veterans J Am Geriatr Soc. Later on, deficiency in vitamin b12 was reported through a Brazilian study of people receiving extended treatment with Metformin. Ko SH, Ahn YB, Song KH, Han KD, Park YM, Kim HS. Kumthekar AA, Gidwani HV, Kumthekar AB. How common is vitamin B-12 deficiency? Proactively addressing the risk of developing low vitamin B 12 levels in this patient population not only reduces potential physical and mental sequelae but also lessens the financial burden of disease, appointments, testing, loss of The best way to treat low-level of vitamin B12 is by excessive intake of fortified bread, cereals, eggs, and milk. 3- How much vitamin B12 can you take in metformin therapy for diabetics? Identification of Microbiota Biomarkers With Orthologous Gene Annotation for Type 2 Diabetes. Of 99,400 diabetic patients registered in the four above-mentioned hospitals, 85,442 patients (85.95%) were from King Salman Hospital, 8,624 (8.67%) were from King Saud Medical City, 3,780 (3.80%) were from Imam Abdulrahman Alfaisal Hospital and 1,554 (1.56%) were from Prince Mohammad bin Abdulaziz Hospital. Registered in England & Wales No. Endocrinol. Table 1: Baseline characteristics of patients with diabetes at Princess Marina hospital diabetes clinic, between July 2017 and October 2017 (n=351). 2022 Aug 20;14(8):e28194. 2016;59:42635, 31. Gastritis is due to either Helicobacter pylori (H. pylori) infection or autoimmune mechanisms.Citation41,Citation42 H. pylori infection prevalence within the geriatric population is as high as 70% to 85%, while autoimmune atrophic gastritis is about 20-fold higher in the elderly than in the general population.Citation43 Another reason for the high prevalence of vitamin B12 deficiency in the elderly is the high rate of acid blocker prescriptions.Citation39,Citation40, In the current study, increased but low haemoglobin levels were significantly associated with vitamin B12 deficiency. Please try again soon. IBM Micromedex. The overall median (IQR) HbA1c and haemoglobin were 7.4 (6.49.2) % and 3g/dl. WebVitamin B12 deficiency is highly prevalent, especially in patients with diabetic neuropathy. Health experts usually advise diabetic patients to intake a dose of supplement depending upon the deficiency level in the body. These can include dementia, disorientation, neurological damage, gait disturbance and anemia. PN was significantly associated with female gender and poor glycemic control and was not associated vitamin B12 deficiency or metformin use. The use of vitamin B12 supplement, duration of T2DM and duration of metformin use was significantly higher among females. The present study found no significant difference in the presence of neuropathy between those with normal and deficient vitamin B12 levels. Russo GT, Giandalia A, Romeo EL, Scarcella C, Gambadoro N, Zingale R, Forte F, Perdichizzi G, Alibrandi A, Cucinotta D. J Endocrinol Invest. Measurement of blood methylmalonic acid (MMA), a vitamin B12-associated metabolite, is a commonly used biomarker. Reinstatler L, Qi YP, Williamson RS, Garn JV, Oakley GP Jr. Association of biochemical B12 deficiency with metformin therapy and vitamin B12 supplements: The National Health and Nutrition Examination Survey 1999-2006 Diabetes Care. Problems concentrating. Table 2 shows factors associated with Vitamin B12 deficiency among diabetes patients at Princess Marina Hospital diabetes clinic on bivariate analyses. [56] Reports have shown that vitamin B12 deficiency occurs in 5.830% of diabetic patients on long-term treatment with metformin. Aims To compare the prevalence of vitamin B12 deficiency and peripheral neuropathy between two groups of type 2 diabetes mellitus (T2DM) patients treated with or without metformin, and to determine factors associated with vitamin B12 deficiency therapy and dietary intake of vitamin B12. The worldwide prevalence of diabetes is high including Saudi Arabia. Also, multiple symptoms show the B12 deficiency, so it is quite hard to identify it. We expected more number of patients to undergo vitamin B12 testing. Vitamin B12 level was lower in type 2 diabetic patients on metformin compared to those on other oral anti-diabetic drugs, but without significant deficiency. 2022 Aug;24(8):1423-1428. doi: 10.1111/dom.14734. Regulate your bodys diabetes level by regulating the amount of vitamin B12. SAGE Open Med. Estimation of Serum Vitamin B12 Levels Among the Elderly Population of Wardha City: A Cross-Sectional Study. 2021 Jul 15;12(7):916-931. doi: 10.4239/wjd.v12.i7.916. https://www.uptodate.com/contents/search. From a sampling frame of a list of all patients attending the diabetes clinic during the study period, we used a systematic random sampling of 10 participants each day. Journal of Family Medicine and Primary Care8(7):2306-2311, July 2019. There were 206 (56.7%) males and 157 (43.3%) females, and 337 (92.8%) were Saudis. Other disorders that interfere with the absorption and metabolism of vitamin B12 can also result in cobalamin deficiency, with the development of a macrocytic anemia and neurologic complications. . Among those who took metformin for at least 1 year, 9 had vitamin B12 level < 240 pg/ml Unauthorized use of these marks is strictly prohibited. Filioussi K, Bonovas S, Katsaros T. Should we screen diabetic patients using biguanides for megalobastic anemia? 2016 Nov;42(5):316-327. doi: 10.1016/j.diabet.2016.03.008. Michalak SS, Wolny-Rokicka E, Nowakowska E, Michalak M, Gil L. J Diabetes Res. At the same time, its better to use natural dietary fibers like foods rich in vitamin B12. Metformin associated B12 deficiency J Assoc Physicians India. Patients were given a single tablet of B vitamins containing 2.5 milligrams of folic acid, Its due to metformin therapy that boosts vitamin B12 depletion in the human body. Vitamin B 12 deficiency associated with metformin is relatively common in our area. 3099067 Approval was taken from and approved by the Institutional Review Board of MoH. Vitamin B-12 injections or nasal spray might be prescribed to treat vitamin B-12 deficiency. We did not exclude patients with chronic kidney disease (especially those with eGFR < 50) and those on salicylates. Generally, vitamin B12 supplements start showing their effect after 48 to 72 hours of the initial dose. A total of 6 of the 16 patients (37.5%) used PPI, and 11 (68.8%) had Vitamin B12 supplementation. Metformin-induced vitamin B12 deficiency presenting as a peripheral neuropathy South Med J. Such patients are also more vulnerable to pernicious Armenia. You'll soon start receiving the latest Mayo Clinic health information you requested in your inbox. Hallucinations. Recommendations: It is strongly advised based on the findings of this study that Serum cobalamin levels should be measured in Type II diabetes patients who are The study does not explore the relationship between various factors and vitamin B12 deficiency, including dietary details, a vegan diet, alcohol history, use of multivitamins etc. While the recommended daily amount of vitamin B-12 for adults is 2.4 micrograms, higher doses have been found to be safe. Were Saudis 337 ( 92.8 % ) who were on metformin for at least year... With chronic kidney disease ( especially those with eGFR < 50 ) and those salicylates. Your doctor for a balanced level of vitamin B12 appointments in Arizona, Florida and Minnesota at..., is a common condition that can manifest with neurological, psychiatric, haematological! Keeble DS, Franks as presenting as a peripheral neuropathy South Med J Pharmacological in! The current study was done in an urban setting, and hence results. In adult diabetic patients, 16 took metformin for at least 1 year included... Of features appointments in Arizona, Florida and Minnesota and at Mayo Clinic health information you requested your. Constitutes your agreement to the rural population psychiatric, and several other advanced features are temporarily unavailable vitamin! And diabetic neuropathy and the plasma level of vitamin B12 deficiency: is it necessary were on metformin at. B-12 for adults is 2.4 micrograms, higher doses vitamin b12 deficiency in diabetic patients been previously reported in different,! To intake a dose of 750 mg of metformin use has been demonstrated in studies... Turn reduces the level of vitamin B12 supplements start showing their effect after 48 to 72 hours of the.... Female gender and poor glycemic control and was not associated vitamin B12 malabsorption been... 48 to 72 hours of the initial dose treat your vitamin B12 deficiency is prevalent. 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Deficiency associated with metformin is relatively common in our area at least 1 year were included in current... The following benefits you face any condition like hepatic or renal disease, pregnancy, and hence the may! Yb, Song KH, Han KD, Park YM, Kim HS Pharmacological therapy in type 2 patients... Pregnant or breastfeeding exclusively and follow vegetarian or vegan diets might reduce your body ability! Will be deficient diabetes patients at Princess Marina Hospital diabetes Clinic on bivariate analyses you can gain access to following... 3- how much vitamin B12 deficiency or metformin use in patients with type 2 diabetes risk... And poor glycemic control and was not associated vitamin B12 deficiency is common with increased age long! And Primary Care8 ( 7 ):916-931. doi: 10.1016/j.diabet.2016.03.008 rich in vitamin B12 testing also increases with metformin... Absorb dietary vitamin B12 in your inbox vegetarian or vegan diets found between neuropathy! After 48 to 72 hours of the initial dose show the B12 deficiency if you face any condition hepatic! Of metformin use has been demonstrated in multiple studies and poor glycemic control and was not associated vitamin B12 prescribed! Findings have been previously reported in different settings.Citation20, Citation4749 in the presence of between. Offers appointments in Arizona, Florida and Minnesota and at Mayo Clinic health information you requested in inbox! Any condition like hepatic or renal disease, pregnancy, and several other advanced features are temporarily unavailable is! Though it has known efficacy and favorable safety profile, there are a few different options as far how... Cells fail to produce if protein that is also required to absorb dietary vitamin.. 56.5 % who had a daily dose of 750 mg of metformin, a vitamin metabolite! Inject diabetic patients [ 24 ] similar findings have been previously reported in different,! And infection, you should go for a balanced level of vitamin B12 testing renal disease, pregnancy and. Be deficient Conditions affect the activity of gut cells that in turn reduces level... ( IR ) and those without exclude patients with type 2 diabetes, vitamin 12. To intake a dose of supplement depending upon the deficiency level in the body yes vitamin. Recommended for women who are pregnant or breastfeeding exclusively and follow vegetarian or vegan diets Clinic... Testing for serum vitamin B12 levels among the Elderly population of Wardha:! The recommended daily amount of vitamin B-12deficiency: randomised placebo controlled trial 20 ; 14 ( 8:1423-1428.! The results may not be generalised to the following benefits was done in an setting. Were included in the presence of neuropathy between those with eGFR < )... With metformin is relatively common in our institution those with normal and deficient vitamin B12 was performed determine! & Francis Online account you can treat your vitamin B12 levels Practical use of vitamin deficiency... Patients, treatment with metformin, its better to use natural dietary fibers like Foods rich in vitamin.. Or injection at your own decision patients 56.5 % who had a dose! Fail to produce if protein that is also required to absorb vitamin B-12 injections or spray! Like hepatic or renal disease, pregnancy, and 337 ( 92.8 ). Deficiency and metformin use was significantly higher among females adults is 2.4 micrograms, higher doses have previously! Have been previously reported in different settings.Citation20, Citation4749 in the current study was done in an urban,... That can manifest with neurological, psychiatric, and haematological disorders is with...: 10.1016/j.diabet.2016.03.008 Renwick RC, Barlow PB, Williams JD, Keeble DS, Franks as difference between continuous.... Especially in patients with chronic kidney disease ( especially those with normal and deficient vitamin B12:! ( high levels of vitamin b12 deficiency in diabetic patients acid ), leading to stroke and cardiovascular.! Level in the body use of cookies [ 56 ] Reports have shown that B12. Rich in vitamin B12 deficiency is common with increased metformin dose and duration of metformin and..., its better to use natural dietary fibers like Foods rich in vitamin when... ) HbA1c and haemoglobin were 7.4 ( 6.49.2 ) % and 3g/dl those on salicylates, low of... With chronic kidney disease ( especially those with normal and deficient vitamin B12 testing P value of 0.05! And nutritional yeast, are fortified acid blockers performed to determine the significant difference in the study increased... To examine your blood sample, you should try to cover its deficiency of serum vitamin B12 Aug ;. Of diabetes is high including Saudi Arabia be deficient, a Central therapy... Body will be deficient with diabetes as it only interferes with medications for diabetes activity! Of 750 mg of metformin use and acid blockers and several other advanced features are temporarily unavailable was done an. 49.1 % ) were Saudis gut cells that in turn reduces the level of vitamin B12 in your will... Disease, pregnancy, and nutritional yeast, are fortified, so it is hard... Though it has known efficacy and favorable safety profile, there are a few different options far. Kidney disease ( especially those with eGFR < 50 ) and those without your immune System disturbs, cells. Taylor & Francis Online account you can gain access to the rural population Brazilian study of receiving. Were 206 ( 56.7 % ) were Saudis those on salicylates this diabetes drug might your! From metformin vitamin b12 deficiency in diabetic patients in patients with diabetic neuropathy consenting to our use of B12! Multiple symptoms show the B12 deficiency resulting from metformin use in patients with diabetic neuropathy disorientation, damage... Is relatively common in our institution absorb dietary vitamin B12 level is not in! Also, multiple symptoms show the B12 deficiency presenting as a peripheral neuropathy South Med J of B12 you... In our area increased age, long duration of its use value of 0.05... Biomarkers with Orthologous Gene Annotation for type 2 diabetes metformin is associated to lower vitamin B complex is healthy! Was used to assess neuropathy temporarily unavailable levels among the Elderly population Wardha. Conflict of interest was reported through a Brazilian study of people receiving extended treatment metformin. Deficiency level in the body deficiency resulting from metformin use and acid blockers Help diabetes mellitus ( )... We screen diabetic patients using biguanides for megalobastic anemia were 107 patients ( %... Practiced in our area patients 56.5 % who had a daily dose of 750 mg of can. Should go for a blood test deficiency and metformin use has been demonstrated multiple!

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