Effects of Ocufolin on retinal microvasculature in patients with mild non-proliferative diabetic retinopathy carrying polymorphisms of the MTHFR gene.

INTRODUCTION: To evaluate effects of Ocufolin on retinal microvasculature in mild non-proliferative diabetic retinopathy patients who carried methylenetetrahydrofolate reductase (MTHFR) polymorphisms (DR+MTHFRP). RESEARCH DESIGN AND METHODS: This is a prospective cohort study. Eight DR+MTHFRP (administrated Ocufolin for 6 months) and 15 normal controls (NCs) were recruited. MTHFR polymorphisms were subtyped as normal, C677T, or A1298C. Best-corrected visual acuity (BCVA) was evaluated. Retinal vessel density (VD) and microstructure were evaluated by optical coherence tomography angiography. RESULTS: BCVA and vascular indices of DR+MTHFRP at baseline were worse than those of NC and improved. Compared with baseline, DR+MTHFRP had significantly improved BCVA during follow-up period (p<0.05). VD of superficial vascular plexus was increased at 4 months (p=0.012), while VD of retinal vascular network did not change (p>0.05). Carriers of A1298C and C677T showed statistically significant increase in VD at all layers by 6 months, while carriers of C677T alone showed no significant change and carriers of A1298C alone showed decreased density from 4 months to 6 months. Microstructure did not change during the follow-up period. CONCLUSION: A 6-month intake of Ocufolin is capable of reversing structural changes of microangiopathy in mild non-proliferative DR+MTHFRP. This suggests a novel way to address these impairments prior to catastrophic vision loss.

Improved conjunctival microcirculation in diabetic retinopathy patients with MTHFR polymorphisms after Ocufolin™ Administration.

PURPOSE: To investigate conjunctival microvascular responses in patients with mild diabetic retinopathy (MDR) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms (D + PM) after administration of Ocufolin™, a medical food containing 900 µg l-methylfolate (levomefolate calcium or [6S]-5-methyltetrahydrofolic acid, calcium salt), methylcobalamin, and other ingredients. METHODS: Eight D + PM patients received Ocufolin™ for six months (6 M). Bulbar conjunctival microvasculature and microcirculation metrics, including vessel diameter (D), axial blood flow velocity (Va), cross-sectional blood flow velocity (Vs), flow rate (Q), and vessel density (VD, Dbox), were measured at baseline, 4 M, and 6 M. RESULTS: The mean age was 54 ± 7 years. No significant demographic differences were found. Conjunctival microcirculation, measured as Va, Vs, and Q was significantly increased at 4 M and 6 M, compared to baseline. Va was 0.44 ± 0.10 mm/s, 0.58 ± 0.13 mm/s, 0.59 ± 0.13 mm/s in baseline, 4 M, and 6 M, respectively (P < 0.01). Similarly, Vs was 0.31 ± 0.07 mm/s, 0.40 ± 0.09 mm/s, 0.41 ± 0.09 mm/s in baseline, 4 M, and 6 M, respectively (P < 0.05). Q was 107.8 ± 49.4 pl/s, 178.0 ± 125.8 pl/s, 163.3 ± 85.8 mm/s in baseline, 4 M, and 6 M, respectively (P < 0.05). The VD at 6 M was significantly higher than that at baseline (P = 0.017). Changes of D were positively correlated with changes of Va, Q, and VD. Effects of MTHFR and haptoglobin polymorphisms on the improvements of conjunctival microcirculation and microvasculature were found. CONCLUSIONS: Ocufolin™ supplementation improves conjunctival microcirculation in patients with diabetic retinopathy and common folate polymorphisms.

Nutritional and medical food therapies for diabetic retinopathy.

Diabetic retinopathy (DR) is a form of microangiopathy. Reducing oxidative stress in the mitochondria and cell membranes decreases ischemic injury and end-organ damage to the retina. New approaches are needed, which reduce the risk and improve the outcomes of DR while complementing current therapeutic approaches. Homocysteine (Hcy) elevation and oxidative stress are potential therapeutic targets in DR. Common genetic polymorphisms such as those of methylenetetrahydrofolate reductase (MTHFR), increase Hcy and DR risk and severity. Patients with DR have high incidences of deficiencies of crucial vitamins, minerals, and related compounds, which also lead to elevation of Hcy and oxidative stress. Addressing the effects of the MTHFR polymorphism and addressing comorbid deficiencies and insufficiencies reduce the impact and severity of the disease. This approach provides safe and simple strategies that support conventional care and improve outcomes. Suboptimal vitamin co-factor availability also impairs the release of neurotrophic and neuroprotective growth factors. Collectively, this accounts for variability in presentation and response of DR to conventional therapy. Fortunately, there are straightforward recommendations for addressing these issues and supporting traditional treatment plans. We have reviewed the literature for nutritional interventions that support conventional therapies to reduce disease risk and severity. Optimal combinations of vitamins B1, B2, B6, L-methylfolate, methylcobalamin (B12), C, D, natural vitamin E complex, lutein, zeaxanthin, alpha-lipoic acid, and n-acetylcysteine are identified for protecting the retina and choroid. Certain medical foods have been successfully used as therapy for retinopathy. Recommendations based on this review and our clinical experience are developed for clinicians to use to support conventional therapy for DR. DR from both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) have similar retinal findings and responses to nutritional therapies.

Folate deprivation reduces homocysteine remethylation in a human intestinal epithelial cell culture model: role of serine in one-carbon donation.

Little is known about homocysteine metabolism in intestine. To address this question, we investigated homocysteine metabolism under conditions of folate adequacy and folate deprivation in the Caco-2 cell line, a model of human intestinal mucosal cells. Caco-2 cells were cultured in media enriched with [3-(13)C]serine and [U-(13)C(5)]methionine tracers, and enrichments of intracellular free amino acid pools of these amino acids as well as homocysteine, cystathionine, and cysteine were measured by using gas chromatography/mass spectrometry. Homocysteine transsulfuration plus folate-dependent and total remethylation were quantified from these amino acid enrichments. Homocysteine remethylation accounted for 19% of the intracellular free methionine pool in cells cultured with supplemental folate, and nearly all one-carbon units used for remethylation originated from the three carbon of serine via folate-dependent remethylation. Labeling of cystathionine and cysteine indicated the presence of a complete transsulfuration pathway in Caco-2 cells, and this pathway produced 13% of the intracellular free cysteine pool. Appearance of labeled homocysteine and cystathionine in culture medium suggests export of these metabolites from intestinal cells. Remethylation was reduced by one-third in folate-restricted cell cultures (P < 0.001), and only approximately 50% of the one-carbon units used for remethylation originated from the three carbon of serine under these conditions. In conclusion, the three carbon of serine is the primary source of one-carbon units used for homocysteine remethylation in folate-supplemented Caco-2 cell cultures. Remethylation is reduced as a result of folate restriction in this mucosal cell model, and one-carbon sources other than the three carbon of serine contribute to remethylation under this condition.