HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by LI, J. Articles by CHARRON, M. J. Search for Related Content PubMed PubMed Citation Articles by LI, J. Articles by CHARRON, M. J.

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^* and MAUREEN J. CHARRON^*1

^* Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461; USA; and
Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA

¹Correspondence: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA. E-mail: charron{at}aecom.yu.edu

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.—Li, J., Houseknecht, K. L., Stenbit, A. E., Katz, E. B., Charron, M. J. Reduced glucose uptake precedes insulin signaling defects in adipocytes from heterozygous GLUT4 knockout mice.

Key Words: adipocyte glucose transport • NIDDM • hyperglycemia • PI3 kinase

This article has been cited by other articles:

				D. P. Sparling, B. A. Griesel, and A. L. Olson Hyperphosphorylation of MEF2A in primary adipocytes correlates with downregulation of human GLUT4 gene promoter activity Am J Physiol Endocrinol Metab, April 1, 2007; 292(4): E1149 - E1156. [Abstract] [Full Text] [PDF]

				J. Li, M. Raghunath, D. Tan, R. R. Lareu, Z. Chen, and R. W. Beuerman Defensins HNP1 and HBD2 Stimulation of Wound-Associated Responses in Human Conjunctival Fibroblasts. Invest. Ophthalmol. Vis. Sci., September 1, 2006; 47(9): 3811 - 3819. [Abstract] [Full Text] [PDF]

				D. A. McClain, M. Hazel, G. Parker, and R. C. Cooksey Adipocytes with increased hexosamine flux exhibit insulin resistance, increased glucose uptake, and increased synthesis and storage of lipid Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E973 - E979. [Abstract] [Full Text] [PDF]

				P. T. Fueger, H. S. Hess, K. A. Posey, D. P. Bracy, R. R. Pencek, M. J. Charron, and D. H. Wasserman Control of Exercise-stimulated Muscle Glucose Uptake by GLUT4 Is Dependent on Glucose Phosphorylation Capacity in the Conscious Mouse J. Biol. Chem., December 3, 2004; 279(49): 50956 - 50961. [Abstract] [Full Text] [PDF]