it is presented by a MEDICAL STUDENT AT UNIVERSITY OF RWANDA topic is about pathophysiology mechanisms of glypcerglycemia in causing microvascular complications. it will help medical student to know deep in cascade how high concentration ogf glucose is converted into other substances to affect blood vessels.

1. BY:
- MWIZERWA Jean-Luc ( 5th year medical student at UNIVERSITY OF
RWANDA)

2.  Consistent with clinical evidence defining the critical role of
hyperglycemia in microvascular disease.
 Data indicate that high intracellular levels of glucose in cells
that cannot down-regulate glucose entry:
 endothelium,
 glomeruli
 nerve cells

3.  result in microvascular damage via four
distinct, diabetes-specific pathways that were
sequentially discovered
(1) increased polyol pathway flux
(2) increased formation of advanced glycation end-
product (AGE),
(3) activation of protein kinase C (PKC)
(4) increased hexosamine pathway flux.

5.  Overproduction of reactive oxygen species (ROS) in response
to high glucose is thought to:
 inhibit glyceraldehyde-3-phosphate dehydrogenase
(GAPDH), thus
 increasing the concentration of upstream glycolytic
metabolites that are shunted into alternative pathways.

6.  Among these are:
(1) conversion of glucose to sorbitol depletes NADPH, thus
preventing the regeneration of ROS scavengers;

7.  (2) conversion of fructose-6-phosphate to uridine
diphosphateN-acetylglucosamine (UDP-GLcNAc) leads to
protein modifications that alter gene expression;

8.  (3) glyceraldehyde-3 phosphate is metabolized to
form diacylglycerol (DAG), which in turn activates protein
kinase C (PKC), resulting in altered vascular hemodynamics

9.  (4) carbonyls formed by multiple mechanisms, including
oxidation of glyceraldehyde-3 phosphate to form
methylglyoxal, react irreversibly with proteins to form
dysfunctional products (advanced glycosylated end-products,
AGE) that cause intracellular and extracellular vascular
changes.

10.  It has been extensively studied in diabetic nerve cells and is also present in
endothelial cells.
 Many cells contain aldose reductase, an enzyme that converts
toxic aldehydes to their respective alcohols (polyol pathway).
 Aldose reductase has a low affinity for glucose, in case of intercellular
hyperglycemia, this pathway can account for up to one-third of glucose
flux, converting glucose to sorbitol.

11.  excess sorbitol was originally thought to cause osmotic damage,
more recent data instead suggest that the real culprit is the
consumption of NADPH during glucose reduction.
 NADPH is required to regenerate reduced glutathione (GSH), a
thiol that detoxifies reactive oxygen species, NADPH
consumption prevents the clearance of damaging free radicals.

12.  Increased shunting of glucose through the hexosamine
pathway via diversion of the glycolytic intermediate,
fructose- 6-phosphate, is also postulated to play a role in
microvascular disease.


13.  The hexosamine pathway contributes
 to insulin resistance,
 producing substrates that, when covalently linked to
transcription factors, stimulate the expression of proteins,
such as transforming growth factor and plasminogen
activator inhibitor, that enhance microvascular damage.

14.  Dicarbonyl formation from direct auto-oxidation of
glucose also contributes to AGE formation
 Intracellular endothelial hyperglycemia stimulates
glycolysis and, with this, an increase in the de novo
synthesis of diacylglycerol (DAG) from the glycolytic
intermediate, glyceraldehyde-3-phosphate
 DAG, in turn, activates several isoforms of protein
kinase C (PKC) that are present in these cells.

15.  This inappropriate activation of PKC alters blood
flow and changes endothelial permeability, in part via
effects on nitric oxide pathways, and also contributes to
thickening of the extracellular matrix.

16.  The formation of irreversibly glycated proteins called (AGEs) also causes
microvascular damage in diabetes.
 When present in high concentrations:
 glucose can react reversibly and nonenzymatically with protein amino groups to
form an unstable intermediate, a Schiff base,
 which then undergoes an internal rearrangement to form a more stable glycated
protein, also known as an early glycosylation product (Amadori
product) such as hemoglobin A1c

17.  Such a reaction accounts for the formation of glycated HbA, also
known as HbA1c.
 In diabetics, elevated glucose leads to increased glycation of
HbA within red blood cells. Because red blood cells circulate
for120 days, measurement of HbA1c in diabetic patients serves
as an index of glycemic control over the preceding months.

18.  Early glycosylation products can undergo a further series of
chemical reactions and rearrangements, often involving the
formation of reactive carbonyl intermediates, leading to the
irreversible formation of AGE.


19.  Via 3 major pathways:
(1) intracellular AGE formation from proteins involved in transcription
alters endothelial gene expression
(2) irreversible cross linking of AGE adducts formed from matrix proteins
results in vascular thickening and stiffness
(3) binding of extracellular AGE adducts to AGE receptors (RAGE) on
macrophages and endothelium stimulates NF-κB-regulated inflammatory
cascades and resultant vascular dysfunction.

21.  The formation of advanced glycosylation end-products (AGEs) occurs via
multiple pathways:
1)The reversible formation of glycated proteins (Amadori products),
such as hemoglobin A1c, through a complex series of chemical reactions, or
2) the direct oxidation of glucose and its metabolites (eg,
glyceraldehyde-3 phosphate, G3P), result in the production of reactive
dicarbonyls.
 These moieties react irreversibly with proteins to form AGE.

22.  More recent information suggests that increased flux through
these four pathways is induced by a common factor
 overproduction of mitochondrial-derived reactive oxygen
species generated by increased flux of glucose through the
TCA cycle
 The end result of these changes in the microvasculature is:
1)an increase in protein accumulation in vessel walls,

23. 2) endothelial cell dysfunction,
3) loss of endothelial cells, and,
4) occlusion.

24.  Evidence suggests that all four of these pathways may actually
be linked by a common mechanistic element:
 Hyperglycemia induced oxidative stress.
 In particular, the increase in electron donors that results from
shunting glucose through the tricarboxylic acid cycle
 increases mitochondrial membrane potential by pumping
proteins across the mitochondrial inner membrane.

25.  This increased potential prolongs the half-life of superoxide
generating enzymes, thus increasing the conversion of O2 to O2–.
 These increased reactive oxygen species lead:
 to inhibition of the glycolytic enzyme, glyceraldehyde-3phosphate
dehydrogenase (GADPH), and
 a resultant increase in upstream metabolites that can now be
preferentially diverted into the four mechanistic pathways

26.  Gary D. H., Stephen J. M.Pathophysiology of diseases- An
introduction to clinical medicine, seventh edition. Chapter 18
Disorders of the Endocrine Pancreas, pg 534-538.
