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Abstract:
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The incidence of diabetes is rapidly increasing and by 2030 an expected 592 million individuals
are projected to be affected (WHO report). Hyperglycaemic condition is recognized as the causal
link between diabetes and its complications. The chronic hyperglycemia resulting from diabetes
brings about a rise in oxidative stress due to overproduction of reactive oxygen species (ROS) as
a result of glucose auto oxidation and protein glycosylation. Generation of ROS leads to
oxidative damage of the structural components (such as lipids, DNA and proteins) of cells and
potentiate diabetes related complications. Oxidative insult in cells is also created by the
impairment in functioning of endogenous antioxidant enzymes because of their non enzymatic
glycosylation and oxidation. The prolonged exposure of oxidative stress may cause insulin
resistance by triggering an alteration in cellular redox balance. Several lines of evidence suggest
that oxidative stress occurs in diabetes and could have a role in the development of insulin
resistance. The cause and cellular mechanism responsible for this abnormality is not fully
understand despite of intense investigative efforts. However it is unknown whether it is the cause
or consequence of diabetes. Despite strong experimental evidence indicating that oxidative stress
may determine the onset and progression of late-diabetic complications, controversy exists
between the cause and associative relationship between oxidative stress and diabetes mellitus.
Disruption of glucose homeostasis is a characteristic feature of Non-insulin dependent diabetes
mellitus (NIDDM) and is associated with some complications including cardiovascular disease
and renal failure. Glucose transport, the rate limiting step in glucose metabolism, can be activated
in peripheral tissues by two distinct pathways. One stimulated by insulin through IRS-1/PI3K,
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the other by muscle contraction/exercise through the activation of AMPK. Both pathways also
increase the phosphorylation and activity of MAPK family components of which p38 MAPK
participates in the full activation of GLUT4.Insulin exerts its biological effect upon binding with the insulin receptor (IR) thereby activating
the downstream signaling that lead to enhanced glucose uptake. In skeletal muscle, it potentiates
glucose transport through PI3K mediated or non-PI3K mediated pathways. Alterations or defects
in its signal transduction pathway was found in diabetic patients associated with decreased levels
of IRb, IRS-1, and PI3K. In the insulin signaling, PI3K is a key molecule and inhibition of PI3K
completely abolish insulin stimulated uptake. Akt or Pkb is an important downstream target of
insulin stimulated glucose transport and metabolism.Impairment in fuel metabolism occurs in obesity, and this impairment is a leading pathogenic
factor in type 2 diabetes. The insulin resistance associated with type 2 diabetes is most profound
at the level of skeletal muscle as this is the primary site of glucose and fatty acid utilization.
Therefore, an understanding of how to activate AMPK in skeletal muscle would offer significant
pharmacologic benefits in the treatment of type 2 diabetes. Metformin and the thiazolidinedione
drugs exert the effects via activation of AMPK. Activation of AMPK occurs in response to
exercise, an activity known to have significant benefit for type 2 diabetics. AMPK serves as
sensor of energy status whose activity is triggered in response to changes in nutritional status in
order to modulate tissue-specific metabolic pathways |