Gangliosides Contribute to Vascular Insulin Resistance

Abstract

Insulin in physiological concentrations is important to maintain vascular function. Moreover, vascular insulin resistance contributes to vascular impairment. In the elderly, other factors including hypertension, dyslipidemia, and chronic inflammation amplify senescence of vascular endothelial and smooth muscle cells. In turn, senescence increases the risk for vascular-related diseases such as arteriosclerosis, diabetes, and Alzheimer's disease. Recently, it was found that GM1 ganglioside, one of the glycolipids localized on the cell membrane, mediates vascular insulin resistance by promoting senescence and/or inflammatory stimulation. First, it was shown that increased GM1 levels associated with aging/senescence contribute to insulin resistance in human aortic endothelial cells (HAECs). Second, the expression levels of gangliosides were monitored in HAECs treated with different concentrations of tumor necrosis factor-alpha (TNFα) for different time intervals to mimic in vivo acute or chronic inflammatory conditions. Third, the levels of insulin signaling-related molecules were monitored in HAECs after TNFα treatment with or without inhibitors of ganglioside synthesis. In this review, we summarize the molecular mechanisms of insulin resistance in aged/senescent and TNFα-stimulated endothelial cells mediated by gangliosides and highlight the possible roles of gangliosides in vascular insulin resistance-related diseases.

Keywords: GM1 ganglioside; aging; endothelial cell; inflammation; senescence; vascular insulin resistance.

Figure 1

Insulin resistance mediated by gangliosides. (A) Pathways of glycolipids and glycosyltransferases contributing to each ganglioside synthetic pathway. Pathways of the major gangliosides are shown within the rectangle. AMP-dNM is a specific inhibitor of glucosylceramide synthase. Symbols are according to Reference [22]. Glc, Glucose; Gal, Galactose; GalNAc, N-acetylgalactosamine; Neu5Ac, N-acetylneuraminic acid. (B) Gangliosides involved in insulin resistance in classic or non-classic sites. In adipocytes, increased GM3 levels upon TNFα stimulation contribute to insulin resistance in pathological conditions such as obesity, but their contribution to aging is unknown. In the liver, GM3 contributes to insulin resistance possibly due to a reduction in NEU3 that occurs with aging. In the muscle, GM1 and GM2 contribute to insulin resistance, and GM3 contributes to insulin resistance due to a reduction in NEU3 that occurs with aging. In both the liver and the muscle, the effect of TNFα stimulation is unknown. In ECs, simultaneous aging and TNFα stimulation contribute to upregulation of GM1, leading to insulin resistance.

Figure 2

Schematic representation of insulin resistance in ECs. In non-aged ECs, activation of eNOS occurs by insulin stimulation. On the other hand, in senescent ECs, which underwent multiple cell divisions or oxidative stress, GM1 levels increase and insulin signaling decreases. The effects of TNFα are the following. 1) When short-term stimulation (acute inflammation) with low concentrations of TNFα is performed on non-aged ECs, insulin signaling decreases and GM1 levels increase. Further stimulation for a long period of time (chronic inflammation) leads to decreased eNOS expression. Removing the stimulus restores physiological conditions. 2) Short-term stimulation in non-aged ECs with high concentrations of TNFα leads to a decrease in the expression of eNOS. Even if the stimulus is removed, the increase in GM1 levels and the decrease in insulin signaling are stable. When GM1 levels are increased, short-term stimulation with low concentrations of TNFα results in decreased expression of eNOS. 3) In senescent ECs, the expression of eNOS decreases even upon short-term stimulation with low concentrations of TNFα, because GM1 levels are already increased. A continued decline in eNOS levels may lead to disease onset due to chronic reduction of NO production.

Figure 3

Overview of GM1-mediated vascular insulin resistance. (A) Proposed model for GM1-mediated vascular diseases. GM1, which is increased in ECs of peripheral blood vessels due to aging/senescence and inflammation, is secreted into blood vessels in exosomes. Exosomes containing GM1 are transported through blood vessels and incorporated by cardiovascular and cerebrovascular ECs. Vascular insulin resistance can be caused by GM1 taken up from the exosome, leading to insulin resistance-related diseases. (B) Improvement of age-related vascular diseases by AMP-dNM treatment. When AMP-dNM is administered, the GM1 increase in ECs associated with aging/senescence and inflammation can be suppressed. Most likely, insulin signaling can be restored, improving age-related vascular diseases. (C) GM1 specific inhibition for improvement of vascular insulin resistance. Specific inhibition of GM1 synthesis targeting B4GALNT1 or inhibition of the interaction between GM1 and IR in senescent and TNFα-stimulated ECs could be employed to develop new efficient therapeutic strategies for vascular insulin resistance.