Diabetes has become a major health problem in the United States and throughout Diabetes is the seventh leading cause of death among Americans, and the sixth …
Mechanisms Causing Complications in Diabetes
Diabetes has become a major health problem in the United States and
throughout much of the world The prevalence of this chronic disease has
increased by 33 over the last decade in the United States Diabetes is the
seventh leading cause of death among Americans, and the sixth leading cause
of death from disease Although it is believed that diabetes is under-
reported as a condition leading to or causing death, 180,000 deaths are
reported each year as being caused by diabetes or its complications
Complications of diabetes include eye problems and blindness, heart
disease, stroke, neurological problems, amputation, and impotence 1, 5
Researchers who have been studying these complications now believe
that the mitochondria may play a primary role in the development of
diabetic complications All glucose is broken down to carbon dioxide and
water in the mitochondria by various complex mechanisms The high levels of
glucose seen in diabetics play a major role in developing complications
because of overactivity and/or alterations of certain mechanisms in
the
mitochondria 7
Researchers have been studying various biochemical pathways leading to
tissue damage due to high blood glucose levels One such pathway is the
Polyol pathway, where excess glucose is removed by the formation of
Sorbitol Another mechanism is the glycation of proteins by excess glucose
Both of these mechanisms will be discussed later in detail
As we understand the role that the various mechanisms play in the
development of diabetic complications, leading to newer and more effective
drugs Clinical studies show the effectiveness of these new drugs A few
studies evaluating the efficacy of these drugs will be discussed in this
paper
Complications of Diabetes:
Various body systems are affected in diabetes The following are some
of the most common complications seen in patients
Retinopathy:
Retinopathy is due to formation of tiny aneurysms on the walls of
blood vessels This results in dots or flame hemorrhages that reduce the
sharpness of vision Figure 1 shows a normal retina far left compared to
two other retinas with small microhemorrhages and a large hemorrhage 8,
10
Figure 1
Nephropathy:
Kidney failure or the inability to adequately excrete waste products
is a serious potential complication of long-standing diabetes Damage to
the tiny blood vessels in the nephrons can eventually lead to progressive
kidney failure, characterized by the excretion of protein and other
nutrients in the urine Diabetes also increases the kidneys vulnerability
to infections 8
Neuropathy:
Diabetes may result in peripheral or, in rare circumstances,
autonomic neuropathy It is thought to be due to nerve degeneration and
grossly diseased blood vessels supplying nerves Diabetes related disorders
of the nervous system cause a variety of symptoms including slowed
reflexes, sexual impotence, loss of sensation, intermittent episodes of
pain, and exacerbation of circulatory disorders 8
Cardiovascular Complications:
People with diabetes have a much higher rate of heart disease and
circulatory disorders than the general population High blood glucose is
believed to be responsible for cardiovascular abnormalities High blood
glucose affects the chemical structure of several blood components,
particularly erythrocytes,
and may play a role in the development of
arteriosclerosis Diabetes also damages the capillaries, causing a
thickening of the basement membranes, which results in poor circulation
10
Mechanisms Causing Diabetic Complications:
Researchers have hypothesized various biochemical pathways resulting
in various diabetic complications This paper will elaborate on two of the
many mechanisms
Accumulation of Sorbitol through the Polyol Pathway
Insulin deficiency, insulin resistance and/or increased hepatic
glucose output are common features of diabetes, which eventually lead to
hyperglycemia The body tries to get rid of this excess glucose
concentration by various pathways or mechanisms
One such pathway is the polyol pathway shown above that shunts
excess glucose away from the glycolysis Embden-Meyerhof pathway
Metabolism of glucose via the polyol pathway is considered to consist of
the two reactions below
Various pathways can further metabolize the product of this pathway
ie fructose In the first reaction glucose is reduced to sorbitol by
the enzyme aldose reductase AR,
with the cofactor NADPH serving as the
hydrogen donor This pathway is activated in hyperglycemia because the KM
of glucose for aldose reductase is high 70 mM In the second reaction,
sorbitol is oxidized to fructose by the enzyme sorbitol polyol
dehydrogenase, with the cofactor NAD serving as the hydrogen acceptor
12
Consequences of Increased Polyol Pathway
Several metabolic consequences of excess polyol pathway metabolism
have been implicated in the pathogenesis of functional and structural
changes associated with diabetic cataracts, neuropathy and other
complications
Sorbitol does not cross cell membranes, accumulates intracellularly
and produces osmotic stress Diabetic cataracts have been suspected of
occurring because of swelling of the lens epithelial cells caused by
accumulation of osmotically significant amounts of sorbitol Swelling of
the epithelial cells then initiates a cascade of metabolic imbalances
culminating in rupture of epithelial cells and formation of cataracts 7,
12
The increased oxidation of sorbitol to fructose in the polyol pathway
depletes the cofactor NAD,
which leads to an increased NADH/NAD ratio
Various metabolic imbalances could result from an increase in the ratio of
NADH/NAD An increased level of tissue triosephosphates can result in
nonenzymatic glycation Beta-oxidation of fatty acids is inhibited by an
increase in the intramitochondrial ratio of NADH/NAD Metabolic imbalances
also lead to impaired synthesis of myo-inositol, leading to decreased
activity of the Na/K ATPase activity in nerve cells This causes decreased
electrophysiological activity and nerve conduction velocity leading to
peripheral nerve complications 7
Possible Treatment Options
Prevention of NAD depletion and excess sorbitol production can be
lowered by administering aldose reductase inhibitors Nicotinamide helps
restore NAD levels The uses of such therapies have been found to be less
effective by various studies Fidarestat has been found to play a minor
role in altering the progress of diabetic peripheral neuropathy Drugs such
as Epalrestat have been shown to produce a minor decline in reactive
intermediate metabolites formation in erythrocytes 2, 4, 6
Glycation Glycosylation of Proteins:
Glycation or nonenzymatic glycosylation is a mechanism by which
glucose sugar in the blood and inside cells form chemical bonds to
proteins and DNA Glucose reacts initially with a lysyl side chain or N-
terminal amino group to form a Schiffs base, which undergoes an Amadori
rearrangement to from a fructosamine as shown below 7, 13
Methylglyoxal is a potent glycating agent Triosephosphates are the
major source of methylglyoxal formation The flux of formation and
concentration of methylglyoxal increases in hyperglycemia Glycation by
glucose, methylglyoxal, 3-DG and glyoxal form insoluble complexes referred
to as advanced glycation endproducts AGEs AGEs are implicated in
crosslinking of extracellular matrix proteins associated with abnormal
renal filtration and glomerulosclerosis AGEs formed on long-lived collagen
in the body, for example in blood vessels can trap more lipoproteins than
usual, increasing the chances of atheroma formation seen below 7
The chemical modifications of glycation and crosslinking can initiate
harmful inflammatory and autoimmune responses Glycation
has been found in
connective tissue collagen, arterial collagen, kidney glomerular basement
membrane, eye lens crystalline, nerve myelin proteins and in the
circulating low-density lipoprotein LDL of the blood 13
Possible Treatment Options
Several drugs and natural substances slow the formation of new
glycation-induced crosslinks Aminoguanidine Pimagedine has been studied
as an inhibitor of AGE crosslinks It has been shown to slow the
progression of diabetic kidney disease and retinopathy
Carnosine beta-alanyl-L-histidine, a dipeptide formed naturally in human
tissues, is also believed to inhibit the formation of crosslinks between
proteins that have been glycated 13
Newer drugs are being developed that break the advanced glycation
products The new thiazolium derivative, ALT-711 3-phenacyl-4,5-
dimethylthiazolium chloride, catalytically breaks established AGE
crosslinks between proteins Research has been done on ALT-711 to see its
effectiveness in improving arterial compliance caused due to a build up of
AGE crosslinks Current research shows that ALT-711 was effective in
improving
arterial compliance in aged humans due to vascular stiffening,
and it may prove to be a novel therapeutic approach for this abnormality,
which occurs in the elderly and in diabetic patients 3, 9, 11
Conclusion:
It is now clear that high blood glucose concentration seen in
diabetes acts on common initiating mechanisms to cause initial metabolic
and functional effects in various microcirculations and arterial walls of
the body This suggests that in efforts to understand how hyperglycemia
incites risks for disease in various tissues, the logical starting point is
to develop a detailed understanding of the sequential consequences of
continual activation of the initiating mechanisms in them
Knowing in detail the mechanisms described in this paper, it would be
beneficial to do further research in these areas in an attempt to develop
better drugs to inhibit or at least slow down the development of diabetic
complications Drugs such as ALT-711 that are currently undergoing phase II
clinical trials could be available for use in less than five years
Note: Pages exceeded 10 due to diagrams/pictures
References:
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7 http://wwwdiabetesselfmanagementcom
8 http://wwwianblumercom/complications
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