Diabetic Microvascular Complications
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Transcript of Diabetic Microvascular Complications
Elizabeth Joan Salim © FK Trisakti 07
TABLE OF CONTENTS
PREFACE…………………………………………………………………………………… 1
TABLE OF CONTENTS……………………………………………………………………. 2
CHAPTER I : INTRODUCTION…………………………………………………………... 3
A. Issue Background……………………………………………………………………. 3
B. History……………………………………………………………………………….. 4
C. Limitation of Problem……………………………………………………………….. 6
CHAPTER II : THE THEORIES ABOUT CHRONIC COMPLICATIONS OF DM……. 7
A. The Aldose Reductase Pathway…………………………………………………….. 9
B. The Advanced Glycation End-Product (AGE) Pathway………………………….. 10
C. The Protein Kinase C Pathway…………………………………………………….. 11
D. Reactive Oxygen Intermediate Theory…………………………………………….. 13
CHAPTER III : THE MICROVASCULAR COMPLICATIONS OF DM…...…………. 16
A. Diabetic Retinopathy………………………………………………………………. 16
B. Diabetic Neuropathy……………………………………………………………….. 18
C. Diabetic Nephropathy……………………………………………………………… 20
CHAPTER IV : PATHOPHYSIOLOGY OF DIABETIC MICROVASCULAR
COMPLICATIONS……………………………………………………………………….. 22
CONCLUSION……………………………………………………………………………. 26
REFERENCES…………………………………………………………………………….. 271
Elizabeth Joan Salim © FK Trisakti 07
CHAPTER I
INTRODUCTION
A. ISSUE BACKGROUND
The term diabetes mellitus describes a metabolic disorder of multiple etiology
characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and
protein metabolism resulting from defects in insulin secretion, insulin action, or both. [1]
Recent estimates indicate there were 171 million people in the world with diabetes
in the year 2000 and this is projected to increase to 366 million by 2030. [2] The American
Diabetes Association (ADA) estimated the national costs of diabetes in the USA for 2002
to be 132 billion USD, increasing to 192 billion USD in 2020 [1]
Diabetes Mellitus becoming a major health problem in Indonesia; it has become
evident in the last two decades as the result of dramatic changes in the Indonesian
population lifestyle. WHO predicted that 8,4 million people in Indonesia with diabetes in
the year 2000 will increase to 21,3 million by 2030. [2]
The effects of diabetes mellitus include long-term damage, dysfunction and
failure of various organs. In its most severe forms, ketoacidosis or a non-ketotic
hyperosmolar state may develop and lead to stupor, coma and, in absence of effective
treatment, death.
WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complication. 2006
2 Wild S, Roglic G, Green A, Sicree R, King H. Global Prevalence of Diabetes: Estimates for the year 2000 and
projections for 2030. Diabetes Care. 2004; 27: 1047-1053
2
Elizabeth Joan Salim © FK Trisakti 07
The long-term effects of diabetes mellitus include progressive development of the
specific complications of retinopathy with potential blindness, nephropathy that may lead
to renal failure, and/or neuropathy with risk of foot ulcers, amputation. People with
diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular
disease.
Because of the warning from WHO and the dangerous effects of its complications, I
choose this issue to be my title. It is very interesting issues nowadays, because this
disease is very common in our life and has many challenges for us to prevent this disease
and complication in our environment.
B. HISTORY
Diabetes Mellitus has apparently plagued man for a very long time. The writings from
the earliest civilisations (Asia Minor, China, Egypt, and India) refer to boils and infections,
excessive thirst, loss of weight, and the passing of large quantities of honey-sweet urine which
often drew ants and flies.
There is a reference to the diabetic condition in the Ebers Papyrus (dating back to
1500 BC and discovered by the Egyptologist Georg Ebers in Thebes in 1872). This
recommended that those afflicted with the malady should go on a diet of beer, fruits, grains,
and honey; which diet was reputed to stifle the excessive urination. Indian writings from the
same era attributed the disease to overindulgence in food and drink. Other later Egyptian
medical papyri [Hearst papyrus and Berlin papyrus] also give recipes against polyuria.
The first known clinical description of diabetes appears to have been made by Aulus
Cornelius Celsus (c.30 BC – 50 AD); but it was Aretaeus of Cappadocia (2nd century AD)
who provided a detailed and accurate account and introduced the name "diabetes". The term
diabetes was derived from the Greek verb diabaínein, meant "to stride, walk” and its
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derivative diabētēs meant "siphon." The sense "siphon" gave rise to the use of diabētēs as the
name for a disease involving the discharge of excessive amounts of urine. Diabetes is first
recorded in English, in the form diabetes, in a medical text written around 1425. In 1675,
Thomas Willis added the word mellitus, from the Latin meaning "honey", a reference to the
sweet taste of the urine. [3]
Sushruta (6th century BCE) identified diabetes and classified it as Medhumeha. He
further identified it with obesity and sedentary lifestyle, advising exercises to help "cure" it.
The ancient Indians tested for diabetes by observing whether ants were attracted to a person's
urine, and called the ailment "sweet urine disease" (Madhumeha).[4]
In 1869 Paul Langerhans, announces in a dissertation that the pancreas contains
contains two systems of cells. One set secretes the normal pancreatic juice, the function of the
other was unknown. Several years later, these cells are identified as the 'islets of Langerhans'.
In summer 1921, Insulin is 'discovered' by Sir Frederick Grant Banting and Charles
Herbert Best. This led to the availability of an effective treatment—insulin injections—and
the first patient was treated in 1922. For this, Banting received the Nobel Prize in Physiology
or Medicine in 1923. Insulin production and therapy rapidly spread around the world. Banting
is honored by World Diabetes Day which is held on his birthday, November 14.
In 1940s the link is made between diabetes and long-term complications (kidney and
eye disease), and in 1955 oral drugs are introduced to help lower blood glucose levels. The
first anti-diabetic drugs is sulfonylureas. Then another anti diabetic oral drugs introduced
later, for examples biguanides. The initial phenformin was withdrawn worldwide due to its
potential for sometimes fatal lactic acidosis.
3 Canadian Diabetes Association. The history of diabetes. 2006.
4 Wivedi, Girish & Dwivedi, Shridhar . History of Medicine: Sushruta. 2007
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Elizabeth Joan Salim © FK Trisakti 07
C. LIMITATION OF PROBLEMS
To clarify the scope of discussion, the issues discussed is limited to Micropathy in Diabetes
Mellitus. Author makes this limitation because there are many complications of Diabetes
Mellitus, and this paper will discuss too many things if all of the complication is explain. If
that happens, I am afraid this paper will losses its focus and discusses something less
important.
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Elizabeth Joan Salim © FK Trisakti 07
CHAPTER II
THE THEORIES ABOUT CHRONIC COMPLICATIONS OF DM
The long-term complications of DM are a major health problem. All types of DM are
associated with the development of diabetes spesific microvascular pathology in the retina,
glomeruli, and peripheral nerves. Diabetes is also associated with accelerated atherosclerotic
macrovascular disease affecting arteries that supply the heart, brain and lower extremities.
Diabetes is the leading cause of blindness in the people aged 24-74 and the leading
cause of end-stage renal disease[5]. Diabetes increases the risk of cardiovascular complications
2 to 6 times[6]
The main risk factors development of long-term for the complications[6]:
Duration of DM
The chronic complications of diabetes are related to the length of time the patient has
had the disease. The longer patients had DM, the complications is more common.
Blood pressure (hypertension)
The complications is also related with hypertension, especially for cardiovascular
complications.
Obesity and hyperlipidemia
It is called obesity if the weight greater than 120% of desirable body weight or BMI
more than 30 kg/m2. Some researches informed that 90% of patients who develop type
2 diabetes mellitus are obese.
5 The American Diabetes Association. Retinopathy in Diabetes. Diabetes Care 2004; 27; S84-87
6 Nathan DM. Long Term Complications of Diabetes Mellitus. N Engl J Med. 1993; 328: 1676-1685
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Elizabeth Joan Salim © FK Trisakti 07
Uncontrolled diabetes
Some research informed that there is a reduction of microvascular complications in
patients with diabetes by intensively controlling serum glucose levels to achieve an
HbA1c concentration of < 8%.
The short-term prospective studies have shown that glycemic control reduces
microalbuminuria and improves nerve conduction velocities in patients with type 2
diabetes.
There are a number of theories, each with adherents as well as supporting data. These
include[7]:
The aldose reductase pathway theory
The advanced glycation end-product (AGE) pathway theory
The diacyl-glycerol stimulated protein kinase C (PKC) pathway theory
The reactive oxygen intermediate (ROI) theory (stress oxidative pathway)
Fig 1. Overall Categorization of Signaling Pathways Involved in Diabetic Complications
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THE ALDOSE REDUCTASE PATHWAY[7,8,9]
Aldose reductase is an enzyme strategically placed in tissues whose intracellular
glucose levels are not regulated by insulin and tissue glucose rises with blood glucose. Such
tissues include peripheral nerve and the ocular lens. Hyperglycemia thus results in
intracellular glucose elevation in such tissues. Intracellular glucose is converted to sorbitol,
which can be further metabolized to fructose. Neither sorbitol nor fructose can move out of
the cells with the same facility that glucose entered.
The first reaction (aldose reductase) consumes NADH and leads to an accumulation of
NAD+. The second reaction (sorbitol dehydrogenase) generates NADPH, consuming NADP+
and leading to an imbalance of NADH/NADPH. In the lens, there is no sorbitol
dehydrogenase, so there is accumulation of sorbitol creating an osmotic gradient leading to
increase in water, lens swelling, and a change in solubility (precipitation) of lens proteins with
cataract formation. In other tissues such as peripheral nerve, tissue swelling is not felt to be
the major contributor to the tissue dysfunction, but rather depletion of vital molecules
required for normal maintenance of function of the axons.
Over time, the loss of function of the axons leads to a length-dependent loss of
function or a stocking glove pattern of symmetric peripheral polyneuropathy. The small, less
well myelinated fibers appear most vulnerable, leading to sensory defects prior to motor
defects. The metabolically compromised axons are also more susceptible to other insults such
as compression and ischemia leading to the mononeuropathies, to which diabetic subjects are
also at increased risk.
7 Sudoyo AW. Buku Ajar Ilmu Penyakit Dalam Jilid III. Jakarta ;2006.p. 1884-8
8 Sheetz MJ, King GL. JAMA. 2002;288:2579-2588
9 Malik RA. The Common Pathophysiology of Diabetic Microvascular Complication.
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Elizabeth Joan Salim © FK Trisakti 07
The proponents of this as a major pathway for the development of diabetic
complications have been supported by animal data where interruption of this pathway
improves nerve conduction velocities and induces axonal regeneration in peripheral nerves. In
animal studies, microalbuminuria is also reduced.
Figure 2. Aldose Reductase Pathway Theory [8]
THE ADVANCED GLYCATION END-PRODUCT (AGE) PATHWAY[7,8,9]
During the normal course of aging, proteins become irreversibly modified by sugars in
a process known as the Maillard reaction, leading to tissue "browning." The AGE theory
began as an attempt to explain diabetic complications as a form of accelerated aging that was
brought about by covalent modification and crosslinking of proteins by glucose. The products
of the nonenzymatic glycation of proteins are varied in chemical structure and, as a group,
have been termed AGEs. Formation of AGE may damage cells by impairing the function of a
wide range of proteins, including modifications of extracellular structural proteins such as
collagen and intracellular proteins.
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Elizabeth Joan Salim © FK Trisakti 07
AGEs can also alter cellular function by binding to receptors, such as the receptor for
AGEs (RAGE), a transmembrane receptor that is a member of the immunoglobulin
superfamily of proteins. Binding of AGE-modified proteins to RAGE produces a cascade of
cellular signaling events, such as activation of mitogen-activated protein (MAP) kinase or
PKC, which can lead to cellular dysfunction. Other receptors, such as the macrophage
scavenger receptor, P60, P90, and galectin-3, have also been reported to bind AGEs.
Figure 3. Advanced Glycation Endproduct (AGE) Pathway Theory[8]
PROTEIN KINASE C PATHWAY THEORY[7,8,9]
Diacylglycerol (DAG) and PKC are critical intracellular signaling molecules that can
regulate many vascular functions, including permeability, vasodilator release, endothelial
activation, and growth factor signaling. Receptor-mediated physiological activation of PKC
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Elizabeth Joan Salim © FK Trisakti 07
occurs through the activation of phospholipase C, which leads to increases in Ca+2 and DAG
levels, which in turn activate PKC.
Pathological activation of PKC can occur in diabetes. Elevated glucose levels will
increase glycolytic pathway flux in the diabetic state and lead to an elevation in the levels of
intracellular glyceraldehyde-3-phosphate. Increased levels of this intermediate can stimulate
increases in the de novo synthesis of DAG through glycerol-3-phosphate. These chronically
elevated levels of DAG can, in turn, activate PKC. In addition, DAG-PKC can indirectly be
activated by ROI and AGE (described below).
Levels of DAG and PKC activation are increased in various tissues of animals with
diabetes. Activation of PKC in blood vessels of the retina, kidney, and nerves can produce
vascular damage that includes increased permeability, nitric oxide dysregulation, increased
leukocyte adhesion, and alterations in blood flow. Activation of PKC may also be involved in
the induction of growth factor expression (VEGF, TGF- ) and signaling (VEGF, ET-1). In
addition, PKC activation can also impact other signaling pathways such as those using MAP
kinase or nuclear transcription factor.
Protein kinase C is a family of enzymes composed of at least 12 members. Not all
isozymes are expressed at detectable levels in all cell types. The PKC- isoforms are activated
in the aorta and heart of diabetic rats, while PKC- , PKC- , and PKC- are all activated in the
retinas of rats with diabetes. In the glomeruli of rats with diabetes, the , , , , and isoforms
of PKC have all been shown to be activated. A PKC inhibitor (ruboxistaurin mesylate) with
high affinity for the 1 and 2 isoforms has been shown to block many vascular abnormalities
in endothelial cells and contractile cells from the retina, arteries, and renal glomeruli. In
animals with diabetes, ruboxistaurin mesylate has been shown to prevent or reverse many
early hemodynamic changes observed in diabetic retinopathy, nephropathy, and even
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Elizabeth Joan Salim © FK Trisakti 07
neuropathy. Chronic oral treatment with this PKC- isoform inhibitor in genetically diabetic
(db/db) mice prevented mesangial expansion and glomerular dysfunction. Ruboxistaurin
mesylate is currently in clinical trials for diabetic retinopathy and neuropathy.
Figure 4. Protein Kinase C Theory[8]
REACTIVE OXYGEN INTERMEDIATE THEORY[7,8,9]
One of the oldest theories of diabetic complications is that hyperglycemia can increase
oxidative stress through both enzymatic and nonenzymatic processes. The metabolism of
glucose through the glycolytic pathway and the tricarboxylic acid cycle produces reducing
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equivalents that are used to drive the synthesis of adenosine triphosphate via oxidative
phosphorylation in the mitochondria.
Byproducts of mitochondrial oxidative phosphorylation include free radicals such as
superoxide anion, and their generation is increased by high glucose levels. Glucose
autoxidation also creates free radicals that can damage cellular proteins as well as
mitochondrial DNA. Increased oxidant stress reduces nitric oxide levels, damages cellular
proteins, and promotes leukocyte adhesion to the endothelium while inhibiting its barrier
function. Diabetic mice overexpressing Cu+2/Zn+2 superoxide dismutase did not exhibit as
much mesangial expansion as did wild-type diabetic mice.
Evidence of increased oxidative stress in patients with diabetes exists, but is not
overwhelmingly persuasive. Levels of antioxidants such as reduced glutathione, vitamin C,
and vitamin E have been reported to be decreased in patients with diabetes, although other
researchers have not been able to identify clear-cut decreases. However, levels of some
markers of oxidative stress, such as oxidized low-density lipoprotein cholesterol and urinary
isoprostanes, appear to be increased in patients with diabetes.
Inhibition of oxidative stress through the delivery of various antioxidants has shown
some success at blocking the microvascular complications of diabetes in various animal
models. Vitamin E at high doses (>1000 IU/d) and lipoic acid have improved early
hemodynamic changes in the kidney, retina, and peripheral nerves. However, results of studies
using antioxidants in humans for the prevention of diabetic microvascular complications have
generally been negative.
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Figure 5. Reactive Oxygen Intermediate Pathway Theory[8]
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CHAPTER III
THE MICROVASCULAR COMPLICATIONS OF DM
A. DIABETIC RETINOPATHY[5,6,7]
Diabetic retinopathy occurs in three fourths of all persons with diabetes after more
than 15 years of the disease. It is the most common cause of blindness in the industrialized
world in persons between the ages of 25 and 74 years. Diabetic retinopathy is diagnosed
by the appearance of retinal vascular lesions of increasing severity, culminating in the
growth of new vessels (proliferative diabetic retinopathy [DR]). A loss of vision can result
through either a nonclearing vitreous hemorrhage or through fibrosis causing traction
retinal detachment. In addition, retinal vessels can leak at any stage of retinopathy and
produce macular edema with potentially irreversible loss of central vision.
Early in the course of diabetes, hyperglycemia is responsible for many of the
functional retinal vascular changes, including impairment of retinal blood flow, increased
leukocyte and monocyte adhesion in the retinal microvessels, and capillary closure
resulting in localized hypoxia. In addition, retinal neuronal function, as assessed by
electroretinography, may also exhibit abnormalities early in the course of the disease.
One of the earliest and most specific retinal changes induced by hyperglycemia is
the death of microvascular contractile cells (pericytes). The death of pericytes and the loss
of vascular intercellular contacts may predispose to endothelial cell proliferation,
facilitating the development of microaneurysms. Alterations in hemodynamics and
vascular autoregulation that are characteristic of the diabetic state can produce venous
dilation and beading as well as intraretinal microvascular abnormalities that represent
dilated small vessels. Impairments of vascular cell-to-cell contacts and altered barrier 15
Elizabeth Joan Salim © FK Trisakti 07
permeability function can lead to small intraretinal hemorrhages and fluid leakage. When
water is reabsorbed, the plasma lipids and proteins precipitate as hard exudates.
When enough vascular damage has impaired the flow of blood to whole segments
of the retina, retinal ischemia occurs. It is characterized by poor perfusion visible on
fluorescein angiograms and by the appearance of soft exudates. In areas with sufficient
retinal ischemia, production of vascular growth factors increases. Several growth factors
have been hypothesized to play a role in the development of the neovascular changes of
diabetic retinopathy, including insulinlike growth factor 1, basic fibroblast growth factor,
hepatocyte growth factor, and vascular endothelial growth factor (VEGF). However,
VEGF has been the most thoroughly studied in terms of its role in the development of
proliferative DR and is clearly regulated by hypoxia. Levels of VEGF increase
dramatically in the aqueous and vitreous fluids of people with proliferative DR and other
ocular neovascular syndromes. When proliferative DR is successfully treated by laser
photocoagulation, VEGF levels decrease accordingly. Recently, retinal pigment
epithelium-derived factor has been reported to inhibit neovascularization in the normal
state. Its expression may be reduced by hypoxia, thereby permitting neovascularization
late in the course of diabetic retinopathy.
Excessive retinal neovascularization, vitreous hemorrhage, and increased levels
of VEGF can lead to fibrosis and retinal detachment. Application of panretinal laser
photocoagulation has dramatically reduced the rate of blindness in persons with diabetic
retinopathy. The effectiveness of panretinal laser photocoagulation is attributed to the
reduced metabolic requirements of the retina by the destruction of up to 75% of the
nonmacular region and facilitation of oxygen diffusion from the choroid circulation.
Adverse effects of panretinal laser therapy include decreased peripheral and night vision
and other derangements of vision.16
Elizabeth Joan Salim © FK Trisakti 07
B. DIABETIC NEUROPATHY [6,7]
About half of all people with diabetes have some degree of diabetic neuropathy,
which can present as either a polyneuropathy or a mononeuropathy. This description will
focus on changes in peripheral sensation in myelinated and nonmyelinated nerves.
Diabetic peripheral neuropathy can produce positive symptoms such as those assessed by
the Total Symptom Score-6, including pain, burning, and allodynia, as well as eventually
lead to negative symptoms (ie, loss of sensation) as the disease progresses.
The most common form of diabetic neuropathy is a polyneuropathy characterized
by the loss of peripheral sensation, which, when coupled with impaired microvascular and
macrovascular function in the periphery, can contribute to nonhealing ulcers, the leading
cause of nontraumatic amputation in the United States. Distal symmetric sensorimotor
polyneuropathy is manifested clinically by paresthesia, dysesthesia, pain, impaired
reflexes, and/or decreased vibratory sensation.
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Elizabeth Joan Salim © FK Trisakti 07
Anatomically, diabetic peripheral polyneuropathy is characterized by a thickening
of axons (sometimes attributed to increased axonal intracellular fluid early in the course of
diabetes), a decrease in microfilaments, and capillary narrowing involving small
myelinated or nonmyelinated C-fibers. As the syndrome progresses, there is axonal loss.
Diabetic neuropathy is thought to occur both from direct hyperglycemia-induced damage
to the nerve parenchyma and from neuronal ischemia brought about indirectly by
hyperglycemia-induced decreases in neurovascular flow. Abnormalities of microvessels,
such as endothelial cell activation and proliferation, pericyte degeneration, basement
membrane thickening, and monocyte adhesion, have all been described.
Glucose-induced damage to the nerve parenchyma is hypothesized to occur
through alteration in the activity of key axonal enzymes (eg, a reduction in neuronal
Na+/K+-adenosine triphosphatase activity) and reduction in levels of neurotrophic factors
leading to neuronal loss through activation of apoptosis. Endoneurial edema, as assessed
by magnetic resonance spectroscopy, may also contribute to neuronal damage by
increasing endoneurial pressure, thereby causing capillary closure and subsequent nerve
ischemia, which is a stimulus for VEGF production. Increased nerve VEGF levels have
been reported in experimental diabetic neuropathy, although its pathophysiological role
has not yet been definitively established.
Impairment of nerve blood flow may result from a reduction in endothelial-
dependent and nitric oxide–dependent vasorelaxation in the endoneurium or from the
increased expression or action of vasoconstrictors such as endothelin 1 (ET-1). In
preclinical models of diabetic neuropathy, decreases in neuronal function were prevented
by oxygen supplementation and by the administration of vasodilatory agents. Animal
models of diabetes support the importance of hyperglycemia as a causative factor in
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Elizabeth Joan Salim © FK Trisakti 07
diabetic neuropathy and support the role of blood glucose control in preventing or
correcting derangements in endoneurial blood flow and nerve conduction.
DIABETIC NEPHROPATHY [6,7,9,10]
Diabetic nephropathy is a major cause of end-stage renal disease. It is first
characterized by glomerular hemodynamic abnormalities that result in glomerular
hyperfiltration, leading to glomerular damage as evidenced by microalbuminuria. As
glomerular function continues to decline, overt proteinuria, decreased glomerular filtration
rate, and end-stage renal failure will result.
Hyperglycemia-induced glomerular hyperfiltration is the result of the dilation of
the afferent glomerular arteriole to a greater extent than dilation of the efferent glomerular
arteriole. This increases the glomerular hydrostatic pressure, forcing an increase in the
passage of fluid through the glomerular filtration apparatus. These hemodynamic
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Elizabeth Joan Salim © FK Trisakti 07
abnormalities are thought to be mediated by an increase in the production of vasodilatory
prostanoids and nitric oxide.
The dysfunction of the glomerular filtration apparatus is manifested by
microalbuminuria and has been attributed to changes in the synthesis and catabolism of
various glomerular basement membrane macromolecules, such as collagen and
proteoglycans, leading to an increase in glomerular basement membrane thickness.
Another possible mechanism to explain the increase in permeability of the glomerulus is
the increase in renal VEGF levels that are observed in preclinical models of diabetes, since
VEGF is both an angiogenic and a permeability factor.
10 The American Diabetes Association. Nephropathy in Diabetes. Diabetes Care 2004; 27; S79-83
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CHAPTER IV
PATHOPHYSIOLOGY OF DIABETIC MICROVASCULAR
COMPLICATIONS
PATHOPHYSIOLOGY (OVERALL) [9,11]
The metabolic abnormalities of inadequately treated relative or absolute insulin
deficiency will in the course of years or decades lead to extensive irreversible changes in the
organism. Hyperglycemia plays a central role in this.
Glucose is reduced to sorbitol in cells that contain the enzyme aldosereductase. This
hexahydric alcohol cannot pass across the cell membrane, as a result of which its cellular
concentration increases and the cell swells. Due to an accumulation of sorbitol in the lens of
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Elizabeth Joan Salim © FK Trisakti 07
the eye, water is incorporated, impairing lenticular transparency (clouding of the lens
[cataract]). Accumulation of sorbitol in the Schwann cells and neurons reduces nerve
conduction (polyneuropathy), affecting mainly the autonomic nervous system, reflexes, and
sensory functions. To avoid swelling, the cells compensate by giving off myoinositol which
then, however, will not be available for other functions.
Cells that do not take up glucose in sufficient amounts will shrink as a result of
extracellular hyperosmolarity. The functions of lymphocytes that have shrunk are impaired
(e.g., the formation of superoxides, which are important for immune defense). Diabetics are
thus more prone to infection, for example, of the skin (boils) or kidney (pyelonephritis).
These infections, in turn, increase the demand for insulin, because they lead to an increased
release of insulin-antagonistic hormones.
Hyperglycemia promotes the formation of sugar containing plasma proteins such as
fibrinogen, haptoglobin, α2-macroglobulin as well as clotting factors V–VIII. In this way
clotting tendency and blood viscosity may be increased and thus the risk of thrombosis
raised.
By binding of glucose to free amino-groups of proteins and a subsequent, not fully
understood, irreversible Amadori reaction, advanced glycation end products (AGEs) are
formed. They also occur in increasing amounts in the elderly. A protein network can be
formed through the formation of pentosin. AGEs bind to respective receptors of the cell
membrane and can thus promote the deposition of collagen in the basement membranes of the
blood vessels. The formation of connective tissue is in part stimulated via transforming
growth factor β (TGF-β).
9 Malik RA. The Common Pathophysiology of Diabetic Microvascular Complication.
11 Silbernagl S, Lang F. Color Atlas of Pathophysiology. New York : Thieme; 2000. p. 300-301
22
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glomerulosclerosis on nephropathy diabetic
Additionally, however, the collagen fibers can be changed by glycosylation. Both
changes produce thickening of the basement membranes with reduced permeability and
luminal narrowing (microangiopathy). Changes occur in the retina, also as a result of
microangiopathies, that ultimately may lead to blindness (retinopathy). In the kidney
glomerulosclerosis (Kimmelstiel– Wilson) develops, which can result in proteinuria, reduced
glomerular filtration rate due to a loss of glomeruli, hypertension, and renal failure. Because
of the high amino acid concentration in plasma, hyperfiltration takes place in the remaining
intact glomeruli, which as a result are also damaged.
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CHAPTER V
CONCLUSION
Several predominant well-researched theories have been proposed to explain how
hyperglycemia can produce the neural and vascular derangements that are hallmarks of
diabetes. These theories can be separated into those that emphasize the toxic effects of
hyperglycemia and its pathophysiological derivatives (such as oxidants, hyperosmolarity, or
glycation products) on tissues directly and those that ascribe pathophysiological importance to
a sustained alteration in cell signaling pathways (such as changes in phospholipids or kinases)
induced by the products of glucose metabolism.
People with diabetes have an increased risk of developing microvascular
complications, diabetic retinopathy, diabetic nephropathy and diabetic neuropathy, which, if
undetected or left untreated, can have a devastating impact on quality of life and place a
significant burden on health care costs. In addition, diabetic microvascular complications can
reduce life expectancy. The strongest risk factors are glycemic control and diabetes duration;
however, other modifiable risk factors such as hypertension, hyperlipidaemia and smoking,
and unmodifiable risk factors including age at onset of diabetes and genetic factors may all
play a part.
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REFERENCES
1. WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and its
Complication. 2006
2. Wild S, Roglic G, Green A, Sicree R, King H. Global Prevalence of Diabetes: Estimates
for the year 2000 and projections for 2030. Diabetes Care. 2004; 27: 1047-1053
3. Canadian Diabetes Association. The history of diabetes. 2006. Available at:
http://www.diabetes.ca/about-diabetes/what/history/
4. Wivedi, Girish & Dwivedi, Shridhar . History of Medicine: Sushruta – the Clinician –
Teacher par Excellence. 2007.
5. The American Diabetes Association. Retinopathy in Diabetes. Diabetes Care 2004; 27;
S84-87
6. Nathan DM. Long Term Complications of Diabetes Mellitus. N Engl J Med. 1993; 328:
1676-1685
7. Waspadji S. Komplikasi Kronik Diabetes. In: Sudoyo AW. Buku Ajar Ilmu Penyakit
Dalam Jilid III. Jakarta ;2006.p. 1884-8
8. Sheetz MJ, King GL. Molecular Understanding of Hyperglycemia's Adverse Effects for
Diabetic Complications. JAMA. 2002;288:2579-2588
9. Malik RA. The Common Pathophysiology of Diabetic Microvascular Complication.
Available at : http://cme.medscape.com/viewarticle/460902_2
10. The American Diabetes Association. Nephropathy in Diabetes. Diabetes Care 2004; 27;
S79-83
11. Silbernagl S, Lang F. Color Atlas of Pathophysiology. New York : Thieme; 2000. p. 300-
301
26