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

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 KKA^y 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 KKA^y 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 KKA^y mice. GFAT mRNA levels was no different between hyperglycemic and normoglycemic mice. In contrast, UCP2 and UCP3 mRNA levels were higher in KK and KKA^y 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
• 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
• 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
• 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
• 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
• 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
• 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
• 8 Wilson J E. Hexokinases.  Rev Physiol Biochem Pharmacol. 1994;  126 65-174
• 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
• 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
• 11 McClain D A, Crook E D. Hexosamines and insulin resistance.  Diabetes. 1996;  45 1003-1009
• 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
• 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
• 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
• 15 Ricquier D, Bouillaud F. The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP.  Biochem J. 2000;  345 161-179
• 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
• 17 Kondo K, Nozawa K, Tomita T, Ezaki K. Inbred strains resulting from Japanese mice.  Bull Exp Anim. 1957;  6 107-112
• 18 Iwatsuka H, Shino A, Suzuoki Z. General survey of diabetic features of yellow KK mice.  Endocrinol Jpn. 1970;  17 23-35
• 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
• 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
• 21 Coleman D L. Obese and diabetes: two mutant genes causing diabetes - obesity syndromes in mice.  Diabetologia. 1978;  14 141-148
• 22 Brooke M H, Kaiser K K. Muscle fiber types: How many and what kind? Arch.  Neurol. 1970;  23 369-379
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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