A major portion of insulin-mediated glucose uptake occurs via the translocation of GLUT 4 glucose transporter proteins from an intracellular depot to the plasma membrane. We have examined gene expression for the GLUT 4 transporter isoform in subcutaneous adipocytes, a classic insulin target cell, to better understand molecular mechanisms causing insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) and obesity. In subgroups of lean (body mass index [BMI] = 24 +/- 1) and obese (BMI = 32 +/- 2) controls and in obese NIDDM (BMI = 35 +/- 2) patients, the number of GLUT 4 glucose transporters was measured in total postnuclear and subcellular membrane fractions using specific antibodies on Western blots. Relative to lean controls, the cellular content of GLUT 4 was decreased 40% in obesity and 85% in NIDDM in total cellular membranes. In obesity, cellular depletion of GLUT 4 primarily involved low density microsomes (LDM), leaving fewer transporters available for insulin-mediated recruitment to the plasma membrane (PM). In NIDDM, loss of GLUT 4 was profound in all membrane subfractions, PM, LDM, as well as high density microsomes. These observations corresponded with decrements in maximally stimulated glucose transport rates in intact cells. To assess mechanisms responsible for depletion of GLUT 4, we quantitated levels of mRNA specifically hybridizing with human GLUT 4 cDNA on Northern blots. In obesity, GLUT 4 mRNA was decreased 36% compared with lean controls, and the level was well correlated (r = + 0.77) with the cellular content of GLUT 4 protein over a wide spectrum of body weight. GLUT 4 mRNA in adipocytes from NIDDM patients was profoundly reduced by 86% compared with lean controls and by 78% relative to their weight-matched nondiabetic counterparts (whether expressed per RNA, per cell, or for the amount of CHO-B mRNA). Interestingly, GLUT 4 mRNA levels in patients with impaired glucose tolerance (BMI = 34 +/- 4) were decreased to the same level as in overt NIDDM. We conclude that, in obesity, insulin resistance in adipocytes is due to depletion of GLUT 4 glucose transporters, and that the cellular content of GLUT 4 is determined by the level of encoding mRNA over a wide range of body weight. In NIDDM, more profound insulin resistance is caused by a further reduction in GLUT 4 mRNA and protein than is attributable to obesity per se. Suppression of GLUT 4 mRNA is observed in patients with impaired glucose tolerance, and therefore, may occur early in the evolution of diabetes. Thus, pretranslational suppression of GLUT 4 transporter gene expression may be an important mechanism that produces and maintains cellular insulin resistance in NIDDM.
W T Garvey, L Maianu, T P Huecksteadt, M J Birnbaum, J M Molina, T P Ciaraldi
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The Journal of biological chemistry | 2003 |
Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney
BJ Lamont, S Andrikopoulos, A Funkat, J Favaloro, JM Ye, EW Kraegen, KF Howlett, JD Zajac, J Proietto |
Diabetologia | 2003 |
Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes
AS Greenberg, ML McDaniel |
European Journal of Clinical Investigation | 2002 |
Insulin Resistance and Insulin Resistance Syndrome
A Cincotta |
Insulin Resistance and Insulin Resistance Syndrome | 2002 |
Sustained Exposure of L6 Myotubes to High Glucose and Insulin Decreases Insulin-Stimulated GLUT4 Translocation but Upregulates GLUT4 Activity
C Huang, R Somwar, N Patel, W Niu, D Torok, A Klip |
Diabetes | 2002 |
Effect of the ovarian hormones on GLUT4 expression and contraction-stimulated glucose uptake
SE Campbell, MA Febbraio |
American journal of physiology. Endocrinology and metabolism | 2002 |
Inhibition of isoprenoid biosynthesis causes insulin resistance in 3T3-L1 adipocytes
LH Chamberlain |
FEBS Letters | 2001 |
Nutrition in the Prevention and Treatment of Disease
JM Ordovas |
Nutrition in the Prevention and Treatment of Disease | 2001 |
Whole-body and adipose tissue glucose metabolism in response to short-term fasting in lean and obese women
JF Horowitz, SW Coppack, S Klein |
The American journal of clinical nutrition | 2001 |
Regulation by Insulin of Gene Expression in Human Skeletal Muscle and Adipose Tissue: Evidence for Specific Defects in Type 2 Diabetes
PH Ducluzeau, N Perretti, M Laville, F Andreelli, N Vega, JP Riou, H Vidal |
Diabetes | 2001 |
Insulin can enhance GLUT4 gene expression in 3T3-F442A cells and this effect is mimicked by vanadate but counteracted by cAMP and high glucose--potential implications for insulin resistance
Z W Yu, J Burén, S Enerbäck, E Nilsson, L Samuelsson, J W Eriksson |
Biochimica et Biophysica Acta | 2001 |
Ganglioside GM3 Participates in the Pathological Conditions of Insulin Resistance
S Tagami, J Inokuchi, K Kabayama, H Yoshimura, F Kitamura, S Uemura, C Ogawa, A Ishii, M Saito, Y Ohtsuka, S Sakaue, Y Igarashi |
The Journal of biological chemistry | 2001 |
Olf-1/Early B Cell Factor Is a Regulator of glut4 Gene Expression in 3T3-L1 Adipocytes
P Dowell, DW Cooke |
The Journal of biological chemistry | 2001 |
Resting leptin responses to acute and chronic resistance training in type 2 diabetic men and women
JA Kanaley, LM Fenicchia, CS Miller, LL Ploutz-Synder, RS Weinstock, R Carhart, JL Azevedo |
International Journal of Obesity | 2001 |
Adipocytes Exhibit Abnormal Subcellular Distribution and Translocation of Vesicles Containing Glucose Transporter 4 and Insulin-Regulated Aminopeptidase in Type 2 Diabetes Mellitus: Implications Regarding Defects in Vesicle Trafficking
L Maianu, SR Keller, WT Garvey |
The Journal of clinical endocrinology and metabolism | 2001 |
The effects of insulin and beta-adrenergic stimulation on glucose transport, glut 4 and PKB activation in the myocardium of lean and obese non-insulin dependent diabetes mellitus rats
B Huisamen, M van Zyl, A Keyser, A Lochner |
Molecular and Cellular Biochemistry | 2001 |
Regulation of Glucose Transporters - Implications for Insulin Resistance States
A Tirosh, A Rudich, N Bashan |
Journal of Pediatric Endocrinology and Metabolism | 2000 |
Tumor Necrosis Factor-alpha-Induced Insulin Resistance in Adipocytes
C Qi, PH Pekala |
Proceedings of the Society for Experimental Biology and Medicine | 2000 |
Tumor Necrosis Factor-α-Induced Insulin Resistance in Adipocytes
C Qi, PH Pekala |
Proceedings of the Society for Experimental Biology and Medicine | 2000 |
Papel del factor de necrosis tumoral en el control de las reservas grasas y la obesidad
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Medicina Clínica | 2000 |
Identification of a 30-Base Pair Regulatory Element and Novel DNA Binding Protein That Regulates the Human GLUT4 Promoter in Transgenic Mice
KM Oshel, JB Knight, KT Cao, MV Thai, AL Olson |
The Journal of biological chemistry | 2000 |
Insulin-Mediated Cellular Insulin Resistance Decreases Osmotic Shock-Induced Glucose Transport in 3T3-L1 Adipocytes**This work was supported by NIH Grant DK-33651 and the Veterans Administration Medical Research Service. Andrej Janez was supported by a grant from Slovenian Ministry of Science and Technology (sklad za mlade raziskovalce)
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Endocrinology | 2000 |
Obesity: Pathology and Therapy
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Journal of Inherited Metabolic Disease | 2000 |
APPLICATIONS OF NMR SPECTROSCOPY TO STUDY MUSCLE GLYCOGEN METABOLISM IN MAN
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Annual Review of Medicine | 1999 |
Regulation of Gene Expression by Activation of the Peroxisome Proliferator-Activated Receptor γ with Rosiglitazone (BRL 49653) in Human Adipocytes
J Rieusset, J Auwerx, H Vidal |
Biochemical and Biophysical Research Communications | 1999 |
Time-dependent and tissue-specific effects of circulating glucose on fetal ovine glucose transporters
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American Journal of Physiology - Regulatory, Integrative and Comparative Physiology | 1999 |
Opposite Translational Control of GLUT1 and GLUT4 Glucose Transporter mRNAs in Response to Insulin: ROLE OF MAMMALIAN TARGET OF RAPAMYCIN, PROTEIN KINASE B, AND PHOSPHATIDYLINOSITOL 3-KINASE IN GLUT1 mRNA TRANSLATION
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The Journal of biological chemistry | 1999 |
Impaired Glucose Transporter Activity in Pressure-Overload Hypertrophy Is an Early Indicator of Progression to Failure
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The American Journal of Medicine | 1998 |
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Five-hour fatty acid elevation increases muscle lipids and impairs glycogen synthesis in the rat
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Five-hour fatty acid elevation increases muscle lipids and impairs glycogen synthesis in the rat
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The Journal of biological chemistry | 1998 |
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The American journal of physiology | 1997 |
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Baillière's Clinical Endocrinology and Metabolism | 1994 |
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Diabetologia | 1994 |
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The Journal of biological chemistry | 1994 |
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The Journal of biological chemistry | 1994 |
Myocyte enhancer factor 2 (MEF2) binding site is essential for C2C12 myotube-specific expression of the rat GLUT4/muscle-adipose facilitative glucose transporter gene
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The Journal of biological chemistry | 1994 |
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Transgenic mice expressing the human GLUT4/muscle-fat facilitative glucose transporter protein exhibit efficient glycemic control
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Proceedings of the National Academy of Sciences | 1993 |
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Proceedings of the National Academy of Sciences | 1993 |
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Proceedings of the National Academy of Sciences | 1993 |
Muscle group-specific regulation of GLUT 4 glucose transporters in control, diabetic, and insulin-treated diabetic rats
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Mammalian passive glucose transporters: members of an ubiquitous family of active and passive transport proteins
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Baillière's Clinical Endocrinology and Metabolism | 1993 |
4 In vivo glucose transport in human skeletal muscle: tools, problems and perspectives
RC Bonadonna, MP Saccomani, C Cobelli |
Baillière's Clinical Endocrinology and Metabolism | 1993 |
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S Lund, H Vestergaard, PH Andersen, O Schmitz, LB Gotzsche, O Pedersen |
American journal of physiology. Endocrinology and metabolism | 1993 |
Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes
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American journal of physiology. Endocrinology and metabolism | 1993 |
The case for metabolic hypertension: Is it time to restructure the hypertension paradigm?
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Progress in Cardiovascular Diseases | 1993 |
New Concepts in the Pathogenesis of NIDDM
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1993 | |
Diabetes und Angiopathie
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Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue
PR Shepherd, L Gnudi, E Tozzo, H Yang, F Leach, BB Kahn |
The Journal of biological chemistry | 1993 |
GLUT-4 and GLUT-1 glucose transporter expression is differentially regulated by contractile activity in skeletal muscle
A Castelló, J Cadefau, R Cussó, X Testar, JE Hesketh, M Palacín, A Zorzano |
The Journal of biological chemistry | 1993 |
Restoration of insulin responsiveness in skeletal muscle of morbidly obese patients after weight loss. Effect on muscle glucose transport and glucose transporter GLUT4
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Journal of Clinical Investigation | 1992 |
Alterations in glucose transporter expression and function in diabetes: Mechanisms for insulin resistance
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Journal of Cellular Biochemistry | 1992 |
Central obesity and hyperinsulinaemia in women are associated with polymorphism in the 5‘ flanking region of the human insulin gene
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European Journal of Clinical Investigation | 1992 |
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The Journal of biological chemistry | 1992 |
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Insulin transport across capillaries is rate limiting for insulin action in dogs
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Insulin transport across capillaries is rate limiting for insulin action in dogs
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