Submit to Biomedicines Review for Biomedicines Propose a Special Issue

Journal Browser

New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Endocrinology and Metabolism Research".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 9206

Share This Special Issue

Special Issue Editors

Dr. Ana Dascalu

E-Mail Website
Guest Editor

Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania
Interests: diabetic retinopathy; glaucoma; inflammation; neurodegeneration; age-related macular degeneration
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Dragos Serban

E-Mail Website
Guest Editor

Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania
Interests: laparoscopic surgery; inflammatory biomarkers; emergency surgery; colorectal cancer; diabetic foot
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Diabetes mellitus is a major health problem globally, with an ascendant trend, expected to reach up to 700 million cases by 2045. The microvascular triad includes diabetic retinopathy, nephropathy, and neuropathy, unique in diabetes. Despite significant achievements in early diagnosis and therapy, diabetic retinopathy remains the leading cause of blindness in the working-age population, with a severe impact on patients' quality of life. Diabetic peripheral neuropathy affects nearly 50% of adults with diabetes during their lifetime, and it represents a major risk factor for diabetic foot ulcer (DFU), the most common cause of non-traumatic amputations worldwide. Classically, the duration of diabetes, level of hyperglycemia, arterial hypertension, and dyslipidemia are the most incriminated risk factors. Novel research has found multiple molecular pathways that may interfere with vascular disfunction, ischemia, and tissular damage.

In this Special Issue, we welcome original articles and reviews providing new research data on diabetic microvascular complications: novel biomarkers, early diagnosis, pathology, molecular mechanisms, and new therapies in the fields of diabetic retinopathy, nephropathy, neuropathy, and diabetic foot ulcers.

Dr. Ana Dascalu
Prof. Dr. Dragos Serban
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

diabetic retinopathy
diabetic foot ulcer
inflammatory biomarkers
microbiota
novel therapies

Published Papers (9 papers)

Download All Papers

Research

Jump to: Review

14 pages, 1487 KiB

Open AccessArticle

Angiopoietin-2 and Angiopoietin-like Proteins with a Prospective Role in Predicting Diabetic Nephropathy

by Eman Alshawaf, Mohamed Abu-Farha, Anwar Mohammad, Sriraman Devarajan, Irina Al-Khairi, Preethi Cherian, Hamad Ali, Hawra Al-Matrouk, Fahd Al-Mulla, Abdulnabi Al Attar and Jehad Abubaker

Biomedicines 2024, 12(5), 949; https://doi.org/10.3390/biomedicines12050949 (registering DOI) - 24 Apr 2024

Viewed by 165

Abstract

Angiopoietins are crucial growth factors for maintaining a healthy, functional endothelium. Patients with type 2 diabetes (T2D) exhibit significant levels of angiogenic markers, particularly Angiopoietin-2, which compromises endothelial integrity and is connected to symptoms of endothelial injury and failure. This report examines the levels of circulating angiopoietins in people with T2D and diabetic nephropathy (DN) and explores its link with ANGPTL proteins. We quantified circulating ANGPTL3, ANGPTL4, ANGPTL8, Ang1, and Ang2 in the fasting plasma of 117 Kuwaiti participants, of which 50 had T2D and 67 participants had DN. The Ang2 levels increased with DN (4.34 ± 0.32 ng/mL) compared with T2D (3.42 ± 0.29 ng/mL). This increase correlated with clinical parameters including the albumin-to-creatinine ratio (ACR) (r = 0.244, p = 0.047), eGFR (r = −0.282, p = 0.021), and SBP (r = −0.28, p = 0.024). Furthermore, Ang2 correlated positively to both ANGPTL4 (r = 0.541, p < 0.001) and ANGPTL8 (r = 0.41, p = 0.001). Multiple regression analysis presented elevated ANGPTL8 and ACRs as predictors for Ang2’s increase in people with DN. In people with T2D, ANGPTL4 positively predicted an Ang2 increase. The area under the curve (AUC) in receiver operating characteristic (ROC) analysis of the combination of Ang2 and ANGPTL8 was 0.77 with 80.7% specificity. In conclusion, significantly elevated Ang2 in people with DN correlated with clinical markers such as the ACR, eGFR, and SBP, ANGPTL4, and ANGPTL8 levels. Collectively, this study highlights a close association between Ang2 and ANGPTL8 in a population with DN, suggesting them as DN risk predictors. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications)

► Show Figures

Figure 1

19 pages, 1283 KiB

Open AccessArticle

Associations between Skin Autofluorescence Levels with Cardiovascular Risk and Diabetes Complications in Patients with Type 2 Diabetes

by Delia Reurean-Pintilei, Anca Pantea Stoian, Teodor Salmen, Roxana-Adriana Stoica, Liliana Mititelu-Tartau, Sandra Lazăr and Bogdan Timar

Biomedicines 2024, 12(4), 890; https://doi.org/10.3390/biomedicines12040890 - 17 Apr 2024

Viewed by 696

Abstract

Advanced Glycation End Products (AGEs) contribute to the pathophysiology of type 2 diabetes mellitus (T2DM) and cardiovascular (CV) diseases (CVDs), making their non-invasive assessment through skin autofluorescence (SAF) increasingly important. This study aims to investigate the relationship between SAF levels, cardiovascular risk, and diabetic complications in T2DM patients. We conducted a single-center, cross-sectional study at Consultmed Hospital in Iasi, Romania, including 885 T2DM patients. The assessment of SAF levels was performed with the AGE Reader™, (Diagnoptics, Groningen, The Netherlands). CVD prevalence was 13.9%, and according to CV risk category distribution, 6.1% fell into the moderate-risk, 1.13% into the high-risk, and 92.77% into the very-high-risk category. The duration of DM averaged 9.0 ± 4.4 years and the mean HbA1c was 7.1% ± 1.3. After adjusting for age and eGFR, HbA1c values showed a correlation with SAF levels in the multivariate regression model, where a 1 SD increase in HbA1c was associated with a 0.105 SD increase in SAF levels (Nagelkerke R² = 0.110; p < 0.001). For predicting very high risk with an SAF cut-off of 2.35, sensitivity was 67.7% and specificity was 56.2%, with an AUC of 0.634 (95% CI 0.560–0.709, p = 0.001). In T2DM, elevated SAF levels were associated with higher CV risk and HbA1c values, with 2.35 identified as the optimal SAF cut-off for very high CV risk. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications)

► Show Figures

Figure 1

18 pages, 4106 KiB

Open AccessArticle

Retinal Functional Impairment in Diabetic Retinopathy

by Cornelia Andreea Tănasie, Alexandra Oltea Dan, Oana Maria Ică, Maria Filoftea Mercuț, George Mitroi, Citto-Iulian Taisescu, Veronica Sfredel, Ramona Ingrid Corbeanu, Carmen Luminița Mocanu and Ciprian Danielescu

Biomedicines 2024, 12(1), 44; https://doi.org/10.3390/biomedicines12010044 - 22 Dec 2023

Cited by 2 | Viewed by 747

Abstract

Background: Diabetic retinopathy (DR) is a neurodegenerative disease of the retina. The aim of our study was to analyze latency changes in a full-field electroretinogram (ERG) in patients with type 2 diabetes. Material: This prospective study included 15 diabetic patients without DR, 16 diabetic patients with non-proliferative DR, 14 patients with pre-proliferative DR, 15 patients with proliferative DR, and 14 age-matched controls. All the participants underwent ophthalmologic examination and full-field ERGs. The ERGs were recorded with the Metrovision MonPackOne system. The latencies were analyzed for “a”- and “b”-waves in the dark-adapted (DA) 0.01 ERG, DA 3.0 ERG, DA oscillatory potentials, light-adapted (LA) 3.0 ERG, and 30 Hz flicker ERG. Results: The delayed responses of healthy subjects compared to diabetic patients without DR were the DA oscillatory potentials (25.45 ± 1.04 ms vs. 26.15 ± 0.96 ms, p = 0.027). When comparing diabetic patients without DR and with non-proliferative DR, we did not obtain statistically significant delays. Significant delays in the DA 0.01 “b”-wave (61.91 ± 5.52 ms vs. 66.36 ± 8.12 ms, p = 0.029), DA 3.0 “b”-wave (41.01 ± 2.50 ms vs. 44.16 ± 3.78 ms, p = 0.035), and LA 3.0 “a”-wave (16.21 ± 0.91 ms vs. 16.99 ± 1.16 ms, p = 0.045) were found between non-proliferative DR and pre-proliferative DR. When comparing the groups of patients with pre-proliferative DR and proliferative DR, the LA 3.0 ERG “b”-wave (32. 63 ± 2.53 ms vs. 36.19 ± 3.21 ms, p < 0.0001), LA 30 Hz flicker ERG “a”-wave (19.56 ± 3.59 vs. 21.75 ± 4.74 ms, p= 0.025), and “b”-wave (32.23 ± 4.02 vs. 36.68 ± 3.48 ms, p = 0.017) were delayed. Conclusions: the electrophysiological findings from our study indicate that there is a substantial dysfunction of the neural retina in all stages of DR. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications)

► Show Figures

Figure 1

15 pages, 5890 KiB

Open AccessArticle

Association of Endotoxemia with Low-Grade Inflammation, Metabolic Syndrome and Distinct Response to Lipopolysaccharide in Type 1 Diabetes

by Aleksejs Fedulovs, Leonora Pahirko, Kaspars Jekabsons, Liga Kunrade, Jānis Valeinis, Una Riekstina, Valdis Pīrāgs and Jelizaveta Sokolovska

Biomedicines 2023, 11(12), 3269; https://doi.org/10.3390/biomedicines11123269 - 10 Dec 2023

Viewed by 1096

Abstract

The association of endotoxemia with metabolic syndrome (MS) and low-grade inflammation in type 1 diabetes (T1D) is little-studied. We investigated the levels of lipopolysaccharide (LPS), lipopolysaccharide-binding protein (LBP), endogenous anti-endotoxin core antibodies (EndoCAb IgG and IgM) and high-sensitivity C-reactive protein (hsCRP) in 74 T1D patients with different MS statuses and 33 control subjects. Within the T1D group, 31 patients had MS. These subjects had higher levels of LPS compared to patients without MS (MS 0.42 (0.35–0.56) or no MS 0.34 (0.3–0.4), p = 0.009). MS was associated with LPS/HDL (OR = 6.5 (2.1; 20.0), p = 0.036) and EndoCAb IgM (OR = 0.32 (0.11; 0.93), p = 0.036) in patients with T1D. LBP (β = 0.30 (0.09; 0.51), p = 0.005), EndoCAb IgG (β = 0.29 (0.07; 0.51), p = 0.008) and the LPS/HDL ratio (β = 0.19 (0.03; 0.41, p = 0.084) were significantly associated with log-transformed hsCRP in T1D. Higher levels of hsCRP and EndoCAb IgG were observed in T1D compared to the control (p = 0.002 and p = 0.091, respectively). In contrast to the situation in the control group, LPS did not correlate with LBP, EndoCAb, leukocytes or HDL in T1D. To conclude, endotoxemia is associated with low-grade inflammation, MS and a distinct response to LPS in T1D. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications)

► Show Figures

Graphical abstract

10 pages, 623 KiB

Open AccessArticle

Optical Coherence Tomography Angiography Changes in Macular Area in Patients with Proliferative Diabetic Retinopathy Treated with Panretinal Photocoagulation

by Irini Chatziralli, Eleni Dimitriou, Chrysa Agapitou, Dimitrios Kazantzis, Petros Kapsis, Nick Morogiannis, Stylianos Kandarakis, George Theodossiadis and Panagiotis Theodossiadis

Biomedicines 2023, 11(12), 3146; https://doi.org/10.3390/biomedicines11123146 - 26 Nov 2023

Viewed by 662

Abstract

Background: The purpose of this study was to investigate the changes in macular microvasculature using optical coherence tomography angiography (OCTA) in association with functional changes in patients with proliferative diabetic retinopathy (PDR) treated with panretinal photocoagulation (PRP) with a follow up of 12 months. Methods: The participants in this study were 28 patients with PDR and no macular oedema, who were eligible for PRP. All participants underwent best-corrected visual acuity (BCVA) measurement, optical coherence tomography (OCT), and OCT angiography (OCTA) at baseline (before treatment) and at months 1, 6, and 12 after the completion of PRP treatment. The comparison of OCTA parameters and BCVA between baseline and months 1, 6, and 12 after PRP was performed. Results: There was a statistically significant decrease in foveal avascular zone (FAZ) area at months 6 and 12 of the follow-up period compared to baseline (p = 0.014 and p = 0.011 for month 6 and 12, respectively). Of note is that FAZ became significantly more circular 6 months after PRP (p = 0.009), and remained so at month 12 (p = 0.015). There was a significant increase in the mean foveal and parafoveal vessel density (VD) at all quadrants at the superficial capillary plexus (SCP) at month 6 and month 12 after PRP compared to baseline. No difference was noticed in VD at the deep capillary plexus (DCP) at any time-point of the follow up. BCVA remained the same throughout the follow-up period. Conclusions: At months 6 and 12 after PRP, foveal and parafoveal VD at SCP significantly increased compared to baseline, while the FAZ area significantly decreased and FAZ became more circular. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications)

► Show Figures

Figure 1

12 pages, 1670 KiB

Open AccessArticle

Cross-Sectional and Longitudinal Associations between Skin Autofluorescence and Tubular Injury Defined by Urinary Excretion of Liver-Type Fatty Acid-Binding Protein in People with Type 2 Diabetes

by Hiroki Yamagami, Tomoyo Hara, Saya Yasui, Minae Hosoki, Taiki Hori, Yousuke Kaneko, Yukari Mitsui, Kiyoe Kurahashi, Takeshi Harada, Sumiko Yoshida, Shingen Nakamura, Toshiki Otoda, Tomoyuki Yuasa, Akio Kuroda, Itsuro Endo, Munehide Matsuhisa, Masahiro Abe and Ken-ichi Aihara

Biomedicines 2023, 11(11), 3020; https://doi.org/10.3390/biomedicines11113020 - 10 Nov 2023

Viewed by 699

Abstract

It has previously been unclear whether the accumulation of advanced glycation end products, which can be measured using skin autofluorescence (SAF), has a significant role in diabetic kidney disease (DKD), including glomerular injury and tubular injury. This study was therefore carried out to determine whether SAF correlates with the progression of DKD in people with type 2 diabetes (T2D). In 350 Japanese people with T2D, SAF values were measured using an AGE Reader^®, and both urine albumin-to-creatinine ratio (uACR), as a biomarker of glomerular injury, and urine liver-type fatty acid-binding protein (uLFABP)-to-creatinine ratio (uL-FABPCR), as a biomarker of tubular injury, were estimated as indices of the severity of DKD. Significant associations of SAF with uACR (p < 0.01), log-transformed uACR (p < 0.001), uL-FABPCR (p < 0.001), and log-transformed uL-FABPCR (p < 0.001) were found through a simple linear regression analysis. Although SAF was positively associated with increasing uL-FABPCR (p < 0.05) and increasing log-transformed uL-FABPCR (p < 0.05), SAF had no association with increasing uACR or log-transformed uACR after adjusting for clinical confounding factors. In addition, the annual change in SAF showed a significant positive correlation with annual change in uL-FABPCR regardless of confounding factors (p = 0.026). In conclusion, SAF is positively correlated with uL-FABP but not with uACR in people with T2D. Thus, there is a possibility that SAF can serve as a novel predictor for the development of diabetic tubular injury. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications)

► Show Figures

Figure 1

13 pages, 4472 KiB

Open AccessArticle

The Multi-Kinase Inhibitor RepSox Enforces Barrier Function in the Face of Both VEGF and Cytokines

by Lina Lietuvninkas, Basma Baccouche and Andrius Kazlauskas

Biomedicines 2023, 11(9), 2431; https://doi.org/10.3390/biomedicines11092431 - 31 Aug 2023

Viewed by 776

Abstract

The therapeutic benefit provided by anti-vascular endothelial growth factor (VEGF) for patients with vision-threatening conditions such as diabetic retinopathy (DR) demonstrates the important role of VEGF in this affliction. Cytokines, which can be elevated in the vitreous of patients with DR, promote leakage of retinal blood vessels, and may also contribute to pathology, especially in those patients for whom anti-VEGF does not provide adequate benefit. In this in vitro study using primary human retinal endothelial cells, we compared anti-VEGF with the (transforming growth factor beta) TGFβ receptor inhibitor RepSox (RS) for their ability to enforce barrier function in the face of VEGF, cytokines, and the combination of both. RS was superior to anti-VEGF because it prevented permeability in response to VEGF, cytokines, and their combination, whereas anti-VEGF was effective against VEGF alone. The inhibitory effect of RS was associated with suppression of both agonist-induced pore formation and disorganization of adherens junctions. RS-mediated inhibition of the TGFβ pathway and increased expression of claudin-5 did not adequately explain how RS stabilized the endothelial cell barrier. Finally, RS not only prevented barrier relaxation, but also completely or partially reclosed a barrier relaxed with tumor necrosis factor α (TNF α) or VEGF, respectively. These studies demonstrate that RS stabilized the endothelial barrier in the face of both cytokines and VEGF, and thereby identify RS as a therapeutic that has the potential to overcome permeability driven by multiple agonists that play a role in the pathology of DR. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications)

► Show Figures

Figure 1

12 pages, 599 KiB

Open AccessArticle

The Value of White Cell Inflammatory Biomarkers as Potential Predictors for Diabetic Retinopathy in Type 2 Diabetes Mellitus (T2DM)

by Ana Maria Dascalu, Dragos Serban, Denisa Tanasescu, Geta Vancea, Bogdan Mihai Cristea, Daniela Stana, Vanessa Andrada Nicolae, Crenguta Serboiu, Laura Carina Tribus, Corneliu Tudor, Adriana Georgescu, Mihail Silviu Tudosie, Daniel Ovidiu Costea and Dan Georgian Bratu

Biomedicines 2023, 11(8), 2106; https://doi.org/10.3390/biomedicines11082106 - 26 Jul 2023

Cited by 3 | Viewed by 1357

Abstract

The pathogenesis of diabetic retinopathy is still challenging, with recent evidence proving the key role of inflammation in the damage of the retinal neurovascular unit. This study aims to investigate the predictive value of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic inflammation index (SII) for diabetic retinopathy (DR) and its severity. We performed a retrospective study on 129 T2DM patients, divided into three groups: without retinopathy (NDR), non-proliferative DR (NPDR), and proliferative DR (PDR). NLR, MLR, and SII were significantly higher in the PDR group when compared to NDR and NPDR (3.2 ± 1.6 vs. 2.4 ± 0.9 and 2.4 ± 1.1; p = 0.005; 0.376 ± 0.216 vs. 0.269 ± 0.083 and 0.275 ± 0.111, p = 0.001; 754.4 ± 514.4 vs. 551.5 ± 215.1 and 560.3 ± 248.6, p = 0.013, respectively). PDR was correlated with serum creatinine (OR: 2.551), NLR (OR: 1.645), MPV (OR: 1.41), and duration of diabetes (OR: 1.301). Logistic regression analysis identified three predictive models with very good discrimination power for PDR (AUC ROC of 0.803, 0.809, and 0.830, respectively): combining duration of diabetes with NLR, MLR, and, respectively, PLR, MPV, and serum creatinine. NLR, MPV, SII, and LMR were associated with PDR and could be useful when integrated into comprehensive risk prediction models. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications)

► Show Figures

Graphical abstract

Review

Jump to: Research

32 pages, 20966 KiB

Open AccessReview

A Closer Look at the Perivascular Unit in the Development of Enlarged Perivascular Spaces in Obesity, Metabolic Syndrome, and Type 2 Diabetes Mellitus

by Melvin R. Hayden

Biomedicines 2024, 12(1), 96; https://doi.org/10.3390/biomedicines12010096 - 02 Jan 2024

Viewed by 1842

Abstract

The recently described perivascular unit (PVU) resides immediately adjacent to the true capillary neurovascular unit (NVU) in the postcapillary venule and contains the normal-benign perivascular spaces (PVS) and pathological enlarged perivascular spaces (EPVS). The PVS are important in that they have recently been identified to be the construct and the conduit responsible for the delivery of metabolic waste from the interstitial fluid to the ventricular cerebrospinal fluid for disposal into the systemic circulation, termed the glymphatic system. Importantly, the outermost boundary of the PVS is lined by protoplasmic perivascular astrocyte endfeet (pvACef) that communicate with regional neurons. As compared to the well-recognized and described neurovascular unit (NVU) and NVU coupling, the PVU is less well understood and remains an emerging concept. The primary focus of this narrative review is to compare the similarities and differences between these two units and discuss each of their structural and functional relationships and how they relate not only to brain homeostasis but also how they may relate to the development of multiple clinical neurological disease states and specifically how they may relate to obesity, metabolic syndrome, and type 2 diabetes mellitus. Additionally, the concept and importance of a perisynaptic astrocyte coupling to the neuronal synapses with pre- and postsynaptic neurons will also be considered as a perisynaptic unit to provide for the creation of the information transfer in the brain via synaptic transmission and brain homeostasis. Multiple electron microscopic images and illustrations will be utilized in order to help explain these complex units. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications)

► Show Figures