New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications

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 13297

Special Issue Editors


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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
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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

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Keywords

  • diabetic retinopathy
  • diabetic foot ulcer
  • inflammatory biomarkers
  • microbiota
  • novel therapies

Published Papers (11 papers)

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Research

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15 pages, 960 KiB  
Article
Postprandial Plasma Glucose between 4 and 7.9 h May Be a Potential Diagnostic Marker for Diabetes
by Yutang Wang, Yan Fang, Christopher L. Aberson, Fadi J. Charchar and Antonio Ceriello
Biomedicines 2024, 12(6), 1313; https://doi.org/10.3390/biomedicines12061313 - 13 Jun 2024
Viewed by 619
Abstract
Postprandial glucose levels between 4 and 7.9 h (PPG4–7.9h) correlate with mortality from various diseases, including hypertension, diabetes, cardiovascular disease, and cancer. This study aimed to assess if predicted PPG4–7.9h could diagnose diabetes. Two groups of participants were involved: Group [...] Read more.
Postprandial glucose levels between 4 and 7.9 h (PPG4–7.9h) correlate with mortality from various diseases, including hypertension, diabetes, cardiovascular disease, and cancer. This study aimed to assess if predicted PPG4–7.9h could diagnose diabetes. Two groups of participants were involved: Group 1 (4420 participants) had actual PPG4–7.9h, while Group 2 (8422 participants) lacked this measure but had all the diabetes diagnostic measures. Group 1 underwent multiple linear regression to predict PPG4–7.9h using 30 predictors, achieving accuracy within 11.1 mg/dL in 80% of the participants. Group 2 had PPG4–7.9h predicted using this model. A receiver operating characteristic curve analysis showed that predicted PPG4–7.9h could diagnose diabetes with an accuracy of 87.3% in Group 2, with a sensitivity of 75.1% and specificity of 84.1% at the optimal cutoff of 102.5 mg/dL. A simulation on 10,000 random samples from Group 2 revealed that 175 participants may be needed to investigate PPG4–7.9h as a diabetes diagnostic marker with a power of at least 80%. In conclusion, predicted PPG4–7.9h appears to be a promising diagnostic indicator for diabetes. Future studies seeking to ascertain its definitive diagnostic value might require a minimum sample size of 175 participants. Full article
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14 pages, 1487 KiB  
Article
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 - 24 Apr 2024
Cited by 1 | Viewed by 679
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 [...] Read more.
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
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19 pages, 1283 KiB  
Article
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 1094
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 [...] Read more.
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
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18 pages, 4106 KiB  
Article
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 977
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 [...] Read more.
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
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15 pages, 5890 KiB  
Article
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 1343
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 [...] Read more.
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
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10 pages, 623 KiB  
Article
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 818
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 [...] Read more.
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
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12 pages, 1670 KiB  
Article
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 864
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 [...] Read more.
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
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13 pages, 4472 KiB  
Article
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 913
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 [...] Read more.
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
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12 pages, 599 KiB  
Article
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 5 | Viewed by 1692
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), [...] Read more.
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
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Review

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17 pages, 1070 KiB  
Review
A Review of Fetal Development in Pregnancies with Maternal Type 2 Diabetes Mellitus (T2DM)-Associated Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation: Possible Links to Pregestational Prediabetes
by Mathuli Ngema, Nombuso D. Xulu, Phikelelani S. Ngubane and Andile Khathi
Biomedicines 2024, 12(6), 1372; https://doi.org/10.3390/biomedicines12061372 - 20 Jun 2024
Viewed by 545
Abstract
Research has identified fetal risk factors for adult diseases, forming the basis for the Developmental Origins of Health and Disease (DOHaD) hypothesis. DOHaD suggests that maternal insults during pregnancy cause structural and functional changes in fetal organs, increasing the risk of chronic diseases [...] Read more.
Research has identified fetal risk factors for adult diseases, forming the basis for the Developmental Origins of Health and Disease (DOHaD) hypothesis. DOHaD suggests that maternal insults during pregnancy cause structural and functional changes in fetal organs, increasing the risk of chronic diseases like type 2 diabetes mellitus (T2DM) in adulthood. It is proposed that altered maternal physiology, such as increased glucocorticoid (GC) levels associated with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis in maternal stress and T2DM during pregnancy, exposes the fetus to excess GC. Prenatal glucocorticoid exposure reduces fetal growth and programs the fetal HPA axis, permanently altering its activity into adulthood. This programmed HPA axis is linked to increased risks of hypertension, cardiovascular diseases, and mental disorders in adulthood. With the global rise in T2DM, particularly among young adults of reproductive age, it is crucial to prevent its onset. T2DM is often preceded by a prediabetic state, a condition that does not show any symptoms, causing many to unknowingly progress to T2DM. Studying prediabetes is essential, as it is a reversible stage that may help prevent T2DM-related pregnancy complications. The existing literature focuses on HPA axis dysregulation in T2DM pregnancies and its link to fetal programming. However, the effects of prediabetes on HPA axis function, specifically glucocorticoid in pregnancy and fetal outcomes, are not well understood. This review consolidates research on T2DM during pregnancy, its impact on fetal programming via the HPA axis, and possible links with pregestational prediabetes. Full article
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32 pages, 20966 KiB  
Review
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 - 2 Jan 2024
Cited by 1 | Viewed by 2401
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 [...] Read more.
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
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