Hexosamine biosynthesis pathway flux contributes to insulin resistance via altering membrane phosphatidylinositol 4,5-bisphosphate and cortical filamentous actin

Padma Bhonagiri, Guruprasad R. Pattar, Emily M. Horvath, Kirk M. Habegger, Alicia M. McCarthy, Jeffrey S. Elmendorf

Research output: Contribution to journalArticle

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Abstract

We recently found that plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP 2)-regulated filamentous actin (F-actin) polymerization was diminished in hyperinsulinemic cell culture models of insulin resistance. Here we delineated whether increased glucose flux through the hexosamine biosynthesis pathway (HBP) causes the PIP 2/F-actin dysregulation and insulin resistance induced by hyperinsulinemia. Increased HBP activity was detected in 3T3-L1 adipocytes cultured under conditions closely resembling physiological hyperinsulinemia (5 nM insulin for 12 h) and in cells where HBP activity was amplified by 2 mM glucosamine (GlcN). Both the physiological hyperinsulinemia and experimental GlcN challenge induced comparable losses of PIP 2 and F-actin. In addition to protecting against the insulin-induced membrane/cytoskeletal abnormality and insulin-resistant state, exogenous PIP 2 corrected the GlcN-induced insult on these parameters. Moreover, in accordance with HBP flux directly weakening PIP 2/F-actin structure, inhibition of the rate-limiting HBP enzyme (glutamine:fructose-6-phosphate amidotransferase) restored PIP 2-regulated F-actin structure and insulin responsiveness. Conversely, overexpression of glutamine:fructose-6-phosphate amidotransferase was associated with a loss of detectable plasma membrane PIP 2 and insulin sensitivity. A slight decrease in intracellular ATP resulted from amplifying HBP by hyperinsulinemia and GlcN. However, experimental maintenance of the intracellular ATP pool under both conditions with inosinedid not reverse the PIP 2/F-actin-based insulin-resistant state. Furthermore, less invasive challenges with glucose, in the absence of insulin, also led to PIP 2/F-actin dysregulation. Accordingly, we suggest that the functionality of cell systems dependent on PIP 2 and/or F-actin status, such as the glucose transport system, can be critically compromised by inappropriate HBP activity.

Original languageEnglish (US)
Pages (from-to)1636-1645
Number of pages10
JournalEndocrinology
Volume150
Issue number4
DOIs
StatePublished - Apr 2009

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Hexosamines
Phosphatidylinositols
Insulin Resistance
Actins
Membranes
Glucosamine
Hyperinsulinism
Insulin
Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
Glucose
Adenosine Triphosphate
Cell Membrane
Adipocytes
Polymerization
Cell Culture Techniques
Maintenance
Enzymes

ASJC Scopus subject areas

  • Endocrinology

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Hexosamine biosynthesis pathway flux contributes to insulin resistance via altering membrane phosphatidylinositol 4,5-bisphosphate and cortical filamentous actin. / Bhonagiri, Padma; Pattar, Guruprasad R.; Horvath, Emily M.; Habegger, Kirk M.; McCarthy, Alicia M.; Elmendorf, Jeffrey S.

In: Endocrinology, Vol. 150, No. 4, 04.2009, p. 1636-1645.

Research output: Contribution to journalArticle

Bhonagiri, Padma ; Pattar, Guruprasad R. ; Horvath, Emily M. ; Habegger, Kirk M. ; McCarthy, Alicia M. ; Elmendorf, Jeffrey S. / Hexosamine biosynthesis pathway flux contributes to insulin resistance via altering membrane phosphatidylinositol 4,5-bisphosphate and cortical filamentous actin. In: Endocrinology. 2009 ; Vol. 150, No. 4. pp. 1636-1645.
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