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It has not been well established whether dietary folate intake reduces the risk of diabetes development. We aimed to clarify the prospective association between dietary folate intake and type 2 diabetes (T2D) risk among 7333 Korean adults aged 40 years or older who were included in the Multi-Rural Communities Cohort. Dietary folate intake was estimated from all 106 food items listed on a FFQ, not including folate intake from supplements. Two different measurements of dietary folate intake were used: the baseline consumption and the average consumption from baseline until just before the end of follow-up. The association between folate intake and T2D risk was determined through a modified Poisson regression model with a robust error estimator controlling for potential confounders. For 29 745 person years, 319 cases of diabetes were ascertained. In multivariable analyses, dietary folate intake was inversely associated with risk of T2D for women, not for men. For women, the incidence rate ratio of diabetes in the third tertile compared with the first tertile was 0·57 (95 % CI 0·38-0·87, P for trend=0·0085) in the baseline consumption model and 0·64 (95 % CI 0·43-0·95, P for trend=0·0244) in the average consumption model. These inverse associations was found in both normal fasting blood glucose group and impaired fasting glucose group among women. Among non-users of multinutrients and vitamin supplements, the significant inverse association remained. Thus, higher dietary intake of folate is prospectively associated with lower risk of diabetes for women.

Lysophosphatidylcholine (LPC), a derivative of phosphatidylcholine, is generated through the hydrolytic action of phospholipase A 2 at the sn-2 position of phosphatidylcholine. In vivo, LPC is claimed to be the major effective component of oxidized low-density lipoprotein [1,2], and is found in high concentrations Lysophosphatidylcholine induces expression of adhesion molecules; however, the underlying molecular mechanisms of this are not well elucidated. In this study, the intracellular signaling by which lysophosphatidylcholine upregulates vascular cell adhesion molecule-1 and P-selectin was delineated using YPEN-1 and HEK293T cells. The results showed that lysophosphatidylcholine dose-dependently induced expression of vascular cell adhesion molecule-1 and P-selectin, accompanied by the activation of transcription factor nuclear factor jB. However, the nuclear factor jB inhibitor caffeic acid phenethyl ester (CAPE) and the antioxidant N-acetylcysteine only partially blocked lysophosphatidylcholine-induced adhesion molecules. Subsequently, we found that the lysophosphatidylcholine receptor G protein-coupled receptor 4 (GPK4) was expressed in YPEN-1 cells and triggered the cAMP ⁄ protein kinase A ⁄ cAMP response element-binding protein pathway, resulting in upregulation of adhesion molecules. Further evidence showed that overexpression of human GPK4 enhanced lysophosphatidylcholine-induced expression of adhesion molecules in YPEN-1 cells, and enabled HEK293T cells to express adhesion molecules in response to lysophosphatidylcholine. In conclusion, the current study suggested two pathways by which lysophosphatidylcholine regulates the expression of adhesion molecules, the lysophosphatidylcholine ⁄ nuclear factor-jB ⁄ adhesion molecule and lysophosphatidylcholine ⁄ GPK4 ⁄ cAMP ⁄ protein kinase A ⁄ cAMP response element-binding protein ⁄ adhesion molecule pathways, emphasizing the importance of the lysophosphatidylcholine receptor in regulating endothelial cell function.Abbreviations AC, adenylyl cyclase; ACREB, dominant-negative mutant CREB protein; AM, adhesion molecule; CAPE, caffeic acid phenethyl ester; CRE, cAMP response element; CREB, cAMP response element-binding protein; EC, endothelial cell; ERK, extracellular signal-related kinase; FSK, forskolin; G2A, G2 accumulation protein; GPR4, G protein-coupled receptor 4; GPR119, G protein-coupled receptor 119; hGPR4, human GPR4 expression vector; LPC, lysophosphatidylcholine; MDL, MDL12330A; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide; NAC, N-acetylcysteine; NF-jB, nuclear factor-kappaB; PKA, protein kinase A; PKC, protein kinase C; TNF-a, tumor necrosis factor-a; VCAM-1, vascular cell adhesion molecule-1.

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