213
(UDP)-N- acetylglucosamine which is used by the enzyme O-linked
N-acetylglucosamine transferase (O-GlcNAc) to modify serine and threonine on
cellular proteins [ 101 ]. Hyperglycemia induces the expression of O-GlcNAc [ 102 ]
which was reported to correlate with cardiomyocyte hypertrophy [ 103 ], fibrosis,
and impaired Ca2+ handling [ 104 ] and insulin signaling [ 2 ].
Exercise was shown to affect the hexosamine pathway in different ways. In lean[ 105 ] and STZ-induced diabetic mice [ 106 ], long-term intensive swim-training
markedly decreased protein O-GlcNAcylation in the heart. On the other hand, tread-
mill running increased cardiac protein OGlcNAcylation in db/db mice [ 107 ]. The
study of Medford et al. [ 108 ] showed very time- and spatial-restricted cardiac pro-
tein O-GlcNAcylation in response to acute exercise training. Therefore, further
studies are required to explore the exercise-induced changes in cardiac
O-GlcNAcylation.
6 Role of ROS in the Progression of Diabetic
Cardiomyopathy and Beneficial Effects of Exercise
6.1 Sources of ROS in the Diabetic Myocardium
ROS are generated and degraded during the physiological and homeostatic func-
tions of the living cells [ 109 , 110 ]. Excessive ROS production leads to oxidative
stress and modifications in DNA, lipids, proteins and other cellular molecules [ 109 ,
110 ]. Diabetes and its complications are well-known to be associated with excessive
ROS and oxidative stress [ 109 , 110 ]. Several experimental and clinical studies dem-
onstrated increased oxidative stress in diabetes [ 111 – 113 ].
Oxidative stress mediates the pathogenesis of DCM and increases ischemic sus-ceptibility in the heart of diabetics [ 115 , 116 ]. Induction of diabetes using STZ led
to oxidative stress and abnormal cardiac contraction and relaxation in guinea pigs
[ 117 ]. In rats with pre-diabetes induced by a single low dose of STZ, diastolic dys-
function, and increased left ventricular mass and wall thickness were recorded
[ 118 ].
Impaired insulin-mediated glucose uptake, glycogenolysis and gluconeogenesisin peripheral tissues in diabetes lead to hyperglycemia and increased ROS produc-
tion in the heart [ 70 ]. Several pathways are implicated in excessive production of
ROS in the diabetic heart, including leakage of the mitochondrial electron transport
chain, uncoupling of nitric oxide synthase (eNOS), interaction of AGEs with
RAGEs, increased activity of xanthine oxidase, 12/15-lipoxygenase (LOX) and
NADPH oxidases [ 110 ] (Fig. 12.1).
12 Exercise Amaliorates Metabolic Disturbances and Oxidative Stress in Diabetic...