Mechanisms of Vascular Endothelial Dysfunction: The Problem with Sugar and Artificial Sweeteners
Authors: Hoffmann Brian R , Greene Andrew S 
Published: November 2023

As diabetes becomes a growing worldwide heath concern there has been an increased awareness of environmental factors like diet that are contributing to the disease. In diabetic patients, a major causal factor contributing to progression of the disease is hyperglycemia. While we know that early intensive glycemic control reduces the risk of cardiovascular complications in humans and rodent models, there is a large gap in studies of the etiology of hyperglycemia‐induced alterations in the disease. To combat high sugar diets that contribute to diabetes and subsequent hyperglycemia, non‐caloric artificial sweeteners have become one of the most utilized food additives worldwide due to their consideration as a low caloric substitute. However, supporting scientific data as to the safety of these non‐caloric artificial sweeteners is limited and controversial. The negative implications of consuming a high sugar diet on overall health have long been linked to diabetes, obesity, and resulting systemic health problems; however, it was not until recently that the negative impact of consuming artificial sweeteners in the place of sugar had been increasingly recognized. This study focused on research to decipher the underlying molecular mechanisms of vascular dysfunction influenced by high glucose and artificial sweetener diets using a combination of high‐throughput molecular analyses and in vitro cell culture models. Initial characterization of the effects of hyperglycemia on in vitro tube formation assays exhibited impaired endothelial phenotypes (p<0.05). PNGaseF enzymatic removal of endothelial cell surface glycosylations was able to restore the healthy tube formation phenotypes (p<0.05) suggesting glycosylation plays an important role in high glucose induced vascular dysfunction. Further glycoproteomic analyses revealed 87 proteins significantly increased in N‐glycosylation and 143 in O‐glycosylation (p<0.05) on the endothelial cell surface following normal (4.5 mM) and high (25 mM) glucose treatments, including important endothelial cell surface receptors, a diverse array of ion channels, and immune regulators. The non‐caloric artificial sweetener aspartame also exhibited impaired endothelial phenotypes during an in vitro tube formation assay (p<0.05). However, insulin signaling gene expression analysis revealed global pathway downregulation as a result of aspartame, a phenomenon that was not observed with the high glucose treatment. Overall, results of this study suggest unique mechanisms of vascular impairment resulting from exposure to high glucose and artificial sweeteners that provide insights into their contribution to the onset and progression of diabetes and obesity.Support or Funding InformationThis work was supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (K01DK105043 to BRH) and through the Mayo Clinic Metabolomics Resource Core pilot grant program (U24DK100469) originating from the National Institutes of Health Director's Common Fund.