Cardiac metabolism in a new rat model of type 2 diabetes using high-fat diet with low dose streptozotocin
Tóm tắt
To study the pathogenesis of diabetic cardiomyopathy, reliable animal models of type 2 diabetes are required. Physiologically relevant rodent models are needed, which not only replicate the human pathology but also mimic the disease process. Here we characterised cardiac metabolic abnormalities, and investigated the optimal experimental approach for inducing disease, in a new model of type 2 diabetes. Male Wistar rats were fed a high-fat diet for three weeks, with a single intraperitoneal injection of low dose streptozotocin (STZ) after fourteen days at 15, 20, 25 or 30 mg/kg body weight. Compared with chow-fed or high-fat diet fed control rats, a high-fat diet in combination with doses of 15–25 mg/kg STZ did not change insulin concentrations and rats maintained body weight. In contrast, 30 mg/kg STZ induced hypoinsulinaemia, hyperketonaemia and weight loss. There was a dose-dependent increase in blood glucose and plasma lipids with increasing concentrations of STZ. Cardiac and hepatic triglycerides were increased by all doses of STZ, in contrast, cardiac glycogen concentrations increased in a dose-dependent manner with increasing STZ concentrations. Cardiac glucose transporter 4 protein levels were decreased, whereas fatty acid metabolism-regulated proteins, including uncoupling protein 3 and pyruvate dehydrogenase (PDH) kinase 4, were increased with increasing doses of STZ. Cardiac PDH activity displayed a dose-dependent relationship between enzyme activity and STZ concentration. Cardiac insulin-stimulated glycolytic rates were decreased by 17% in 15 mg/kg STZ high-fat fed diabetic rats compared with control rats, with no effect on cardiac contractile function. High-fat feeding in combination with a low dose of STZ induced cardiac metabolic changes that mirror the decrease in glucose metabolism and increase in fat metabolism in diabetic patients. While low doses of 15–25 mg/kg STZ induced a type 2 diabetic phenotype, higher doses more closely recapitulated type 1 diabetes, demonstrating that the severity of diabetes can be modified according to the requirements of the study.
Tài liệu tham khảo
Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H: Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia. 2001, 44 (Suppl 2): S14-S21.
Boudina S, Abel ED: Diabetic cardiomyopathy revisited. Circulation. 2007, 115 (25): 3213-3223. 10.1161/CIRCULATIONAHA.106.679597.
McGill JB, Peterson LR, Herrero P, Saeed IM, Recklein C, Coggan AR, Demoss AJ, Schechtman KB, Dence CS, Gropler RJ: Potentiation of abnormalities in myocardial metabolism with the development of diabetes in women with obesity and insulin resistance. J Nucl Cardiol. 2011, 18 (3): 421-429. 10.1007/s12350-011-9362-3. quiz 432–423
Rijzewijk LJ, van der Meer RW, Lamb HJ, De Jong HW, Lubberink M, Romijn JA, Bax JJ, De Roos A, Twisk JW, Heine RJ, et al: Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging. J Am Coll Cardiol. 2009, 54 (16): 1524-1532. 10.1016/j.jacc.2009.04.074.
Labbe SM, Grenier-Larouche T, Noll C, Phoenix S, Guerin B, Turcotte EE, Carpentier AC: Increased myocardial uptake of dietary fatty acids linked to cardiac dysfunction in glucose-intolerant humans. Diabetes. 2012, 61 (11): 2701-2710. 10.2337/db11-1805.
Dutka DP, Pitt M, Pagano D, Mongillo M, Gathercole D, Bonser RS, Camici PG: Myocardial glucose transport and utilization in patients with type 2 diabetes mellitus, left ventricular dysfunction, and coronary artery disease. J Am Coll Cardiol. 2006, 48 (11): 2225-2231. 10.1016/j.jacc.2006.06.078.
Bugger H, Abel ED: Rodent models of diabetic cardiomyopathy. Dis Model Mech. 2009, 2 (9–10): 454-466.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM: Positional cloning of the mouse obese gene and its human homologue. Nature. 1994, 372 (6505): 425-432. 10.1038/372425a0.
Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, et al: Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 1996, 84 (3): 491-495. 10.1016/S0092-8674(00)81294-5.
Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM: Abnormal splicing of the leptin receptor in diabetic mice. Nature. 1996, 379 (6566): 632-635. 10.1038/379632a0.
Phillips MS, Liu Q, Hammond HA, Dugan V, Hey PJ, Caskey CJ, Hess JF: Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet. 1996, 13 (1): 18-19. 10.1038/ng0596-18.
Goto Y, Kakizaki M, Masaki N: Production of spontaneous diabetic rats by repetition of selective breeding. Tohoku J Exp Med. 1976, 119 (1): 85-90. 10.1620/tjem.119.85.
Desrois M, Sidell RJ, Gauguier D, King LM, Radda GK, Clarke K: Initial steps of insulin signaling and glucose transport are defective in the type 2 diabetic rat heart. Cardiovasc Res. 2004, 61 (2): 288-296. 10.1016/j.cardiores.2003.11.021.
Srinivasan K, Ramarao P: Animal models in type 2 diabetes research: an overview. Indian J Med Res. 2007, 125 (3): 451-472.
Wang P, Chatham JC: Onset of diabetes in Zucker diabetic fatty (ZDF) rats leads to improved recovery of function after ischemia in the isolated perfused heart. Am J Physiol Endocrinol Metab. 2004, 286 (5): E725-E736. 10.1152/ajpendo.00295.2003.
Sidell RJ, Cole MA, Draper NJ, Desrois M, Buckingham RE, Clarke K: Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the Zucker fatty rat heart. Diabetes. 2002, 51 (4): 1110-1117. 10.2337/diabetes.51.4.1110.
Cole MA, Murray AJ, Cochlin LE, Heather LC, McAleese S, Knight NS, Sutton E, Jamil AA, Parassol N, Clarke K: A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart. Basic Res Cardiol. 2011, 106 (3): 447-457. 10.1007/s00395-011-0156-1.
Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Gadbois TM, Reaven GM: A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism. 2000, 49 (11): 1390-1394. 10.1053/meta.2000.17721.
Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P: Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res. 2005, 52 (4): 313-320. 10.1016/j.phrs.2005.05.004.
Schnedl WJ, Ferber S, Johnson JH, Newgard CB: STZ transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells. Diabetes. 1994, 43 (11): 1326-1333. 10.2337/diab.43.11.1326.
Gunnarsson R, Berne C, Hellerstrom C: Cytotoxic effects of streptozotocin and N-nitrosomethylurea on the pancreatic B cells with special regard to the role of nicotinamide-adenine dinucleotide. Biochem J. 1974, 140 (3): 487-494.
Watts LM, Manchem VP, Leedom TA, Rivard AL, McKay RA, Bao D, Neroladakis T, Monia BP, Bodenmiller DM, Cao JX, et al: Reduction of hepatic and adipose tissue glucocorticoid receptor expression with antisense oligonucleotides improves hyperglycemia and hyperlipidemia in diabetic rodents without causing systemic glucocorticoid antagonism. Diabetes. 2005, 54 (6): 1846-1853. 10.2337/diabetes.54.6.1846.
Cao S, Li B, Yi X, Chang B, Zhu B, Lian Z, Zhang Z, Zhao G, Liu H, Zhang H: Effects of exercise on AMPK signaling and downstream components to PI3K in rat with type 2 diabetes. PLoS One. 2012, 7 (12): e51709-10.1371/journal.pone.0051709.
Salman ZK, Refaat R, Selima E, Sarha AE, Ismail MA: The combined effect of metformin and L-cysteine on inflammation, oxidative stress and insulin resistance in streptozotocin-induced type 2 diabetes in rats. Eur J Pharmacol. 2013, 714 (1–3): 448-455.
Sahin K, Onderci M, Tuzcu M, Ustundag B, Cikim G, Ozercan IH, Sriramoju V, Juturu V, Komorowski JR: Effect of chromium on carbohydrate and lipid metabolism in a rat model of type 2 diabetes mellitus: the fat-fed, streptozotocin-treated rat. Metabolism. 2007, 56 (9): 1233-1240. 10.1016/j.metabol.2007.04.021.
Epp RA, Susser SE, Morissettee MP, Kehler DS, Jassal DS, Duhamel TA: Exercise training prevents the development of cardiac dysfunction in the low-dose streptozotocin diabetic rats fed a high-fat diet. Can J Physiol Pharmacol. 2013, 91 (1): 80-89. 10.1139/cjpp-2012-0294.
Zhang F, Ye C, Li G, Ding W, Zhou W, Zhu H, Chen G, Luo T, Guang M, Liu Y, et al: The rat model of type 2 diabetic mellitus and its glycometabolism characters. Exp Anim. 2003, 52 (5): 401-407. 10.1538/expanim.52.401.
Seymour AM, Chatham JC: The effects of hypertrophy and diabetes on cardiac pyruvate dehydrogenase activity. J Mol Cell Cardiol. 1997, 29 (10): 2771-2778. 10.1006/jmcc.1997.0512.
Lehman TC, Hale DE, Bhala A, Thorpe C: An acyl-coenzyme A dehydrogenase assay utilizing the ferricenium ion. Anal Biochem. 1990, 186 (2): 280-284. 10.1016/0003-2697(90)90080-S.
Srere P: Citrate synthase. Methods Enzymol. 1969, 13: 3-5.
Heather LC, Cole MA, Lygate CA, Evans RD, Stuckey DJ, Murray AJ, Neubauer S, Clarke K: Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart. Cardiovasc Res. 2006, 72 (3): 430-437. 10.1016/j.cardiores.2006.08.020.
Bonen A, Luiken JJ, Arumugam Y, Glatz JF, Tandon NN: Acute regulation of fatty acid uptake involves the cellular redistribution of fatty acid translocase. J Biol Chem. 2000, 275 (19): 14501-14508. 10.1074/jbc.275.19.14501.
Heather LC, Cole MA, Atherton HJ, Coumans WA, Evans RD, Tyler DJ, Glatz JF, Luiken JJ, Clarke K: Adenosine monophosphate-activated protein kinase activation, substrate transporter translocation, and metabolism in the contracting hyperthyroid rat heart. Endocrinology. 2010, 151 (1): 422-431. 10.1210/en.2009-0593.
Holman GD, Kozka IJ, Clark AE, Flower CJ, Saltis J, Habberfield AD, Simpson IA, Cushman SW: Cell surface labeling of glucose transporter isoform GLUT4 by bis-mannose photolabel. Correlation with stimulation of glucose transport in rat adipose cells by insulin and phorbol ester. J Biol Chem. 1990, 265 (30): 18172-18179.
Sugden MC, Kraus A, Harris RA, Holness MJ: Fibre-type specific modification of the activity and regulation of skeletal muscle pyruvate dehydrogenase kinase (PDK) by prolonged starvation and refeeding is associated with targeted regulation of PDK isoenzyme 4 expression. Biochem J. 2000, 346 (Pt 3): 651-657.
Nikooie R, Rajabi H, Gharakhanlu R, Atabi F, Omidfar K, Aveseh M, Larijani B: Exercise-induced changes of MCT1 in cardiac and skeletal muscles of diabetic rats induced by high-fat diet and STZ. J Physiol Biochem. 2013, doi:10.1007/s13105-013-1263-6
Islam MS, Choi H: Nongenetic model of type 2 diabetes: a comparative study. Pharmacology. 2007, 79 (4): 243-249. 10.1159/000101989.
King LM, Sidell RJ, Wilding JR, Radda GK, Clarke K: Free fatty acids, but not ketone bodies, protect diabetic rat hearts during low-flow ischemia. Am J Physiol Heart Circ Physiol. 2001, 280 (3): H1173-H1181.
Schroeder MA, Cochlin LE, Heather LC, Clarke K, Radda GK, Tyler DJ: In vivo assessment of pyruvate dehydrogenase flux in the heart using hyperpolarized carbon-13 magnetic resonance. Proc Natl Acad Sci USA. 2008, 105 (33): 12051-12056. 10.1073/pnas.0805953105.
Aasum E, Hafstad AD, Severson DL, Larsen TS: Age-dependent changes in metabolism, contractile function, and ischemic sensitivity in hearts from db/db mice. Diabetes. 2003, 52 (2): 434-441. 10.2337/diabetes.52.2.434.
Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW, Yun UJ, Cooksey RC, Litwin SE, Abel ED: Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology. 2005, 146 (12): 5341-5349. 10.1210/en.2005-0938.
Turley SD, Hansen CT: Rates of sterol synthesis in the liver and extrahepatic tissues of the SHR/N-corpulent rat, an animal with hyperlipidemia and insulin-independent diabetes. J Lipid Res. 1986, 27 (5): 486-496.
Randle PJ, Garland PB, Hales CN, Newsholme EA: The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963, 1: 785-789.
Belke DD, Larsen TS, Gibbs EM, Severson DL: Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. Am J Physiol Endocrinol Metab. 2000, 279 (5): E1104-E1113.
Mazumder PK, O’Neill BT, Roberts MW, Buchanan J, Yun UJ, Cooksey RC, Boudina S, Abel ED: Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes. 2004, 53 (9): 2366-2374. 10.2337/diabetes.53.9.2366.
Finck BN, Kelly DP: Peroxisome proliferator-activated receptor alpha (PPARalpha) signaling in the gene regulatory control of energy metabolism in the normal and diseased heart. J Mol Cell Cardiol. 2002, 34 (10): 1249-1257.
Eriksson JW, Smith U, Waagstein F, Wysocki M, Jansson PA: Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients: is cellular insulin resistance a secondary phenomenon?. Diabetes. 1999, 48 (8): 1572-1578. 10.2337/diabetes.48.8.1572.
Sarkozy M, Zvara A, Gyemant N, Fekete V, Kocsis GF, Pipis J, Szucs G, Csonka C, Puskas LG, Ferdinandy P, et al: Metabolic syndrome influences cardiac gene expression pattern at the transcript level in male ZDF rats. Cardiovasc Diabetol. 2013, 12: 16-10.1186/1475-2840-12-16.
Panagia M, Schneider JE, Brown B, Cole MA, Clarke K: Abnormal function and glucose metabolism in the type-2 diabetic db/db mouse heart. Can J Physiol Pharmacol. 2007, 85 (3–4): 289-294.
Hafstad AD, Solevag GH, Severson DL, Larsen TS, Aasum E: Perfused hearts from Type 2 diabetic (db/db) mice show metabolic responsiveness to insulin. Am J Physiol Heart Circ Physiol. 2006, 290 (5): H1763-H1769. 10.1152/ajpheart.01063.2005.
Marsh SA, Dell’italia LJ, Chatham JC: Interaction of diet and diabetes on cardiovascular function in rats. Am J Physiol Heart Circ Physiol. 2009, 296 (2): H282-H292.