Oxidative stress-induced insulin resistance in rat skeletal muscle: Role of glycogen synthase kinase-3

Betsy B Dokken, Vitoon Saengsirisuwan, John S. Kim, Mary K. Teachey, Erik J Henriksen

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Abstract

Oxidative stress can contribute to the multifactorial etiology of whole body and skeletal muscle insulin resistance. No investigation has directly assessed the effect of an in vitro oxidant stress on insulin action in intact mammalian skeletal muscle. Therefore, the purpose of the present study was to characterize the molecular actions of a low-grade oxidant stress (H 2O2) on insulin signaling and glucose transport in isolated skeletal muscle of lean Zucker rats. Soleus strips were incubated in 8 mM glucose for 2 h in the absence or presence of 100 mU/ml glucose oxidase, which produces H2O2 at ∼90 μM. By itself, H 2O2 significantly (P < 0.05) activated basal glucose transport activity, net glycogen synthesis, and glycogen synthase activity and increased phosphorylation of insulin receptor (Tyr), Akt (Ser473), and GSK-3β (Ser9). In contrast, this oxidant stress significantly inhibited the expected insulin-mediated enhancements in glucose transport, glycogen synthesis, and these signaling factors and allowed GSK-3β to retain a more active form. In the presence of CT-98014, a selective GSK-3 inhibitor, the ability of insulin to stimulate glucose transport and glycogen synthesis during exposure to this oxidant stress was enhanced by 20% and 39% (P < 0.05), respectively, and insulin stimulation of the phosphorylation of insulin receptor, Akt, and GSK-3 was significantly increased by 36-58% (P < 0.05). These results indicate that an oxidant stress can directly and rapidly induce substantial insulin resistance of skeletal muscle insulin signaling, glucose transport, and glycogen synthesis. Moreover, a small, but significant, portion of this oxidative stress-induced insulin resistance is associated with a reduced insulin-mediated suppression of the active form of GSK-3β.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume294
Issue number3
DOIs
StatePublished - Mar 2008

Fingerprint

Glycogen Synthase Kinase 3
Oxidative stress
Muscle
Insulin Resistance
Rats
Skeletal Muscle
Oxidative Stress
Insulin
Oxidants
Glycogen
Glucose
Insulin Receptor
Phosphorylation
Zucker Rats
Glycogen Synthase
Glucose Oxidase

Keywords

  • Glucose transport
  • Hydrogen peroxide
  • Type 2 diabetes

ASJC Scopus subject areas

  • Physiology
  • Endocrinology
  • Biochemistry

Cite this

Oxidative stress-induced insulin resistance in rat skeletal muscle : Role of glycogen synthase kinase-3. / Dokken, Betsy B; Saengsirisuwan, Vitoon; Kim, John S.; Teachey, Mary K.; Henriksen, Erik J.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 294, No. 3, 03.2008.

Research output: Contribution to journalArticle

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AB - Oxidative stress can contribute to the multifactorial etiology of whole body and skeletal muscle insulin resistance. No investigation has directly assessed the effect of an in vitro oxidant stress on insulin action in intact mammalian skeletal muscle. Therefore, the purpose of the present study was to characterize the molecular actions of a low-grade oxidant stress (H 2O2) on insulin signaling and glucose transport in isolated skeletal muscle of lean Zucker rats. Soleus strips were incubated in 8 mM glucose for 2 h in the absence or presence of 100 mU/ml glucose oxidase, which produces H2O2 at ∼90 μM. By itself, H 2O2 significantly (P < 0.05) activated basal glucose transport activity, net glycogen synthesis, and glycogen synthase activity and increased phosphorylation of insulin receptor (Tyr), Akt (Ser473), and GSK-3β (Ser9). In contrast, this oxidant stress significantly inhibited the expected insulin-mediated enhancements in glucose transport, glycogen synthesis, and these signaling factors and allowed GSK-3β to retain a more active form. In the presence of CT-98014, a selective GSK-3 inhibitor, the ability of insulin to stimulate glucose transport and glycogen synthesis during exposure to this oxidant stress was enhanced by 20% and 39% (P < 0.05), respectively, and insulin stimulation of the phosphorylation of insulin receptor, Akt, and GSK-3 was significantly increased by 36-58% (P < 0.05). These results indicate that an oxidant stress can directly and rapidly induce substantial insulin resistance of skeletal muscle insulin signaling, glucose transport, and glycogen synthesis. Moreover, a small, but significant, portion of this oxidative stress-induced insulin resistance is associated with a reduced insulin-mediated suppression of the active form of GSK-3β.

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