The prevalence of diabetes (DM) is constantly increasing worldwide at an alarming
rate. According to the International Diabetes Federation in 2015, an estimated 415
million people globally were suffering from this condition [1]. Complications of DM
account for increased morbidity, disability, and mortality and represent a threat
for the economies of all countries, especially the developing ones [2]. The present
special issue has been devoted to the recent progress in our understanding of diabetic
complications, including the underlying molecular mechanisms, new diagnostic tools
that facilitate early diagnosis, and novel treatment options. It consists of 20 articles
covering 5 thematic areas: (a) epidemiology and pathogenesis of diabetic complications,
(b) microvascular complications, (c) macrovascular complications, (d) miscellaneous
complications, and (e) treatment options.
(a) Epidemiology and Pathogenesis of Diabetic Complications. There is growing evidence
that the underlying mechanisms in the pathogenesis of diabetic complications include
certain genetic and epigenetic modifications, nutritional factors, and sedentary lifestyle
[3]. In a paper of this special issue entitled “Epigenetic Studies Point to DNA Replication/Repair
Genes as a Basis for the Heritable Nature of Long Term Complications in Diabetes,”
A. A. Leontovich et al., using a zebrafish diabetic model, have explored the role
of epigenetic mechanisms on the persistence of diabetic complications even after euglycemic
control is achieved, a condition known as metabolic memory. They found that DNA-methylation,
in or near genes belonging to the DNA replication/DNA metabolism process group, might
play a key role in this process. Regarding basic risk factors for macro- and microvascular
complications, the Irish Longitudinal Study on Ageing (TILDA), as M. L. Tracey et
al. describe in their article “Risk Factors for Macro- and Microvascular Complications
among Older Adults with Diagnosed Type 2 Diabetes: Findings from The Irish Longitudinal
Study on Ageing,” has recognized ageing, male gender, smoking, low level of physical
activity, and high cholesterol as independent predictors of macrovascular complications.
Conversely, smoking, hypertension, and duration of DM over 10 years proved to be predictive
factors for microvascular complications.
(b) Microvascular Complications. Diabetic nephropathy, neuropathy, and retinopathy
are the main microvascular complications induced by chronic hyperglycemia via several
mechanisms such as the production of advanced glycation end products (AGEs), the creation
of a proinflammatory microenvironment, and the induction of oxidative stress [4, 5].
Four articles in this special issue focus on diabetic nephropathy (DN). The first,
by K. Sawada et al. entitled “Upregulation of α3β1-Integrin in Podocytes in Early-Stage
Diabetic Nephropathy” shed light on the mechanism of podocyte detachment from the
glomerular basement membrane, which is considered to be a key factor in the development
of DN. The authors conclude that the early stages of this procedure are mediated by
an upregulation of α3β1-integrin in podocytes. In the second article about DN entitled
“Oxidative Stress in Diabetic Nephropathy with Early Chronic Kidney Disease,” A. G.
Miranda-Díaz et al. have reviewed the effects of hyperglycemia-induced production
of reactive oxygen species (ROS) on the renin-angiotensin system and the signaling
pathway of the transforming growth factor-beta (TGF-β). They have concluded that oxidative
stress leads to the production of chronic inflammation and the glomerular and tubular
hypertrophy, which characterize the early stages of DN. Turning their attention to
the diagnosis of early diabetic nephropathy, C. Gluhovschi et al., in another paper
of this issue titled “Urinary Biomarkers in the Assessment of Early Diabetic Nephropathy,”
have attempted to review novel biomarkers indicating renal injury such as transferrin,
ceruloplasmin, podocalyxin, and VEGF. These markers can detect renal injury even before
the presence of microalbuminuria, which still remains the most valid biomarker for
DN in clinical practice. The last paper on the same topic, by X. Li et al., entitled
“Histone Acetylation and its Modifiers in the Pathogenesis of Diabetic Nephropathy,”
provides an overview of the potential involvement of epigenetic mechanisms, such as
histone acetylation and other cellular processes in the development and progression
of DN. It may be hoped that these mechanisms can help towards defining new therapeutic
approaches for this microvascular complication of DM.
Three more articles have been included in the present special issue referring to diabetic
retinopathy and neuropathy. The article entitled “Diabetic Retinopathy Is Strongly
Predictive of Cardiovascular Autonomic Neuropathy in Type 2 Diabetes” has evaluated
risk factors for cardiovascular autonomic neuropathy (CAN) in patients with T2DM.
In this article, C.-C. Huang et al., using the deep breathing test, the Valsalva maneuver
method, and the Composite Autonomic Scoring Scale to estimate the severity of autonomic
neuropathy, found that diabetic retinopathy is the most significant predictive factor
for CAN. In a further work, L. Forga et al. have conducted an observational, retrospective
study in order to identify risk factors for the development of diabetic retinopathy
(DR) in patients with type 1 DM. In their study entitled “Influence of Age at Diagnosis
and Time-Dependent Risk Factors on the Development of Diabetic Retinopathy in Patients
with Type 1 Diabetes,” they maintain that age at onset of type 1 DM, indexes of glycemic
control, HDL-cholesterol levels, and diastolic blood pressure are all parameters predicting
DR. In this regard, the study “Heart Rate Variability as Early Biomarker for the Evaluation
of Diabetes Mellitus Progress” by R. E. Arroyo-Carmona et al. has used heart rate
variability (HRV) as a tool to identify early diabetic complications and progress
of DM in streptozotocin-induced diabetic mice.
(c) Macrovascular Complications. Atherosclerosis is more common in people with DM
than in those without. For example, DM increases the risk for stroke in people aged
20 to 65 years more than 5 times [6]. The present special issue includes articles
on macrovascular complications of DM as well. J. Zhang et al. in the article entitled
“Coronary Plaque Characteristics Assessed by 256-Slice Coronary CT Angiography and
Association with High-Sensitivity C-Reactive Protein in Symptomatic Patients with
Type 2 Diabetes” have performed a coronary Computed Tomography Angiography to evaluate
coronary plaque subtypes and luminal narrowing in patients with and without type 2
DM. They report that patients with DM are more prone to have significant stenosis
with calcified plaques and such findings are accompanied by higher hs-CRP levels.
Moreover, in a review article entitled “The Role of AGE/RAGE Signaling in Diabetes-Mediated
Vascular Calcification,” A. M. Kay et al. emphasize the key role of AGE/RAGE signaling
on the promotion of DM-mediated vascular calcification. In this process, many intracellular
signaling pathways contribute to increased oxidative stress, which in turn leads to
deposition of hydroxyapatite minerals into the extracellular matrix and vascular calcification.
Furthermore, M. Samoš et al. in their work “The Impact of Type 2 Diabetes on the Efficacy
of ADP Receptor Blockers in Patients with Acute ST Elevation Myocardial Infarction:
A Pilot Prospective Study” have presented data from a prospective study that aimed
to investigate platelet reactivity in patients with acute ST elevation myocardial
infarction (STEMI) with or without T2DM, who have been treated with adenosine diphosphate
(ADP) receptor blockers. Of note, this study has shown no difference between the two
groups regarding platelet reactivity and the number of nonresponders to ADP receptor
blockers. The last article of this thematic area is a retrospective quantitative study
conducted in Australia. As B. T. Rodrigues et al. describe in their manuscript entitled
“Prevalence and Risk Factors for Diabetic Lower Limb Amputation: A Clinic-Based Case
Control Study,” ethnicity has been recognized as an independent risk factor for lower
limb amputation in patients with diabetic foot, among whom indigenous Australians
were most commonly affected.
(d) Miscellaneous Complications. Diabetic cardiomyopathy is a specific complication
that develops independently of coronary artery disease or hypertension and it is possible
to lead to increased morbidity and mortality [7]. The aim of the study “Assessment
of Left Ventricular Structural Remodelling in Patients with Diabetic Cardiomyopathy
by Cardiovascular Magnetic Resonance” by Y. Shang et al. was to evaluate the structural
remodeling of left ventricular (LV) mass in patients with diabetic cardiomyopathy
(DCM) using cardiovascular magnetic resonance (CMR). The authors contend that CMR
can be a valid tool to estimate LV remodeling and its severity in patients with DCM.
Y. Yu et al. in their article entitled “The Protective Effect of Low Dose Ethanol
on Myocardial Fibrosis through Downregulating the JNK Signaling Pathway in Diabetic
Rats” have explored the protective role of low dose ethanol on myocardial fibrosis
in diabetic rats. In this study, low dose ethanol consumption was associated with
lower mean arterial pressure, lower heart rate, high hydroxyproline content, and collagen
volume fraction in myocardial tissue, together with decreased expression of ALDH2
and downregulation of the JNK pathway. Finally, in the review paper “Molecular and
Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus,”
G. Tse et al. discuss in detail the role of several cardiac factors (e.g., abnormalities
in conduction or repolarization, electrophysiological, and structural remodeling)
on arrhythmogenesis in patients with DM. They suggest that deeper investigation of
these mechanisms can help towards defining new target molecules for potential future
antiarrhythmic therapy for patients with DM.
(e) Treatment Options. The last thematic area covered by the present special issue
relates to novel therapeutic options and it comprises four articles. In the first
entitled “The Yin and Yang of the Opioid Growth Regulatory System: Focus on Diabetes:
The Lorenz E. Zimmerman Tribute Lecture,” J. W. Sassani et al. provide an extensive
overview of the role of the Opioid Growth Regulatory System on the development of
diabetic complications. The authors have summarized all recent evidence indicating
that certain pharmaceutical modifications in the function of this system can have
profitable effects on diabetic animals. Clearly, there is a lot to learn about these
intricate issues in the future. The second manuscript, “Implementation of a Diabetes
Educator-Care Model to Reduce Paediatric Admission for Diabetic Ketoacidosis” by A.
Deeb et al., has evaluated a diabetes educator-care model aiming to reduce the frequency
of hospital admission of children and adolescents due to Diabetic Ketoacidosis (DKA).
The authors have demonstrated that this model was an effective and sustainable measure
for DM treatment achieving a significant reduction in the admission rate for DKA.
L. Voroneanu et al. in their article entitled “Silymarin in Type 2 Diabetes Mellitus:
A Systematic Review and Meta-Analysis of Randomized Controlled Trials” have conducted
a comprehensive review and meta-analysis to evaluate the efficacy and safety of silymarin
administration in patients with T2DM. They have found that this extract of milk thistle
is an efficient and safe antidiabetic agent that might also have beneficial effects
on renal function. However, significant heterogeneity and low quality of the available
evidence were noted and lead to the need for further investigation of this issue.
The final study pertains to the treatment of diabetic foot ulcers. M. Janka-Zires
et al. in their article titled “Topical Administration of Pirfenidone Increases Healing
of Chronic Diabetic Foot Ulcers: A Randomized Crossover Study” have conducted a randomized
crossover study to assess the effect of topical administration of pirfenidone on noninfected
chronic diabetic foot ulcers. Their findings confirm that the healing of these ulcers
improves significantly by topical addition of pirfenidone.