Urinary corticosterone and normetanephrine levels after voluntary wheel and forced treadmill running in the db/db mouse

Cassandra R. Parrott, Priya Ghosh, Jamie Tedeschi, Gayan Gunasekara, Tom L. Broderick

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DOI: 10.4236/jdm.2011.14011                

Abstract

Exercise is recommended for the treatment of type 2 diabetes because of its benefits on body weight and glycemic control. Our recent work using the db/db mouse, a model that mimics the phenotype of type 2 diabetes, demonstrated that forced treadmill training exerted detrimental effects on obesity, hyperglycemia and insulin resistance. We investigated whether this response is explained by increased corticosterone and norepinephrine secretion, measured as urinary byproducts, since these hormones are known to alter glucose homeostasis. Male db/db mice and lean littermates serving as controls, were assigned to sedentary, voluntary wheel, and forced treadmill training groups for a period of 5 weeks. After 5 weeks of treadmill running, db/db mice remained hyperglycemic compared to sedentary db/db mice and were hyperinsulinemic compared to db/db voluntary runners. Urine glucose and corticosterone levels were also highest in db/db treadmill runners compared to all groups. Urine normetanephrine levels, although lower in db/db mice compared to control mice, were increased after treadmill running. Our results indicate that treadmill running leads to perturbations in plasma levels of hormones associated with glucose homeostasis. A greater stress response may be invoked by treadmill training, worsening glycemic control in this model of type 2 diabetes.

Keywords

Diabetes; Db/Db; Treadmill; Stress; Corticosterone; Normetanephrine

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Boule, N.G., Haddad, E., Kenny, G.P., Wells, G.A. and Sigal, R.J. (2001) Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: A meta-analysis of controlled clinical trials. Journal of the American Medical Association, 286, 1218-1227. doi:10.1001/jama.286.10.1218
[2]	Tuomilehto, J., Lindstrom, J., Eriksson, J.G., Valle, T.T., Hamalainen, H., Ilanne-Parikka, P., et al. (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New England Journal of Medicine, 344, 1343-1350. doi:10.1056/NEJM200105033441801
[3]	Cortez, M.Y., Torgan, C.E., Brozinick, J.T. Jr. and Ivy, J.L. (1991) Insulin resistance of obese Zucker rats exercise trained at two different intensities. American Journal of Physiology Endocrinology and Metabolism, 261, E613-E619.
[4]	Banks, E.A., Brozinick, J.T. Jr., Yaspelkis, B.B. III, Kang, H.Y. and Ivy, J.L. (1992) Muscle glucose transport, GLUT-4 content, and degree of exercise training in obese Zucker rats. American Journal of Physiology, 263, E1010-E1015.
[5]	Brozinick, J.T. Jr., Etgen, G.J. Jr., Yaspelkis, B.B. III, Kang, H.Y. and Ivy, J.L. (1993) Effects of exercise training on muscle GLUT-4 protein content and translocation in obese Zucker rats. American Journal of Physiology Endocrinology and Metabolism, 265, E419-E427.
[6]	Podolin, D.A., Wei, Y. and Pagliassotti, M.J. (1999) Effects of a high-fat diet and voluntary wheel running on gluconeogenesis and lipolysis in rats. Journal of Applied Physiology, 86, 1374-1380.
[7]	Davidoff, A.J., Mason, M.M., Davidson, M.B., Carmody, M.W., Hintz, K.K., Wold, L.E., et al. (2004) Sucrose-induced cardiomyocyte dysfunction is both preventable and reversible with clinically relevant treatments. American Journal of Physiology Endocrinology and Metabolism, 286, E718-E724. doi:10.1152/ajpendo.00358.2003
[8]	Sennott, J., Morrissey, J., Standley, P.R. and Broderick, T.L. (2008) Treadmill exercise training fails to restore defects in glucose, insulin and muscle glut4 content in the db/db mouse model of diabetes. Pathophysiology, 15, 173-179. doi:10.1016/j.pathophys.2008.06.001
[9]	Leibel, R.L., Chung, W.K. and Chua, S.C. Jr. (1997) The molecular genetics of rodent single gene obesities. Journal of Biological Chemistry, 272, 31937-31940. doi:10.1074/jbc.272.51.31937
[10]	Esser, K.A., Su, W., Matveev, S., Wong, V., Zeng, L., McCarthy, J.J., et al. (2007) Voluntary wheel running ameliorates vascular smooth muscle hyper-contractility in type 2 diabetic db/db mice. Applied Physiology Nutrition and Metabolism, 32, 711-720. doi:10.1139/H07-058
[11]	Moien-Afsahri, F., Ghosh, S., Elmi, S., Rahman, M.M., Sallam, N., Khazaei, M., Kieffer, T.J., et al. (2008) Exercise restores endothetial function independently of weight loss or hyperglycemic status in db/db mice. Diabetologia, 51, 1327-1337. doi:10.1007/s00125-008-0996-x
[12]	Ghosh, S., Golbidi, S., Werner, I., Verchere, B. and Laher, I. (2010) Selecting exercise regimens and strains to modify obesity and diabetes in rodents: An overview. Clinical Science, 119, 57-74. doi:10.1042/CS20090389
[13]	Moraska, A., Deak, T., Spencer, R.L., Roth, D. and Fleshner, M. (2000) Treadmill running produces both positive and negative physiological adaptations in Sprague-Dawley rats. American Journal of Physiology Regulatory Integrative and Comparative Physiology, 279, R1321-R1329.
[14]	Tharp, G.D. (1975) The role of glucocorticoids in exercise. Medicine in Science and Sports, 7, 6-11. doi:10.1249/00005768-197500710-00003
[15]	Rosmond, R., Dallman, M.F. and Bjorntorp, P. (1998) Stress-related cortisol secretion in men: Relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities. Journal of Clinical Endocrinology and Metabolism, 83, 1853-1859. doi:10.1210/jc.83.6.1853
[16]	Rosmond, R. (2003) Stress induced disturbances of the HPA axis: A pathway to type 2 diabetes? Medical Science Monitor, 9, RA35-RA39.
[17]	Carroll, J.F. and Kyser, C.K. (2002) Exercise training in obesity lowers blood pressure independent of weight change. Medicine in Science Sports and Exercise, 34, 596-601.
[18]	Naeser, P. (1976) Adrenal function in the diabetic mutant mouse (gene symbol dbm). Acta Physiologica Scandinavia, 98, 395-399. doi:10.1111/j.1748-1716.1976.tb10327.x
[19]	Coleman, D.L. and Burkart, D.L. (1977) Plasma corticosterone concentrations in diabetic (db) mice. Diabetologia, 13, 25-26. doi:10.1007/BF00996323
[20]	Kjaer, M., Hollenbeck, C.B., Frey-Hewitt, B., Galbo, H., Haskell, W. and Reaven, G.M. (1990) Glucoregulation and hormonal responses to maximal exercise in non-insulin-dependent diabetes. Journal of Applied Physiology, 68, 2067-2074.
[21]	Raber, W., Raffesberg, W., Waldhausl, W., Gasic, S. and Roden, M. (2003) Exercise induces excessive normetanephrine responses in hypertensive diabetic patients. European Journal of Clinical Investigation, 33, 480-487. doi:10.1046/j.1365-2362.2003.01155.x
[22]	James, D.E., Burleigh, K.M., Kraegen, E.W. and Chisholm, D.J. (1983) Effect of acute exercise and prolonged training on insulin response to intravenous glucose in vivo in rat. Journal of Applied Physiology, 55, 1660-1664.
[23]	Bray, G.A. and York, D.A. (1997) Clinical review 90: Leptin and clinical medicine: A new piece in the puzzle of obesity. Journal of Clinical Endocrinology and Metabolism, 82, 2771-2776. doi:10.1210/jc.82.9.2771
[24]	Wang, X., Hu, Z., Hu, J., Du, J. and Mitch, W.E. (2006) Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. Endocrinology, 147, 4160-4168. doi:10.1210/en.2006-0251
[25]	Cunningham, E.T. Jr. and Sawchenko, P.E. (1988) Anatomical specificity of noradrenergic inputs to the para-ventricular and supraoptic nuclei of the rat hypothalamus. Journal of Comparative Neurology, 274, 60-76. doi:10.1002/cne.902740107
[26]	Robertson, D.M. and Sima, A.A. (1980). Diabetic neuropathy in the mutant diabetic mouse [C57BL/ks(db/db)]: A morphometric study. Diabetes, 29, 60-67. doi:10.2337/diabetes.29.1.60
[27]	Valerio, A., Ghisi, V., Dossena, M., Tonello, C., Giordano, A., Frontini, A., et al. (2006) Leptin increases axonal growth cone size in developing mouse cortical neurons by convergent signals inactivating glycogen synthase kinase-3β. Journal of Biological Chemistry, 281, 12950-12958. doi:10.1074/jbc.M508691200
[28]	Drel, V.R., Mashtalir, N., IInytska, O., Shin, J., Li, F., Lyzogubov, V.V., et al. (2006) The leptin-deficient (ob/ob) mouse: A new animal model of peripheral neuropathy of type 2 diabetes and obesity. Diabetes, 55, 3335-3343. doi:10.2337/db06-0885
[29]	Hilsetd, J. (1995) Catecholamines and diabetic autonomic neuropathy. Diabetic Medicine, 12, 296-297. doi:10.1111/j.1464-5491.1995.tb00479.x
[30]	Vettor, R., Macor, C., Rossi, E., Liemonte, G. and Ferderspil, G. (1997) Impaired counterregulatory and metabolic response to exhaustive exercise in obese subjects. Acta Diabetologica, 34, 61-66. doi:10.1007/s005920050068
[31]	Wong, D.L. (2006) Epinephrine biosynthesis: Hormonal and neural control during stress. Cellular and Molecular Neurobiology, 26, 891-900. doi:10.1007/s10571-006-9056-6
[32]	Cowley, M.A., Smart, J.L., Rubinstein, M., Cerdán, M.G., Diano, S., Horvath, T.L., et al. (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature, 411, 480-484. doi:10.1038/35078085
[33]	Tataranni, P.A., Larson, D.E., Snitker, S., Young, J.B., Flatt, J.P. and Ravussin, E. (1996) Effects of glucocorticoids on energy metabolism and food intake in humans. American Journal of Physiology Endocrinology and Metabolism, 271, E317-E325.
[34]	Uchoa, E.T., Sabino, H.A., Ruginsk, S.G., Antunes-Rodrigues, J. and Elias, L.L. (2009) Hypophagia induced by glucocorticoid deficiency is associated with an increased activation of satiety-related responses. Journal of Applied Physiology, 106, 595-604.
[35]	Park, S., Jang, J.S., Jun, D.W. and Hong, S.M. (2005) Exercise enhances insulin and leptin signaling in the cerebral cortex and hypothalamus during dexamethazone-induced stress in diabetic rats. Neuroendocrinology, 82, 282-293. doi:10.1159/000093127
[36]	Asakawa, A., Ueno, N., Katagi, M., Ijuin, Y., Morita, Y., Mizuno, S., et al. (2006) Mosapride improves food intake, while not worsening glycemic control and obesity, in ob/ob obese mice with decreased gastric emptying. Journal of Diabetes and Complications, 20, 56-58. doi:10.1016/j.jdiacomp.2005.04.001
[37]	Harsch, I.A., Koebnick, C., Tasi, A.M., Hahn, E.G. and Konturek, P.C. (2009) Ghrelin and obestatin levels in type 2 diabetic patients with and without delayed gastric emptying. Digestive Diseases and Sciences, 54, 2161-2166. doi:10.1007/s10620-008-0622-2
[38]	Morton, G.J., Kaiyala, K.J., Fisher, J.D., Ogimoto, K., Schwartz, M.W. and Wisse, B.E. (2011) Identification of a physiological role for leptin in the regulation of ambulatory activity and wheel running in mice. American Journal of Physiology Endocrinology and Metabolism, 300, E392-E401. doi:10.1152/ajpendo.00546.2010