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.