title: Relationship between metformin use, vitamin B12 deficiency, hyperhomocysteinemia and vascular complications in patients with type 2 diabetes.
abstract: Aim of the study was to clarify the relationship between metformin-induced vitamin B12 (B12) deficiency, hyperhomocysteinemia and vascular complications in patients with type 2 diabetes. Serum B12 concentrations, homocysteine plasma levels, the presence of retinopathy and history of macroangiopathy (stroke or coronary heart disease) were analyzed in patients without renal dysfunction (serum creatinine<115 μmol/L). Firstly, B12 status was analyzed in 62 consecutive metformin-treated patients. Secondly, the relationship between B12, homocysteine and vascular complications was analyzed in 46 metformin-treated and 38 age- and sex-matched non-metformin-treated patients. Among the 62 consecutive metformin-treated patients, B12 was deficient (<150 pmol/L) in 8 (13%) and borderline-deficient (150-220 pmol/L) in 18 (29%): the larger the metformin dosage, the lower the B12 (P=0.02, Spearman's ρ=-0.30). There were independent correlations between metformin use and B12 lowering (P=0.02, r = -0.25), and B12 lowering and elevation of homocysteine (P<0.01, r=-0.34). Elevation of homocysteine was a risk for retinopathy (P=0.02, OR 1.26, 95%CI 1.04-1.52). There was no significant relation between homocysteine and macroangiopathy. Correlation between B12 and homocysteine was stronger in metformin-treated (P<0.01, r=-0.48) than non-metformin-treated (P=0.04, r=-0.38) patients. In ten B12 deficient patients, B12 supplementation (1,500 μg/day) for 2.2±1.0 months with continued use of metformin raised B12 levels: 152±42 and 299±97 pmol/L before and after treatment, respectively (P<0.01). Metformin-induced B12 lowering in diabetes was associated with elevation of homocysteine, and hyperhomocysteinemia was independently related to retinopathy. Metformin-induced B12 deficiency was correctable with B12 supplementation.
authors.affiliation: Diabetes Center, Aizawa Hospital, Matsumoto, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sato
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Ouchi
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Funase
authors.forename: Keishi
authors.initials: K
authors.lastname: Yamauchi
authors.forename: Toru
authors.initials: T
authors.lastname: Aizawa
mesh_terms: D000368:Aged; D003327:Coronary Disease / Q000139:chemically induced / Q000150:complications / Q000453:epidemiology / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D003925:Diabetic Angiopathies / Q000139:chemically induced* / Q000150:complications / Q000453:epidemiology / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000139:chemically induced / Q000150:complications / Q000453:epidemiology / Q000503:physiopathology; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D005260:Female; D006710:Homocysteine / Q000819:agonists / Q000097:blood; D006801:Humans; D020138:Hyperhomocysteinemia / Q000139:chemically induced* / Q000150:complications / Q000453:epidemiology / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D007564:Japan / Q000453:epidemiology; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D015995:Prevalence; D012307:Risk Factors; D012720:Severity of Illness Index; D020521:Stroke / Q000139:chemically induced / Q000150:complications / Q000453:epidemiology / Q000503:physiopathology; D014805:Vitamin B 12 / Q000037:antagonists & inhibitors / Q000097:blood / Q000627:therapeutic use; D014806:Vitamin B 12 Deficiency / Q000139:chemically induced* / Q000150:complications / Q000178:diet therapy / Q000453:epidemiology
chemical_list: D007004:Hypoglycemic Agents; D006710:Homocysteine; D008687:Metformin; D014805:Vitamin B 12