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Horm Metab Res 2004; 36(8): 513-518
DOI: 10.1055/s-2004-825752
Original Basic
© Georg Thieme Verlag Stuttgart · New York

Glucose Catabolic Gene mRNA Levels in Skeletal Muscle Exhibit Non-coordinate Expression in Hyperglycemic Mice

M.  Kato1 , A.  Suwa1 , T.  Shimokawa1
  • 1Molecular Medicine Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan
Further Information

Publication History

Received 11 November 2003

Accepted after Revision 24 February 2004

Publication Date:
24 August 2004 (online)

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Abstract

To assess the correlation between hyperglycemia and glucose catabolic gene levels in diabetic and healthy mice, we determined mRNA levels of pivotal proteins such as glucose transporters, hexokinase II, glycogen synthase, glutamine:fructose-6-phosphate amidotransferase and uncoupling proteins. Both KK and KKAy mice showed marked decreases of Glut1 and Glut4 mRNA levels in soleus compared to C57BL; db/db and ob/ob mice exhibited significantly decreased Glut4 mRNA levels, but not Glut1, in soleus. KK and KKAy mice showed a decrease of soleus HKII gene level, which may indicate decreased intracellular catabolism of glucose. Likewise, GS mRNA level was decreased in soleus muscle tissue in KK and KKAy mice. GFAT mRNA levels was no different between hyperglycemic and normoglycemic mice. In contrast, UCP2 and UCP3 mRNA levels were higher in KK and KKAy mice. Conversely, db/db and ob/ob mice showed a significant decrease in UCP3 mRNA. Individual correlation analysis indicated that the decrease in Glut4 gene levels was only observed in hyperglycemic mice. The more important observation is that the glucose catabolic genes do not exhibit any clear coordinate expression. Abnormal expression of glucose catabolic genes may contribute to hyperglycemia and muscle insulin resistance in these four strains.

Key words

Glucose transporter · Glutamine:fructose-6-phosphate amidotransferase · Glycogen synthase · Hexokinase II · Uncoupling protein

References

  • 1 DeFronzo R A. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes.  Diabetes Rev. 1997;  5 177-269
    PubMedGoogle Scholar
  • 2 Stenbit A E, Tsao T-S, Li J, Burcelin R, Geenen D L, Factor S M, Houseknecht K, Katz E B, Charron M J. GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes.  Nature Med. 1997;  3 1096-1101
    PubMedGoogle Scholar
  • 3 Malkki M, Laakso M, Deeb S S. The human hexokinase II gene promoter: functional characterization and detection of variants among patients with NIDDM.  Diabetologia. 1997;  40 1461-1469
    CrossrefPubMedGoogle Scholar
  • 4 Hojlund K, Stahr P, Hansen F B, Green A K, Hardie G D, Richter A K, Beck-Nielsen H, Wojtaszewski F PJ. Increased phosphorylation of skeletal muscle glycogen synthase at NH2-terminal sites during physiological hyperinsulinemia in Type 2 diabetes.  Diabetes. 2003;  52 1393-1402
    PubMedGoogle Scholar
  • 5 Garvey W T, Maianu L, Hancock J A, Golichowski A M, Baron A. Gene expression of GLUT4 in skeletal muscle from insulin-resistant patients with obesity, IGT, GDM, and NIDDM.  Diabetes. 1992;  41 465-475
    PubMedGoogle Scholar
  • 6 Houmard J A, Weidner M D, Dolan P L, Leggett-Frazier N, Gavigan K E, Hickey M S, Tyndall G L, Zheng D, Alshami A, Dohm L. Skeletal muscle GLUT4 protein concentration and aging in humans.  Diabetes. 1995;  44 555-560
    PubMedGoogle Scholar
  • 7 Garvey W T, Maianu L, Zhu J H, Brechtel-Hook G, Wallace P, Baron A D. Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance.  J Clin Invest. 1998;  101 2377-2386
    CrossrefPubMedGoogle Scholar
  • 8 Wilson J E. Hexokinases.  Rev Physiol Biochem Pharmacol. 1994;  126 65-174
    PubMedGoogle Scholar
  • 9 Kruszynska Y T, Mulford M I, Baloga J, Yu J G, Olefsky J M. Regulation of skeletal muscle hexokinase II by insulin in nondiabetic and NIDDM subjects.  Diabetes. 1998;  47 1107-1113
    PubMedGoogle Scholar
  • 10 Dent P, Lavoinne A, Nakielny S, Caudwell F B, Watt P, Cohen P. The molecular mechanism by which insulin stimulates glycogen synthesis in mammalian skeletal muscle.  Nature. 1990;  348 302-308
    CrossrefPubMedGoogle Scholar
  • 11 McClain D A, Crook E D. Hexosamines and insulin resistance.  Diabetes. 1996;  45 1003-1009
    PubMedGoogle Scholar
  • 12 Giaccari A, Morviducci L, Zorretta D, Sbraccia P, Leonetti F, Caiola S, Buongiorno A, Bonadonna R C, Tamburrano G. In vivo effects of glucosamine on insulin secretion and insulin sensitivity in the rat: possible relevance to the maladaptive responses to chronic hyperglycemia.  Diabetologia. 1995;  38 518-524
    PubMedGoogle Scholar
  • 13 Yki-Jårvinen H, Daniels M C, Virkamåki A, Måkimattila S, DeFronzo R A, McClain D. Increased glutamine:fructose-6-phosphate amidotransferase activity in skeletal muscle of patients with NIDDM.  Diabetes. 1996;  45 302-307
    PubMedGoogle Scholar
  • 14 Hebert L F, Jr, Daniels M C, Zhou J, Crook E D, Turner R L, Simmons S T, Neidigh J L, Zhu J S, Baron A D, McClain D A. Overexpression of glutamine:fructose-6-phosphate amidotransferase in transgenic mice leads to insulin resistance.  J Clin Invest. 1996;  98 930-936
    PubMedGoogle Scholar
  • 15 Ricquier D, Bouillaud F. The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP.  Biochem J. 2000;  345 161-179
    CrossrefPubMedGoogle Scholar
  • 16 Horvath T L, Diano S, Miyamoto S, Barry S, Gatti S, Alberati D, Livak F, Lombardi A, Moreno M, Goglia F, Mor G, Hamilton J, Kachinskas D, Horwitz B, Warden C H. Uncoupling proteins-2 and 3 influence obesity and inflammation in transgenic mice.  Int J Obesity. 2003;  27 433-442
    PubMedGoogle Scholar
  • 17 Kondo K, Nozawa K, Tomita T, Ezaki K. Inbred strains resulting from Japanese mice.  Bull Exp Anim. 1957;  6 107-112
    PubMedGoogle Scholar
  • 18 Iwatsuka H, Shino A, Suzuoki Z. General survey of diabetic features of yellow KK mice.  Endocrinol Jpn. 1970;  17 23-35
    CrossrefPubMedGoogle Scholar
  • 19 Lee G-H, Proenca R, Montez J M, Carroll K M, Darvishzadeh J G, Lee J I, Friedman J M. Abnormal splicing of the leptin receptor in diabetic mice.  Nature. 1996;  379 632-635
    CrossrefPubMedGoogle Scholar
  • 20 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J M. Positional cloning of the mouse obese gene and its human homologue.  Nature. 1994;  372 425-432
    CrossrefPubMedGoogle Scholar
  • 21 Coleman D L. Obese and diabetes: two mutant genes causing diabetes - obesity syndromes in mice.  Diabetologia. 1978;  14 141-148
    PubMedGoogle Scholar
  • 22 Brooke M H, Kaiser K K. Muscle fiber types: How many and what kind? Arch.  Neurol. 1970;  23 369-379
    CrossrefPubMedGoogle Scholar
  • 23 Shimokawa T, Kato M, Ezaki O, Hashimoto S. Transcriptional regulation of muscle-specific genes during myoblast differentiation.  Biochem Biophys Res Commun. 1998;  246 287-292
    CrossrefPubMedGoogle Scholar
  • 24 Villar-Palasi C, Guinovart J J. The role of glucose 6-phosphate in the control of glycogen synthase.  FASEB J. 1997;  11 544-558
    PubMedGoogle Scholar
  • 25 Katz E B, Stenbit A E, Hatton K, DePinho R, Charron M J. Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4.  Nature. 1995;  377 151-155
    CrossrefPubMedGoogle Scholar
  • 26 Ren J M, Marshall B A, Mueckler M M, McCaleb M, Amatruda J M, Shulman G I. Overexpression of glut4 protein in muscle increases basal and insulin-stimulated whole body glucose disposal in conscious mice.  J Clin Invest. 1995;  95 429-432
    PubMedGoogle Scholar
  • 27 Tsao T-S, Burcelin R, Katz E B, Huang L, Charron M J. Enhanced insulin action due to targeted glut4 overexpression exclusively in muscle.  Diabetes. 1996;  45 28-36
    PubMedGoogle Scholar
  • 28 Hansen P A, Gulve E A, Marshall B A, Gao J, Pessin J E, Holloszy J O, Mueckler M. Skeletal muscle glucose transport and metabolism are enhanced in transgenic mice overexpressing the glut4 glucose transporter.  J Biol Chem. 1995;  270 1679-1684
    CrossrefPubMedGoogle Scholar
  • 29 Gibbs E M, Stock J L, McCoid S C, Stukenbrok H A, Pessin J E, Stevenson R W, Milici A J, McNeish J D. Glycemic improvement in diabetic db/db mice by overexpression of the human insulin-regulatable glucose transporter (Glut4).  J Clin Invest. 1995;  95 1512-1518
    PubMedGoogle Scholar
  • 30 Gulve E A, Ren J M, Marchall B A, Gao J, Hansen P A, Holloszy J O, Mueckler M. Glucose transport activity in skeletal muscles from transgenic mice overexpressing glut1.  J Biol Chem. 1994;  269 18 366-18 370
    PubMedGoogle Scholar
  • 31 Ducluzeau P-H, Perretti N, Laville M, Andreelli F, Vega N, Riou J-P, Vidal H. Regulation by insulin of gene expression in human skeletal muscle and adipose tissue.  Diabetes. 2001;  50 1134-1142
    CrossrefPubMedGoogle Scholar
  • 32 Sochor M, Baquer N Z, Hothersall J S, McLean P. Effect of experimental diabetes on the activity of hexokinase isoenzymes in tissues of the rat.  Biochem Int. 1990;  22 467-474
    PubMedGoogle Scholar
  • 33 Nerlich A G, Sauer U, Kolm-Litty V, Wagner E, Koch M, Schleicher E D. Expression of glutamine:fructose-6-phosphate amidotransferase in human tissues. Evidence for high variability and distinct regulation in diabetes.  Diabetes. 1998;  47 170-178
    PubMedGoogle Scholar
  • 34 Traxinger R R, Marchall S. Coordinated regulation of glutamine:fructose-6-phosphate amidotransferase activity by insulin, glucose, and glutamine. Role of hexosamine biosynthesis in enzyme regulation.  J Biol Chem. 1991;  266 10 148-10 154
    PubMedGoogle Scholar
  • 35 Buse M G, Robinson K A, Gettys T W, McMahon E G, Gulve E A. Increased activity of the hexosamine synthesis pathway in muscles of insulin-resistant ob/ob mice.  Am J Physiol. 1997;  272 E1080-E1088
    PubMedGoogle Scholar
  • 36 Tartaglia L A, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards G J, Campfield L A, Clark F T, Deeds J, Muir C, Sanker S, Moriarty A, Moore K J, Smutko J S, Mayo G G, Woolf E A, Monroe C A, Tepper R I. Identification and expression cloning of a leptin receptor, OB-R.  Cell. 1995;  83 1263-1271
    CrossrefPubMedGoogle Scholar
  • 37 Pelleymounter M A, Cullen W J, Baker M B, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice.  Science. 1995;  269 540-543
    CrossrefPubMedGoogle Scholar
  • 38 Liu Q, Bai C, Chen F, Wang R, MacDonald T, Gu M, Zhang W, Morsy M A, Caskey T. Uncoupling protein-3: a muscle-specific gene upregulated by leptin in ob/ob mice.  Gene. 1998;  207 1-7
    CrossrefPubMedGoogle Scholar
  • 39 Zhou Y-T, Shimabukuro M, Koyama K, Lee Y, Wang M-Y, Trieu F, Newgard C B, Unger R H. Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation.  Proc Natl Acad Sci USA. 1997;  94 6386-6390
    CrossrefPubMedGoogle Scholar
  • 40 Takahashi N, Patel H R, Qi Y, Dushay J, Ahima R S. Divergent effects of leptin in mice susceptible or resistant to obesity.  Horm Metab Res. 2002;  34 691-697
    Article in Thieme ConnectPubMedGoogle Scholar

T. Shimokawa, Ph. D.

Molecular Medicine Laboratories, Institute for Drug Discovery Research

Yamanouchi Pharmaceutical Co., Ltd. · 21 Miyukigaoka · Tsukuba · Ibaraki 305-8585 · Japan

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Email: simokawa@yamanouchi.co.jp