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Current Vascular Pharmacology, 2020, 18, 117-124

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ISSN: 1570-1611
eISSN: 1875-6212

Current Vascular
Pharmacology
The journal for current and in-depth reviews on Vascular Pharmacology

Microvascular Complications of Type 2 Diabetes Mellitus Impact

Factor:
2.58

BENTHAM
SCIENCE

Charles Faselis1,*, Alexandra Katsimardou2, Konstantinos Imprialos2, Pavlos Deligkaris3, Manolis

Kallistratos4 and Kiriakos Dimitriadis5

1
VA Medical Center, Washington, D.C., USA; 22nd Prop Department of Internal Medicine, Aristotle University, Thessa-
loniki, Greece; 3Department of Neurology, Hippokrateion Hospital, Thessaloniki, Greece; 4Cardiology Department,
Asklepeion Hospital, Athens, Greece; 51st Department of Cardiology, University of Athens, Athens, Greece

Abstract: Background: Type 2 diabetes mellitus (T2DM) is a chronic, non communicable, multi-
system disease that has reached epidemic proportions. Chronic exposure to hyperglycaemia affects the
microvasculature, eventually leading to diabetic nephropathy, retinopathy and neuropathy with high
impact on the quality of life and overall life expectancy. Sexual dysfunction is an often-overlooked mi-
crovascular complication of T2DM, with a complex pathogenesis originating from endothelial dysfunction.
Objective: The purpose of this review is to present current definitions, epidemiological data and risk
factors for diabetic retinopathy, nephropathy, neuropathy and sexual dysfunction. We also describe the
ARTICLE HISTORY clinical and laboratory evaluation that is mandatory for the diagnosis of these conditions.
Methods: A comprehensive review of the literature was performed to identify data from clinical studies
Current Vascular Pharmacology

Received: October 18, 2018

Revised: November 06, 2018
Accepted: November 12, 2018
DOI:
10.2174/1570161117666190502103733
Keywords: Diabetes mellitus, diabetic kidney disease, diabetic retinopathy, diabetic neuropathy, erectile dysfunction, mi-
crovascular complications.
for the prevalence, risk factors and diagnostic methods of microvascular complications of T2DM.
Results: Diabetic nephropathy and retinopathy affect approximately 25% of patients with T2DM; diabetic
neuropathy is encountered in almost 50% of the diabetic population, while the prevalence of erectile dys-
function ranges from 35-90% in diabetic men. The duration of T2DM along with glycemic, blood pressure
and lipid control are common risk factors for the development of these complications. Criteria for the diag-
nosis of these conditions are well established, but exclusion of other causes is mandatory.
Conclusion: Early detection of microvascular complications associated with T2DM is important, as
early intervention leads to better outcomes. However, this requires awareness of their definition,
prevalence and diagnostic modalities.

1. INTRODUCTION diabetic neuropathy is the major risk factor for amputation

Diabetes mellitus (DM) has emerged as a major public
health issue; it is estimated that 8.8% of the adult population
were affected in 2015, while future estimates are even more
alarming. In 2040, the proportion of the world’s adult popu-
lation with DM is expected to increase to 10.4%, translating
to 642 million diabetic patients [1]. Type 2 DM (T2DM) is
the major form of DM, accounting for 90-95% of all cases of
DM.
Chronic intracellular hyperglycemia and genetic predis-
position eventually affect the microvasculature, leading to
complications mainly from the kidneys, the eyes and the
nervous system (Fig. 1). Diabetic nephropathy is the leading
cause of end-stage renal disease (ESRD), diabetic retinopathy
(DR) is the main cause of blindness in the developed world,
*Address correspondence to this author at the VA Medical Center 50, Irving
Street, NW Washington, DC 20422, USA; E-mail: CharlesFaselis@va.gov
and foot ulceration and finally, sexual dysfunc-
tion disproportionately affects diabetic patients. High clinical
suspicion and early recognition of diabetic microvascular
complications are mandatory, as it is estimated that up to
25% of newly diagnosed patients with T2DM have already
developed one or more complications of DM.
The aim of this review is to report the prevalence, risk
factors and tools for the evaluation of microvascular compli-
cations.
2. DIABETIC KIDNEY DISEASE (DKD)
DKD is a common microvascular complication of DM,
affecting approximately 25% of the diabetic population [2].
Moreover, DM is the major cause of ESRD in the developed
world, accounting for 50% of all cases [3]. Meanwhile, there
is an established relationship between albuminuria and car-
diovascular disease (CVD). Specifically, microalbuminuria

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118 Current Vascular Pharmacology, 2020, Vol. 18, No. 2
Sexual
Dysfunction
Fig. (1). Microvascular complications in diabetes mellitus.
is considered as a risk factor for CVD, while interventions to
lower albuminuria have a positive effect on cardiovascular
protection [4]. Considering the above, early diagnosis of
DKD and appropriate intervention is of great importance.
DKD is defined as the presence of altered kidney func-
tion in diabetic patients, provided that other causes of
chronic kidney disease are excluded. According to the
American Diabetes Association’s latest guidelines, the diag-
nosis is based upon the findings of decreased estimated
glomerular filtration rate (eGFR <60 ml/min/1.73m2) and/or
increased urinary albumin excretion (≥30 mg/g creatinine)
persisting for >3 months [3].
Due to the insidious course of T2DM, it is mandatory to
assess patients for the presence of DKD at the time of the
diagnosis of T2DM and annually thereafter. Screening
should include the estimation of eGFR after measuring
serum creatinine and the assessment of urinary albumin to
creatinine ratio (UACR) in a spot urine sample [5]. Several
validated formulas have been proposed for the estimation of
eGFR. The most accurate seems to be the Chronic Kidney
Damage Epidemiology Collaboration equation (CKD-EPI)
[6]. In the first stages of diabetic nephropathy, the eGFR
may be high-normal or elevated due to hyperfiltration
despite changes in kidney function. Therefore, more
sensitive biomarkers, such as albuminuria, are required to
establish the diagnosis of DKD early enough to prevent
progression and improve outcomes.
The estimation of albuminuria can be performed either by
the calculation of the UACR in a spot urine sample or by the
measurement of albumin excretion over a predefined period of
time (24h collection). The measurement of UACR from a spot
urine sample is mostly used due to simplicity and
convenience. However, there are limitations. The estimated
day-to-day variability can reach up to 40% [3]. Moreover,
several clinical conditions may cause a rise in albuminuria,
such as urinary tract infections, fever, congestive heart failure,
high blood pressure, exercise, episodic hyperglycaemia or
high-protein intake. Therefore, an elevated UACR has to be
Faselis et al.
Diabetic
Nephropathy
Type 2 Diabetes Diabetic
Mellitus Retinopathy
Diabetic
Neuropathy
confirmed during the next 3 -6 months with 2 additional first-
void measurements. To confirm the diagnosis, 2 of the 3
samples should fulfill the required criteria for albuminuria [5].
The traditional classification of albuminuria into macro- and
microalbuminuria has been recently altered. In the KDIGO
2012 Clinical Practice Guidelines, albuminuria is divided into
3 categories, A1 (normal to mildly increased, UACR <30
mg/g creatinine), A2 (moderately increased, UACR 30-300
mg/g creatinine) and A3 (severely increased, UACR >300
mg/g creatinine) [6].
The high incidence of T2DM in the adult population sug-
gests that not all diabetic patients with altered kidney func-
tion have DKD, instead, non-diabetic renal disease (NDRD)
or mixed forms (superimposed NDRD on underlying DKD)
may be responsible [7]. According to a recent meta-analysis,
the prevalence of NDKD in the diabetic population ranges
from 3-82.9% [8]. This wide range is attributed to the het-
erogeneity of the population in the studies included. Renal
biopsy is the cornerstone for the diagnosis of diabetic glome-
rulopathy but it is rarely performed as standardized criteria
are lacking [9, 10]. It is usually reserved for conditions that
strongly indicate other etiologies of chronic kidney disease.
Specifically, the presence of a rapidly decreasing eGFR, ac-
tive urinary sediment, signs or symptoms of other systemic
disease or rapidly increasing proteinuria are usual indications
for renal biopsy [11]. Systolic blood pressure, the duration of
DM, the presence of DR and the range of HbA1c are in-
versely correlated with NDRD diagnosis [8]. Moreover, the
absence of albuminuria in the context of a reduced eGFR
possibly indicates NDRD.
Traditionally, the evolvement of diabetic nephropathy con-
sists of 5 well-defined stages based on data mainly derived
from studies including type 1 diabetic patients [12]. Hyperfil-
tration, the first stage of DKD, leads to albuminuria; in the
beginning microalbuminuria and in later stages macroalbu-
minuria, with a subsequent decrease in GFR and elevation in
blood pressure. The last stage refers to ESRD with detrimental
effects on patient’s quality of life and overall mortality. How-
Microvascular Complications of Type 2 Diabetes Mellitus
ever, this predefined course of events has been recently ques-
tioned. Recent studies proved that microalbuminuria does not
always progress to macroalbuminuria, while spontaneous re-
mission has also been observed. In the Steno-2 Study, over a
7.8-year follow-up, only 31.1% of the 151 subjects with mi-
croalbuminuria had progression to macroalbuminuria, whereas
38.4% remained microalbuminuric and 30.5% showed remis-
sion to normoalbuminuria. Regression of microalbuminuria
was correlated with antihypertensive treatment and a drop in
HbA1c due to improved glycaemic control [13]. On the other
hand, diabetic patients may show a decline in renal function,
as indicated by a rise in creatinine levels, without coexisting
albuminuria. In the United Kingdom Prospective Diabetes
Study (UKPDS), 38% of diabetic patients developed albumin-
uria over a median period of 15 years, while the proportion of
patients with renal impairment was 29%. Of those patients
with renal impairment, 51% had normal albumin concentra-
tions in the urine [14]. Similar results were reported in the
Renal Insufficiency and Cardiovascular Events Italian multi-
center study (RIACE), an observational, prospective cohort
study that included 15,773 patients with T2DM. According to
the analysis of data obtained at the baseline visit, the percent-
age of patients with renal impairment (eGFR
<60mL/min/1.73m2) and normoalbuminuria was 56.6%, with
microalbuminuria 30.8% and with macroalbuminuria 12.6%.
Non-albuminuric renal impairment was associated with female
gender and lower levels of HbA1c but the association with DR
and hypertension was weaker compared with albuminuric
patients. It should be pointed that in this population the preva-
lence of any CVD event was higher (OR: 1.66) than in pa-
tients with albuminuria alone (OR: 1.21) but lower than in
patients with renal impairment and albuminuria (OR: 2.27).
Treatment with angiotensin converting enzyme inhibitors
(ACEi) or angiotensin receptor blockers (ARBs) and better
control of DM and hypertension are considered possible ex-
planations for the higher prevalence of this phenotype in the
diabetic population. Finally, the possible pathophysiologic
mechanism for the development of non-albuminuric DKD is
macroangiopathy rather than microangiopathy [15], though
another possible explanation is that this condition is caused
after repeated and/or unresolved episodes of acute kidney in-
jury [16].
Taking the above into consideration, albuminuria and
eGFR are the currently used biomarkers for the diagnosis
and monitoring of DKD. However, not all CKD in diabetic
patients should be attributed to DM. More sensitive bio-
markers, as well as standardized criteria for renal biopsy, are
mandatory for better classification, earlier intervention and
better management of the diabetic population.
3. DIABETIC RETINOPATHY
DR is the most common cause of blindness worldwide.
In DR, vision loss is usually attributed to diabetic macular
edema (DME) that impairs central vision, or proliferative DR
(PDR), that might lead to the formation of new blood vessels
and fibrous tissue, resulting in fractional retinal detachment
and preretinal or vitreous haemorrhage. Although DR is tra-
ditionally considered as a primary vasculopathy, recent data
suggest that it could be a result of diabetic retinal
neurodegeneration (DRN); however, more research is
required for a causal relationship to be established [17].
Current Vascular Pharmacology, 2020, Vol. 18, No. 2 119
According to a meta-analysis that included 35 studies
conducted worldwide from 1980 to 2008, the prevalence of
DR in patients with T2DM is 25.16%, of PDR 2.97% and of
DME 5.57% [18], while in a recent systematic review, the
annual incidence of DR worldwide ranged from 2.2-12.7%
and the annual incidence of disease progression ranged from
3.4-12.3% [19].
Glycaemic control, blood pressure control and dyslipi-
daemia are well-established risk factors for the development
and progression of DR. The UKPDS study proved that inten-
sive glycaemic control resulted in a reduction in microvascu-
lar complications when compared with conventional treat-
ment. Specifically, a 25% risk reduction in the need for reti-
nal photocoagulation was observed in the intensive glycae-
mic control group [20]. Another major finding of the
UKPDS study was that tight blood pressure control resulted
in a 34% reduction in the rate of DR progression, while dete-
rioration of visual activity was reduced by 47%. The need for
retinal photocoagulation was reduced by 35% [21]. In the
Fenofibrate Intervention and Event Lowering in Diabetes
(FIELD) study, fenofibrate reduced the need for laser treat-
ment for any DR compared with placebo (3.4 vs. 4.9%,
p=0.0002), mainly due to a reduction in the prevalence of
DME in this population [22]. The favourable effects of fen-
ofibrate were verified in the Action to Control Cardiovascu-
lar Risk in Diabetes (ACCORD) Eye Study, where the addi-
tion of fenofibrate to simvastatin resulted in better outcomes
regarding DR (6.5% in the fenofibrate group vs. 10.2% in the
placebo group). In the same study, participants receiving
intensive glycemic control had lower rates of progression of
DR compared with those receiving standard medical treat-
ment (7.3 vs. 10.4%), while intensive blood pressure control
was not correlated with a slower progression of DR [23].
As in diabetic nephropathy, all patients should be evalu-
ated by an ophthalmologist at the diagnosis of T2DM. A
careful eye examination is mandatory to detect early signs of
DR, which usually are asymptomatic. Ophthalmoscopy on
dilated fundi allows detection of DR and staging of the dis-
ease. A 7-field stereoscopic fundus photography provides
similar results, with the advantage of giving data on patients’
status that can be used for comparison in the future [24].
Nonmydriatic digital stereoscopic retinal imaging is another
technique that could be used as a telemedicine tool for as-
sessing diabetic patients for the presence of DR, although it
cannot replace a detailed eye examination [25, 26]. In pa-
tients with documented DR, ultra-wide-field fluorescein an-
giography can be used for better visualization of vascular
leakage, retinal nonperfusion and neovascularization, assist-
ing in management with targeted photocoagulation [27]. Op-
tical coherence tomography (OCT) is a valuable non-
invasive technique in quantifying retinal thickness, a meas-
ure of macular edema, while OCT angiography provides
information regarding the retinal vasculature with results
comparable to fluorescein angiography [28, 29]. Finally,
recent advances in technology offer new tools in the diagno-
sis and staging of DR, such as smartphone fundoscopy, al-
though evidence regarding sensitivity and specificity are still
equivocal indicating the need for further research [30-32].
According to the 2018 American Diabetes Association
(ADA) Guidelines, if the eye examination is normal for 2
120 Current Vascular Pharmacology, 2020, Vol. 18, No. 2
consecutive years, then repeated examination may be per-
formed in wider time intervals, meaning every 1 to 3 years,
provided there is good glycaemic control. Otherwise, follow-
up intervals are determined by the stage of the disease to
assure that progression is promptly detected as early inter-
vention results in better outcome.
For years the classification of DR and macular edema is
based upon the international clinical DR disease severity
scale (ICDR) that determines 5 stages of DR [33]. DME may
be present at any stage of DR, although the incidence in-
creases as DR progresses to later stages. DR is classified into
2 general categories, nonproliferative DR (NPDR) and PDR.
NPDR is further classified as mild, moderate and severe
NPDR.
Mild NPDR is characterized by the presence of microan-
eurysms, which are outpouchings of blood capillary walls,
and haemorrhages (dots and blots) in the retina. Another
manifestation of this stage is hard exudates, which form due
to lipoprotein leakage from microaneurysms. Patients be-
longing to this category should be followed every 9-12
months. As NPDR progresses, retinal hypoxia and further
circulatory changes lead to the formation of more severe
lesions. Haemorrhages are more extensive, while venous
beading, cotton-wool spots resulting from localized infrac-
tions of the nerve fiber layer in the retina and intraretinal
microvascular abnormalities (IRMA), a type of intraretinal
neovascularization, are characteristic findings in the later
stages of NPDR. In moderate disease, patients should be
examined every 4-6 months, while in severe NPDR, where
lesions are extensive due to retinal ischaemia and progres-
sion to PDR is imminent, referral to an ophthalmologist for
possible early intervention is mandatory.
DR eventually progresses to the proliferative stage where
new vessels form on the disc or elsewhere on the retina that
can rupture spontaneously or after rigorous exercise, result-
ing in preretinal or vitreous haemorrhage. These patients
should be referred immediately for treatment as they are at
increased risk of visual loss. After the active phase of
neovascularization, remission follows with the subsequent
formation of fibrous tissue and fear of retinal detachment.
Summing up, DR is a frequent complication of T2DM that
when left unnoticed and untreated will eventually evolve into
severe complications. Close monitoring, early referral to an
ophthalmologist and modification of risk factors mentioned
above is of great importance. Interventions that could reverse
the natural course of DR or stem progression in the very early
stages are lacking, indicating the need for further research.
4. DIABETIC NEUROPATHY
Diabetic neuropathy refers to a heterogeneous group of
medical conditions that affect the diabetic population with
diverse clinical manifestations. It is a diagnosis of exclusion
in patients with T2DM and symptoms and/or signs of pe-
ripheral nerve dysfunction [34]. It is the most common mi-
crovascular complication of T2DM as it affects almost 50%
of patients after 10 years of disease duration, while it is esti-
mated that 20% of diabetic patients are affected at the time
of the diagnosis [35]. Despite its high prevalence in the dia-
betic population the diagnosis is often missed, as almost 50%
Faselis et al.
of patients are asymptomatic [36]. If left unnoticed and un-
treated, the condition may result in the development of Char-
cot neuroarthropathy, foot ulceration and finally foot ampu-
tation with high impact on quality of life and overall life
expectancy.
Several classifications have been proposed for diabetic
neuropathy, based on prevalence (typical or atypical), ana-
tomical distribution (distal or proximal, focal or multifocal),
clinical course (progressive or monophasic), pathophysiol-
ogy and characteristic features (motor, sensory or auto-
nomic) of diabetic neuropathy (Table 1). Traditionally, dia-
betic peripheral neuropathies (DPN) are divided into 3 cate-
gories; symmetric polyneuropathies with motor, sensory and
autonomic manifestations, focal and multifocal neuropathies
and finally mixed forms [37]. More recently, DPN is further
classified into typical DPN, particularly distal symmetric
sensorimotor polyneuropathy (DSPN), the most common
form of DPN and the one that will be further analyzed, and
the atypical forms (mononeuritis multiplex, thoracic radicu-
lopathy, etc.) [38].
Table 1. Types of diabetic neuropathy.
Types of Diabetic Neuropathy Based on the Thomas et al.
Classification [37]
1. Symmetric polyneuropathy
Distal sensorimotor symmetric polyneuropathy (DSPN)
Autonomic
Cardiovascular
Gastrointestinal
Urogenital
Sudomotor dysfunction
Acute sensory
2. Focal and multifocal neuropathies
Cranial neuropathies
Intercostal and truncal radiculopathies
Limp mononeuropathies
Amyotrophy
3. Mixed forms
DSPN is the most frequently encountered form of the dis-
ease, accounting for 75% of diabetic neuropathies [39]. It is
defined as a symmetrical, chronic, length-dependent sensori-
motor polyneuropathy, resulting from chronic hyperglycaemia
exposure in combination with cardiovascular risk factors [40].
There is no current treatment that reverses the progressive
axon degeneration and demyelination of the nerve fibers in-
volved highlighting the need for early prevention.
Glycemic control is considered as the most valuable pre-
ventive measure; however, results from previous randomized
control trials concerning the effect on DSPN progression are
conflicting. The first trial that proved a positive correlation
Microvascular Complications of Type 2 Diabetes Mellitus
between tight glycaemic control and beneficial outcomes
regarding diabetic neuropathy was conducted in Japan [41].
Similar results were found in ACCORD [42]. In contrast, the
UKPDS study failed to prove a positive effect of better gly-
caemic control on diabetic neuropathy [20]. Moreover, in the
Veterans Affairs Diabetes Trial (VADT) there was no differ-
ence between the intensive and standard treatment arm re-
garding the incidence of new diabetic neuropathy despite the
fact that differences in HbA1c between the 2 arms were sig-
nificant [43]. Similarly, in the Multicenter Anglo-Danish-
Dutch Study of Intensive Treatment in People with Screen-
Detected Diabetes in Primary Care (ADDITION) study, after
a follow-up period of 5.9 years, no statistically significant
difference was observed between the 2 study groups. This
could be attributed mainly to the fact that both groups
achieved identical values of HbA1c at the end of the study,
while the follow-up period was not long enough to observe a
beneficial effect [44]. Apart from glycaemic control, lifestyle
modifications are another preventive measure for diabetic
neuropathy. In the University of Utah T2DM study, patients
without evidence of peripheral neuropathy were assigned to
a mentoring program of exercise and dietary counselling vs.
standard of care. Intraepidermal nerve fiber density at the
ankle and proximal thigh was increased in the intensive ex-
ercise group, while it was slightly decreased in the standard
of care group, proving that metabolic improvement may re-
sult in regeneration of cutaneous axons [45].
As with the other microvascular complications in T2DM,
patients should be assessed for DSPN at the diagnosis of the
disease and every year thereafter. Nerve conduction studies
are considered as the gold standard for the diagnosis of
DSPN but their use in clinical practice is limited and re-
served for patients with atypical findings from the physical
examination. The diagnosis of DSPN is basically a clinical
one [36]. Small and large nerve fibers are involved in DSPN
with different symptoms and clinical findings. In small nerve
fiber involvement, pain, typically worse at night, and dyses-
thesias are the most common symptoms, while hyperalgesia
and allodynia may also be observed. In large nerve fiber in-
volvement, numbness and loss of protective sensation are
key findings. The small-fiber function is assessed by the
evaluation of pinprick and temperature sensation, while vi-
bration perception, proprioception, the presence of ankle
reflexes and light-touch perception are used for estimating
large-fiber function. Light-touch perception is evaluated with
the use of the 10-g monofilament, which is a valuable tool in
predicting the risk for ulceration and amputation. According
to the 2009 Toronto Consensus Panel on Diabetic Neuropa-
thies, there are 4 distinct categories of diagnostic certainty
based on the presence of symptoms and signs of neuropathy,
including possible, probable, confirmed and subclinical
DSPN [38]. Several instruments have been proposed for the
evaluation of patients with suspected DSPN, which are usu-
ally a combination of self-administered questions and foot
examination. Other sensitive estimates of DSPN that are not
currently proposed for routine evaluation in clinical practice,
but have proven as useful tools in clinical trials for a more
objective small fiber measure, are intraepidermal nerve fiber
density and corneal confocal microscopy [46].
Other etiologies of peripheral neuropathy must be ex-
cluded in patients tested positive before attributing the symp-
Current Vascular Pharmacology, 2020, Vol. 18, No. 2 121
tomatology to DSPN. Alcohol abuse, uraemia, environmental
or iatrogenic toxins, HIV infection, thyroid disease, paraprote-
inaemia, connective tissue disorders, paraneoplastic neuropa-
thies and inherited neuropathies are other causes of peripheral
neuropathy, which clinicians should try to exclude with care-
ful assessment of the medical and family history and perform-
ance of appropriate investigations [47]. In a previous retro-
spective study, the coexistence of DSPN with other causes of
neuropathy was estimated at 53%. Sensory abnormalities in
the hands of those patients were observed more frequently
suggesting that this finding should alert clinicians to search for
additional causes of peripheral neuropathy. The most common
additional findings in this population were alcohol abuse, the
use of neurotoxic medications, vitamin B12 deficiency and
kidney disease [48]. Electrodiagnostic tests and neuroaxis
MRI are not generally used because their contribution to
therapeutic management has proven to be little; however, re-
ferral to a neurologist is necessary when symptoms and signs
suggest an aetiology other than diabetic neuropathy, such as
rapid progression, motor neuropathy greater than sensory,
asymmetry of findings or unclear diagnosis [49].
DM is the most common cause of autonomic neuropathy
with great heterogeneity in clinical manifestations. It affects
the parasympathetic and the sympathetic nervous system or
both leading to symptoms from the cardiovascular, gastroin-
testinal, urogenital and submotor systems.
Cardiovascular autonomic neuropathy (CAN) is the most
studied form of diabetic autonomic neuropathy. It is defined
as the impairment of cardiovascular autonomic control, pro-
vided that other causes are excluded. It is estimated that it
affects approximately 60% of T2DM patients after 15 years
of the diagnosis [36] and is an independent risk factor for
silent ischaemia and cardiovascular mortality. In ACCORD,
the presence of CAN increased all-cause mortality by 1.55-
2.14 times, depending on the definition used for its presence
[50]. The most common symptoms and signs are resting
tachycardia, abnormal blood pressure regulation, exercise
intolerance and orthostatic hypotension, with weakness, diz-
ziness and syncope, although the condition is usually asymp-
tomatic in the early stages. The first indication for the pres-
ence of CAN is decreased heart rate variability (HRV), but
as the disease progresses, resting tachycardia and eventually
exercise intolerance, orthostatic hypotension, silent myocar-
dial ischaemia and cardiomyopathy with left ventricular dys-
function develop.
Screening should be performed at the diagnosis of
T2DM, especially in those with other chronic complications
of DM, cardiovascular risk factors and hypoglycaemia un-
awareness [36]. Diagnostic evaluation for the presence of
CAN includes the estimation of cardiovascular autonomic
reflex tests (CARTs), meaning beat-to-beat HRV, heart rate
response to standing, heart rate response to the Valsalva
maneuver, systolic blood pressure response to standing and
diastolic blood pressure response to isometric exercise.
Time-domain and frequency-domain HRV tests are other
useful tools in the evaluation of CAN. The presence of even
one abnormal CART (among the 7 tests: 5 CARTs, time-
domain HRV test and frequency-domain HRV test) is suffi-
cient for the early diagnosis of CAN. For a definite CAN
diagnosis 2 or 3 abnormal tests must be present, while if or-
122 Current Vascular Pharmacology, 2020, Vol. 18, No. 2
thostatic hypotension develops, then CAN is characterized as
severe [40]. Before a definite diagnosis it is important to
exclude other possible treatable causes with similar manifes-
tations, such as adrenal insufficiency, anaemia, intravascular
volume depletion, dehydration, medications, etc. [51].
Summarizing the above, DSPN is the most common
manifestation of diabetic neuropathy and the one that has
been more studied, however, in the randomized trials regard-
ing diabetic neuropathy, there is lack of uniformity due to
different definitions and measures for this disease. Standard-
ized criteria are needed for the diagnosis of the other diabetic
neuropathies that up till now are underdiagnosed and under-
treated.
5. SEXUAL DYSFUNCTION
Sexual dysfunction in T2DM patients is an often-
overlooked complication, despite the high impact of this
condition on quality of life. The pathogenesis of erectile dys-
function (ED) in diabetic patients is very complex and it is a
mixture of vasculopathic, neuropathic and hormonal changes
that are attributed to DM. It is a manifestation of microan-
giopathy, autonomic neuropathy and macroangiopathy and
as a result, ED could be possibly exploited as an early bio-
marker for diabetic complications enabling early intervention
and better outcomes.
ED is defined as the persistent or recurrent inability to
attain and/or maintain a penile erection sufficient for suc-
cessful sexual intercourse. Before a diagnosis can be made,
the symptom must be present for at least 3 months [52]. In
several studies the prevalence of ED ranged from 35-90% in
diabetic men. This wide range could be attributed to differ-
ences in methodology and population characteristics in those
studies [53]. ED is encountered 3 times more often in the
diabetic population [54], while it is estimated that within 10
years of the diagnosis, at least 50% of diabetic patients are
affected [55]. In a previous observational multicenter pro-
spective study, recently diagnosed T2DM patients were
evaluated for the presence of ED. ED was reported in 33.3%,
while 19.4% had mild, 15.4% mild-to-moderate, 10.4%
moderate and 21.6% severe ED, highlighting the fact that ED
may be present in the early stages of T2DM [56].
The correlation between ED and the development of
coronary artery disease (CAD) is well established, as it is
estimated that ED precedes the development of CAD in large
coronary arteries by 3-5 years. Therefore, screening patients
for the presence of ED may offer a valuable window of op-
portunity for the primary prevention of CAD, especially in
younger patients [57]. The former findings apply to diabetic
men, as ED has been confirmed to independently predict
CAD in patients without clinically overt CVD [58]. ED cor-
relates with diabetic nephropathy, retinopathy and neuropa-
thy [59-61], although with up to date data it cannot be used
as a screening tool for these conditions as further research is
necessary.
The diagnosis of ED is easily made with the use of vali-
dated questionnaires; the one that is most widely used is the
International Index of Erectile Dysfunction (IIEF). It is a 15-
item questionnaire that investigates 4 main domains of sex-
ual function in men; erectile function, orgasmic function,
Faselis et al.
sexual desire and intercourse satisfaction. Moreover, it can
be a valuable tool in the assessment of response to treatment
[62]. A careful review of the medical history is the next step
in the assessment of ED. DM often coexists with other co-
morbidities that are implicated in the development of ED,
such as hypertension, dyslipidaemia, depression and cardio-
vascular disease. Moreover, the modification of common risk
factors, such as obesity, physical inactivity, smoking and
alcohol consumption, may result in better outcomes regard-
ing ED in the general population [63]. In DM, the presence
of ED is associated with the duration of DM, while con-
sumption of small amounts of alcohol, leisure time and
physical activity had a positive impact on erectile function
[64]. Several common medications in clinical practice are
responsible for the presence of ED such as antihypertensive
and antidepressant agents. However, not all antihypertensive
medications are the same, as angiotensin receptor blockers
might have a positive effect on sexual function, while others,
such as calcium antagonists and angiotensin-converting en-
zyme inhibitors, have a neutral effect. Older antihypertensive
drugs, such as beta-blockers and diuretics may be the cause
of ED [65]. Physical examination alone rarely reveals the
cause of ED; however, specific signs may assist in the diag-
nosis, such as the presence of gynecomastia, alterations in
hair distribution or absence of peripheral pulses. Patients
reporting ED should be assessed for the presence of hypogo-
nadism using testosterone testing, as it is frequently reported
in patients with T2DM. The prevalence of hypogonadism in
recently diagnosed men with T2DM is almost 20% [56],
while it is estimated that as the disease progresses, in the
average diabetic population rates of hypogonadism can reach
up to 50% [66].
More specific diagnostic tests are not routinely used and
are reserved for specific indications [67]. Testing nocturnal
penile tumescence and rigidity using Rigiscan provides use-
ful information about the integrity of the neurovascular
mechanisms of erection. The performance of duplex ultra-
sound of the cavernous arteries after the intracavernous in-
jection of a vasoactive drug may reveal the presence of
penile arterial insufficiency. The integrity of the arterial and
venous systems in the penis can be examined after
intracavernous injection of a vasoactive drug and finally,
conduction of dynamic infusion cavernosometry and
cavernosonography are used when there is suspicion for the
presence of a corporal veno-occlusive dysfunction.
Female sexual dysfunction (FSD) is defined as persistent
or recurring decrease in sexual desire, persistent or recurring
decrease in sexual arousal, dyspareunia and difficulty in or
inability to achieve an orgasm [68]. According to a recent
meta-analysis, FSD is more frequent in women with T2DM
than in controls (odds ratio: 2.49) [69], while the prevalence
of FSD in women with T2DM ranges from 12-88% in previ-
ous trials [70]. Depression was more frequently observed in
diabetic women and BMI was the only variable that corre-
lated with FSD [69]. The presence of FSD can be evaluated
by the use of the Female Sexual Function Index (FSFI), a
brief, multidimensional score that assesses 6 domains of fe-
male sexuality; sexual desire, arousal, orgasm, lubrication,
satisfaction and pain [71].
Microvascular Complications of Type 2 Diabetes Mellitus
The pathogenesis of FSD is not completely understood in
diabetic women and the risk factors for the development of
FSD in this population are not well established. However,
women with FSD should be screened for the presence of
T2DM, as they are at increased risk for glycaemic alterations
[70].
CONCLUSION
The burden of T2DM microvascular complications is
rising substantially. However, up to date the pathogenesis of
most of these complications is not fully understood. More
sensitive biomarkers are needed for early diagnosis of these
complications, as well as interventions that could reverse the
pathophysiologic mechanisms implicated in the development
and progression of these disorders. Clinicians involved in the
medical care of diabetic patients should be instructed to fol-
low the standards of care for T2DM, with early detection and
careful monitoring of diabetic complications, while advances
in technology may prove to be a valuable tool in improving
adherence of the diabetic population.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Declared none.
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