217
2 diabetic rats after long-term endurance training. In the study of Sharma et al.
[ 138 ], type 2 diabetic rats underwent a 3 week treadmill endurance exercise proto-
col exhibited significantly reduced expression of NADPH oxidase subunits. This
study added support to the findings of Bidasee et al. [ 142 ] and suggested how exer-
cise training improves cardiac function in diabetes. A recent study conducted by
Veeranki et al. [ 143 ] showed that moderate intensity exercise improved mitochon-
drial function through restoration of connexin 43 (Cx43) networks and mitochon-
drial trans-membrane potential in db/db mice.
6.4 Effect of Exercise on eNOS Uncoupling
Cardiovascular endothelial function depends on the physiological coupling of eNOS
haem group with the substrate L-arginine, using the co-factor tetrahydrobiopterin
(BH4) during NO synthesis [ 144 ]. Under oxidative stress conditions (Fig. 12.4),
BH4 is converted to 7,8-dihydrobiopterin (BH2), which promote uncoupling of
eNOS and induce the synthesis of O 2 • instead of NO [ 144 ]. O 2 • can react with NO
produced by the activity the inducible form of NOS (iNOS) to form the versatile
oxidant peroxynitrite [ 145 ]. In diabetes, hyperglycemia favors the expression of
iNOS and uncoupling of eNOS leading to increased production of O 2 • [ 146 ]. The
resultant NO bioavailability and formation of peroxynitrite are associated with the
progression of DCM and increase in myocardiocytes cell death [ 147 , 148 ]. The
study of Jo et al. [ 149 ] showed up-regulation of iNOS, increased levels of the reac-
tive nitrogen species, 4-hydroxy-2-nonenal (4-HNE) and nitrotyrosine, in the heart
of diabetic mice.
Fig. 12.4 Uncoupling
of eNOS and generation
of superoxide (O 2 •) rather
than nitric oxide (NO)
under oxidative stress
conditions. eNOS
endothelial nitric oxide
synthase, BH4
tetrahydrobiopterin, BH2
7,8-dihydrobiopterin,
GTPCH GTP-
cyclohydrolase-I
12 Exercise Amaliorates Metabolic Disturbances and Oxidative Stress in Diabetic...