description): Diabetes is associated with increased incidence of vascular disease and hypertension; however, there is evidence of a diabetic cardiomyopathy independent of other risk factors for heart disease. Despite the fact that approximately 90% of diabetic patients have Type 2 diabetes, the majority of the experimental studies on the effects of diabetes on the myocardium use acute models of uncontrolled Type 1 diabetes. Therefore, the goal of this project is to determine the consequences of Type 2 diabetes on cardiac metabolism and function. The investigators have shown that contractile dysfunction following diabetes can be attributed, in part, to alterations in energy metabolism. Preliminary studies also demonstrate that metabolic abnormalities are associated with the transition from insulin resistance to Type 2 diabetes and precede the development of overt contractile dysfunction. In light of these results, the hypothesis to be tested is that the development of Type 2 diabetes is associated with impaired energy production as a result of a decrease in both carbohydrate and fatty acid entry into the mitochondria. The investigators propose that these alterations in energy metabolism contribute to the development of impaired contractile function and increased susceptibility to ischemic injury. To test this hypothesis, experiments will be carried out on isolated perfused hearts form Zucker rats (ZF, fa/fa); lean non-diabetic litter mates (fa/?) and obese, non-diabetic Zucker rats (ZF, fa/fa) will be used as controls. The effects of the development of Type 2 diabetes, on myocardial substrate utilization, contractile function and the regulation of coronary flow will be investigated. They will determine whether treatment with anti-hyperglycemic agents prevent the myocardial changes associated with the development of Type 2 diabetes in the ZDF rat. 13C-NMR spectroscopic techniques will be used to quantify fluxes through metabolic pathways critical to the regulation of energy metabolism under normal conditions and following ischemia and reperfusion derangement of the myocardium that occur as a result of obesity, insulin resistance as well as Type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL067464-01
Application #
6335560
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Linder, Barbara
Project Start
2000-08-20
Project End
2003-07-31
Budget Start
2000-08-20
Budget End
2001-07-31
Support Year
1
Fiscal Year
2000
Total Cost
$240,250
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Marsh, Susan A; Powell, Pamela C; Dell'italia, Louis J et al. (2013) Cardiac O-GlcNAcylation blunts autophagic signaling in the diabetic heart. Life Sci 92:648-56
Medford, H M; Chatham, J C; Marsh, S A (2012) Chronic ingestion of a Western diet increases O-linked-?-N-acetylglucosamine (O-GlcNAc) protein modification in the rat heart. Life Sci 90:883-8
Laczy, Boglárka; Fülöp, Norbert; Onay-Besikci, Arzu et al. (2011) Acute regulation of cardiac metabolism by the hexosamine biosynthesis pathway and protein O-GlcNAcylation. PLoS One 6:e18417
Des Rosiers, Christine; Labarthe, Francois; Lloyd, Steven G et al. (2011) Cardiac anaplerosis in health and disease: food for thought. Cardiovasc Res 90:210-9
Marsh, Susan A; Chatham, John C (2011) The paradoxical world of protein O-GlcNAcylation: a novel effector of cardiovascular (dys)function. Cardiovasc Res 89:487-8
Marsh, Susan A; Dell'Italia, Louis J; Chatham, John C (2011) Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice. Amino Acids 40:819-28
Teo, Chin Fen; Ingale, Sampat; Wolfert, Margreet A et al. (2010) Glycopeptide-specific monoclonal antibodies suggest new roles for O-GlcNAc. Nat Chem Biol 6:338-43
Chatham, John C; Marchase, Richard B (2010) The role of protein O-linked beta-N-acetylglucosamine in mediating cardiac stress responses. Biochim Biophys Acta 1800:57-66
Laczy, Boglarka; Marsh, Susan A; Brocks, Charlye A et al. (2010) Inhibition of O-GlcNAcase in perfused rat hearts by NAG-thiazolines at the time of reperfusion is cardioprotective in an O-GlcNAc-dependent manner. Am J Physiol Heart Circ Physiol 299:H1715-27
Chatham, John C; Marchase, Richard B (2010) Protein O-GlcNAcylation: A critical regulator of the cellular response to stress. Curr Signal Transduct Ther 5:49-59

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