Antidiabetogenic effects of chromium mitigate hyperinsulinemia-induced cellular insulin resistance via correction of plasma membrane cholesterol imbalance

Emily M. Horvath, Lixuan Tackett, Alicia M. McCarthy, Priya Raman, Joseph T. Brozinick, Jeffrey Elmendorf

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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 insulinregulated 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-β-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.

Original languageEnglish
Pages (from-to)937-950
Number of pages14
JournalMolecular Endocrinology
Volume22
Issue number4
DOIs
StatePublished - Apr 2008

Fingerprint

Hyperinsulinism
Chromium
Insulin Resistance
Cholesterol
Cell Membrane
Insulin
Adipocytes
Actins
Glucose
Membranes
Cyclodextrins
Membrane Lipids
Dietary Supplements
Phosphatidylinositols
Signal Transduction
Skeletal Muscle
picolinic acid
Lipids
Muscles

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Antidiabetogenic effects of chromium mitigate hyperinsulinemia-induced cellular insulin resistance via correction of plasma membrane cholesterol imbalance. / Horvath, Emily M.; Tackett, Lixuan; McCarthy, Alicia M.; Raman, Priya; Brozinick, Joseph T.; Elmendorf, Jeffrey.

In: Molecular Endocrinology, Vol. 22, No. 4, 04.2008, p. 937-950.

Research output: Contribution to journalArticle

Horvath, Emily M. ; Tackett, Lixuan ; McCarthy, Alicia M. ; Raman, Priya ; Brozinick, Joseph T. ; Elmendorf, Jeffrey. / Antidiabetogenic effects of chromium mitigate hyperinsulinemia-induced cellular insulin resistance via correction of plasma membrane cholesterol imbalance. In: Molecular Endocrinology. 2008 ; Vol. 22, No. 4. pp. 937-950.
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