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Oxidative stress in diabetic neuropathy
Diabetes mellitus
Diabetes is a chronic, metabolic disease characterized by elevated levels of blood glucose
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Type I diabetes mellitus typically has an
early onset and occurs when the pancreas produces little or no insulin, as a result of
autoimmune destruction of the beta cells of the islets of langerhans
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5 million people have diabetes mellitus (DM) in the uk, 5-10% have type
I DM, and 85-95% have type II DM
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Insulin signaling
Insulin is a hormone released by the pancreatic beta cells in response to elevated levels of
nutrients in the blood
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The insulin receptor, located on the surface of
target cells such as liver, fat and muscle, is composed of two extracellular alpha subunits
and two transmembrane beta subunits linked together by disulfide bonds
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These residues are recognized by
phosphotyrosine-binding (PTB) domains of adaptor proteins such as members of the insulin
receptor substrate family (IRS)
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The catalytic subunit of PI3-kinase
p110, then phosphorylates phosphatidylinositol (4,5) bisphosphatase (ptdins (4,5)p2)leading
to formation of ptdins (3,4,5)p3
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Activation of AKT also requires the protein kinase
3-phosphoinositide dependent protein kinase 1 (PDK1), which phosphorylates AKT
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A major substrate of GSK3 is glycogen synthase, an
enzyme that catalyzes the final step in glycogen synthesis
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Insulin inhibits the production and release of glucose
by the liver by blocking gluconeogenesis and glycogenesis
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Insulin
stimulates glucose uptake into cells by inducing translocation of the glucose transporter,
GLUT4, from intracellular storage to the plasma membrane
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In addition, a PI3-kinase independent pathway recruits GLUT4 to
the plasma membrane
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following phosphorylation the
cb1-CAP complex translocates to lipid rafts in the plasma membrane, cb1 then interacts with
the adaptor protein crk, which is associated with the rho-family guanine nucleotide exchange
factor, C3G
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Increasing intracellular fatty acid metabolites, such as diacylglycerol, fatty acyl CoA, or
ceramides activates a serine/threonine kinase cascade, initiated by protein kinase C-theta,
leading to phosphorylation of serine/threonine sites on insulin receptor substrates
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Thus, accumulation of intracellular fatty acid
metabolites induces insulin resistance
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DN affects small and large sensory nerve fibres in the peripheral
nervous system (PNS)
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The PNS is formed by many different classes of motor, sensory, and autonomic
neurons supported by both myelin-forming and nonmyelinating schwann cells
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Dorsal root ganglia
The 31 right and left paired spinal nerves in humans are formed from afferent sensory dorsal
axons (the dorsal root) and motor ventral efferent axons (the ventral root)
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the
DRG is a group of cell bodies responsible for the transmission of sensory messages from
receptors such as thermoreceptors that detect deviations in temperature, pain receptors that
detect signals from damaged tissue or the threat of damage, proprioceptors that detect
changes in position or movement of the body or its limbs, chemoreceptors that detect levels
of carbon dioxide in the blood, Meissner’s and Krause’s corpuscle receptors that detect
touch, mechanoreceptors that detect stretch, and Meisner’s and Pacinian corpuscle
receptors that detect vibration, to the central nervous system (CNS) for a response
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DRG neurons are pseudounipolar neurons, with one axon that bifurcates
into two separate branches resulting in a distal process and proximal processes
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The DRG contains most of the body’s sensory neurons, sensory neurons relay sensory
neuronal messages from the periphery to the CNS
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Patients with DN typically
present with numbness, tingling, pain, and/or weakness that begins in the feet and spreads
proximally in a length-dependent fashion (stocking and glove distribution)
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DN
associated numbness often causes balance problems which can lead to falls
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Frequently patients develop allodynia (painful sensations to innocuous stimuli), and
hyperalgesia (increased sensitivity to painful stimuli)
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5 meters long
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DRG are situated outside of the blood brain
barrier (BBB), hence, molecules circulating in the vascular system can directly access the
DRG
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DRG neurons lie outside of the BBB, and so lack the protection of the
BBB
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Only the
proximal axon that enters the dorsal horn lies within the blood-nerve barrier
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DRG neurons must regularly replace and recycle worn membrane bound structures
and cytoplasmic proteins from throughout the cell
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After signals are
received in the nucleus and necessary and inserted into correct locations along axon
membranes, thus DRG neurons are vulnerable to damage for two reasons; the neurons
position in the body’s periphery uniquely exposes them to toxins and systemic metabolic
derangements, and their unusual morphology places extreme spatial demands on DRG
survival functions
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The
first enzyme in the pathway, aldose reductase (AR), reduces glucose to sorbitol, which is
then converted to fructose by sorbitol dehydrogenase (SDH)
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mechanisms by which the
polyol pathway contributes to oxidative stress; AR activity depletes its cofactor NADPH,
which is also required for glutathione reductase to regenerate GSH, under hyperglycaemic
conditions, as much as 30% of the glucose is channeled into the polyol pathway, causing a
substantial depletion of NADPH and consequently a significant decrease in the GSH level,

thus, during hyperglycemia, AR activity diminishes cellular antioxidant capacity; oxidation of
sorbitol to fructose by SDH causes oxidative stress because its cofactor NAD+ is converted
to NADPH in the process, and NADPH is the substrate for NADPH oxidase to generate
reactive oxygen species; the polyol pathway converts glucose to fructose, because fructose
and its metabolites fructose-3-phosphate and 3-deoxyglucosone are more potent
nonenzymatic glycation agents than glucose, the flux of glucose through the polyol pathway
would increase AGE formation, AGE are known to cause oxidative stress
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In the wild type mouse, diabetes caused a significant decrease in GSH in their
sciatic nerves, indicative of oxidative stress (chang, et al, 2003)
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Both NADPH and GSH have antioxidant functions such as
electron transfer
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Glucose at elevated concentration undergoes non enzymatic reactions with primary amino
groups of proteins to form glycated residues called Amadori products
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These reactions are
catalysed by transition metal ions
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Glycation of proteins is directly related to the concentration of glucose and therefore is
produced through poor glycaemic control
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The glycation process is
enhanced in the peripheral nerve in diabetics
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Fructose can be metabolized to
fructose-3-phosphate and triose phosphate by phosphatase and fructokinase, respectively
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Hence, these metabolites promote the
formation of AGEs which when involving structural neuronal proteins, interfere with their
polymerization and normal function
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AGEs
have an effect on matrix metalloproteinases which damages nerve fibres
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Uncoupling proteins are a family of proton carriers that are expressed at the inner
mitochondrial membrane and are responsible for proton leak across the membrane into the
cristae
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Activity of uncoupling proteins, therefore, decreases the inner mitochondrial membrane
potential and can relieve stress of excess NADPH entering the electron transport chain
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Oxidative stress in the mitochondria critically aters energy
regulation and survival through three mechanisms
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Thus, peroxynitrite affects mitochondrial function and inhibits ATP synthesis
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Thirdly, oxidative damage of existing inner membrane proteins induces membrane
permeability transition, a permeabilization of the mitochondrial inner membrane that
precedes cytochrome c release and apoptosis
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Mitochondria in the DRG
are especially vulnerable, because in the hyperglycaemia neuron they are the origin of
production of reactive oxygen species, which can damage their DNA membranes,
deregulation of fission and fusion proteins that control mitochondrial shape and number can
impair cell functions and might leads to degeneration and neuronal injury may be the
greatest contributor to DN
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