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Reduced glucose uptake precedes insulin signaling defects in adipocytes from heterozygous GLUT4 knockout mice

J Li1, K L Houseknecht, A E Stenbit

  • 1Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|June 2, 2000
PubMed

Insights

Reduced glucose transporter type 4 (GLUT4) expression is a key factor in insulin resistance. This study in GLUT4(+/-) mice shows hyperinsulinemia and hyperglycemia impair insulin signaling, with GLUT4 levels limiting glucose uptake.

Area of Science:

  • Metabolic diseases
  • Cellular signaling
  • Molecular endocrinology

Background:

  • Insulin resistance is characterized by impaired insulin signaling and reduced glucose transporter type 4 (GLUT4) expression in adipocytes.
  • The precise sequence of events leading to these defects and the role of GLUT4 reduction remain unclear.

Purpose of the Study:

  • To investigate the development of insulin signaling defects in adipocytes using heterozygous GLUT4 knockout (GLUT4(+/-)) mice.
  • To determine the impact of progressing whole-body insulin resistance and diabetes on adipocyte insulin signaling.

Main Methods:

  • Utilized male GLUT4(+/-) mice categorized by glycemia and insulinemia (N/N, N/H, H/H).
  • Assessed GLUT4 protein expression, glucose transport, and insulin signaling components (insulin receptor, IRS-1, PI3 kinase) in adipocytes.
  • Quantified tyrosine phosphorylation and protein expression levels.

Main Results:

  • GLUT4 expression and insulin-stimulated glucose transport were reduced by 50% in all GLUT4(+/-) groups.
  • Insulin signaling was impaired in N/H and H/H adipocytes, with reduced tyrosine phosphorylation of key signaling proteins.
  • Hyperglycemia exacerbated insulin receptor (IR) tyrosine kinase activity reduction, while GLUT4 content emerged as the rate-limiting factor for glucose uptake.

Conclusions:

  • Hyperinsulinemia initiates a reduction in IR tyrosine kinase activity, further worsened by hyperglycemia.
  • The insulin signaling cascade exhibits plasticity, accommodating some component changes without further reducing glucose uptake.
  • Adipocyte GLUT4 expression is the critical determinant of maximal insulin-stimulated glucose uptake capacity.

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