OBJECTIVE -Of patients who are prescribed metformin, 10-30% have evidence of reduced vitamin B 12 absorption. B 12 -intrinsic factor complex uptake by ileal cell surface receptors is known to be a process dependent on calcium availability. Metformin affects calciumdependent membrane action. The objective of this study was to determine the magnitude and mechanism of the reduction in serum vitamin B 12 after metformin administration. RESEARCH DESIGN AND METHODS-A comparative study design was employed using 2 groups (metformin and control). A total of 21 patients with type 2 diabetes received sulfonylurea therapy; 14 of these 21 patients were switched to metformin. Monthly serum total vitamin B 12 measurements and holotranscobalamin (holoTCII) (B 12 -TCII) were performed. After 3 months of metformin therapy, oral calcium supplementation was administered.RESULTS -Serial serum vitamin B 12 determinations revealed a similar decline in vitamin B 12 and holoTCII. Oral calcium supplementation reversed the metformin-induced serum holoTCII depression.CONCLUSIONS -Patients receiving metformin have diminished B 12 absorption and low serum total vitamin B 12 and TCII-B 12 levels because of a calcium-dependent ileal membrane antagonism, an effect reversed with supplemental calcium.

No abstract

The neurotoxic actions of methamphetamine (METH) may be mediated in part by reactive oxygen species (ROS). Methamphetamine administration leads to increases in ROS formation and lipid peroxidation in rodent brain; however, the extent to which proteins may be modi®ed or whether affected brain regions exhibit similar elevations of lipid and protein oxidative markers have not been investigated. In this study we measured concentrations of TBARs, protein carbonyls and monoamines in various mouse brain regions at 4 h and 24 h after the last of four injections of METH (10 mg/kg/injection q 2 h). Substantial increases in TBARs and protein carbonyls were observed in the striatum and hippocampus but not the frontal cortex nor the cerebellum of METH-treated mice. Furthermore, lipid and protein oxidative markers were highly correlated within each brain region. In the hippocampus and striatum elevations in oxidative markers were signi®cantly greater at 24 h than at 4 h. Monoamine levels were maximally reduced within 4 h (striatal dopamine [DA] by 95% and serotonin in striatum, cortex and hippocampus by 60± 90%). These decrements persisted for 7 days after METH, indicating effects re¯ective of nerve terminal damage. Interestingly, NE was only transiently depleted in the brain regions investigated (hippocampus and cortex), suggesting a pharmacological and non-toxic action of METH on the noradrenergic nerve terminals. This study provides the ®rst evidence for concurrent formation of lipid and protein markers of oxidative stress in several brain regions of mice that are severely affected by large neurotoxic doses of METH. Moreover, the differential time course for monoamine depletion and the elevations in oxidative markers indicate that the source of oxidative stress is not derived directly from DA or 5HT oxidation.

Although folate deficiency and increased requirements for folate are observed in most alcoholics, the possibility that acetaldehyde generated from ethanol metabolism may increase folate catabolism has not been previously demonstrated. Folate cleavage was studied in vitro during the metabolism of acetaldehyde by xanthine oxidase, measured as the production of p-aminobenzoylglutamate from folate using h.p.l.c. Acetaldehyde/xanthine oxidase generated superoxide, which cleaved folates (5-methyltetrahydrofolate greater than folinic acid greater than folate) and was inhibited by superoxide dismutase. Cleavage was increased by addition of ferritin and inhibited by desferrioxamine (a tight chelator of iron), suggesting the importance of catalytic iron. Superoxide generated from the metabolism of ethanol to acetaldehyde in the presence of xanthine oxidase in vivo may contribute to the severity of folate deficiency in the alcoholic.