Effects Of Metformin On Serum Vitamin B12 Levels And Diabetic Peripheral Neuropathy

Diabetes develops as a result of the interactions of genetic and environmental factors, which represents as a group of metabolic syndromes. With the changes of lifestyle and the increase in the percentage of aging population, the incidence of diabetes rises rapidly. Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes. It occurs in about 50% of diabetes patients, which may implicate the sensory, motor and/or autonomic nerves, and can cause severe clinical consequences such as diabetic foot. Similar to many other diseases, diabetes may cause neurological diseases when vitamin B12 is lacking. Metformin, as one of the first line hypoglycemic agents for type 2 diabetes has been widely used. However, long-term medication with metformin may reduce the gastrointestinal absorption of vitamin B12, leading to the decrease of the serum vitamin B12 level, which may precipitate the onset or aggravation of diabetic neuropathy. Therefore, for the diabetes patients under treatment with metformin, the early diagonosis of DPN and detection of vitamin B12 deficiency and in time supply with vitamin B12 become of great importance. Vitamin B12 can change homocysteine (Hcy) into methionine. The lack of vitamin B12 may increase Hcy level. Serum Hcy is therefore a common indicator of lack of VitB12. Currently neural electrophysiological examination remains a reliable method for the early diagnosis of DPN. However this method is costly, time consuming, and invasive. As alternatives,10g monofilament and vibration perception threshold inspection are commonly used in physical examination for DPN. They are economic, simple, noninvasive, and proves as effective and practivcal in the diagnosis of DPN. The aim of our study is to investigate the effects of metformin on vitamin B12 level and DPN. Objective:1) To investigate the effects of metformin on vitamin B12 levels and DPN;2) To analyze the correlation between viatmin B12 levels and other clinical data, including Hcy. To study evaluation role of Hcy on vitamin B12 level;3) To analyze the risk factors of DPN;4) To evaluate the effectiveness of 10g monofilament and vibration perception threshold check methods in the diagnosis of DPN.Methods:1) As a case-control study, the diabetes patients were randomly divided into group A and B. Group A included 58 patients who had taken metformin for more than 6 months. Group B included 68 patients without the application history of metformin during the past 6 months. The dosage and duration of metformin treatment were recorded. The laboratory indexes (vitamin B12, folic acid, homocysteine, blood urea nitrogen, serum creatinine, hemoglobin, mean corpuscular volume, ferritin, blood lipids, glycated hemoglobin, etc.)were determined.2) The light-touch sense was determined with lOg monofilament and vibration sense with Biothesiometer electronics. All the nerve electromyography examinations were completed by quanlified technicians.3) The levels of serum viatmin B12, homocysteine and results of EMG, 10g monofilament, vibration perception test of two groups were compared and analyzed.4) The correlation between vitamin B12 levels and dosage and duration of metformin treatment was analyzed in group A.5) The correlation between vitamin B12 levels and other clinical data was analyzed.6) Multiple linear regression analysis was used to screen risk factors with vitamin B12 as an dependent variable.7) Logistic regression analysis was used to screen risk factors using the results of the EMG as criteria for diagnosis of DPN.8) The sensitivity, specificity and Youden index of the lOg monofilament and vibration perception threshold for diagnosing DPN were evaluated using the results of the EMG as criteria for diagnosis of DPN.Results:1) In group A:the average serum vitamin B12 level was 501.62±219.98ng/L, serum Hcy level was 19.75±6.08 umol/L. In group B:serum vitamin B12 level was 762.86±360.92ng/L, serum Hcy level was 16.41±3.61umol/L, the differences were significant (P<0.001, respectively). The DPN of patients in group A were severer revealed by the neural electrophysiological examination, and the abnormality rate of vibration perception threshold inspection was higher as well.The differences were statistically significant (P <0.05, respectively). The results of 10g monofilament examination had no significant difference between the two groups.2) The dosage and course of metformin treatment had no correlation with vitamin B12 level.3) The level of vitamin B12 had linear relationship with the levels of Hcy and folic acid. Hcy and folic acid were the most powerful factor for vitamin B12(R2=0.5437).4) The duration of diabetes and vitamin B12 were the most powerful factors for DPN.5) Using the results of the EMG as criteria for diagnosis of DPN, the sensitivity of vibration perception threshold for the diagnosis of DPN was 77.5%, specificity was 97.83%, Youden index was 0.753, with higher diagnostic value; Sensitivity of 10g monofilament test was 42.5% and specificity was 95.65%, Youden index was 0.382;If abnormalities in both examinations were used for diagnosis of DPN, the sensitivity was 42.5% and specificity was 100%, Youden index was 0.425; If abnormalities in either examination were used for diagnosis of DPN, the sensitivity was 82.50% and specificity was 95.65%, Youden index was 0.782.Conclusions:1) Metformin exposure may be an iatrogenic factor for vitamin B12 reduction or deficiency and aggravation of peripheral neuropathy in patients with type 2 diabetes. Interval tests of vitamin B12 may help identify secondary cause for peripheral neuropathy. Systemic vitamin B12 supply may prevent neuropathy aggravation.2) Higher Hcy levels may be suggestive of vitamin B12 reduction or deficiency; Dertermination of Hcy may be a valuable method for the estimate of vitamin B12 levels.3) The duration of diabetes and vitamin B12 levels were correlated with DPN. As duration of diabetes getting longer or vitamin B12 levels getting lower, the incidence of DPN will get higher.4) Biothesiometer vibration threshold check may serve as an effective method in diagnosis of DPN; Diagnostic value of 10g monofilament alone is not high. Combination of the above two methods is of higher value for the diagnosis of DPN if either examination reveals a positive result. This combination can be used for the screening of DPN.