Molecular and Cellular Biochemistry

, Volume 368, Issue 1–2, pp 37–45 | Cite as

Early cardiovascular changes occurring in diet-induced, obese insulin-resistant rats

  • Barbara Huisamen
  • Daneel Dietrich
  • Nicole Bezuidenhout
  • John Lopes
  • Brian Flepisi
  • Dee Blackhurst
  • Amanda Lochner
Article

Abstract

The metabolic syndrome is recognized as a cluster of disturbances associated with obesity, type 2 diabetes and hypertension. Over the past two decades, the number of people with the metabolic syndrome has increased at an alarming rate. This increase is associated with the global epidemic of both obesity and diabetes. Cardiovascular mortality is increased among diabetics and obesity-related insulin-resistant patients, and obesity is currently recognized as independent risk factor for cardiovascular disease. We aimed to establish the effects of a short period of an altered diet on the heart using a rat model of hyperphagia-induced obesity (diet supplemented with sucrose and condensed milk for 8 weeks = DIO) compared to age-matched controls. Isolated, perfused hearts were subjected to global or regional ischaemia/reperfusion. Function on reperfusion was recorded and infarct size determined. A plasma lipid profile was established via HPLC-based methods and proteins involved in metabolic signalling determined either by western blotting or RT-PCR. 8 weeks of diet resulted in whole-body but not myocardial insulin resistance, increased plasma triglyceride and phospholipid levels as well as increased lipid peroxidation. Despite the similar baseline function, hearts from DIO animals showed significantly poorer postischaemic recovery than controls (41.9 % RPP recovery vs 57.9 %, P < 0.05, n = 7–11/group) but surprisingly, smaller infarct size (24.95 ± 1.97 vs 47.26 ± 4.05 % of the area at risk, P < 0.005, n = 8/group). Basal phosphorylation of PKB/Akt was elevated but IRS-1 and SERCA-2 expression severely downregulated. In conclusion, after only 8 weeks of a slight change in diet, the rat heart shows signs of metabolic remodelling. Some of these changes may be protective but others may be detrimental and eventually lead to maladaptation.

Keywords

Heart Obesity Insulin resistance Ischaemia/reperfusion Insulin signalling 

References

  1. 1.
    Reaven GM (1988) The role of insulin resistance in human disease. Diabetes 37:1595–1602PubMedCrossRefGoogle Scholar
  2. 2.
    Haffner SM (2000) Obesity and the metabolic syndrome: the San Antonio Heart Study. British J Nutr 83(Suppl 1):S67–S70Google Scholar
  3. 3.
    Grundy SM (2006) Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol 47:1093–1100PubMedCrossRefGoogle Scholar
  4. 4.
    Alexander CM, Landsman PB, Teusch SM, Haffner SM (2003) NCEP-defined metabolic syndrome, diabetes and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 52:1210–1213PubMedCrossRefGoogle Scholar
  5. 5.
    Balkau B, Charles MA (1999) Comment on the provisional report from the WHO Consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med 16:441–443CrossRefGoogle Scholar
  6. 6.
    National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High blood Cholesterol in Adults (2002) Third report of the NCEP—adult treatment panel III, final report. Circulation 106:3143–3421Google Scholar
  7. 7.
    Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of diabetes epidemic. Nature 414:782–787PubMedCrossRefGoogle Scholar
  8. 8.
    Pyörälä K (1991) Hyperinsulinaemia as predictor of atherosclerotic vascular disease, epidemiological evidence. Diabetes Metab 17:87–92Google Scholar
  9. 9.
    Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR (1998) Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom prospective Diabetes Study (UKPDS:23). BMJ 316:823–828PubMedCrossRefGoogle Scholar
  10. 10.
    Smith SC Jr (2007) Multiple risk factors for cardiovascular disease and diabetes mellitus. Am J Med 120:S3–S11PubMedCrossRefGoogle Scholar
  11. 11.
    Rader DJ (2007) Effect of insulin resistance, dyslipidemia and intra-abdominal adiposity on the development of cardiovascular disease and diabetes mellitus. Am J Med 120:S12–S18PubMedCrossRefGoogle Scholar
  12. 12.
    Hu FB, Stampfer MJ, Haffner SM, Soloman CG, Willett WC, Manson JF (2002) Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care 25:1129–1134PubMedCrossRefGoogle Scholar
  13. 13.
    Huisamen B, Pêrel SJC, Friedrich SO, Salie R, Strijdom H, Lochner A (2011) AngII receptor antagonism improves nitric oxide production, eNOS and PKB expression in hearts from a rat model of insulin resistance. Mol Cell Biochem 349:21–31PubMedCrossRefGoogle Scholar
  14. 14.
    Du Toit EF, Smith W, Muller C, Strijdom H, Stouthammer B, Woodiwiss AJ, Norton GR, Lochner A (2008) Myocardial susceptibility to ischemic–reperfusion injury in a prediabetic model of dietary-induced obesity. Am J Physiol Heart Circ Physiol 294:H2343–H2366Google Scholar
  15. 15.
    Naderali EK, Pickavance LC, Wilding JPH, Williams G (2001) Diet-induced endothelial dysfunction in the rat is independent of the degree of increase in total body weight. Clin Sci 100:635–641PubMedCrossRefGoogle Scholar
  16. 16.
    Huisamen B, Genis A, Lochner A (2011) Pre-treatment with a DPP-4 inhibitor is infarct sparing in hearts from obese, pre-diabetic rats. Cardiovasc Drugs Ther 25:13–20PubMedCrossRefGoogle Scholar
  17. 17.
    Folch J, Lees M, Stanley GHS (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226:497–509PubMedGoogle Scholar
  18. 18.
    Esterbauer H, Striegl G, Puhl H, Rotheneder M (1989) Continuous monitoring of in vitro oxidation of human low density lipoprotein. Free Radic Res Commun 6:67–75PubMedCrossRefGoogle Scholar
  19. 19.
    Pryor WA, Castle L (1984) Chemical methods for the detection of lipid hydroperoxides. Methods Enzymol 105:293–299PubMedCrossRefGoogle Scholar
  20. 20.
    Jiang Z-Y, Woollard ACS, Wolff SP (1991) Lipid hydroperoxide measurement by oxidation of Fe2+ in the presence of xylenol orange. Comparison with the TBA Assay and an iodometric method. Lipids 26:853–856PubMedCrossRefGoogle Scholar
  21. 21.
    Jiang Z-Y, Hunt JV, Wolff SP (2002) Ferrous ion oxidation in the presence of xylenol orange for detection of lipid hydroperoxide in low density lipoprotein. Anal Biochem 202:384–389CrossRefGoogle Scholar
  22. 22.
    Markwell MA, Haas SM, Bieber LL, Tolbert NE (1979) A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal Biochem 87:206–210CrossRefGoogle Scholar
  23. 23.
    Lochner A, Genade S, Moolman JA (2003) Ischemic preconditioning: infarct size is a more reliable endpoint than functional recovery. Basic Res Cardiol 98:337–346PubMedCrossRefGoogle Scholar
  24. 24.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254PubMedCrossRefGoogle Scholar
  25. 25.
    Venter H, Genade S, Mouton R, Huisamen B, Harper IS, Lochner A (1991) Myocardial membrane cholesterol: effects of ischaemia. J Mol Cell Cardiol 23:1271–1286PubMedCrossRefGoogle Scholar
  26. 26.
    Ritchie SA, Connell JMC (2007) The link between abdominal obesity, metabolic syndrome and cardiovascular disease. Nutr Metab Cardiovasc Dis 17:319–326PubMedCrossRefGoogle Scholar
  27. 27.
    Bergman RN, Kim SP, Hsu IR, Catalano KJ, Chiu JD, Kabir M, Richey JM, Ader M (2007) Abdominal obesity: role in the pathophysiology of metabolic disease and cardiovascular risk. Am J Med 120:S3–S8PubMedCrossRefGoogle Scholar
  28. 28.
    Olefsky JM, Glass CK (2010) Macrophages, inflammation and insulin resistance. Ann Rev Physiol 72:219–246CrossRefGoogle Scholar
  29. 29.
    Matthews DR, Hosaker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (2002) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetes Care 25:1891–1892CrossRefGoogle Scholar
  30. 30.
    Cacho J, Sevillano J, De Castro J, Herrera E, Ramos MP (2008) Validation of simple indexes to assess insulin sensitivity during pregnancy in Wistar and Sprague-Dawley rats. Am J Physiol Endocrinol Metab 295:E1269–E1276PubMedCrossRefGoogle Scholar
  31. 31.
    Park S-Y, Cho Y-R, Kim H-J et al (2005) Unraveling the temporal pattern of diet-induced insulin resistance in individual organs and cardiac dysfunction in C57BL/6 mice. Diabetes 54:3530–3540PubMedCrossRefGoogle Scholar
  32. 32.
    Araki E, Lipes MA, Patti ME et al (1994) Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372:186–190PubMedCrossRefGoogle Scholar
  33. 33.
    Matsiu T, Tao J, Del Monte F et al (2001) Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 104:330–335CrossRefGoogle Scholar
  34. 34.
    Jonassen AK, Sack MN, Mjøs OD, Yellon DM (2001) Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ Res 89:1191–1198PubMedCrossRefGoogle Scholar
  35. 35.
    Young ME, McNulty P, Taegtmeyer H (2002) Adaptation and maladaptation of the heart in diabetes: part II: potential mechanisms. Circ 105:1861–1870CrossRefGoogle Scholar
  36. 36.
    Russell RR III, Coven DL, Pypaert M et al (2004) AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 114:495–503PubMedGoogle Scholar
  37. 37.
    Stanley WC, Dabkowski ER, Fibeiro RF Jr, O’Connell KA (2012) Dietary fat and heart failure: moving from lipotoxicity to lipoprotection. Circ Res 110:764–776PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Barbara Huisamen
    • 1
    • 2
  • Daneel Dietrich
    • 3
  • Nicole Bezuidenhout
    • 1
  • John Lopes
    • 1
  • Brian Flepisi
    • 1
  • Dee Blackhurst
    • 4
  • Amanda Lochner
    • 1
    • 2
  1. 1.Division Medical Physiology, Department of Biomedical SciencesFaculty of Health Sciences, University of StellenboschTygerbergSouth Africa
  2. 2.Cape Heart CentreUniversity of Cape TownCape TownSouth Africa
  3. 3.Department of Medical BiosciencesUniversity of Western CapeBellvilleSouth Africa
  4. 4.Cape Heart Centre Lipid ClinicUniversity of Cape TownCape TownSouth Africa

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