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Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice
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Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice

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Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous

K T Tonks1, Y Ng, S Miller

  • 1Diabetes and Obesity Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, 2010 NSW, Australia.

Diabetologia
|January 25, 2013
PubMed
Abstract

Insights

Muscle insulin resistance in type 2 diabetes involves the Akt pathway. Obesity, not insulin resistance, impairs AS160 phosphorylation, while FOXO gene expression is downregulated, suggesting pathway hyperactivation.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Metabolic Syndrome Research

Background:

  • Muscle insulin resistance is an early defect in type 2 diabetes, linked to the phosphoinositide 3-kinase/Akt signaling network.
  • The distinct roles of obesity and insulin resistance in disrupting this pathway remain unclear.

Purpose of the Study:

  • To investigate the differential effects of obesity and insulin resistance on the Akt signaling pathway in muscle.
  • To understand the relationship between insulin sensitivity, adiposity, and specific Akt pathway components.

Main Methods:

  • Utilized phosphospecific antibodies to examine Akt signaling in muscle tissue from lean, overweight/obese, and type 2 diabetic individuals.
  • Employed a hyperinsulinemic-euglycemic clamp to assess insulin action before and during the clamp.

Main Results:

  • Insulin-stimulated Akt phosphorylation (Thr309, Ser474) strongly correlated with whole-body insulin sensitivity.
  • Impaired phosphorylation of Akt substrate of 160 kDa (AS160) was linked to adiposity, independent of insulin sensitivity.
  • Insulin sensitivity and obesity did not correlate with defects in insulin-dependent forkhead box O (FOXO) phosphorylation.
  • Downregulation of FOXO-targeted genes was observed in insulin-resistant individuals, despite normal FOXO phosphorylation.

Conclusions:

  • Akt signaling exhibits non-linearity, with distinct responses to insulin and obesity.
  • The pathway from Akt to glucose transport is complex and not fully elucidated.
  • Insulin-spared pathways like FOXO may become hyperactivated due to basal hyperinsulinemia in insulin resistance.
  • This hyperactivation of specific Akt pathway components could contribute to metabolic syndrome features.

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