Because of the large liver stores (about 5 mg), low turnover rate (0.143%) and small daily requirement (3 micrograms), vitamin B12 deficiency does not occur under normal circumstances. This is not the case in individuals with chronic inflammatory or trophic changes at vitamin B12 absorption sites. Without supplementation, vitamin B12 deficiency can be expected within 5 years of gastrectomy. Characteristic features of type A gastritis are hyposecretion and mucosal atrophy in the fundus and body of the stomach, with absent intrinsic factor. In the small intestine, active and/or passive absorption is impaired by extensive ileal resection, exocrine pancreatic insufficiency and chronic inflammatory disorders such as Crohn's disease. Definitive plasma concentrations cannot be quoted for vitamin B12 deficiency. Dietary habits, subjective symptoms, hematological laboratory results, function tests and gastrointestinal endoscopic and histological findings must all be taken into account in the diagnosis. Modern diagnostic parameters, such as methylmalonic acid and homocysteine serum assays, are useful for achieving early diagnosis and hence optimal treatment. With their assured availability, parenteral vitamin B12 preparations remain the treatment of choice. Results from vitamin B12 bioavailability studies in healthy subjects suggest that > 300 micrograms probably suffices as an oral maintenance dose after parenteral loading. Further well-documented cases are needed in order to establish whether these doses are adequate in malabsorption syndromes and gastrointestinal diseases. Various case reports indicate the value of prophylactic and therapeutic oral vitamin B12 administration, especially in disorders of homocysteine metabolism, a substance postulated as a further important risk factor for atherosclerosis.

OBJECTIVE -We studied the association between polymorphisms in the UCP genes and diabetes complications in patients with type 1 diabetes.RESEARCH DESIGN AND METHODS -We analyzed 227 patients with type 1 diabetes using PCR and subsequent cleavage by restriction endonucleases for the promoter variants A-3826G in the UCP1 gene, G-866A in the UCP2 gene, and C-55T in the UCP3 gene.RESULTS -No effect of the A-3826G polymorphism in the UCP1 gene on diabetes complications was found. Patients who were heterozygous or homozygous for the G-866A polymorphism in the UCP2 gene or the C-55T polymorphism in the UCP3 gene had a significantly reduced prevalence of diabetic neuropathy (UCP2: odds ratio 0.44 [95% CI 0.24 -0.79], P ϭ 0.007; UCP3: 0.48 [0.25-0.92], P ϭ 0.031), whereas there was no association with other diabetes complications. This effect was stronger when G-866A and C-55T occurred in a cosegregatory manner (UCP2 and UCP3: 0.28 [0.12-0.65], P ϭ 0.002). Furthermore, a multiple logistic regression model showed an age-and diabetes duration-independent effect of the cosegregated polymorphisms on the prevalence of diabetic neuropathy (P ϭ 0.013).CONCLUSIONS -Our data indicate that both the G-866A polymorphism in the UCP2 gene and the C-55T polymorphism in the UCP3 gene are associated with a reduced risk of diabetic neuropathy in type 1 diabetes. Thus, the results presented here support the hypothesis that higher expression of uncoupling protein might prevent mitochondria-mediated neuronal injury and, ultimately, diabetic neuropathy. Diabetes Care 29:89 -94, 2006D iabetic neuropathy is the most common neuropathy in the western world. Hyperglycemia triggers a number of mechanisms thought to underlie diabetic neuropathy (1). Next to others, increased production of reactive oxygen species (ROS) (2,3) and formation of advanced glycation end products (AGEs) (4,5) are of pathophysiological importance. In patients with diabetes, mitochondrial ROS generation, especially at high blood glucose levels, is one of the main sources of oxidative stress (6,7). Increased levels of ROS are known to promote nonenzymatic glycation and AGE formation. AGEs and, in particular, carboxymethyllysine accumulate in peripheral nerves of patients with diabetes (4,8,9). Subsequent enhanced AGE-RAGE (receptor of AGEs) interaction leads to sustained nuclear factor-B activation (10,11) with consecutively increased interleukin-6 and tumor necrosis factor-␣ expression, resulting in neuronal dysfunction and, ultimately, diabetic neuropathy (11-13).To neutralize ROS and prevent harm, several antioxidant defense mechanisms exist. One of these is represented by the uncoupling proteins (UCPs). Cellular energy and mitochondrial membrane function in response to glucose are regulated in part by a group of UCPs. Members of this family of inner mitochondrial membrane proteins function as anion carriers. The originally identified uncoupling protein, now classified as UCP1, is expressed exclusively in brown adipocytes and can disperse the mitochondrial proton gradient, ...