BIOCHEMICAL IMPACT OF

DIABETIC COMPLICATIONS

Introduction:
Diabetes is on of the most common
ailment that researchers are interested to
study all over the world, due to devastating
effects of the diseases such as blindness,
kidney failure, nerve damage, accelerated
arterioseclerosis of diabetes and increase in
the danger of myocardial infarction,
amputation and stroke.
The specific microvascular disease of diabetes
is the cause of many of these such diseases, so
there are four major molecular instruments
involved with harm to blood vessels in the
blood.
All these factors appear to reflect excessive
excretion of hyperglycemia, due to increase in
creation of superoxide through the electron
transport chain. The continous rise in sugar
level leads to uncontrolled diabetes , which
cause metabolic imbalances , resulting in
many severe complications that cause
immediate medical attention.
High blood sugar (HYPER GLYCEMIA) leads
to increased protein glycation , which leads
to chronic conditions requiring constant
monitoring and treatment. People with
diabetes may also have high level of
cholestrol , which leads to high blood
pressure causing severe problems which
can be fatal if not monitered. This problem
needs persistant medical attention and
care.
MAJOR COMPLICATIONS OF DIABETES

MICRO VASCULAR:
Eye , kidney and neuro pathy.
EYE:
High blood glucose and high blood
pressure can cause damage to eye blood
vessels causing retinopathy and other
sever eye problem.
KIDNEY:
High blood pressure and glucose
level can damage small blood vessels
present in kidney and also cause severe
damage to kidney affecting its proper
functioning.

NEUROPATHY:
Hyper glycemia or high blood
glucose level can damage nerves in
peripheral nervous system. This may result
in pain and other complications.

MACRO VASCULAR
BRAIN:
Increased risk of strokes and cerebro
vascular diseases including cerebral attack
and cerebral impairment.
HEART:
High blood pressure and insulin and
may increase risk of coronary heart
diseases.
EXTREMITIES:
Peripheral vascular disease results
in narrowing of the blood vessels
increasing the risk of lack or reduced blood
flow in vessels of leg so feet wounds are
slowly heeling process contributing to the
gangrena and other types of severe
complications.
DIABETES COMPLICATIONS:
1.Glaucoma
2.Cataract
3.Diabetic foot
4.Stroke
5.Heart attack
6.Diabetic nephro pathy
7.Peripheral neuro pathy
8.Peripheral artery disease
9.Diabetic retion pathy
These are all complications resulting due to
diabetes.
COMPLICATIONS OF HYPER GLYCEMIA:
These are divided into two categories
1: acute complications
2: chronic complications
 ACUTE COMPLICATIONS:
Complications
that require surgical intervention including

KETO ACIDOSES:
Although high blood glucose
level , fats cells are hungry due to intra
cellular glucose deficiency , where if the
amount of food is low , or if the insulin
dose is excessively high , the cell begin to
use fat as an energy source , liver cells
produce keton groups of unsaturated fats.
At the points when glucose levels are low ,
high centeralization of ketones can make
up the pee acidic and cause psychic odor
of fruit , this condition can develop into
coma condition.

HPER OSMOLAR HYPER GMOLIC HYPER

GLYCEMIC NON KETOTIC SYNDROME
(HHNS):
High blood glucose level leads to
increased urination , in this case an
individual becomes severaly dehydrated.
High blood glucose level can lead to
altered mental states.

CHRONIC COMPLICATIONS:
A)COMPLICATIONS OF MICRO VASCULAR:
These complications in
some cases lead to retino pathy , nephro
pathy and nerve cells , individual with
impaired glucose level of al least one of
these complications in the propelled
phases of malady; diabetes patient also
need foot care. So customary checking of
glucose level or sugar level are basics to
keeping up metabolic equalization and
dodging inconvenience of micro vascular.
B)COMPLICATIONS OF MACRO VASCULAR:
Complications of macro
vascular on large blood vessels , which in
turn effect the large blood vessels , the
reason for these complications originate
from narrowing of blood vessels or veins
because of glycation , irritation , fat
affidavit and different elements.intricacies
coming about because of major vascular
harm may prompt myocardial dead
tissues , rheumatoid joint pain , stroke ,
osteo poroses , and degenerating
maturing.
The main worry among these intricacies is
myocardial dead tissue at present , it
seemscthat control of blood glucose does
not altogather lessen the hazard or
postpone the presence of vascular
difficulties.
Vascular diseases caused by diabetes
complicatons have similar physiological
features. In the beginning period of
diabetes , hyper glycemia in cells leads to
blood stream dysfunction and expanded
vascular porousness. This leads to several
things which are as follows,
A ) decreased activity in inflated blood
vessels for example , nitric oxide.
B ) increased constriction action , for
example , endothelin-1 and angiotensin II.
C ) develpoment of transport factors , for
example , vascular endo thelial growth
factor (VEGF).
D ) the quantitative and subjective
variations from the normal of the extra
cellular frame work add to an irreversible
increment in vascular porousness.
E ) microbial cell misfortune due
apoptosis.
F ) the gradual blockage of hair resulting
from each extra cellular matrix results
from development factors , for example ,
TGF development and the deposition of
other plasma proteins.
All of these changes leads to ischemia ,
proteinuria , and edema , multiple nerve
damage to peripheral nerves , hyper
trophic glomerulus mesothelomia ,
glomerular nephritis and retinal hypoxia.
Entholial dysfunction occure in diabetic
arteries including insulin resistance to
pathway of nino-3-OH kinase , as well as
hyper glycemia resulting in a decline in the
creation of endothelial nitric oxide for
arterioseclerosis , the increased
amplification of smooth vascular cells ,
plasmogen -1 by RAZ →RAF →MEK
KINASE→PROTIEN KINASE pathway with
MAP activation.
The icrease in blood glucose level itself
leads to decrease intric oxide production in
blood vessels endothelial cells.

THE MECHANISM OF INDUCED

HYPERGLYCEMIA DAMAGE:
Diseases of micro vascular and macro
vascular result from hyper glycemia. This is
illustrated by four main hypotheses:
A ) Increase the flow of polyol path.
B ) Increased composition of final product
of glycation(AGE).
C ) Activation of the isoforms of the C
Kinase Protein (PKC).
D ) Increase the flow of the hexamine
pathway.
INCREASED POLYOL PATHWAY FLUX:
Aldose reductase is the first
enzyme in polyol pathway. It is a
cytosolic , monomeric oxido reductase
that catalyses the NADPH-dependent
reduction of a wide variety of carbonyl
compounds , including glucose. As
NADPH is required for regenerating
reduced glutathion (GSH), this could
induce or exacerbate intra cellular
oxidative stress. Decreased level of GSH
have been founded in the lenses of
 transgenic mice that express aldose
reductase , and this is most likely
mechanism by which increased flux
through polyol pathway has deleterious
sequence. This conclusion is further
more supported by recent experiments
with Homozy-gous knockout mice
deficient in aldose reductase , which
showed that in contrast to wild mice ,
diabetes neither decreased the GSH
content of sciatic nerve nor reduced
motor nerve conduction velocity.

INCREASED COMPOSITION OF THE

FINAL PRODUCT OF GLYCATION (AGE):
 AGEs were found in expanding
sums in retinal vessels and kidney
gloerulii in diabetic patient. AGE can
be created from intracellular
glucose oxidation to glyoxal23, and
amadori item disintegrated
(glucose-inferred 1-amino-1-
deoxyfructose lysine adducts) to 3-
deoxy glucasone phosphates to
methyl glyoxal . AGEs role in
diabetes can be clarified by the
prevention of different practical
appearances of micro vascular
illness in retina , kidney , and nerve.
Production of intracellular AGE
precursors damages the targeted
cells by three general mechanisms.
 First , intracellular proteins modified
by AGEs have altered functions.
Second , extra cellular matrix
components modified by AGEs
precursors intract abnormally with
other matrix components and
receptors for matrix proteins. Third ,
plasma protein modified by AGE
precursors bind to AGE receptors on
endothelial cells , mesangial cells
and macro phages , inducing
receptor-mediated production of
reactive oxygen species.AGE
formation alters the functional
properties of several matrix
proteins.
ACTIVATION OF PROTEIN KINASE C:
The PKC family comprises atleast
eleven isoforms , nine of which are
activated by lipid second messenger
DAG. Intracellular hyper glycemia
increases the amount of DAG in
cultured micro vascular cells and in
the retina and renal glumeruli of
diabetic animals. Hyper glycemia
may also activate PKC isoforms
indirectly through both ligation of
AGE receptors and increased activity
of the polyol pathway , presumeably
by increasing reactive oxygen
species. Abnormal activation of PKC
has been implicated in the
decreased glomerular production of
the nitric oxide induced by
experimental diabetes and in
decreased production of nitric oxide
in smooth muscle cells that is
induced by hyper glycemia.
Activation of PKC also inhibit insulin-
stimulated expression of the
mesenger RNA for endothelial nitric
oxide synthase in cultured
endothelial cells. Hyper glycemia
increases endothelin-1-stimulated
MAP-kinase activity in glomerular
masangial cells by activating PKC
isoforms. Activation of PKC by raised
glucose also induces expression of
the permiability enhancing factor
VEGF in smooth muscle cells.
INCREASED FLUX THROUGh
HEXOSAMINE PATHWAY:
Shunting of the excess intra cellular
glucose into hexosamine pathway
might also cause several
menifestations of diabetic
complications. In this pathway ,
fructose-6-phosphate is diverted
from glycolyses to to provide
substrate for reaction thatrequires
UDP-N-acetylglucosamine , such as
proteglycan synthesis and the
formation of O-linked glycoproteins.
Inhibition of the rate limiting
enzymes in the coversion of the
glucose to glucosamine-
glutamine:fructose-6-
phosphateamido transferase (GFAT)
—blocks hyper glycemia-induced
increase in the transcription of TGF-
α, TGF-β1. This pathway plays also
important role in hyper glycemia
induced and fat induced insulin
resistance.the mechanism by which
increased flux through the
hexosamine pathway mediates
hyper glycemia-induced increase in
gene transcription is not certain ,
but the observation that binding
sites for the transcription factor Sp1
regulate hyper glycemia-induced
activation of PAI-1 promoter in
vascular smooth muscle cells
suggested that covalent
modification of the Sp1 by N-
acetylglucosamine might explain
link between the activation of the
hexosamine pathway and hyper
glycemia-induced changes in
transcription of the gene for PAI-1.
Activation of the hexosamine
pathway by hyper glysemia may
result in many changes in both gene
expression and protein function ,
which togather contribute to the
pathogenesisof the diabetic
complication.