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5 Effect of Exercise on Hyperglycemia-Induced Cellular
Pathways in the Myocardium
Hyperglycemia can aggravate cardiovascular dysfunction in diabetes via altering
different cellular pathways, including PKC pathway, advanced glycation end prod-
ucts (AGEs) pathway, polyol pathway and hexosamine pathway. All of these path-
ways have a strong potential to increase oxidative stress in the myocardium [ 69 , 70 ].
5.1 DAG/PKC Pathway
Hyperglycemia increases the synthesis of DAG from glycerol-3-phosphate (G3P),
which then triggers activation of PKC pathway in the diabetic myocardium [ 71 ].
Activated PKC-β and -δ isoforms inhibit endothelial nitric oxide synthase (eNOS)
and NO bioavailability, impair vascular permeability, and induce pro-inflammatory
pathway and microvascular matrix remodelling [ 72 – 76 ]. Activated PKC pathway
has been reported to induce cardiac hypertrophy, fibrosis and adverse Ca2+ handling
[ 77 ]. In addition, the activity of PKC pathway was associated with reduced cardiac
performance [ 77 ] and increased reactive oxygen species (ROS) production through
activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases [ 78 ,
79 ]. These finding has been supported from studies on type 1 diabetic hearts where
pharmacological PKC-β inhibition reduced collagen deposition and preserve the
diastolic function [ 80 ]. Moreover, transgenic mice overexpressing cardiac PKC-β 2
showed increased cardiomyocytes death, dystrophic calcification, cardiac hypertro-
phy and fibrosis [ 77 ].
The role of PKC pathway in exercise-induced improvement of cardiac functionin diabetes is not-fully understood. The study of Loganathan et al. [ 81 ] showed
reduction in myocardial DAG levels following exercise in autoimmune type 1 dia-
betic rats. However, the reduced DAG in this study was not associated with PKC-β 2
both expression and activity.
5.2 Polyol Pathway
Activation of the polyol pathway occurs when the intracellular glucose concentra-
tion increases. This pathway is marked by the increased activity of aldose reductase
which converts glucose to sorbitol using NADPH as a cofactor. The activity of
aldose reductase results in depletion of the intracellular NADPH [ 82 ] and can thus
impair the myocardial antioxidant capacity [ 20 ]. Studies have demonstrated
increased activity of aldose reductase in the myocardium of type 1 diabetic mice
[ 83 ]. Isolated hearts exposed to hyperglycemia showed increased activity of aldose
reductase, impaired left ventricular diastolic function and excessive production of
12 Exercise Amaliorates Metabolic Disturbances and Oxidative Stress in Diabetic...