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  • The discovery that GLUT in

    2022-06-23

    The discovery that GLUT1 in the microvasculature represents an important target of VEGF thereby affecting 4SC-202 function is highly relevant. The work of Jais et al. identified VEGF as a determining player in the regulation of cognitive performance and provides an important link to the unfavorable effects of obesity and HFD for the risk of developing dementia [7]. Peripheral insulin resistance was suggested to represent an attempt to improve brain glucose supply by reducing peripheral glucose utilization [7], [27]. Indeed, in our study insulin sensitivity decreased in response to HFD as suggested by a significant increase in HOMA-IR values [28]. Cognitive function, operationalized by a sensitive verbal memory task, was not directly affected by the high fat diet and was unrelated to VEGF serum concentrations and SLC2A1 gene expression in AT. Improvements in measures of learning, delayed recall, and consolidation memory were most likely affected by the repetitive testing. The large variation of basal expression levels of SLC2A1 and VEGF apparently did not translate into differences in these tests in healthy and non-obese subjects. However, after stratification for rs9472159 genotypes, we observed significantly declined consolidation memory scores in carriers of the polymorphism (AA) compared to non- or heterozygous carriers (CC/CA). Consolidation memory score is generally considered to represent a quite reliable measure of delayed memory function [10], [11], [13], [14]. Homozygous carriers of the polymorphism (AA) showed the lowest concentrations of serum VEGF and highest levels of GLUT1 gene expression in AT. The observation therefore warrants further investigation and the availability of a single SNP facilitates testing in more adequate larger cohorts. Notably, it was shown that under insulin-induced hypoglycemia, increases in serum VEGF were significantly correlated with preserved cognitive performance in healthy man [29]. Furthermore, low VEGF has been identified as a biomarker for Alzheimer's disease in cerebrospinal fluid [30]. We attempted to identify a possible source of the elevated serum VEGF levels. The absence of any correlation of circulating VEGF with its expression in circulating PBMCs, monocytes or adipose tissue suggests that other sources might be involved. Jais and coworkers established a myeloid source in mice using genetic deletion and suggested that perivascular macrophages might provide the increased VEGF [7]. The same may apply in humans. A difference remains that we did not observe a rapid upregulation of VEGF upon the introduction of high fat intake, which may imply a slower regulation of the system in humans. Our intervention was relatively modest since we used an isocaloric high fat diet, which induces mild insulin resistance in contrast to paradigms of hypercaloric high fat diets which very rapidly elicit massive insulin resistance [31] and also corresponds to the dietary approach in the animal experiments. Moreover, responses may be more pronounced in obese subjects.
    Author contributions
    Funding The NUGAT study was funded by the German Federal Ministry of Education and Research (BMBF; grant no. 0315424). The BMBF had no role neither in designing the study nor with respect to analysis or interpretation of the data.
    Acknowledgements
    Carbohydrate-based drug development is a highly promising area in contemporary medicine. With the development of glycobiology, many biological functions of carbohydrates have been recognized., , The studies of carbohydrate drugs have also been paid more and more attention, and carbohydrates are also considered to be one of the important sources of current drug-discovery leads. Carbohydrate drugs are saccharide-containing drugs in narrow sense, including glycoside compounds (also known as carbohydrate-modified drugs, such as Erythrimicin A and Rebeccamycin et al.), and some compounds without other ingredients except carbohydrates (also named as carbohydrate-based drugs, such as Heparin Pentasaccharide, Topiremate and Therafectin et al.)., , Carbohydrate structure is essential for activity in the vast majority carbohydrate-modified drugs.