Ministry of Health of the Republ ic of Moldova [601877]

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Ministry of Health of the Republ ic of Moldova

Public Institution "N icolae Test emițanu"
State University of Medicine and Pharmacy of the Republic of Moldova

FACULTY OF MEDICINE II
Endocrinology department

DIPLOMA THESIS
MICROVACULAR COML ICATIONS OF DIABETES MELLITUS

Represented by :
Musa Said
VI y.Student: [anonimizat].1645

Scientific advisor :
Dr.Dumitru Harea
lecturer assistant

Chisinau 2015

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LIST OF ABBREVIATIONS
AR Aldose Reductase
ARs Aldose Reductase Inhibitors
ACEs Angiotensin converting enzyme inhibitors
CDC Center of disease control and prevention
CT Computed tomography
DCCT Diabetes Control &Complication trial
DM Diabetes mellitus
DM1 Diabetes mellitus type 1
DM2 Diabetes mellitus type 2
ESRD End Stage Renal Disease
ETGF Endothelial transforming growth factor
GBM Glomerular basement membrane
GFR Glomerular filtration rate
GIP Glucose dependent Insulin tropic Polypeptide
GIPR Glucose dependent Insulin tropic Polypeptide receptor
GLP -1 Glucagon Like Peptide
GLUT1 Glucose transporter type 1
GLUT4 Glucose transporter type 4
HbA1C Hemoglobin A1C
IDF International Diabetes Federation

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INSR Insulin Receptor Gene
MAP kinase Mitogen -Activated Protein Kinase
PDR Proliferative Diabetic Retinopathy
PDGF Platelet Derived Growth Factor
Pi3 Kinase phosphoinositide 3 -kinase
PKC Protein Kinase C
ROS Reactive oxygen species
SNPs Single Nucleotide Polymorphism
SP1 Specific Protein 1
UKPD United kingdom Prospective Diabetes study
US United states

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CONTENTS
ACKNOWLEDGMENTS –––––––––––– –––––––––– 6
ABSTRACT –––––––––––– –––––– ––––––––––- 7
INTRODUCTION –– –––- –––––– –––– ––––––– –––– 8
CHAPTER I REVIEW OF THE LITERATURE –––––––- –––––– 9
2.1Chronic complications of DM ––––––- ––- –––––––- –-9
2.1.1 General Pathophysiology –––––– ––- –––––––– 9
2.1.2 Microvascular Complications in DM ––––– –––- ––– 12
2.2 Diabetic R etinopathy –––––––––– ––––- –––––– 12
2.2.1 Signs & Symptoms –– ––––––– ––––– ––––– 12
2.2.2 Classification ––––––––––– –––––––––– 13
2.2.3 Diagnosis ––––––––––––– –––––––––- 14
2.2.4 Pathological mechanism ––––––– ––- ––––––– 14
2.2.5 Etiology ––––––––––––– ––– ––––––- 16
2.2.6 Epidemiology –––––––––––––– ––––––- 17
2.2.7 Prognosis ––––––––––––- ––––- ––––– 17
2.3 Diabetic Nephropathy ––––––––––- –– ––– ––––- 18
2.3.1 Diagnostic criteria and classification ––––––– –––- 18
2.3.2 pathology ––––––––––- –––––––– –––– 18
2.3.3Epidemiology –––––––––––– –––––– –––22
2.3.4Prognosis –––––––––––––––––––– –––24
2.4Diabetic Neuropathy ––––––- ––– –––––––- –––– -25
2.4.1 Signs & Symptoms ––––––––––––––––– –26
2.4.2 Diagnosis –––––––––––– –––––––––– -26
2.4.3 Pathological mechanism –––––– –––––––––– -26
2.4.4 Classification –––––––––––– –––––––– –28
2.4.5 Etiology ––––––––––––- –––––––––- –28
2.4.6 Epidemiology –––- ––––––– –––––––––- –29
2.4.7 Prognosis –––––––––––– ––––––––– –-30

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2.5 Management of Microvascular Complications –––––––- ––- 31
2.5.1 Management of DR –––– ––- –––––––––––– 31
2.5.2 Management of DN –––––––– –––––––––– 34
2.5.3 Management of DNr ––––––– ––––––––––– 39
2.6 Measures for prevention of Microvascular com plications ––––– 43
2.6.1 Prevention of DR –––––––– –– ––––––––– 43
2.6.2 Prevention of DN –––––––– ––– –––––––– 43
2.6.3 Prevention of DNr –––––––- –––– –––- –––– 44
CHAPTER II SUMMARY AND RECOMMENDATIONS –––– ––––- 45
CONCLUSION –––––––– ––––- ––––––– ––– ––––– 46
REFERENCES ––––––––––––––- –––––– ––––––- 47

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ACKNOWLEDGMENT

I would like to thank Dr. Assistant Dumitru Harea & principal Conf.Dr.L.Vudu
who gave me the golden opportunity to do this wonderful study on the topic “micro
vascular complications of diabetes mellitus II ”, and whose guidance and
encouragement all throughout their periodic assessment and ,specific corrections,
coupled with their rich knowledge and keen interest in the topic, I feel I have
accomplished this as a result of her support, guidance, flexibility and encourage ment .
I would like to deeply thank My Father ,Dr.Musa Fua d ,he was my constant
source of inspiration leading to the success of this study, and hopefully my future
ones as well . Finally, I would like to acknowledge the suppor t and encouragement
that I hav e
received from my wonderful Mother & wife; sisters and brother's in law, it has
truly been instrumental throughout my time as a university student and particularly
during my time as a graduate student. I am grateful to them for being there along the
way a nd appreciate all that they have Sacrificed for me during my pursuit of this
degree, thank -you.

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ABSTRACT
DM is a chronic, lifelong condition that affects the human body's ability to use
the energy found in food. There are three major ty pes of diabetes: DM1,DM2, and
GD. All types of DM have something in common. No rmally, the body breaks down
sugars and carbohydrates consumed into a special sugar called glucose. Glucose f uels
the cells in body. But cells need insulin, a hormone, in bloodstrea m in order to take
in the glucose and use it for energy. With DM, either a pure insulin deficient state or
an insulin resistant state may be encoun tered or a combination of both. Since the cells
can't take in the glucose, it builds up in blood. High levels of blood glucose can
damage the microvasculature in kidneys, heart, eyes, or nervous system. That's why if
left untreated – can eventually cause heart disease, stroke, kidney disease, blindness,
and nerve damage mostly to nerves in the feet [1,2] .

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INTRODUCTION
DM2 consists of an array of dysfunctions characterized by hyperglycemia and
resulting from the combination of resistance to insulin action, inadequate insulin
secretion, and excessive or inappropriate glucagon secretion. Poorly controlled DM2
is associated wi th an array of none -vascular and vascular comlications
(microvascular, macrovascular ).Microvascular complications of diabetes include
retinal, renal, and possibly neuropathic disease. Macrovascular complications include
coronary artery and peripheral vasc ular disease [3]. However, ma ny patients with
DM2 are ultimately treated with insulin. Because they retain the ability to secrete
some endogenous insulin, they are considered to require insulin but not to depend on
insulin. Nevertheless, given the potential for confusion due to classification based on
treatment rather than etiology, the older terms have been abandoned. Currently,
because of the epidemic of obesity and inactivity in children, DM2 is occurring at
younger and younger ages [4]. Although DM2 typically affects individuals older than
40 years, it has been diagnosed in children as young as 2 years of age who have a
family history of diabetes. In many communities, DM2 now outnumbers DM 1 among
children with newly diagn osed diabetes. DM is a chronic disease that requires long –
term medical attention t o limit the development of its devastating complications and
to manage them when they do occur. [5]
The aim
The aim of this thesis is study the pathophysiology of micro vascular
complications of DM , predisposing factors, management and prev entive measures to
both prevent or reduce DM associated complications .
The objectives
Objective of this thesis includes different points
 Study the General pathways explaining late complications .
 Study of Diabetic retinopathy .
 Study of Diabetic nephropathy.
 Study of diabetic neuropathy .

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 Study available Measures of prevention and there role in reduction or
prevention of Micro vascular complications.

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CHAPTER I REVIEW OF THE LI TRATURE
The review of literature consists of six parts, first the General pathological
mechanisms by which chronic complications of DM2 develop , while starting from
the second will be a full view of microvascular complications their clinical picture ,
etiology prognosis and treatments, fifth and sixth will discuss preve ntive measures .
2.1Chronic complications of DM2
2.1.1 General Pathophysiology of Micro vascular complications
Diabetic hyperglycemia causes a variety of pathologic changes in small
vessels, arteries, and peripheral nerves . Three major hypotheses about how
hyperglycemia causes diabetic complications have generated extensive data as well
as several clinical trials based on specific inhibitors of these pathways . These three
pathways ; activation of protein kinase C isoforms , increased formation of glucos e-
derived AGEs , and increased glucose flux through the AR pathway ,recently have
been shown to be consequences of a single common mechanism, hyperglycemia –
induced mitochondrial superoxide overproduction ROS. A fourth hypothesis about
how hyperglycemia ca uses diabetic complications has been formulated recently , in
which glucose is shunted into the hexosamine pathway [6]. Inhibition of the rate –
limiting enzyme in the conversion of glucose to glucosamine, glutamine:fructose -6-
phosphate amidotransferase, bloc ks hyperglycemia -induced increases in the
transcription of both TGFα and TGFβ1. This pathway has been shown previously to
play an important role in hyperglycemia -induced and fat -induced insulin
resistance.The mechanism by which increased flux through the hexosamine pathway
mediates hyperglycemia -induced increases in gene transcription is not known, but the
observation that Sp1 sites regulate hyperglycemia -induced activation of the PAI -1
promoter in vascular smooth muscle cells suggests that covalent modif ication of Sp1
by GlcNAc may explain the link between hexosamine pathway activation and
hyperglycemia -induced changes in gene transcription [7]. Virtually every RNA
polymerase II transcription factor examined has been found to be O -GlcNAcylated ,
and the gl ycosylated form of Sp1 seems to be more transcriptionally active than the

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deglycosylated form of the protein . A 4 -fold increase in Sp1 O -GlcNAcylation
caused by inhibition of the enzyme O -GlcNAc -β-N-acetylglucosaminidase resulted in
a reciprocal 30% decre ase in its level of serine/threonine phosphorylation, supporting
the concept that O -GlcNAcylation and phosphorylation compete to modify the same
sites on this protein . In the present study, we show that hyperglycemia -induced
mitochondrial superoxide overp roduction inhibits glyceraldehyde -3-phosphate
dehydrogenase (GAPDH) activity and activates the hexosamine pathway, presumably
by diverting the upstream metabolite fructose -6-phosphate from glycolysis to
glucosamine formation. Hyperglycemia -induced activati on of the hexosamine
pathway increases O -GlcNAcylation and decreases serine/threonine phosphorylation
of the transcription factor Sp1. Hyperglycemia -induced O -GlcNAcylation of Sp1 –
increased Sp1 transactivation and Sp1 -dependent expression of both TGFβ1 and PAI-
1 .
[8]. Chronic hyperglycemia is a major initiator of diabetic micro – and
cardiovascular complications, such as retinopathy, neuropathy and nephropathy.
Several hyperglycemia -induced mechanisms may induce vascular dysfunctions,
which include increas ed polyol pathway flux, altered cellular redox state, increased
formation of diacylglycerol (DAG) and the subsequent activation of protein kinase C
(PKC) isoforms and accelerated non -enzymatic formation of advanced glycated end
products[9]. It is likely th at each of these mechanisms may contribute to the known
pathophysiologic features of diabetic complications. Others and we have shown that
activation of the DAG -PKC pathway is associated with many vascular abnormalities
in the retinal, renal, neural and ca rdiovascular tissues in diabetes mellitus. DAG -PKC
pathway affects cardiovascular function in many ways, such as the regulation of
endothelial permeability, vasoconstriction, extracellular matrix (ECM)
synthesis/turnover, cell growth, angiogenesis, cytokin e activation and leucocyte
adhesion, to name a few. Increased DAG levels and PKC activity, especially alpha,
beta1/2 and delta isoforms in retina, aorta, heart, renal glomeruli and circulating
macrophages have been reported in diabetes[10]. Increased PKC a ctivation have been

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associated with changes in blood flow, basement membrane thickening, extracellular
matrix expansion, increases in vascular permeability, abnormal angiogenesis,
excessive apoptosis and changes in enzymatic activity alterations su ch as Na (+)-
K(+) -ATPase, cPLA , PI3Kinase and MAP kinase. Inhibition of PKC, especially the
beta1/2 isoform has been reported to prevent or normalize many vascular
abnormalities in the tissues described above[11]. Clinical studies have shown that
ruboxistaurin, a P KCbeta isoform selective inhibitor, normalize endothelial
dysfunction, renal glomerular filtration rate and prevented loss of visual acuity in
diabetic patients. Thus, PKC activation involving several isoforms is likely to be
responsible for some of the pa thologies in diabetic retinopathy, nephropathy and
cardiovascular disease. PKC isoform selective inhibitors are likely new therapeutics,
which can delay the onset or stop the progression of diabetic vascular disease with
very little side effects[12].
2.1.2 Microvascular Complications in DM2
This thesis will deal with the following complications :
Diabetic retinopathy , growth of friable and poor -quality new blood vessels in
the retina as well as macular edema (swelling of the macula), which can lead to
sever e vision loss or blindness. Retinal damage (from microangiopathy) makes it the
most common cause of blindness among non -elderly adults in the US[13] .
Diabetic nephropathy , damage to the kidney which can lead to chronic renal
failure, eventually requiring dialysis. Diabetes mellitus is the most common cause of
adult kidney failure in the developed world [14].
Diabetic neuropathy , abnormal and decreased sensation, usually in a 'glove
and stocking' distribution starting with the feet but potentially in other n erves, later
often fingers and hands. When combined with damaged blood vessels this can lead to
diabetic foot .Other forms of diabetic neuropathy may present as mononeuritis or
autonomic neuropathy. Diabetic amyotrophy is muscle weakness due to
neuropathy .[15]
2.2Diabetic retinopathy

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Diabetic retinopathy is the leading cause of new blindness in persons aged 25 –
74 years in the United States. The exact mechanism by which diabetes causes
retinopathy remains unclear, but several theories have been postulated t o explain the
typical course and h istory of the disease.
2.2.1 Signs and symptoms
In the initial stages of diabetic retinopathy, patients are generally
asymptomatic; in the more advanced stages of the disease, however, patients may
experience symptoms tha t include floaters, blurred vision, distortion, and progressive
visual acuity loss. Signs of diabetic retinopathy include the following :
 Microaneurysms: The earliest clinical sign of diabetic retinopathy; these occur
secondary to capillary wall outpouching due to pericyte loss; they appear as
small, red dots in the superficial retinal layers
 Dot and blot hemorrhages: Appear similar to microaneurysms if they are small;
they occur as microaneurysms rupture in the deeper layers of the retina, such as
the inner nuclear and outer plexiform layers
 Flame -shaped hemorrhages: Splinter hemorrhages that occur in the more
superficial nerve fiber layer
 Retinal edema and hard exudates: Caused by the breakdown of the blood -retina
barrier, allowing leakage of serum proteins, lipids, and protein from the vessels
 Cotton -wool spots: Nerve fiber layer infarctions from occlusion of precapillary
arterioles; they are frequently bordered by microaneurysms and vascular
hyperpermeability
 Venous loops and venous beading: Freque ntly occur adjacent to areas of
nonperfusion; they reflect increasing retinal ischemia, and their occurrence is
the most significant predictor of progression to proliferative diabetic
retinopathy (PDR .)
 Intraretinal microvascular abnormalities: Remodeled c apillary beds without
proliferative changes; can usually be found on the borders of the nonperfused
retina

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 Macular edema: Leading cause of visual impairment in patients with
diabetes [16,17,18,19,20]
2.2.2 Classification
Nonproliferative diabetic retinopat hy
Mild: Indicated by the presence of at least 1 microaneurysm
Moderate: Includes the presence of hemorrhages, microaneurysms, and hard
exudates . Severe (4 -2-1): Characterized by hemorrhages and microaneurysms in 4
quadrants, with venous beading in at lea st 2 quadrants and intraretinal microvascular
abnormalities in at least 1 quadrant
Proliferative diabetic retinopathy
Neovascularization: Hallmark of PDR
Preretinal hemorrhages: Appear as pockets of blood within the potential space
between the retina and t he posterior hyaloid face; as blood pools within this space,
the hemorrhages may appear boat shaped
Hemorrhage into the vitreous: May appear as a diffuse haze or as clumps of
blood clots within the gel
Fibrovascular tissue proliferation: Usually seen assoc iated with the neovascular
complex; may appear avascular when the vessels have already regressed
Traction retinal detachments: Usually appear tented up, immobile, and concave
Macular edema [21]
2.2.3 Diagnosis
Laboratory studies of HbA1c levels are important in the long -term follow -up
care of patients with diabetes and diabetic retinopathy . Imaging studies used in the
diagnosis of diabetic retinopathy include the following : Fluorescein angiography:
Microaneurysms appear as pinpoint, hyperfluorescent lesions i n early phases of the
angiogram and typically leak in the later phases of the test . Optical coherence
tomography scanning: Administered to determine the thickness of the retina and the
presence of swelling within the retina, as well as vitreomacular tract ion . B -scan
ultrasonography [21].

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2.2.4 pathological mechanism
The exact mechanism by which diabetes causes retinopathy remains unclear,
but several theories have been postulated to explain the typical co urse and history of
the disease. In NPDR , loss of retinal pericytes , increased retinal vascular
permeability, alterations in retinal blood flow, and abnormal retinal microvasculature
all of which lead to retinal ischemia. The appearance of neovascularization in
response to retinal hypoxemia is th e hallmark of PDR
Growth hormone
Growth hormone appears to play a causative role in the development and
progression of diabetic retinopathy. Diabetic retinopathy has been shown to be
reversible in women who had postpartum hemorrhagic necrosis of the pitu itary gland
(Sheehan syndrome). This led to the controversial practice of pituitary ablation to
treat or prevent diabetic retinopathy in the 1950s. This technique has since been
abandoned because of numerous systemic complications and the discovery of the
effectiveness of laser treatment [22].
Platelets and blood viscosity
The variety of hematologic abnormalities seen in diabetes, such as increased
erythrocyte aggregation, decreased red blood cell deformability, increased platelet
aggregation, and adhesion, predispose the patient to sluggish circulation, endothelial
damage, and focal capillary occlusion. This leads to retinal ischemia, which, in turn,
contributes to the development of diabetic retinopathy .
Aldose reductase and vasoproliferative factors
Hyperg lycemia shunts excess glucose into the aldose reductase pathway in
certain tissues, which converts sugars into alcohol through the sorbitol pathway .
Intramural pericytes of retinal capillaries seem to be affected by this increased level
of sorbitol, event ually leading to the loss of their primary function .This results in
weakness and eventual saccular outpouching of capillary walls. These
microaneurysms are the earliest det ectable signs of DM retinopathy [23 ,24].
Macular edema PKC -pathway

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A theory to explain the development of macular edema focuses on the
increased levels of diacylglycerol from the shunting of excess glucose. This is
thought to activate PK C isoforms (most commonly beta and gamma are associated
with both DR and DN) , which, in turn, affects retinal blood dynamics, especially
permeability and flow, leading to fluid leakage and retinal thickening .
Hypoxia & Neovascularization
Further increases in retinal ischemia trigger the production of vasoproliferative
factors that stimulate new vessel formation. The extracellular matrix is broken down
first by proteases, and new vessels arising mainly from the retinal venules penetrate
the internal limiting membrane and form capillary networks between the inner
surface of the retina and the p osterior hyaloid face . Neovascularization is most
commonly observed at the borders of perfused and nonperfused retina and most
commonly occurs along the vascular arcades and at the optic nerve head. The new
vessels break through and grow along the surface of the retina and into the scaffold of
the posterior hyaloid face. By themselves, these vessels rarely cause visual
compromise, but they are fragile and highly permeable. These delicate vessels are
disrupted easily by vitreous traction, which leads to hem orrhage into the vitreous
cavity or the preretinal space . These new blood vessels initially are associated with a
small amount of fibroglial tissue formation. However, as the density of the
neovascular frond increases, so does the degree of fibrous tissue formation . In later
stages, the vessels may regress, leaving only networks of avascular fibrous tissue
adherent to both the retina and the posterior hyaloid face. As the vitreous contracts, it
may exert tractional forces on the retina via these fibroglial connections. Traction
may cause retinal edema, retinal heterotropia, and both tractional retinal detachments
and retinal tear formation with subsequent detachment [26].
2.2.5 Etiology
Duration of diabetes
In patients with type I diabetes, no clinically significant retinopathy can be
seen in the first 5 years after the initial diagnosis of diabetes is made. After 10 -15

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years, 25 -50% of patients show some signs of retinopathy. This prevalence increases
to 75 -95% after 15 years and approaches 100% after 30 years of diabetes.
Proliferative diabetic retinopathy (PDR) is rare within the first decade of type I
diabetes diagnosis but increases to 14 -17% by 15 years, rising steadily thereafter .In
patients with type I I diabetes, the incidence of diabetic retinopathy increases with the
disease duration. Of patients with type II diabetes, 23% have nonproliferative diabetic
retinopathy (NPDR) after 11 -13 years, 41% have NPDR after 14 -16 years, and 60%
have NPDR after 16 y ears[27].
Hypertension and hyperlipidemia
Systemic hypertension, in the setting of diabetic nephropathy, correlates well
with the presence of retinopathy. Independently, hypertension also may complicate
diabetes in that it may result in hypertensive retina l vascular changes superimposed
on the preexisting diabetic retinopathy, further compromising retinal blood
flowץProper management of hyperlipidemia (elevated serum lipids) may result in less
retinal vessel leakage and hard exudate formation, but the reaso n behind this is
unclear [28].
2.2.6 Epedimiology
Of the approximately 16 million Americans with diabetes, 50% are unaware
that they have it. Of those who know they have diabetes, only half receive
appropriate eye care. Thus, it is not surprising that diabet ic retinopathy is the leading
cause of new blindness in persons aged 25 -74 years in the United States .
Approximately 700,000 Americans have proliferative diabetic retinopathy, with an
annual incidence of 65,000. Approximately 500,000 persons have clinicall y
significant macular edema, with an annual incidence of 75,000 . Diabetes is
responsible for approximately 8000 eyes becoming blinded each year, meaning that
diabetes is responsible for 12% of blindne ss. The rate is even higher among certain
ethnic groups. An increased risk of diabetic retinopathy appears to exist in patients of
Native American, Hispanic, and African American heritage .With increasing duration
of diabetes or with increasing age since its o nset, there is a higher risk of developing

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diabetic retinopathy and its complications, including diabetic macular edema or
proliferative diabetic retinopathy [29,30] .
2.2.7 Prognosis :
Prognostic factors that are favorable for visual loss include the follo wing :
 Circinate exudates of recent onset
 Well -defined leakage
 Good perifoveal perfusion
Prognostic factors that are unfavorable for visual loss include the following :
 Diffuse edema/multiple leaks
 Lipid deposition in the fovea
 Macular ischemia
 Cystoid macular edema
 Preoperative vision of less than 20/200
 Hypertension
Approximately 8,000 eyes become blind yearly because of diabetes [31]. The
treatment of diabetic retinopathy entails tremendous costs, but it has been estimated
that this represents only one eighth of the costs of Social Security payments for vision
loss. This cost does not compare to the cost in terms of loss of productivity and
quality of life .The Early Treatment for Diabetic Retinopathy Study has found that
laser surgery for macular edema reduces the incidence of moderate visual loss
(doubling of visual angle or roughly a 2 -line visual loss) from 30% to 15% over a 3 –
year period. The Diabetic Retinopathy Study has found that adequate scatter laser
panretinal photocoagulation reduces the risk of severe visual loss (< 5/200) by more
than 50%.
2.3Diabetic nephropathy
2.3.1 Diagnostic criteria
Diabetic nephropathy is a clinical syndrome characterized by the following :

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 Persistent albuminuria (>300 mg/d or >200 μg/min) that is confirmed on
at leas t 2 occasions 3 -6 months apart
 Progressive decline in the glomerular filtration rate (GFR )
 Elevated arterial blood pressure [32] .
2.3.2 Pathological mechanism , Staging and classification
The mechanisms by which chronic hyperglycemia leads to ESRD though
incompletely defined, involve the effects of soluble factors (growth factors,
angiotensin II , endothelin, AGEs), hemodynamic alterations in the renal
microcirculation (glomerular hyperfiltration/hyperperfusion,increased glomerular
capillary pressure), and structural changes in the glomerulus (increased extracellular
matrix , basement membrane thickening, mesangial expansion, fibrosis)some of these
effects may be modulated by angiotensin II receptors.
Proteinuria was first recognized in diabetes mellitus i n the late 18th century. In
the 1930s, Kimmelstiel and Wilson described the classic lesions of nodular
glomerulosclerosis in diabetes associated with proteinuria and hypertension. By the
1950s, kidney disease was clearly recognized as a common complication of diabetes,
with as many as 50% of patients with diabetes of more than 20 years having this
complication[33]. Currently, diabetic nephropathy is the leading cause of chronic
kidney disease in the United States and other Western societies. It is also one of the
most significant long -term complications in terms of morbidity and mortality for
individual patients with diabetes.

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Fig. 2.1 Natural History of Diabetic Nephropathy

Fig. 2.2 Rate of decline in glomerular filtration rate

Diabetes is responsible for 30 -40% of all ESRD cases in the United States.
Generally, diabetic nephropathy is considered after a routine urinalysis and screening
for microalbuminuria in the setting of diabetes. Patients may have physical findings
associate d with long -standing diabetes mellitus. Good evidence suggests that early
treatment delays or prevents the onset of diabetic nephropathy or diabetic kidney

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disease [34]. Regular outpatient follow -up is key in managing diabetic nephropathy
successfully. Recently, attention has been called to atypical presentations of diabetic
nephropathy with dissociation of proteinuria from reduced kidney function. Also
noted is that microalbuminuria is not always pred ictive of diabetic nephropathy.
Nevertheless, a major ity of the cases of diabetic nephropathy presents with
proteinuria, which progressively gets worse as the disease progresses, and is almost
uniformly associated with hypertension .Three major histologic changes occur in the
glomeruli of persons with diabeti c nephropathy. First, mesangial expansion is directly
induced by hyperglycemia, perhaps via increased matrix production or glycosylation
of matrix proteins. Second, thickening of th e GBM occurs. Third, glomerular
sclerosis is caused by intraglomerular hype rtension (induced by dilatation of the
afferent renal artery or from ischemic injury induced by hyaline narrowing of the
vessels supplying the glomeruli). These different histologic patterns appear to have
similar prognostic significance . The key change in diabetic glomerulopathy is
augmentation of extracellular matrix. The earliest morphologic abnormality in
diabetic nephropathy is the thickening of the GBM and expansion of the mesangium
due to accumulation of extracellular matrix.Light microscopy findings show an
increase in the solid spaces of the tuft, most frequently observed as coarse branching
of solid (positive periodic -acid Schiff react ion) material (diffuse diabetic
glomerulopathy). Large acellular accumulations also may be observed within these
areas. These are circular on section and are known as the Kimmelstiel -Wilson
lesions/nodules . Immunofluorescence microscopy may reveal deposition of albumin,
immunoglobulins, fibrin, and other plasma proteins along the GBM in a linear
pattern, most likely a s a result of exudation from the blood vessels, but this is not
immunopathogenetic or diagnostic and does not imply an immunologic
pathophysiology [35]. The renal vasculature typically displays evidence of
atherosclerosis, usually due to concomitant hyperli pidemia and hypertensive
arteriosclerosis .Electron microscopy provides a more detailed definition of the
structures involved. In advanced disease, the mesangial regions occupy a large

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proportion of the tuft, with prominent matrix content. Further, the base ment
membrane in the capillary walls (ie, the peripheral basement membrane) is thicker
than normal . The severity of diabetic glomerulopathy is estimated by the thickness of
the peripheral basement membrane and mesangium and matrix expressed as a
fraction o f appropriate spaces ; eg, volume fraction of mesangium/glomerulus,
matrix/mesangium, or matrix/glomerulus . The glomeruli and kidneys are typically
normal or increased in size initially, thus distinguishing diabetic nephropathy from
most other forms of chro nic renal insufficiency, where in renal size is reduced –
except renal amyloidosis and polycystic kidney disease . In addition to the renal
hemodynamic alterations, patients with overt diabetic nephropathy (dipstick -positive
proteinuria and decreasing GFR ) generally develop systemic hypertension.
Hypertension is an adverse factor in all progressive renal diseases and seems
especially so in diabetic nephropathy. The deleterious effects of hypertension are
likely directed at the vasculature and microvasculature . Evidence suggests that
hypertension associated with obesity, metabolic syndrome, and diabetes may play an
important role in the pathogenesis of diabetic nephropathy. Central obesity, metabolic
syndrome, and diabetes lead to increased blood pressure . Cent ral obesity induces
hypertension initially by increasing renal tubular reabsorption of sodium and causing
a hypertensive shift of renal -pressure natriuresis through multiple mechanisms,
including activation of the sympathetic nervous system and renin -angio tensin –
aldosterone system, as well as physi cal compression of the kidneys. Hypertension,
along with increases in intraglomerular capillary pressure and the metabolic
abnormalities (eg, dyslipidemia, hyperglycemia) likely interact to accelerate renal
injury . Similar to obesity -associated glomerular hyperfiltration, renal vasodilation,
increases in the glomerular filtration rate and intraglomerular capillary pressure, and
increased blood pressure also are character istics of diabetic nephropathy. Increased
systolic blood pressure further exacerbates the disease progression to proteinuria and
a decline in the glomerular filtration rate, leading to end -stage kidney disease [36].
2.3.3 Epidemiology

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Since the 1950s, kidney disease has been clearly recognized as a common
complication of diabetes mellitus (DM), with as many as 50% of patients with DM of
more than 20 years’ duration having this complication .
United States statistics
Diabetic nephropathy rarely develops before 10 years’ duration of type 1 DM
(also know n as insulin -dependent diabetes mellitus [IDDM]). Approximately 3% of
newly diagnosed patients with type 2 DM (also known as non –insulin -dependent
diabetes mellitus [NIDDM]) have overt nephropathy. The peak incidence (3%/y) is
usually found in persons who have had diabetes for 10 -20 years, after which the rate
progressively declines .The risk for the development of diabetic nephropathy is low in
a normoalbuminuric patient with diabetes’ duration of greater than 30 years. Patients
who have no proteinuria afte r 20-25 years have a risk of developing overt renal
disease of only approximately 1% per year . In terms of diabetic kidney disease in the
United States, the prevalence increased from 1988 -2008 in proportion to the
prevalence of diabetes. Among people with diabetes, the prevalence of diabetic
kidney disease remained stable [37].
International statistics
Striking epidemiologic differences exist even among European countries. In
some European countries, particularly Germany, the proportion of patients admitted
for renal replacement therapy exceeds the figures reported from the United States. In
Heidelberg (southwest Germany), 59% of patients admitted for renal replacement
therapy in 1995 had diabetes and 90% of those had type 2 DM. An increase in end –
stage renal disease (ESRD) from type 2 DM has been noted even in countries with
notoriously low incidences of type 2 DM, such as Denmark and Australia. Exact
incidence and prevalence from Asia are not readily available [38].
Sex distribution for diabetic nephropathy
Diabetic nephropathy affects males and females equally .
Age distribution for diabetic nephropathy

24
Diabetic nephropathy rarely develops before 10 years’ duration of type 1 DM.
The peak incidence (3%/y) is usually found in persons who have had diabetes for 10-
20 years. The mean age of patients who reach end -stage kidney disease is about 60
years. Although in general, the incidence of diabetic kidney disease is higher among
elderly persons who have had type 2 diabetes for a longer generation, the role of age
in the development of diabetic kidney disease is unclear. In Pima Indians with type 2
diabetes, the onset of diabetes at a younger age was associated with a higher risk of
progression to end -stage kidney disease [39].
Prevalence of diabetic nephropathy by race
The severity and incidence of diabetic nephropathy are especially great in
blacks (the frequency being 3 – to 6-fold higher than it is in whites), Mexican
Americans, and Pima Indians with type 2 DM. The relatively high frequency of the
condition in the se genetically disparate populations suggests that socioeconomic
factors, such as diet, poor control of hyperglycemia, hypertension, and obesity, have a
primary role in the development of diabetic nephropathy. It also indicates that
familial clustering may be occurring in these populations . By age 20 years, as many
as half of all Pima Indians with diabetes have developed diabetic nephropathy, with
15% of these individuals having progressed to ESRD.
2.3.4 Prognosis in diabetic nephropathy
Diabetic nephropathy accounts for significant morbidity and mortality .
Proteinuria is a predictor of morbidity and mortality. The overall prevalence of
microalbuminuria and macroalbuminuria in both types of diabetes is approximately
30-35%. Microalbuminuria indepen dently predicts cardiovascular morbidity, and
microalbuminuria and macroalbuminuria increase mortality from any cause in
diabetes mellitus. Microalbuminuria is also associated with increased risk of coronary
and peripheral vascular disease and death from c ardiovascular disease in the general
nondiabetic population . Patients in whom proteinuria did not develop have a low and
stable relative mortality rate, whereas patients with proteinuria have a 40 -fold higher
relative mortality rate. Patients with type 1 D M and proteinuria have the

25
characteristic bell -shaped relationship between diabetes duration/age and relative
mortality, with maximal relative mortality in the age interval of 34 -38 years (as
reported in 110 females and 80 males .ESRD is the major cause of death, accounting
for 59 -66% of deaths in patients with type 1 DM and nephropathy. In a prospective
study in Germany, the 5 -year survival rate was less than 10% in the elderly
population with type 2 DM and no more than 40% in the younger population with
type 1 DM .The cumulative incidence of ESRD in patients with proteinuria and type 1
DM is 50% 10 years after the onset of proteinuria, compared with 3 -11% 10 years
after the onset of proteinuria in European patients with type 2 DM .A study by
Rosolowsky et al found that despite renoprotective treatment, including
transplantation and dialysis, patients with type 1 diabetes and macroalbuminuri a
remain at high risk for ESRD [39].
Although both type 1 and type 2 DM lead to ESRD, the great majority of
patients are t hose with type 2 diabetes. The fraction of patients with type 1 DM who
develop renal failure seems to have declined over the past several decades. However,
20-40% still have this complication. On the other hand, only 10 -20% of patients with
type 2 DM devel op uremia due to diabetes. Their nearly equal contribution to the
total number of patients with diabetes who develop kidney failure results from the
higher prevalence of type 2 DM ;5- to 10 fold. Cardiovascular disease is also a major
cause of death (15 -25%) in persons with nephropathy and type 1 DM, despite their
relatively young age at death [40].
2.4Diabetic N europathy
Diabetic neuropathy is the most common complication of diabetes mellitus
(DM), affecting as many as 50% of patients with type 1 and type 2 DM. Diabetic
peripheral neuropathy involves the presence of symptoms or signs of peripheral nerve
dysfunction in people with diabetes after other possible causes have been excluded.
Neuropathies are characterized by a progressive loss of nerve fiber funct ion. A
widely accepted definition of diabetic peripheral neuropathy is "the presence of
symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after

26
exclusion of other causes." Neuropathies severely decrease patients' quality of life
(QOL). Furthermore, while the primary symptoms of neuropathy can be highly
unpleasant, the secondary complications (eg, falls, foot ulcers, cardiac arrhythmias,
and ileus) are even more serious and can lead to fractures, amputations, and even
death in pat ients with DM . Since diabetic neuropathy can manifest with a wide
variety of sensory, motor, and autonomic symptoms, a structured list of symptoms
can be used to help screen all diabetic patients for possible neuropathy (see History).
Physical examination of patients with suspected distal sensory motor or focal (ie,
entrapment or noncompressive) neuropathies should include assessments for both
peripheral and autonomic neuropathy (see Physical Examination) [41].
2.4.1 Signs and symptoms
In type 1 DM, distal polyneuropathy typically becomes symptomatic after
many years of chronic prolonged hyperglycemia, whereas in type 2, it may be
apparent after only a few years of known poor glycemic control or even at diagnosis.
Symptoms include the following : First Sensor y – Negative or positive, diffuse or
focal; usually insidious in onset and showing a stocking -and-glove distribution in the
distal extremities , second ; Motor – Distal, proximal, or more focal weakness,
sometimes occurring along with sensory neuropathy -sensorimotor neuropathy ,&
third; Autonomic – Neuropathy that may involve the cardiovascular, gastrointestinal,
and genitourinary systems and the sweat glands [42].
2.4.2 Diagnosis :
In the presence of diagnosed diabetes , screening tools are as follows
 Tuni ng fork: 87 -99% (sensitivity); 1 -19% (specificity)
 Coarse monofilament: 16% (sensitivity); 64% (specificity)
 Fine monofilament: 73% (sensitivity); 87% (specificity)
 Biothesiometer: 61 -80% (sensitivity); 64 -76% (specificity).
2.4.3pathological mechanism :
The factors leading to the development of diabetic neuropathy are not
understood completely, and multiple hypotheses have been advanced. It is generally

27
accepted to be a multifactorial process. Development of symptoms depends on many
factors, such as total hyperglycemic exposure and other risk factors such as elevated
lipids, blood pressure, smoking, increased height, and high exposure to other
potentially neurotoxic agents such as ethanol. Genetic factors may also play a
role.Important contributing biochem ical mechanisms in the development of the more
common symmetrical forms of diabetic polyneuropathy likely include the polyol
pathway, advanced glycation end products, and oxidative stress .
Polyol pathway
Hyperglycemia causes increased levels of intracellul ar glucose in nerves,
leading to saturation of the normal glycolytic pathway. Extra glucose is shunted into
the polyol pathway and converted to sorbitol and fructose by the enzymes aldose
reductase and sorbitol dehydrogenase .Accumulation of sorbitol and fr uctose lead to
reduced nerve myoinositol, decreased membrane Na+/K+ -ATPase activity, impaired
axonal transport, and structural breakdown of nerves, causing abnormal action
potential propagation. This is the rationale for the use of aldose reductase inhibi tors
to improve nerve conduction.
Advanced glycation end products
The nonenzymatic reaction of excess glucose with proteins, nucleotides, and
lipids results in advanced glycation end products (AGEs) that may have a role in
disrupting neuronal integrity and repair mechanisms through interference with nerve
cell metabolism and axonal transport .
Oxidative stress
The increased production of free radicals in diabetes may be detrimental via
several mechanisms that are not fully understood. These include direct damage to
blood vessels leading to nerve ischemia and facilitation of AGE reactions. Despite the
incomplete understanding of these processes, use of the antioxidant alpha -lipoic acid
may hold promise for improving neuropathic symptoms .
Related contributing factors

28
Problems that are a consequence of or co -contributors to these disturbed
biochemical processes include altered gene expression with altered cellular
phenotypes, changes in cell physiology relating to endoskeletal structure or cellular
transport, r eduction in neu rotrophins, and nerve ischemia. Clinical trials of the best –
studied neurotrophin, human recombinant nerve growth factor, were disappointing.
With future refinements, however, pharmacologic intervention targeting one or more
of these mechanis ms may prove successful . In the case of focal or asymmetrical
diabetic neuropathy syndromes, vascular injury or autoimmunity may play more
important roles [43,44] .
2.4.4 Classification :
 Symmetric polyneuropathy (Most common)
 Autonomic neuropathy
 Polyradiculopathies
– Diabetic amyotrophy (lumbar polyradiculopathy )
– Thoracic polyradiculopathy
– Diabetic neuropathic cachexia
 Mononeuropathies ( least common)
– Cranial mononeuropathy
– Peripheral mononeuropathy
– Mononeuropathy multiplex
 Acute painful diabetic neuropathies
– Treatment -induced neuropathy of diabetes (Due to hypoglycemic
loss of perception).
2.4.5 Etiology
Risk factors that are associated with more severe symptoms include the
following : Poor glycemic control, Advanced age , Hypertension, Long duration of
DM, Dyslipidemia, Smoking, Heavy alcohol intake , HLA -DR3/4 phenotype, Tall
height. Development of symptoms depends on many factors, such as total
hyperglycemic exposure and other risk factors such as elevated lipids, blood pressure,

29
smokin g, increased height, and high exposure to other potentially neurotoxic agents
such as ethanol. Genetic factors may also play a role. Peripheral neuropathies have
been described in patients with primary DM (types 1 and 2) and in those with
secondary diabete s of diverse causes, suggesting a common etiologic mechanism
based on chronic hyperglycemia. The contribution of hyperglycemia has received
strong support from the Diabetes Control and Complications Trial (DCCT). An
association between impaired glucose tol erance and peripheral neuropathy has been
construed as further evidence of a dose -dependent effect of hyperglycemia on nerves,
although this relationship remains an area of some controversy for t ype 2 diabetes
and prediabetes [45].
2.4.6 Epidemiology :
United States statistics
A large American study estimated that 47% of patients with diabetes have
some peripheral neuropathy .Neuropathy is estimated to be present in 7.5% of patients
at the time of diabetes diagnosis. More than half of cases are distal sym metric
polyneuropathy. Focal syndromes such as c arpal tunnel syndrome (14 -30%),
radiculopathies/plexopathies, and cranial neuropathies account for the rest. Solid
prevalence data for the latter 2 less -common syndromes is lacking .The wide
variability in symmetric diabetic polyneuropathy prevalence data is due to lack of
consistent criteria for diagnosis, variable methods of selecting patients for study, and
differing assessment techniques. In addition, because many patients with diabet ic
polyneuropathy ar e initially asymptomatic, detection is extremely dependent on
careful neurologic examination by the primary care clinician. The use of additional
diagnostic techniques, such as autonomic or quantitative sensory testing, might result
in a higher recorded pr evalence [46].
International statistics
In a cohort of 4400 Belgian patients, Pirart et al found that 7.5% of patients
already had neuropathy w hen diagnosed with diabetes. After 25 years, the number

30
with neuropathy rose to 45%. In the United Kingdom, the pr evalence of diabetic
neuropathy among the hospital clinic populatio n was noted to be around 29%.
Diabetic neuropathy in racial minorities
No definite racial predilection has been demonstrated for diabetic neuropathy.
However, members of minority groups (eg , Hispanics, African Americans) have
more secondary complications from diabetic neuropathy, such as lower -extremity
amputations, than whites. They also have more hospitalizations for neuropathic
complications .
Sex differences in diabetic neuropathy
DM affe cts men and women with equal frequency. However, male patients
with type 2 diabetes may develop diabetic polyneuropathy earlier than female
patients, and neuropathic pain causes more morbidity in females than in males .
Diabetic neuropathy can occur at any age but is more common with increasing age
and severity and duration of diabetes.
2.4.7 Prognosis
Patients with untreated or inadequately treated diabetes have higher morbidity
and complication rates related to neuropathy than patients with tightly control led
diabetes. Repetitive trauma to affected areas may cause skin breakdown, progressive
ulceration, and infection. Amputations and death may result . Treating diabetic
neuropathy is a difficult task for the physician and patient. Most of the medicines
menti oned in the Medication section do not lead to complete symptom relief. Clinical
trials are under way to help find new ways to treat symptoms and delay disease
progression . Mortality is higher in people with cardiovascular autonomic neuropathy
(CAN). The ov erall mortality rate over periods up to 10 years was 27% in patients
with DM and CAN detected, compared with a 5% mortality rate in those without
evidence of CAN. Morbidity results from foot ulceration and lower -extremity
amputation. These 2 complications are the most common causes of hospitalization
among people with DM in Western countries. Severe pain, dizziness, diarrhea, and
impotence are common symptoms that decrease the QOL of a patient with DM. In

31
patients with diabetic peripheral neuropathy, the pr ognosis is good, but the patient's
QOL is reduced [47].
2.5 Management of microvascular complications
2.5.1 Management of dr
Controlling diabetes and maintaining the HbA1c level in the 6 -7% range are
the goals in the optimal management of diabetes and diabetic retinopathy. If the
levels are maintained, then the progression of diabetic retinopathy is reduced
substantially, according to The Diabetes Control and Complications Trial [48]. The
Early Treatment for Diabetic Retinopathy Study has found that lase r surgery for
macular edema reduces the incidence of moderate visual loss (doubling of visual
angle or roughly a 2 -line visual loss) from 30% to 15% over a 3 -year period.The
Diabetic Retinopathy Study has found that adequate scatter laser panretinal
photoc oagulation reduces the risk of severe visual loss (< 5/200) by more than 50%
[49].
Glucose Control
The Diabetes Control and Complications Trial has found that intensive glucose
control in patients with insulin -dependent diabetes mellitus (IDDM) has decrea sed
the incidence and progression of diabetic retinopathy. Although no similar clinical
trials for patients with non -insulin -dependent diabetes mellitus (NIDDM) exist, it
may be logical to assume that the same principles apply. In fact, the ADA has
suggest ed that all patients with diabetes (NIDDM and IDDM) should strive to
maintain glycated hemoglobin levels of less than 7% (reflecting long -term glucose
levels) to prevent or at least minimize the long -term complications of DM, including
DM retinopathy.
Ovin e Hyaluronidase Therapy
In large phase III clinical trials, intravitreal injections of ovine hyaluronidase
(Vitrase) have been shown to be safe and to have modest efficacy for the clearance of
severe vitreous hemorrhage. More than 70% of subjects in these studies had diabetes,

32
and the most frequent etiology of the vitreous hemorrhage was proliferative diabetic
retinopathy.
VEGF Inhibitors
In a DRCR.net clinical trial comparing Eylea (aflibercept), Lucentis
(ranibizumab), and Avastin (bevacizumab) for diabet ic macular edema (DME), Eylea
provided greater visual improvement, on average, than did the other 2 drugs for
vision of 20/50 or worse at the start of the trial. The 3 drugs achieved similar average
improvement for vision of 20/40 to 20/32. No major differ ences in safety were found
for the 3 drugs .Vision substantially improved for most participants at one year after
the trial began. For people whose vision was 20/32 or 20/40 at the start of the trial,
vision improved almost two lines on an eye chart in tho se receiving each of the 3
drugs. However, for those whose vision was 20/50 or worse at the start of the trial,
Eylea improved vision on average almost four lines, Avastin improved vision on
average almost 2.5 lines, and Lucentis improved vision on average almost 3 lines [50].
Laser Photocoagulation
The advent of laser photocoagulation in the 1960s and early 1970s provided a
noninvasive treatment modality that has a relatively low complication rate and a
significant degree of success. This involves directing a high -focused beam of light
energy to create a coagulative response in the target tissue. In nonproliferative
diabetic retinopathy, laser treatment is indicated in the treatment of clinically
significant macular edema. The strategy for treating macular e dema depends on the
type and extent of vessel leakage . If the edema is due to leakage of specific
microaneurysms, the leaking vessels are treated directly with focal laser
photocoagulation. In cases where the foci of leakage are nonspecific, a grid pattern of
laser burns is applied. Medium intensity burns (100 -200 µm) are placed 1 burn -size
apart, covering the affected area. Other off -label potential treatments of diabetic
macular edema include intravitreal triamcinolone acetonide (Kenalog) and
bevacizumab; these medications can result in a substantial reduction or resolution of
macular edema [51].

33
Treatment of Proliferative Diabetic Retinopathy
Panretinal photocoagulation (PRP) is the preferred form of treatment of
proliferative diabetic retinopathy (PDR). It involves applying laser burns over the
entire retina, sparing the central macular area, and may be performed using a variety
of delivery systems, including the slit lamp, an indirect ophthalmoscope, and the
EndoProbe. Application starts in a circumferen ce of 500 µm from the disc and 2 disc
diameters from the fovea to wall off the central retina. Moderate intensity burns of
200-500 µm (gray -white burns) are placed 1 spot -size apart, except in areas of
neovascularization where the entire frond is treated i f DRS criteria are used, but most
specialists today avoid directly treating neovascularization. This procedure is
continued peripherally to achieve a total of 1200 -1600 applications in 2 to 3 sessions .
The presence of high -risk PDR is an indication for imm ediate treatment.
Vitrectomy
Vitrectomy may be necessary in cases of long -standing vitreous hemorrhage
(where visualization of the status of the posterior pole is too difficult), tractional
retinal detachment, and combined tractional and rhegmatogenous ret inal detachment.
More uncommon indications include epiretinal membrane formation and macular
dragging . According to The Diabetic Retinopathy Vitrectomy Study, vitrectomy is
advisable for eyes with vitreous hemorrhage that fails to resolve spontaneously within
6 months.
Cryotherapy
When laser photocoagulation is precluded in the presence of an opaque media ,
such as in cases of cataracts and vitreous hemorrhage, cryotherapy may be applied
instead . The principles behind the treatment are basically the same —that is, to ablate
retinal tissue for oxygen demand to be decreased and to induce a chorioretinal
adhesi on, which could increase oxygen supply to the retina in the hope of preventing
or down -regulating the vasoproliferative response [51].

34
2.5.2 Management of DN
Several issues are key in the medical care of pati ents with diabetic
nephropathy. These include glycemic control, management of hypertension, and
reducing dietary salt intake and phosphorus and potassium restriction in advanced
cases[52] . In an outcome and cost -effective analysis of the United Kingdom
Prospective Diabetes Study (UKPDS), the authors concluded that intensive blood
glucose control in patients with type 2 DM significantly increased treatment costs but
substantially reduced the cost of complications and increased the time free of
complications. Newer agents in diabeti c patients with kidney disease [53].
Dipeptidyl peptidase inhibitors
The dipeptidyl peptidase (DPP) –4 inhibitors (ie, gliptins) are a new class of
antidiabetic agents that can be used in type 2 diabetes. These agents include
sitagliptin, saxagliptin, linagl iptin, and alogliptin, and they decrease the breakdown of
the incretin hormones such as GLP -1. GLP -1 is secreted by the GI tract in response to
food intake and leads to insulin secretion in a glucose -dependent manner, while also
decreasing glucagon release . GLP -1 also slows gastric emptying . Sitagliptin was the
first available DPP -4 inhibitor [54]. Approximately 80% of sitagliptin is cleared by
the kidney; therefore, the standard dose of 100 mg daily should be reduced in patients
with reduced glomerular filt ration rates (GFRs). With an estimated GFR (eGFR) of
30 or greater to less than 50 mL/min/1.73 m2, the recommended dose is 50 mg once
daily, and with an eGFR less than 30 mL/min/1.73 m2, a dose of 25 mg once daily is
advised [55].
Alpha -glucosidase inhibito rs
Alpha -glucosidase inhibitors (acarbose, miglitol) decrease the breakdown of
oligosaccharides and disaccharides in the small intestine, slowing the absorption of
glucose after a meal. The major adverse effects are bloating, flatulence, and
abdominal cram ping. Acarbose is minimally absorbed, with less than 2% of the drug
and active metabolites present in the urine. However, in patients with reduced renal
function, serum levels of acarbose and metabolites are significantly higher. Miglitol

35
has greater syste mic absorption with greater than 95% renal excretion. It is
recommended that miglitol be avoided if the GFR is less than 25 mL/min/1.73 m2.
These drugs have not been studied in patients with advanced kidney disease, and their
use should be avoided in this population [56].
Sodium -glucose cotransporter 2 (SGLT2) inhibitors
There are several SGLT2 inhibitors under development or consideration by the
US Food and Drug Administration (FDA), and canagliflozin (Invokana) is the first
SGLT2 inhibitor approved for use in the United States. Canagliflozin inhibits renal
glucose absorption in the proximal tubule, the site in the kidney where approximately
90% of glucose reabsorption occurs. This leads to increased excretion of glucose in
the urine, which may help subjects lose up to 5 kg of weight over a year. The
decreased glucose reabsorption is also accompanied by increased urinary excretion of
sodium, which, in turn, may help with further blood pressure lowering, which could
be an advantage in patients with diabetic ki dney disease and hypertension . At this
time, the maximum dose in patients with an eGFR of 45 to less than 60 mL/min/1.73
m2 is 100 mg once daily and it is not recommended in patients with an eGFR of less
than 45 mL/min/1.73 m2. Increased glucosuria is believed to increase the risk of
urinary tract infections, especially candidal infections, and more frequently in
women [57].
Glucagonlike peptide -1 (GLP -1) receptor agonistsor incretin mimetics
The GLP -1 agonists exenatide (Byetta) and liraglutide (Victoza ) are also
known as injectable incretin mimetics. These drugs enhance central satiety and
reduce appetite, thus helping with weight loss. These drugs promote insulin release,
delay glucagon release, and slow gastric emptying and are less likely to cause
hypoglycemia. There is some concern, however, about safety, as they may cause
pancreatitis. Exenatide clearance is GFR dependent and is reduced at low GFRs.
Although disputed, there are cases of acute renal failure associated with exenatide,
and it is recomm ended to be used with caution in patients with a GFR of 30 -50
mL/min and not be used at all if the eGFR is less than 30 mL/min. Liraglutide is not

36
metabolized by the kidney, and no dose adjustment is necessary in patients with a
decreased GFR, including ES RD, although data in this population are limited .Cases
of acute renal failure and worsening of chronic renal impairment have been reported
with liraglutide, and the manufacturer advises caution in initiating or increasing the
dose in patients with kidney d isease [58].
Amylin analogs
Amylin is a 37 -amino acid peptide co -secreted by β cells with insulin and is
deficient in diabetes. Its levels parallel insulin levels, and its actions are
complementary to insulin in regulating plasma glucose concentration. Amyl in slows
gastric emptying, reduces postprandial glucagon, and can suppress appetite .
Pramlintide (Symlin) is the only available amylin analog; it is given as an injection
along with insulin therapy at meals. Dose adjustments for pramlintide are not
require d in the presence of mild -to-moderate renal disease, but there are no data on its
use in end -stage kidney disease [59].
Management of hypertension
Careful blood pressure control is needed to prevent the progression of diabetic
nephropathy and other complica tions; however the optimal lower limit for systo lic
blood pressure is unclear. In the UKPDS, a 12% risk reduction in diabetic
complications was found with each 10 mm Hg drop in systolic pressure, the lowest
risk being associated with a sys tolic pressure bel ow 120 mm Hg [60,61,62] .
Angiotensin -converting enzyme inhibitors
From a therapeutic standpoint, preventing the progression of kidney disease is
better achieved with a nonglycemic intervention, such as treatment with ACEs , which
confer superior long -term protection even in comparison with triple therapy with
reserpine, hydralazine, and hydrochlorothiazide or a calcium channel blocker
nifedipine . Long -term treatment with ACE s, usually combined with diuretics, reduces
blood pressure and albuminuria and prote cts kidney function in patients with
hypertension, type 1 DM, and nephropathy. Beneficial effects on kidney function
have also been reported in patients with normotension, type 1 DM, and nephropathy .

37
ACE inhibit ion has been shown to delay the development o f diabetic nephropathy. In
the ACE inhibition arm of a large trial, only 7% of patients with microalbuminuria
experienced progression to overt nephropathy; however, in the placebo -treated group,
21% of patients experienced progression to overt nephropathy [63]. The beneficial
effect of ACE inhibition on preventing progression from microalbuminuria to overt
diabetic nephropathy is long -lasting (8 y) and is associated with the preservation of a
normal GFR .The impact of ACE inhibition in patients with microalbu minuric type 2
DM has also been evaluated. Treatment with an ACE inhibitor for 12 months has
significantly reduced mean arterial blood pressure and the urinary albumin excretion
rate in type 2 DM patients who have microalbuminuria . In a study of normotensi ve
patients with microalbuminuric type 2 DM who received enalapril or placebo for 5
years, 12% of those in the actively treated group experienced diabetic nephropathy,
with a rate of decline in kidney function of 13%, and 42% of those in the placebo
group experienced nephropathy [64,65] .
Endothelin antagonist therapy
Endothelin antagonists have demonstrated antifibrotic, anti -inflammatory, and
antiproteinuric effects in experimental studies . A randomized, placebo -controlled,
double -blind, parallel -design, do sage-range study on the effect of the endothelin -A
antagonist avosentan on urinary albumin excretion rate in 286 patients with diabetic
nephropathy, macroalbuminuria, and a blood pressure of < 180/110 mm Hg found
that all dosages of avosentan, administered in addition to standard treatment with an
ACE inhibitor or an ARB, reduced the mean relative urinary albumin excretion rate ( –
16.3% t o -29.9%, relative to baseline) [66].
Renal Replacement Therapy
As for any other patient with ESRD, diabetic patients with ESRD can be
offered renal replacement therapy. Carefully explain the therapeutic options and
modalities of renal replacement therapy to patients, their partners, and their families
in an early stage of renal failure. In chronically ill patients with diabe tes, this tends to
be much more important than in those renal patients who do not have diabetes . In

38
patients with diabetic nephropathy, starting at a creatinine clearance or estimated
GFR of 10 -15 mL/min is wise. In diabetic patients, starting earlier is u seful when
hypervolemia renders blood pressure uncontrollable, when the patient experiences
anorexia and cachexia or other uremic symptoms, and when severe vomiting is the
combined result of uremia and gastroparesis . In principle, diabetic patients who
require renal replacement therapy have the following 4 options :
 Refusal of further treatment for uremia, leading to a progressive decline in
general health and ultimately leading to death
 Peritoneal dialysis (eg, machine -assisted intermittent peritoneal dialysis,
continuous ambulatory peritoneal dialysis, continuous cyclic peritoneal
dialysis )
 Hemodialysis ; eg, facility hemodialysis, home hemodialysis
 Renal transplantation ; eg, cadaver donor kidney, living related -donor kidney,
living unrelated -donor ki dney ;emotionally related donor , living unrelated –
donor kidney unrelated by family or emotionally; the so -called altruistic donor,
pancreas plus kidney transplantation [67,68] .
Peritoneal dialysis and hemodialysis
Dialysis treatment partially reverses insulin resistance so that insulin
requirements are often reduced. Adequate control of glycemia is important to prevent
hyperglycemia -induced thirst, which can lead to volume overload and hyperkalemia.
Proper attention must be given to optimizing nutrition, corre cting anemia, controlling
hypertension and hyperlipidemia, and modifying associated cardiovascular risk
factors . Regarding peritoneal dialysis, in a recently completed study, female patients
with diabetes mellitus had a better outcome in the first 3 years of requiring renal
replacement therapy when they chose peritoneal dialysis over hemodialysis. This
positive effect did not continue beyond 3 years [69].
Kidney transplantation and kidney -pancreas transplantation
Except in patients with severe macroangiopath ic complications, renal
transplantation should be considered a first -line objective because it offers the best

39
degree of medical rehabilitation in patients with uremia and diabetes. This option
must be discussed early on with the patient and his or her fam ily. Transplantation
even before dialysis (preemptive transplantation) is becoming increasingly popular in
some centers . Renal transplantation is generally restricted to younger patients with
type 1 DM; this may not be completely justified because good results have also been
achieved in patients with type 2 DM if high -risk patients with macrovascular disease
are excluded. Because of higher cardiovascular mortality, long -term survival of
patients with diabetes with renal allografts is definitely inferior to that of those
without diabetes [70].
Dietary Changes
The American Diabetic Association suggests diets of various energy intake
(caloric values), depending on the patient. With advancing renal disease, protein
restriction of as much as 0.8 -1 g/kg/d may re tard the progression of nephropathy [71].
2.5.3 MANAGEMENT OF DIABETIC NEUROPATHY
Management of diabetic neuropathy should begin at the initial diagnosis of
diabetes. The primary care physician needs to be alert for the development of
neuropathy —or even its presence at the time of initial diabetes diagnosis —because
failure to diagnose diabetic polyneuropathy can lead to serious consequences,
inclu ding disability and amputation [72,73] . Consider any patient with clinical
evidence of diabetic peripheral neuropa thy to be at risk for foot ulceration, and
provide education on foot care. If necessary, refer the patient to a podiatrist. Admit
patients for an infected diabetic foot ulcer or gangrene. Patients with diabetic
peripheral neuropathy require more frequent f ollow -up, with particular attention to
foot inspection to reinforce the need for regular self -care[74,75] . The provision of
regular foot examinations and reinforcement of the educational message on foot care
have been shown in several studies to significan tly reduce rates of ulceration and
even amputation. The primary care physician is responsible for educating patients
about the acute and chr onic complications of diabetes, including the psychological
impact of sexual dysfunction in both men and women [76]. The importance of

40
involving a neurologist (preferably with expertise in peripheral neuropathy) in the
treatment of patients with diabetic neuropathy cannot be overemphasized [77,78] .
Glycemic Control
A 2012 Cochrane review indicates that tight glycemic cont rol prevents the
development of clinical neuropathy and reduces nerve conduction and vibration
threshold abnormalities in patients with either type 1 or type 2 diabetes. However,
tight glucose control also increases the risk of severe hypoglycemic episodes , and this
should be considered when as sessing its risk/benefit ratio [79,80,81] .
Diabetic Neuropathic Pain Management
According to a Cochrane review evaluating gabapentin for chronic neuropathic
pain and fibromyalgia, gabapentin leads to significant pain r elief in patients with
chronic neuropathic pain when compared with a placebo. Although patients
frequently experience adverse side effects, these are usually tolerable, and serious
side effects were not increased when compared with side effe cts associated with the
placebo [82] .Topical therapy with capsaicin or transdermal lidocaine may be useful
in some patients, especially those with more localized pain or those in whom
interactions with existing oral medications is a concern. There was no difference
identified between gabapentin and tricyclic antidepressants in the achievement of
pain relief of diabetic neuropathy or postherpetic neuralgia in a study by Chou et al
[83]. The authors performed a meta -analysis of head -to-head trials comparing the
results of gabapentin and tricyclic antidepressants for pain relief in diabetic
neuropathy [84].
Diabetic Gastroparesis
Erythromycin, cisapride, and metoclopramide are used to treat diabetic
gastroparesis. Additionally, MiraLax (polyethylene glycol 3350) is gainin g increasing
popularity as the first -line agent for severe constipat ion and lower motor unit bowel.
A newer agent, tegaserod (Zelnorm), may be helpful in patients with chronic ileus. In
early 2010, however, tegaserod marketing was suspended because of a me ta-analysis
showing an excess number of serious cardiovascular adverse events, including

41
angina, myocardial infarction, and stroke, in those taking tegaserod compared with
placebo. Tegaserod is currently available only on an emergency basis [85].
Treatment of Autonomic Dysfunction
Erectile dysfunction
Although several modalities are available, erectile dysfunction from diabetic
neuropathy is a very difficult condition to treat. All other causes of impotence must
be excluded. Once the diagnosis has been confi rmed, the oral agent sildenafil Viagra)
and related phosphodiesterase type 5 (PDE5) inhibitors can be used (if not
contraindicated in the patient). Older methods such as vacuum devices or
intracavernosal papaverine injections may be tried. Referral to a ur ologist is
suggested .
Orthostatic hypotension
Symptomatic orthostatic hypotension can be troubling in patients with diabetic
neuropathy. Increasing the dietary fluid and salt intake, along with use of
compression stockings, may help. If these modalities do not improve symp toms, then
medication may help.
Gustatory sweating
Glycopyrrolate is an antimuscarinic compound that can be used for the
treatment for diabetic gustatory sweating. When applied topically to the affected area,
it results in a marked reduction i n sweating while eating a meal [86].
Surgical Treatment
Surgery is indicated in patients with infected foot ulcers when the infection
cannot be controlled medically. Aggressive debridement or amputation may be
necessary if signs of necrosis or in fection do n ot improve with IV antibiotics.
Jejunostomy may be performed in patients with intractable gastroparesis (ie, severe
nausea and vomiting, severe weight loss). This will allow patients to be fed enterally,
bypassing the paralytic stomach . When impotence is a continual problem, the patient
may pursue the option of a penile prosthesis . The feet of patients with DM often
become insensate and are highly susceptible not only to ulcers but also to the Charcot

42
foot (ie, a foot that loses its structure secondary to trauma and acute arthropathy; see
Charcot -Marie -Tooth Disease) from frequent and multiple traumas. Charcot foot can
be treated with bracing or special boots. In some cases, surgery is used to correct the
deformity [86,87]. Rehabilitation
Physic al therapy may be a useful adjunct to other therapy, especially when
muscular pain and weakness are a manifestation of the patient's neuropathy. The
physical therapist can instruct the patient in a general exercise program to maintain
his or her mobility a nd strength. An aquatic therapist can also be helpful .
Occupational therapy
Occupational therapy may be necessary in cases where there is severe loss of
functional status. When only the lower limbs are involved, patients may need home
modifications and equ ipment. When the upper limbs are involved, patients may need
more extensive functional restoration and adaptive equipment. When secondary
complications require amputation of a limb, even more intensive functional retraining
is required .
Speech therapy
Involvement of a speech therapist rarely is indicated, but professionals from
this discipline can help with patients affected by gastroparesis or dysphagia .
Recreational therapy
A recreational therapist may help the patient with performance of community
activi ties. Many patients with chronic disease, especially elderly patients, become
isolated and are at risk for comorbid conditions such as depression [88].
2.6 Measures of prevention of microvascular complications
2.6.1 Measures of Prevention of Diabetic Retinopathy
Prospective Diabetes Study were large randomized clinical trials that
demonstrated the importance of tight glucose control with respect to reducing the
incidence and progression of diabetes complications, including diabetic retinopathy
for both type I and type II diabetes . All individuals with diabetes should be aware of
the importance of regular dilated retinal examinations. Early diagnosis and treatment

43
of diabetic retinopathy can help prevent blindness in more than 90% of cases. In spite
of treatment, however, individuals can sometimes still lose vision [89].
Consultations
The patient, ophthalmologist or retina specialist, and internist or
endocrinologist must work together as a team to optimize the diabetes control and
help to reduce the risk of blindness.
2.6.2 Measures for Pre vention of Diabetic Nephropathy
Efforts should be made to modify and/or treat associated risk factors such as
hyperlipidemia, smoking, and hypertension [90].
Specific goals for prevention include the following :
Optimal blood glucose control (hemoglobin A 1c [HbA 1c] < 7% )
Control of hypertension – no borderline was found but to prevent
hypoperfusion blood pressure is not preferred to be droped below 140 -133/80 -70
mmhg. – preferred drugs are ACEs and ARBs.
Avoidance of pot entially nephrotoxic substances such as none steroidal anti-
inflammatory medications and aminoglycosides , also adequate hydration prior to
contrast administration have been shown to prevent contrast nephropathy as diabetic
patients are highly susceptible .Early detection and optimal management of diabetes,
especially in the settin g of family history of diabetes .
Long -Term Monitoring
Regular outpatient follow -up is key in managing diabetic nephropathy
successfully. Regular annual urinalysis is recommended for screening for
microa lbuminuria . Ensuring optimal glucose control, optimizing blood pressure, and
screening for other associated complications of diabetes (eg, retinopathy, diabetic
foot, cardiovasc ular disease) are also crucial [91].
2.6.3 Measures of prevention of diabetic neuropathy
Long -Term Monitoring
Patients with diabetic neuropathy should have regular monitoring by a primary
care physician. Patients should be monitored every 4 weeks to 3 months to try to

44
assess whether therapy is wor king to decrease pain or nausea or vomiting and also to
taper off medications for painful peripheral neuropathy. Objective measures of
function and improvement should be taken at every visit. Examine the patient's feet
and assess with monofilament and tuni ng fork on every visit when the patient comes
in for DM care. Monitoring patients closely for glycemic control is essential [92].

45
CHAPTER II SUMMARY AND RECOMMENDATIONS
As DM2 is on the rise , and sedentary life style id frequently met in patients
,patients should be encouraged to be more active to minimize risk of those
complications and should be motivated to achieve a better glycemic and hypertensive
control especially if met together , physicians should monitor patients frequently to
detect early changes . neurologists ophthalmologists nephrologists and
endocrinologists must work together to have a wholestic view of patients situations ,
especially if patients are on m ultiple medications which warrants change of
medications or just a minimal dose adjustment.
Family history and full view of clinical picture and understanding correlation
of symptoms allows early detection and prevention of complications. And might aid
in avoidance of a mo re invasive treatment like transplants.

46
CONCLUSIONS
1. Pathophysiology is not associated only with hyperglycemia but also with
hypertension and dyslipidemia. Genetic factors may reduce development of MVC .
ROS was found to unify pathology of micro vascular complications ,pericyte and
podocyte death was associated with ultered redox potentials and increased
oxidative stress ,inhancing cell death and ischemic changes in tissues .
2. The clinical course of the disease is almost always as ymtomatic in first decade ,
increasing the development of complications
3. The longer the duration of asymptomatic hyperglysemia was associated with
higher rates of NPDR and PDR where ischemic changes lead to
neovascularization by various growth factors invol vement (e.g VEGF -A, TGF -B).
4. Significant reduction in Nephropathy by use of ACE'S and BP monitoring resulted
in reduction of DM related mortality as it was the leading cause of morbidity in
DM.
5. By the time of diagnosis of diabetic neuropathy no reduction or prevention
showed to reverse neuronal damage. Neurons show prolonged resistance yet
reduced reversabile damage, as some none ischemic factors or pathways may be
involved.
6. Early detection, frequent monitoring Strict BP & Glycemic control showed to be
benifitial for both retino&nephropathy, but once neuropathy appear ,delay and
prevention is not feasible . ACEs and Ars shown clinical evidence of improvement
and delay in retino and nephropathy

47
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56
Declaration

I hereby declare that the license thesis titled “ MICROVACULAR
COMLICATIONS OF DIABETES MELLITUS ” is written by me under the guidance
of Dr. Dumitru Harea, Department of Endocrinology .U.S.M.F. State University of
Medicine and Pharmacy “Nicolae Testemitanu” Of Republic of Moldova, and has
never been submitted to another university or institution of higher education in the
country or abroad. Also, that all sources used, including those on the Internet, are
given in the paper with the rules for avoiding plagiarism:
– All the fragments of text reproduced exactly, even in his own translation from
another language are written between quotation marks and have a detailed reference
source;
– Reformulation of the texts in own words written by other authors have
detailed refere
– Summarizing the ideas of other a uthors has detailed reference to the original
text.

Date: Graduate’s Name Surname
11/05/2015
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