Summary
To elucidate the cellular mechanisms of glucose intolerance associated with aging, both the protein and mRNA levels of glucose transporter isoforms were studied in the various tissues of young (7-week-old) and aged (20-monthold) rats. GluT4 (adipose/muscle-type glucose transporter) protein, which is specifically expressed in insulin-responsive tissues, was selectively decreased per milligramme of cellular membrane protein in both the epididymal fat tissues and the gastrocnemius muscle of the aged rats compared with the young rats. When the changes in total cellular membranes per gramme of tissue are taken into account, a further decrease in GluT4 protein per gramme of tissue was observed in the tissues of the aged rats compared with the young rats. The decreased amount of GluT4 protein in the fat tissues of the aged rats is probably due to the decreased protein synthesis rather than the stability, since GluT4 mRNA/μg of cellular total RNA was also decreased. In contrast, GluT4 mRNA in the gastrocnemius muscle was rather increased and a ratio of GluT4 protein/GluT4 mRNA was decreased by 70% in the aged rats, suggesting that the translational efficiency and/or stability of GluT4 protein is decreased in the skeletal muscle of the aged rats compared with the young rats. GluT2 (livertype glucose transporter) protein and mRNA in the liver were also decreased in the aged rats, while no apparent decrease in GluT1 (HepG2/brain-type glucose transporter) protein/mg of cellular membrane protein was observed in the skeletal muscle and fat tissues of the aged rats compared with the young rats. Thus, the tissue and isoform-specific alterations of glucose transporter expression are associated with aging and may contribute to glucose intolerance observed with aging.
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DeFronzo RA (1979) Glucose intolerance and aging: evidence for tissue insensitivity to insulin. Diabetes 28: 1095–1101
Fink RI, Kolterman OG, Griffin J, Olefsky JM (1983) Mechanisms of insulin resistance in aging. J Clin Invest 71: 1523–1535
Fink RI, Kolterman OG, Kao M, Olefsky MJ (1984) The role of the glucose transport system in the postreceptor defect in insulin action associated with human aging. J Clin Endocrinol Metab 58: 721–725
Lonnroth P, Smith U (1986) Aging enhances the insulin resistance in obesity through both receptor and postreceptor alterations. J Clin Endocrinol Metab 62: 433–437
Pagano G, Cassader M, Perin-Cavallo P et al. (1984) Insulin resistance in the aged: a quantitative evaluation in in vivo insulin sensitivity and in vitro glucose transport. Metabolism 33: 976–981
Fink RI, Wallace P, Olefsky JM (1986) Effects of aging on glucose-mediated glucose disposal and glucose transport. J Clin Invest 77: 2034–2041
Nishimura H, Kuzuya H, Okamoto M et al. (1988) Change of insulin action with aging in conscious rats determined by euglycemic clamp. Am J Physiol 254: E92-E98
Meneilly GS, Minaker KL, Elahi D, Rowe JW (1987) Insulin action in aging man: Evidence for tissue-specific differences at low physiological insulin levels. J Gerontology 42: 196–201
Wheeler TJ, Hinkle PC (1985) The glucose transporter of mammalian cells. Ann Rev Physiol 47: 503–517
Simpson IA, Cushman SW (1986) Hormonal regulation of mammalian glucose transport. Ann Rev Biochem 55: 1059–1089
Mueckler M, Caruso C, Baldwin SA et al. (1985) Sequence and structure of a human glucose transporter. Science 229: 941–945
Birnbaum MJ, Haspel HC, Rosen OM (1986) Cloning and characterization of a cDNA encoding the rat brain glucose transporter protein. Proc Natl Acad Sci USA 83: 5784–5788
Fukumoto H, Seino S, Imura H et al. (1988) Sequence, tissue distribution, and chromosomal localization of mRNA encoding a human glucose transporter-like protein. Proc Natl Acad Sci USA 85: 5434–5438
Thorens B, Sarkar HK, Kaback HR, Lodish HF (1988) Cloning and functional expression in bacteria of a novel glucose transporter present in liver, intestine, kidney, and ß pancreatic islet cells. Cell 55: 281–290
Kayano T, Fukumoto H, Eddy RL et al. (1988) Evidence for a family of human glucose transporter-like proteins. J Biol Chem 263: 15245–15248
James DE, Strube M, Mueckler M (1989) Molecular cloning and characterization of an insulin-regulatable glucose transporter. Nature 338: 83–87
Fukumoto H, Kayano T, Buse JB et al. (1989) Cloning and characterization of the major insulin-responsive glucose transporter expressed in human skeletal muscle and other insulin-responsive tissues. J Biol Chem 264: 7776–7779
Birnbaum MJ (1989) Identification of a novel gene encoding an insulin-responsive glucose transporter protein. Cell 57: 305–315
Charron MJ, Brosius III FC, Alper SL, Lodish HF (1989) A glucose transport protein expressed predominantly in insulin-responsive tissues. Proc Natl Acad Sci USA 86: 2535–2539
Kaestner KH, Christy RJ, McLenithan JC et al. (1989) Sequence, tissue distribution, and differential expression of mRNA for a putative insulin-responsive glucose transporter in mouse 3T3-L1 adipocytes. Proc Natl Acad Sci USA 86: 3150–3154
Asano T, Shibasaki Y, Kasuga M et al. (1988) Cloning of a rabbit brain glucose transporter cDNA and alteration of glucose transporter mRNA during tissue development. Biochem Biophys Res Commun 154: 1204–1211
Berger J, Biswas C, Vicario PP, Strout HV, Saperstein R, Pilch PF (1989) Decreased expression of the insulin-responsive glucose transporter in diabetes and fasting. Nature 340: 70–72
Sivitz WI, DeSautel SL, Kayano T, Bell GI, Pessin JE (1989) Regulation of glucose transporter messenger RNA in insulindeficient states. Nature 340: 72–74
Garvey WT, Huecksteadt TP, Birnbaum MJ (1989) Pretranslational suppression of an insulin-responsive glucose transporter in rats with diabetes mellitus. Science 245: 60–63
Oka Y, Asano T, Shibasaki Y, Kasuga M, Kanazawa Y, Takaku F (1988) Studies with antipeptide antibody suggest the presence of at least two types of glucose transporter in rat brain and adipocyte. J Biol Chem 263: 13432–13439
Oka Y, Asano T, Shibasaki et al. (1990) Increased liver glucosetransporter protein and mRNA in streptozocin-induced diabetic rats. Diabetes 39: 441–446
Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680–685
Burnette WN (1981) “Western blotting”: Electrophoretic transfer of proteins from sodium dodecyl sulfate-polyacrylamide gels to unmodified nitrocellulose and radiographic detection with antibody and radioiodinated protein A. Anal Biochem 112: 195–203
Lehrach H, Diamond D, Wozney JM, Boedtker H (1977) RNA molecular weight determination by gel electrophoresis under denaturing conditions, a critical examination. Biochemistry 16: 4743–4748
James DE, Brown R, Navarro J, Pilch PF (1988) Insulin-regulatable tissues express a unique insulin-sensitive glucose transporter protein. Nature 333: 183–185
Bjorntorp P, Krotkieski M, Larsson B, Somlo-Szucs (1970) Effects of feeding states on lipid radioactivity in liver, muscle and adipose tissue after injection of labelled glucose in the rat. Acta Physiol Scan 80: 29–38
Asano T, Shibasaki Y, Lin J-L, Akanuma Y, Takaku F, Oka Y (1989) The nucleotide sequence of cDNA for a mouse liver-type glucose transporter protein. Nucleic Acids Res 17: 6386
Fink RI, Huecksteadt T, Karaoghlanian Z (1986) The effects of aging on glucose metabolism in adipocytes from Fisher rats. Endocrinology 118: 1139–1147
Narimiya M, Azhar S, Dolkas CB et al. (1984) Insulin resistance in older rats. Am J Physiol 246: E397-E404
Klip A, Ramlal T, Young DA, Holloszy JO (1987) Insulin-induced translocation of glucose transporter in rat hind-limb muscle. FEBS Lett 224: 224–230
Goodman MN, Dluz SM, McElaney MA, Belur E, Ruderman NB (1983) Glucose uptake and insulin sensitivity in rat muscle: changes during 3–96 week of age. Am J Physiol 244: E93-E100
Williams TF, Exton JH, Park CR, Regen DM (1968) Stereospecific transport of glucose in the perfused rat liver. Am J Physiol 215: 1200–1209
Bauer H, Heldt HW (1977) Transport of hexoses across the livercell membrane. Eur J Biochem 74: 397–403
Jackson RA, Hawa MI, Roshania RD, Sim BM, DiSilvio L, Jaspan JB (1988) Influence of aging on hepatic and peripheral glucose metabolism in humans. Diabetes 36: 119–129
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Lin, J.L., Asano, T., Shibasaki, Y. et al. Altered expression of glucose transporter isoforms with aging in rats — selective decrease in GluT4 in the fat tissue and skeletal muscle. Diabetologia 34, 477–482 (1991). https://doi.org/10.1007/BF00403283
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DOI: https://doi.org/10.1007/BF00403283