Biomedical Engineering Reference
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(hypoxia/ischemia). A corollary to this hypothesis is that lactate and hydrogen ions
from the brain interstitial space are transported into the blood by MCT1 in brain
endothelial cells. Interestingly, fasting induces ketonemia and confers neuroprotec-
tion in rats subject to hypoxic insult
102
,
104
while also enhancing MCT function.
105
Elevated MCT1 expression correlates with a reduced risk of ischemic damage, and
MCT1 may play a key role in this neuroprotection. Complementary to increased
numbers of MCT1 proteins is the possibility that increased functional activity of ex-
isting transporters by intracellular regulatory mechanisms also may play a key role
in facilitating lactic acid processing and efflux from the brain.
49
−
51
Diabetes
Diabetes (types I and II) is a disease involving disturbances in insulin sig-
naling and disruption of glucose metabolism. Altered glucose transport and oxidation
generates products such as pyruvate and lactate that utilize MCTs for cellular trans-
port. Therefore, a significant role of MCTs in diabetes may be hypothesized. It is
reported that elevated levels of plasma lactate may be a significant risk factor for the
development of type II diabetes.
106
,
107
Skeletal muscle contributes significantly to
insulin-dependent glucose uptake and is a major source of lactate in human body.
In both type I and type II diabetes, MCT expression is altered severely. MCT1 pro-
tein content in skeletal muscle in men with type II diabetes was about 35% lower than
in healthy men and increased to normal levels following moderate exercise training.
108
In contrast, MCT4 protein was not significantly different between the two groups,
but after exercise training, MCT4 content increased in healthy men and remained
unchanged in men with type II diabetes.
108
This would indicate that the expression of
MCT1 and MCT4 in muscle is altered in diabetes and that their regulation in response
to exercise is modified.
In rats with streptozotocin (STZ)-induced type I diabetes, it was found that MCT1
protein was reduced in heart, and MCT1 and MCT4 protein were reduced in skeletal
muscle.
109
Consistent with previous observations, this decrease in MCT1 and MCT4
protein was elevated back to normal levels in both heart and skeletal muscle with
intense exercise training.
109
This suggests that it may take a high level of exercise
training to elevate MCT4 protein levels in patients with diabetes. In addition to skeletal
muscle, adipocytes are also important sites of lactate production, where MCT1 is
expressed to facilitate lactate efflux. In a STZ-induced type I diabetes rat model
it was shown that MCT1 protein expression in adipocytes is decreased by almost
80% that of control rats.
110
It is apparent from these results that MCT expression
is severely altered in both skeletal muscle and adipocytes in rats and humans with
diabetes. Whether these changes in MCT expression contribute to disease progression
or are a result of altered glucose metabolism (or a combination of the two) is unknown.
Pharmacological manipulation of MCT expression and/or activity to maintain normal
plasma lactate levels may aid in the prevention and treatment of diabetes.
7.4.4. Drug Design
Currently, only structural comparisons of substrates have been performed to exam-
ine the minimum requirements necessary for MCT-mediated transport. Generally,
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