Protection Against Insulin Resistance by Apolipoprotein M/Sphingosine-1-Phosphate

Abstract

Subjects with low serum HDL cholesterol levels are reported to be susceptible to diabetes, with insulin resistance believed to be the underlying pathological mechanism. Apolipoprotein M (apoM) is a carrier of sphingosine-1-phosphate (S1P), a multifunctional lipid mediator, on HDL, and the pleiotropic effects of HDL are believed to be mediated by S1P. In the current study, we attempted to investigate the potential association between apoM/S1P and insulin resistance. We observed that the serum levels of apoM were lower in patients with type 2 diabetes and that they were negatively correlated with BMI and the insulin resistance index. While deletion of apoM in mice was associated with worsening of insulin resistance, overexpression of apoM was associated with improvement of insulin resistance. Presumably, apoM/S1P exerts its protective effect against insulin resistance by activating insulin signaling pathways, such as the AKT and AMPK pathways, and also by improving the mitochondrial functions through upregulation of SIRT1 protein levels. These actions of apoM/S1P appear to be mediated via activation of S1P1 and/or S1P3. These results suggest that apoM/S1P exerts protective roles against the development of insulin resistance.

Apolipoprotein M and Sphingosine-1-Phosphate: A Potentially Antidiabetic Tandem Carried by HDL

“…However, these differences were rather small. Likewise, correlations between apoM plasma levels and indices of insulin resistance were weak but statistically significant (8). Similar weak associations and correlations of apoM and S1P with T2D and measures of insulin resistance, respectively, were found in some but not all previous studies (9,24).…”

“…Overexpression of the S1P-generating enzyme sphingosine kinase 1 (SPHK1) reduced muscle insulin resistance in HFD-fed mice (12). Kurano et al (8) did not find any effect of apoM/S1P on b-cell function. However, in a previous study by the same authors, adenovirus-mediated overexpression of APOM in mice enhanced insulin secretion (13).…”

“…In this issue of Diabetes, Kurano et al (8) provide evidence that at least a part of HDL's antidiabetic action involves apolipoprotein M (apoM) and its lipid ligand sphingosine-1-phosphate (S1P), two quantitatively minor components of HDL. S1P is the agonist of five G-proteincoupled receptors named S1P1, S1P2, S1P3, S1P4, and S1P5 (9).…”

“…In Apom knockout mice fed with a high-fat diet (HFD), Kurano et al (8) found plasma levels of S1P decreased and insulin resistance of liver, muscle, and adipose tissue increased. Conversely, HFD-fed mice overexpressing human APOM showed increased plasma levels of S1P, lower blood glucose levels, and less insulin resistance.…”

“…Oxygen consumption and the expression of mitochondrial proteins such as Ucp2 were decreased in livers of Apom knockout mice but increased in livers of APOM transgenic mice. Cell culture experiments provided evidence that the activation of S1P1 by apoM/S1P inhibits the degradation of sirtuin 1, which is regulated by AMPK and promotes mitochondrial function (8).…”