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
A. Diabetic Retinopathy………………………………………………………………. 16
B. Diabetic Neuropathy……………………………………………………………….. 18
C. Diabetic Nephropathy……………………………………………………………… 20
COMPLICATIONS……………………………………………………………………….. 22
CONCLUSION……………………………………………………………………………. 26
REFERENCES…………………………………………………………………………….. 27
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Elizabeth Joan Salim © FK Trisakti 07
CHAPTER I
INTRODUCTION
A. ISSUE BACKGROUND
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
[2]
in the year 2000 and this is projected to increase to 366 million by 2030. The American
Diabetes Association (ADA) estimated the national costs of diabetes in the USA for 2002
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
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
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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
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
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
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
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
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
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
3
Canadian Diabetes Association. The history of diabetes. 2006.
4
Wivedi, Girish & Dwivedi, Shridhar . History of Medicine: Sushruta. 2007
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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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CHAPTER II
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]
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.
complications.
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
6
Nathan DM. Long Term Complications of Diabetes Mellitus. N Engl J Med. 1993; 328: 1676-1685
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Uncontrolled diabetes
The short-term prospective studies have shown that glycemic control reduces
diabetes.
There are a number of theories, each with adherents as well as supporting data. These
include[7]:
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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
which can be further metabolized to fructose. Neither sorbitol nor fructose can move out of
The first reaction (aldose reductase) consumes NADH and leads to an accumulation of
NAD+. The second reaction (sorbitol dehydrogenase) generates NADPH, consuming NADP +
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
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
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
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Malik RA. The Common Pathophysiology of Diabetic Microvascular Complication.
complications have been supported by animal data where interruption of this pathway
improves nerve conduction velocities and induces axonal regeneration in peripheral nerves. In
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
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AGEs can also alter cellular function by binding to receptors, such as the receptor for
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.
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Diacylglycerol (DAG) and PKC are critical intracellular signaling molecules that can
occurs through the activation of phospholipase C, which leads to increases in Ca+2 and DAG
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
elevated levels of DAG can, in turn, activate PKC. In addition, DAG-PKC can indirectly be
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
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
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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
neuropathy. Chronic oral treatment with this PKC- isoform inhibitor in genetically diabetic
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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
equivalents that are used to drive the synthesis of adenosine triphosphate via oxidative
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
Evidence of increased oxidative stress in patients with diabetes exists, but is not
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
Inhibition of oxidative stress through the delivery of various antioxidants has shown
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
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CHAPTER III
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
growth of new vessels (proliferative diabetic retinopathy [DR]). A loss of vision can result
retinal detachment. In addition, retinal vessels can leak at any stage of retinopathy and
functional retinal vascular changes, including impairment of retinal blood flow, increased
leukocyte and monocyte adhesion in the retinal microvessels, and capillary closure
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
vascular autoregulation that are characteristic of the diabetic state can produce venous
dilated small vessels. Impairments of vascular cell-to-cell contacts and altered barrier
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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
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
dramatically in the aqueous and vitreous fluids of people with proliferative DR and other
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
nonmacular region and facilitation of oxygen diffusion from the choroid circulation.
Adverse effects of panretinal laser therapy include decreased peripheral and night vision
About half of all people with diabetes have some degree of diabetic neuropathy,
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
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
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of axons (sometimes attributed to increased axonal intracellular fluid early in the course of
to the nerve parenchyma and from neuronal ischemia brought about indirectly by
through alteration in the activity of key axonal enzymes (eg, a reduction in neuronal
increasing endoneurial pressure, thereby causing capillary closure and subsequent nerve
ischemia, which is a stimulus for VEGF production. Increased nerve VEGF levels have
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diabetic neuropathy and support the role of blood glucose control in preventing or
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
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microalbuminuria and has been attributed to changes in the synthesis and catabolism of
the increase in renal VEGF levels that are observed in preclinical models of diabetes, since
10
The American Diabetes Association. Nephropathy in Diabetes. Diabetes Care 2004; 27; S79-83
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CHAPTER IV
COMPLICATIONS
deficiency will in the course of years or decades lead to extensive irreversible changes in the
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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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
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
clotting tendency and blood viscosity may be increased and thus the risk of thrombosis
raised.
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
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
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changes produce thickening of the basement membranes with reduced permeability and
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
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CHAPTER V
CONCLUSION
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
glycation products) on tissues directly and those that ascribe pathophysiological importance to
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
Complication. 2006
for the year 2000 and projections for 2030. Diabetes Care. 2004; 27: 1047-1053
http://www.diabetes.ca/about-diabetes/what/history/
4. Wivedi, Girish & Dwivedi, Shridhar . History of Medicine: Sushruta – the Clinician –
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
8. Sheetz MJ, King GL. Molecular Understanding of Hyperglycemia's Adverse Effects for
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
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