Transcript Effect of glucose on insulin promoter activity.

Diabetes Complications and
Control Trial (DCCT)
• Tight control of blood glucose levels
significantly decreased risk of diabetic
complications.
• Finding strongly implicates hyperglycemia
or other metabolic abnormalities as the
overriding pathogenic abnormality.
Most commonly cited metabolic
defects include:
• Polyol or sorbitol pathway.
• Abnormal lipid metabolism (increased de
novo diacylglycerol synthesis).
• Advanced glycation end product formation.
• Increased oxidative stress.
• Inflammation (leukocyte adhesion)*
These metabolic defects may:
• Directly damage specific critical cellular
components in a complications-prone tissue.
example: peripheral nerve axons or
Schwann cells
• Indirectly damage functional or structural
elements.
example: extracellular matrix or
microvasculature
Sorbitol Hypotheses
(example, microvascular complication and diabetic peripheral
neuropathy)
hyperglycemia
glutathione
reductase
NO
synthase
arginine
GS-SG myo-inositolnitric
GSH oxide
+ citrulline
taurine
NADPH
glucose
NADP
Aldose reductase
glycolysis
dihydroxyacetone
phosphate
SORBITOL
Sorbitol
dehydrogenase
NAD+
Fructose
NADH
Pyruvate
Diacylglycerol
(DAG)
TCA cycle
Increased PKC activity
Aldose Reductase Inhibitors
• Effective for treatment of retinopathy and
neuropathy in diabetic rats and dogs.
• Limited usefulness in human trials due to
toxicity associated with delivery of drug
through blood-retinal barrier.
Advanced Glycation End Products
• Form non-enzymatically from sugar derived
intermediates.
• Glucose has slowest rate of AGE formation
compared to other sugars such as glucose-6phosphate or glyceraldehyde.
• AGE formation is much more rapid inside
the cell that outside (ie extracellular matrix).
Non-enzymatic formation of advanced
glycation end products (AGES).
protein
sugar
Amadori
product
General mechanisms by which AGE
formation cause pathological changes.
• AGE can directly alter protein function in target
tissue.
• AGE can alter signal transduction pathways by
altering matrix-matrix and matrix-cell interactions.
• AGE can alter the levels of soluble signals, such
as cytokines, hormones or free radicals, through
interactions with AGE-specific receptors.
AGE inhibitor:
• Aminoguanidine
• Reacts with dicarbonyl intermediates (one
step distal to Amidori product formation)
• Improves pathologies of the retina, kidney,
nerve and artery in diabetic animal models.
Oxidative Stress and Free
Radicals
• Free radicals are highly reactive molecules
with unpaired electrons.
• Excessive free radicals or inadequate
antioxidant defense mechanisms lead to
damage of cellular structures and enzymes.
Common Players
•
•
•
•
Superoxide anion
Hydrogen peroxide
Hydroxyl radical
Nitric oxide
superoxide + NO
peroxynitrite
peroxynitrite
hydroxyl radical
Production of free radicals and lipid
peroxidation by hyperglycemia.
• Direct autooxidation of glucose.
• Increased glucose metabolism (mitochondrial
respiration).
• Activation of glycation pathways.
• Reduction of antioxidant mechanisms.
• Interaction of NO with superoxide to generate
peroxynitrite and hydroxyl radicals.
• Induction and activation of lipoxygenase
pathways.
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