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


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


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

3


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

4

http://medind.nic.in/iae/t07/i4/iaet07i4p243.pdf

http://en.wikipedia.org/wiki/Phenformin

http://en.wikipedia.org/wiki/World_Diabetes_Day

http://en.wikipedia.org/wiki/Insulin

http://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicine

http://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicine

http://en.wikipedia.org/wiki/Charles_Herbert_Best

http://en.wikipedia.org/wiki/Charles_Herbert_Best

http://en.wikipedia.org/wiki/Frederick_Grant_Banting

http://en.wikipedia.org/wiki/Ant

http://en.wikipedia.org/wiki/India

http://en.wikipedia.org/wiki/Sedentary

http://en.wikipedia.org/wiki/Obesity

http://en.wikipedia.org/wiki/Sushruta


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.

5


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

6


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

7


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.

8


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.

9


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

10


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

11


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

12


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.

13


Figure 5. Reactive Oxygen Intermediate Pathway Theory[8]

14


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


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


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.

17


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

18


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

19


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

20


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

21


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


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.

23


24


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.

25


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

http://cme.medscape.com/viewarticle/460902_2



http://www.diabetes.ca/about-diabetes/what/history/

diabetic microvascular complications

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