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

Jing Li, Karen L. Houseknecht, Antine E. Stenbit, Ellen B. Katz, Maureen J. Charron

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Decreased GLUT4 expression, impaired insulin receptor (IR), IRS-1, and pp60/IRS-3 tyrosine phosphorylation are characteristics of adipocytes from insulin-resistant animal models and obese NIDDM humans. However, the sequence of events leading to the development of insulin signaling defects and the significance of decreased GLUT4 expression in causing adipocyte insulin resistance are unknown. The present study used male heterozygous GLUT4 knockout mice (GLUT4(+/-)) as a novel model of diabetes to study the development of insulin signaling defects in adipocytes with the progression of whole body insulin resistance and diabetes. Male GLUT4(+/-) mice with normal fed glycemia and insulinemia (N/N), normal fed glycemia and hyperinsulinemia (N/H), and fed hyperglycemia with hyperinsulinemia (H/H) exist at all ages. The expression of GLUT4 protein and the maximal insulin- stimulated glucose transport was 50% decreased in adipocytes from all three groups. Insulin signaling was normal in N/N adipose cells. From 35 to 70% reductions in insulin-stimulated tyrosine phosphorylation of IR, IRS-1, and pp60/IRS-3 were noted with no changes in the cellular content of IR, IRS-1, and p85 in N/H adipocytes. Insulin-stimulated protein tyrosine phosphorylation was further decreased to 12-23% in H/H adipose cells accompanied by 42% decreased IR and 80% increased p85 expression. Insulin- stimulated, IRS-1-associated PI3 kinase activity was decreased by 20% in N/H and 68% reduced in H/H GLUT4(+/-) adipocytes. However, total insulin- stimulated PI3 kinase activity was normal in H/H GLUT4(+/-) adipocytes. Taken together, these results strongly suggest that hyperinsulinemia triggers a reduction of IR tyrosine kinase activity that is further exacerbated by the appearance of hyperglycemia. However, the insulin signaling cascade has sufficient plasticity to accommodate significant changes in specific components without further reducing glucose uptake. Furthermore, the data indicate that the cellular content of GLUT4 is the rate-limiting factor in mediating maximal insulin-stimulated glucose uptake in GLUT4(+/-) adipocytes.

Original languageEnglish (US)
Pages (from-to)1117-1125
Number of pages9
JournalFASEB Journal
Volume14
Issue number9
StatePublished - 2000

Fingerprint

adipocytes
Adipocytes
Knockout Mice
hyperinsulinemia
insulin
Insulin
uptake mechanisms
Glucose
Defects
glucose
Hyperinsulinism
mice
hyperglycemia
Hyperglycemia
Insulin Receptor
tyrosine
insulin resistance
Phosphorylation
phosphorylation
phosphotransferases (kinases)

Keywords

  • Adipocyte glucose transport
  • Hyperglycemia
  • NIDDM
  • PI3 kinase

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Reduced glucose uptake precedes insulin signaling defects in adipocytes from heterozygous GLUT4 knockout mice. / Li, Jing; Houseknecht, Karen L.; Stenbit, Antine E.; Katz, Ellen B.; Charron, Maureen J.

In: FASEB Journal, Vol. 14, No. 9, 2000, p. 1117-1125.

Research output: Contribution to journalArticle

Li, Jing ; Houseknecht, Karen L. ; Stenbit, Antine E. ; Katz, Ellen B. ; Charron, Maureen J. / Reduced glucose uptake precedes insulin signaling defects in adipocytes from heterozygous GLUT4 knockout mice. In: FASEB Journal. 2000 ; Vol. 14, No. 9. pp. 1117-1125.
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