Previously, we found that a loss of plasma membrane (PM)
phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated filamentous actin (
F-actin) structure contributes to
insulin-induced
insulin resistance. Interestingly, we also demonstrated that
chromium picolinate (CrPic), a dietary supplement thought to improve glycemic status in
insulin-resistant individuals, augments
insulin-regulated
glucose transport in
insulin-sensitive 3T3-L1 adipocytes by lowering PM
cholesterol. Here, to gain mechanistic understanding of these separate observations, we tested the prediction that CrPic would protect against
insulin-induced
insulin resistance by improving PM features important in cytoskeletal structure and
insulin sensitivity. We found that
insulin-induced
insulin-resistant adipocytes display elevated PM
cholesterol with a reciprocal decrease in PM PIP2. This
lipid imbalance and
insulin resistance was corrected by the
cholesterol-lowering action of CrPic. The PM
lipid imbalance did not impair
insulin signaling, nor did CrPic amplify
insulin signal transduction. In contrast, PM analyses corroborated
cholesterol and PIP2 interactions influencing cytoskeletal structure. Because extensive in vitro study documents an essential role for cytoskeletal capacity in
insulin-regulated
glucose transport, we next evaluated intact skeletal muscle from obese,
insulin-resistant Zucker (fa/fa) rats. Because
insulin resistance in these animals likely involves multiple mechanisms, findings that
cholesterol-lowering restored
F-actin cytoskeletal structure and
insulin sensitivity to that witnessed in lean control muscle were striking. Also, experiments using
methyl-beta-cyclodextrin to shuttle
cholesterol into or out of membranes respectively recapitulated the
insulin-induced
insulin-resistance and protective effects of CrPic on membrane/cytoskeletal interactions and
insulin sensitivity. These data predict a PM
cholesterol basis for
hyperinsulinemia-associated
insulin resistance and importantly highlight the reversible nature of this abnormality.