D-chiro-inositol glycans in insulin signaling and insulin resistance

Abstract

Classical actions of insulin involve increased glucose uptake from the bloodstream and its metabolism in peripheral tissues, the most important and relevant effects for human health. However, nonoxidative and oxidative glucose disposal by activation of glycogen synthase (GS) and mitochondrial pyruvate dehydrogenase (PDH) remain incompletely explained by current models for insulin action. Since the discovery of insulin receptor Tyr kinase activity about 25 years ago, the dominant paradigm for intracellular signaling by insulin invokes protein phosphorylation downstream of the receptor and its primary Tyr phosphorylated substrates-the insulin receptor substrate family of proteins. This scheme accounts for most, but not all, intracellular actions of insulin. Essentially forgotten is the previous literature and continuing work on second messengers generated in cells in response to insulin. Treatment and even prevention of diabetes and metabolic syndrome will benefit from a more complete elucidation of cellular-signaling events activated by insulin, to include the actions of second messengers such as glycan molecules that contain D-chiro-inositol (DCI). The metabolism of DCI is associated with insulin sensitivity and resistance, supporting the concept that second messengers have a role in responses to and resistance to insulin.

Figure 1

INS-2 structure showing Mn²⁺ as the chelating metal.

Figure 2

Pathways of insulin signaling.

Figure 3

Structure-activity relationship of phosphate analogues on PDP activity. Percent activation of PDP by 100 μmol/L analogue (40).

Figure 4

Myo-inositol, L-chiro-inositol and DCI. Inversion of the C1 hydroxyl C1 produces L-chiro, and inversion of the C3 hydroxyl produces D-chiro.

Figure 5

Conversion of D-glucose-6-phosphate to myo-inositol-1-phosphate by cyclization. Myo-inositol-1-phosphate is then dephosphorylated to myo-inositol, which then is converted by epimerization of the C3 hydroxyl (dashed left arrow) to DCI.