Lysophosphatidylcholine Activates Adipocyte Glucose Uptake and Lowers Blood Glucose Levels in Murine Models of Diabetes

Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang 790-784, South Korea.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2009; 284(49):33833-40. DOI: 10.1074/jbc.M109.024869
Source: PubMed


Glucose homeostasis is maintained by the orchestration of peripheral glucose utilization and hepatic glucose production, mainly
by insulin. In this study, we found by utilizing a combined parallel chromatography mass profiling approach that lysophosphatidylcholine
(LPC) regulates glucose levels. LPC was found to stimulate glucose uptake in 3T3-L1 adipocytes dose- and time-dependently,
and this activity was found to be sensitive to variations in acyl chain lengths and to polar head group types in LPC. Treatment
with LPC resulted in a significant increase in the level of GLUT4 at the plasma membranes of 3T3-L1 adipocytes. Moreover,
LPC did not affect IRS-1 and AKT2 phosphorylations, and LPC-induced glucose uptake was not influenced by pretreatment with
the PI 3-kinase inhibitor LY294002. However, glucose uptake stimulation by LPC was abrogated both by rottlerin (a protein
kinase Cδ inhibitor) and by the adenoviral expression of dominant negative protein kinase Cδ. In line with its determined
cellular functions, LPC was found to lower blood glucose levels in normal mice. Furthermore, LPC improved blood glucose levels
in mouse models of type 1 and 2 diabetes. These results suggest that an understanding of the mode of action of LPC may provide
a new perspective of glucose homeostasis.

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    • "Treatment of diabetic patients with metformin led to decreased lysoPC levels [43] and in vitro inhibition of PLA2 prevented palmitic acid-induced insulin resistance in L6 myotubes by reduced generation of lysoPC [44]. In contrast to these results, other studies demonstrated that lysoPCs stimulate glucose uptake in 3T3-L1 adipocytes by elevating glucose transporter type 4 levels at the plasma membrane yielding to lower blood glucose levels in normal and diabetic mice [45]. Treatment of cultured islet cells with phospholipase increased lysoPC contents and insulin secretion [46]. "
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    ABSTRACT: Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene have been shown to display a powerful association with type 2 diabetes. The aim of the present study was to evaluate metabolic alterations in carriers of a common TCF7L2 risk variant. Seventeen non-diabetic subjects carrying the T risk allele at the rs7903146 TCF7L2 locus and 24 subjects carrying no risk allele were submitted to intravenous glucose tolerance test and euglycemic-hyperinsulinemic clamp. Plasma samples were analysed for concentrations of 163 metabolites through targeted mass spectrometry. TCF7L2 risk allele carriers had a reduced first-phase insulin response and normal insulin sensitivity. Under fasting conditions, carriers of TCF7L2 rs7903146 exhibited a non-significant increase of plasma sphingomyelins (SMs), phosphatidylcholines (PCs) and lysophosphatidylcholines (lysoPCs) species. A significant genotype effect was detected in response to challenge tests in 6 SMs (C16:0, C16:1, C18:0, C18:1, C24:0, C24:1), 5 hydroxy-SMs (C14:1, C16:1, C22:1, C22:2, C24:1), 4 lysoPCs (C14:0, C16:0, C16:1, C17:0), 3 diacyl-PCs (C28:1, C36:6, C40:4) and 4 long-chain acyl-alkyl-PCs (C40:2, C40:5, C44:5, C44:6). Plasma metabolomic profiling identified alterations of phospholipid metabolism in response to challenge tests in subjects with TCF7L2 rs7903146 genotype. This may reflect a genotype-mediated link to early metabolic abnormalities prior to the development of disturbed glucose tolerance.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "Interestingly, recently lyso-PC C16:0 was found to enhance glucose uptake in an insulin-independent and protein kinase C-δ–dependent manner in adipocytes (31). This finding was confirmed in vivo by glucose-lowering effects of lyso-PC C16:0 in type 1 and type 2 diabetes mouse models (31). Whether these effects and putatively beneficial effects of lyso-PC C16:0 on glucose uptake in other tissues translate into a positive effect on whole-body glucose uptake needs to be investigated in future studies. "
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    ABSTRACT: OBJECTIVE Nonalcoholic fatty liver (NAFL) is thought to contribute to insulin resistance and its metabolic complications. However, some individuals with NAFL remain insulin sensitive. Mechanisms involved in the susceptibility to develop insulin resistance in humans with NAFL are largely unknown. We investigated circulating markers and mechanisms of a metabolically benign and malignant NAFL by applying a metabolomic approach.RESEARCH DESIGN AND METHODSA total of 265 metabolites were analyzed before and after a 9-month lifestyle intervention in plasma from 20 insulin-sensitive and 20 insulin-resistant subjects with NAFL. The relevant plasma metabolites were then tested for relationships with insulin sensitivity in 17 subjects without NAFL and in plasma from 29 subjects with liver tissue samples.RESULTSThe best separation of the insulin-sensitive from the insulin-resistant NAFL group was achieved by a metabolite pattern including the branched-chain amino acids leucine and isoleucine, ornithine, the acylcarnitines C3:0-, C16:0-, and C18:0-carnitine, and lysophosphatidylcholine (lyso-PC) C16:0 (area under the ROC curve, 0.77 [P = 0.00023] at baseline and 0.80 [P = 0.000019] at follow-up). Among the individual metabolites, predominantly higher levels of lyso-PC C16:0, both at baseline (P = 0.0039) and at follow-up (P = 0.001), were found in the insulin-sensitive compared with the insulin-resistant subjects. In the non-NAFL groups, no differences in lyso-PC C16:0 levels were found between the insulin-sensitive and insulin-resistant subjects, and these relationships were replicated in plasma from subjects with liver tissue samples.CONCLUSIONS From a plasma metabolomic pattern, particularly lyso-PCs are able to separate metabolically benign from malignant NAFL in humans and may highlight important pathways in the pathogenesis of fatty liver-induced insulin resistance.
    Full-text · Article · Mar 2013 · Diabetes care
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    • "It is interesting to note that impaired vitamin E regulation appears to play a role in glucose control through unknown mechanisms [7]. The finding that lysoPC are involved in both adipocyte glucose uptake [38] and glucose-dependent insulin secretion [39], and that lyso-PC have been shown to be potential biomarkers of type 2 diabetes [40] does link these various lines of evidence and warrants further study. "
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    ABSTRACT: Background Vitamin E is a nutrient with both antioxidant and non-antioxidant activities and has been shown to modulate the function of a number of cell types in vitro and in human studies. However studies have also shown vitamin E to have detrimental interactions and therefore it is important to establish the extent to which this nutrient influences metabolism. Metabolomics can potentially identify nutrient-metabolism interactions and therefore the aim of this study was to use a non-targeted metabolomic approach to identify changes to the plasma metabolome following vitamin E supplementation in humans. Methods A relatively homogenous healthy adult male population (n = 10) provided a fasting blood sample immediately before and after a 4-week vitamin E supplementation regime (400 mg/d of RRR-α-tocopheryl acetate)) on top of their habitual diet. Plasma samples were analysed for vitamin E and clinical markers. Plasma underwent non-targeted metabolite profiling using liquid chromatography/mass spectroscopy and data was processed using multivariate statistical analysis. Results Plasma vitamin E concentrations were significantly increased following supplementation (p < 0.001). A partial least squares-discriminant analysis (PLS-DA) model was able to discriminate between samples taken pre and post vitamin E supplementation (goodness of fit R2Y = 0.82, predictive ability Q2 = 0.50). Variable influence on projection and PLS-DA loadings highlighted a number of discriminating ions that were confirmed as discriminatory through pairwise analysis. From database searches and comparison with standards these metabolites included a number of lysophosphatidylcholine species (16:0, 18:0, 18:1, 18:2, 20:3 and 22:6) that were increased in intensity post supplementation by varying degrees from 4% to 29% with the greatest changes found for lysoPC 22:6 and 20:3. Conclusions Although a small scale study, these results potentially indicate that vitamin E supplementation influences phospholipid metabolism and induces lysoPC generation; a general pro-inflammatory response. Moreover the study identifies novel areas of vitamin E interactions and highlights the potential of metabolomics for elucidating interactions between nutrients and metabolic pathways in nutritional research.
    Full-text · Article · Dec 2012 · Nutrition & Metabolism
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