A review on vitamin B12 deficiency induced by metformin

Multiple studies have established a higher prevalence of vitamin B12 deficiency in patients who have type 2 diabetes mellitus (T2DM). Metformin is prescribed as the 1st line oral glucose-lowering medication for individuals with T2DM. However, metformin therapy has been linked to vitamin B12 malabsorption, which can result in both biochemical and clinical manifestations of vitamin B12 deficiency. The long-term use of metformin is associated with a significant decrease in vitamin B12 levels, particularly in doses greater than 2000 mg per day over a period of 4 years. Vitamin B12 is a water-soluble vitamin. It acts as a cofactor for enzymes involved in DNA synthesis and neuroprotection at the cellular level. Hence, vitamin B12 deficiency can lead to various clinical consequences, including hematologic abnormalities such as megaloblastic anemia and hypersegmented neutrophil formation, peripheral neuropathy, and progressive axonal demyelination, hyperhomocysteinemia (HHcy). The latest "standards of medical care in diabetes-2017" issued by the American diabetes association recommends periodic assessment of B12 status and, if necessary, the use of B12 replacement therapy in diabetic patients taking metformin. In order to address the vitamin B12 deficiency associated with metformin several therapies are available including prophylactic supplements of calcium and vitamin B12, discontinuation of metformin, and replenishment of vitamin B12 stores through intramuscular or oral therapy. It is important to regularly monitor vitamin B12 levels for at least annually to prevent complications of vitamin B12 deficiency and continue with supplementation if metformin is still being used.

Polimorfismo de los genes C677T de la enzima metil-n-tetrahidrofolato reductasa, A2756G de la enzima metionina sintasa y A66G de la enzima metionina sintasa reductasa y su relación con la homocisteína en pacientes con enfermedades cardiovasculares / C677T gene polymorphism of the enzyme-n-methyl-tetrahydrofolate reductase, A2756G gene polymorphism of the enzyme methionine synthase and A66G gene polymorphism of methionine synthase reductase and its relationship with homocysteine in patients with cardiovascular disease

La Hiperhomociteinemia (HHcy) se considera como un factor de riesgo idenpendiente para el desarrollo de aterosclerosis y de enfermedad arterial coronaria (EAC). Los polimorfismos en encimas involucradas en la regulación del metabolismo de la Hcy como la metiltetrahidrofolato reductasa (MTHFR), metionina sintasa (MTR), y la metionina sintasa reductasa (MTRR) pueden contribuir a la variación de los niveles de homocisteína en plasma (Hcy). En este estudio investigamos la asociación de los polimorfismos genéticos de las enzimas involucradas en la remetilación de la homocisteínia: metionina sintasa (MTR), metil N-tetrahidrofolato reductasa (MTHFR) y metionina sintasa reductasa (MTRR), con los niveles de Hcy en pacientes con EAC y sujetos sanos. Población 136 individuos de los cuales 90 presentaron diagnóstico de enfermedad cardiovascular (IAM y ACV) y 46 eran aparentemente sanos (controles). La concentración de Hcy fue significativamente más alta en pacientes con ECV que en los sujetos control (P<0,001). HHcy (>15 µmol/L) confirió un RR de IAM de 2.52 (95% IC: 1.4-4.4, P<0,001) y de ACV de 1.88 (95% IC: 1.0-3-5, P<0,05). Los niveles de vitamina B12 y folato se encontraba en el rango de los valores de referencia en el 86% de los individuos. La frecuencia del alelo T para C677T de MTHFR, del alelo G para A66G de MTRR y del alelo G para A2756G de MTR fueron 0.31, 0.30, 0.22 respectivamente para los sujetos casos. Los polimorfismos C677T, A66G y A276G de los genes MTHFR, MTRR y MTR no tuvieron diferencia estadísticamente significativa entre el grupo de casos con respecto al grupo control. Los polimorfismos estudiados no se relacionaron estadísticamente con la HHcy en los individuos en estudio. Sugerimos que HHcy confiere riesgo para ECV. En nuestro estudio encontramos evidencia de que la regulación de Hcy es poligénica.

The Hiperhomocysteinemia (HHcy) is considered an independent risk factor for developing atherosclerosis and cardiovascular arterial disease (CAD). The polymorphisms of the enzymes involved in the regulation of homocysteine (Hcy) metabolism as the methyltetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR) may contribute to the elevation of Hcy in plasma. The main aim of the this study was to investigate the association of genetic polymorphisms of the enzymes involved in remethylation of homocysteine: methionine synthase (MTR), N-methyl tetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), with levels of Hcy in patients with CHF and healthy subjects. Population: 136 subjects of whom 90 had a diagnosis of cardiovascular disease (heart failure and stroke) and 46 were apparently healthy (controls). The concentration of Hcy was significantly higher in patients with cardiovascular disease than compare with the control group (P<0.001). HHcy (>15 mmol/L) conferred a relative risk (RR) of heart failure of 2.52 (95% CI: 1.4-4.4, P <0.001) and stroke, RR of 1.88 (95% CI: 1.0-3.5, P <0.05). The levels of vitamin B12 and folate was in the range of reference values in 86% of subjects. The frequency of the T allele of MTHFR C677T was 0,31, for the G allele of MTRR A66G was 0,30 and for the G allelwe for MTR A2756G was 0.22 for the subjects with heart failure and stroke referred as case. C677T polymorphism, A66G and A2756G of the genes MTHFR, MTRR and MTR had no associated statistically with HHcy in the subjects of the study. We suggest that HHcy confers risk for CVD. In our study we found evidence that the regulation of Hcy is polygenic.