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Effects of Diabetes on Neurodegenerative and Neurovascular Changes

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Endocrinology & Metabolism".

Deadline for manuscript submissions: closed (1 November 2020) | Viewed by 49957

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Prof. Dr. Marek Postuła

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Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CEPT), Medical University of Warsaw, Warsaw, Poland
Interests: pharmacogenomics; miRNA; diabetes; stroke; cardiovascular diseases; acute coronary syndrome; heart failure
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Special Issue Information

Dear Colleagues,

The incidence of diabetes is projected to double by 2030. Diabetes shows several associated alterations, including vascular dysfunction, neuropathies, as well as central complications All nerve fibre types are adversely affected by diabetes and, in addition to glycemic control and duration of diabetes, conventional and non-conventional markers of macro- and micro-vascular disease are strongly associated with neurodegenerative changes. In this Special Issue, we are making a call to action to stimulate researchers and clinicians to submit their most valuable studies on neurodegenerative and neurovascular changes in diabetes. Original investigations, review articles, and research letters are especially welcome.

Prof. Dr. Marek Postuła
Guest Editor

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Keywords

diabetes mellitus
neurodegeneration
neurovascular changes
complications

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Published Papers (9 papers)

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Research

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13 pages, 974 KiB

Open AccessArticle

Mild Cognitive Impairment Subtypes and Type 2 Diabetes in Elderly Subjects

by Silvia Valenza, Lucia Paciaroni, Susy Paolini, Anna Rita Bonfigli, Mirko Di Rosa, Rosa Anna Rabini, Elena Tortato, Paolo Pelliccioni and Giuseppe Pelliccioni

J. Clin. Med. 2020, 9(7), 2055; https://doi.org/10.3390/jcm9072055 - 30 Jun 2020

Cited by 13 | Viewed by 2822

Abstract

Background: Type 2 diabetes (T2D) is correlated to amnestic mild cognitive impairment (aMCI) and to non-amnestic mild cognitive impairment (naMCI). This study evaluated whether the T2D variable characterizes a peculiar cognitive profile in elderly patients. Moreover, it explores the association between glycated hemoglobin levels (HbA1c), T2D duration, insulin and oral hypoglycemic agent treatment, and cognition in elderly diabetic patients. Methods: Detailed neuropsychological battery was used to diagnose MCI subtypes. A total of 39 MCI subjects with T2D (T2D-MCI) and 37 MCI subjects without T2D (ND-MCI), matched for age, educational level, and Mini-Mental State Examination score, were included. Results: ND-MCI performed worse in memory and language domains than T2D-MCI. The amnestic subtype is more frequent among ND-MCI and non-amnestic subtype in T2D-MCI. In T2D-MCI, high HbA1c levels correlate with episodic memory (immediate recall) and T2D duration. Some indexes of episodic memory (immediate recall), attention, and visual-spatial ability correlate with insulin treatment. Conclusions: An association between T2D and non-amnestic MCI is suggested. In the T2D-MCI group, significant associations between insulin treatment and memory (immediate recall), complex figure copy, and attention were found. Full article

(This article belongs to the Special Issue Effects of Diabetes on Neurodegenerative and Neurovascular Changes)

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11 pages, 797 KiB

Open AccessArticle

Association between the Use of Dipeptidyl Peptidase 4 Inhibitors and the Risk of Dementia among Patients with Type 2 Diabetes in Taiwan

by Kuan-Chan Chen, Chi-Hsiang Chung, Chieh-Hua Lu, Nian-Sheng Tzeng, Chien-Hsing Lee, Sheng-Chiang Su, Feng-Chih Kuo, Jhih-Syuan Liu, Chang-Hsun Hsieh and Wu-Chien Chien

J. Clin. Med. 2020, 9(3), 660; https://doi.org/10.3390/jcm9030660 - 29 Feb 2020

Cited by 21 | Viewed by 4087

Abstract

Study Objectives: Diabetes mellitus per se and its related therapy have been frequently associated with an increased risk of developing dementia. However, studies that explored the risk of dementia from the use of the novel oral antidiabetic medication dipeptidyl peptidase 4 inhibitor (DPP-4i) have been limited, especially in Asian populations. The present study aimed to determine the effect of DPP-4i on the subsequent risk of dementia among patients with type 2 diabetes (T2D) in Taiwan. Methods: This study utilized data from the Longitudinal Health Insurance Database between 2008 and 2015. We enrolled 2903 patients aged ≥50 years, who were on DPP-4i for a diagnosis of T2D and had no dementia. A total of 11,612 subjects were included and compared with a propensity score-matched control group who did not use DPP-4i (non-DPP-4i group). Survival analysis was performed to estimate and compare the risk of dementia—including Alzheimer’s disease, vascular dementia, and other dementia types—between the two groups. Results: Both groups had a mean age of 68 years, had a preponderance of women (61.8%), and were followed up for a mean duration of 7 years. The risk of all-cause dementia was significantly lower in the DPP-4i group than in the non-DPP-4i group (hazard ratio (HR) 0.798; 95% confidence interval (CI) 0.681–0.883; p < 0.001), with a class effect. This trend was particularly observed for vascular dementia (HR 0.575; 95% CI 0.404–0.681; p < 0.001), but not in Alzheimer’s disease (HR 0.891; 95% CI 0.712–1.265; p = 0.297). The Kaplan–Meier analysis showed that the preventive effect on dementia was positively correlated with the cumulative dose of DPP-4i. Conclusions: DPP-4i decreased the risk of dementia with a class effect, especially vascular dementia, but not in Alzheimer’s disease. Our results provide important information on the drug choice when managing patients with T2D in clinical practice. Full article

(This article belongs to the Special Issue Effects of Diabetes on Neurodegenerative and Neurovascular Changes)

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12 pages, 254 KiB

Open AccessArticle

Novel Biochemical Markers of Neurovascular Complications in Type 1 Diabetes Patients

by Bogusz Falkowski, Anita Rogowicz-Frontczak, Ewelina Szczepanek-Parulska, Aleksandra Krygier, Elzbieta Wrotkowska, Aleksandra Uruska, Aleksandra Araszkiewicz, Marek Ruchala and Dorota Zozulinska-Ziolkiewicz

J. Clin. Med. 2020, 9(1), 198; https://doi.org/10.3390/jcm9010198 - 10 Jan 2020

Cited by 15 | Viewed by 3074

Abstract

Type 1 diabetes mellitus (T1DM) is associated with chronic complications, which are the result of neurovascular changes. There is still a lack of universal biochemical markers of microvascular damage. The present study aimed to investigate whether selected inflammatory proteins are related to the prevalence of microvascular complications in adult T1DM patients. The following markers were determined in a group of 100 T1DM participants: epidermal growth factor (EGF), metalloproteinase 2 (MMP-2), growth/differentiation factor 15 (GDF-15), and interleukin 29 (IL-29). Screening for microvascular complications, such as autonomic and peripheral neuropathy, diabetic kidney disease, and retinopathy, was conducted. The group was divided according to the occurrence of microvascular complications. At least one complication was required for the patient to be included in the microangiopathy group. The median EGF concentration in the microangiopathy group was higher than in the group without microangiopathy (p = 0.03). Increasing EGF concentration was a statistically significant predictor of the presence of microangiopathy in multivariate logistic regression analysis (p < 0.0001). Additionally, a higher GDF-15 level was associated with diabetic kidney disease, peripheral neuropathy, and proliferative retinopathy vs. nonproliferative retinopathy. GDF-15 concentration correlated negatively with estimated glomerular filtration rate (eGFR) (r = −0.28; p = 0.02). To conclude, higher EGF concentration is an independent predictor of the presence of microvascular complications in T1DM patients. Besides the relation between GDF-15 and diabetic kidney disease, it may be also associated with peripheral neuropathy and retinopathy. Full article

(This article belongs to the Special Issue Effects of Diabetes on Neurodegenerative and Neurovascular Changes)

Review

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18 pages, 3462 KiB

Open AccessReview

Retinal Vascular Endothelial Cell Dysfunction and Neuroretinal Degeneration in Diabetic Patients

by Malgorzata Mrugacz, Anna Bryl and Katarzyna Zorena

J. Clin. Med. 2021, 10(3), 458; https://doi.org/10.3390/jcm10030458 - 25 Jan 2021

Cited by 87 | Viewed by 8581

Abstract

Diabetes mellitus (DM) has become a vital societal problem as epidemiological studies demonstrate the increasing incidence of type 1 and type 2 diabetes. Lesions observed in the retina in the course of diabetes, referred to as diabetic retinopathy (DR), are caused by vascular abnormalities and are ischemic in nature. Vascular lesions in diabetes pertain to small vessels (microangiopathy) and involve precapillary arterioles, capillaries and small veins. Pericyte loss, thickening of the basement membrane, and damage and proliferation of endothelial cells are observed. Endothelial cells (monolayer squamous epithelium) form the smooth internal vascular lining indispensable for normal blood flow. Breaking its continuity initiates blood coagulation at that site. The endothelium controls the process of exchange of chemical substances (nutritional, regulatory, waste products) between blood and the retina, and blood cell passing through the vascular wall. Endothelial cells produce biologically active substances involved in blood coagulation, regulating vascular wall tension and stimulating neoangiogenesis. On the other hand, recent studies have demonstrated that diabetic retinopathy may be not only a microvascular disease, but is a result of neuroretinal degeneration. Neuroretinal degeneration appears structurally, as neural apoptosis of amacrine and Muller cells, reactive gliosis, ganglion cell layer/inner plexiform (GCL) thickness, retinal thickness, and retinal nerve fiber layer thickness, and a reduction of the neuroretinal rim in minimum rim width (MRW) and functionally as an abnormal electroretinogram (ERG), dark adaptation, contrast sensitivity, color vision, and microperimetric test. The findings in early stages of diabetic retinopathy may precede microvascular changes of this disease. Furthermore, the article’s objective is to characterize the factors and mechanisms conducive to microvascular changes and neuroretinal apoptosis in diabetic retinopathy. Only when all the measures preventing vascular dysfunction are determined will the risk of complications in the course of diabetes be minimized. Full article

(This article belongs to the Special Issue Effects of Diabetes on Neurodegenerative and Neurovascular Changes)

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23 pages, 874 KiB

Open AccessReview

The Importance of Non-Coding RNAs in Neurodegenerative Processes of Diabetes-Related Molecular Pathways

by Joanna Jarosz-Popek, Marta Wolska, Aleksandra Gasecka, Pamela Czajka, Daniel Jakubik, Lucia Sharif, Taqwa Adem, Wei-Ling Liu, Dagmara Mirowska-Guzel, Marek Postula and Ceren Eyileten

J. Clin. Med. 2021, 10(1), 9; https://doi.org/10.3390/jcm10010009 - 23 Dec 2020

Cited by 16 | Viewed by 3540

Abstract

Diabetes mellitus (DM) is a complex condition and serious health problem, with growing occurrence of DM-associated complications occurring globally. Persistent hyperglycemia is confirmed as promoting neurovascular dysfunction leading to irreversible endothelial cell dysfunction, increased neuronal cell apoptosis, oxidative stress and inflammation. These collaboratively and individually result in micro- and macroangiopathy as well as neuropathy demonstrated by progressive neuronal loss. Recently, major efforts have been pursued to select not only useful diagnostic and prognostic biomarkers, but also novel therapeutic approaches. Both microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) belong to a class of non-coding RNAs identified in most of the body fluids i.e., peripheral blood, cerebrospinal fluid, brain tissue and neurons. Numerous miRNAs, lncRNAs and their target genes are able to modulate signaling pathways known to play a role in the pathophysiology of progressive neuronal dysfunction. Therefore, they pose as promising biomarkers and treatment for the vast majority of neurodegenerative disorders. This review provides an overall assessment of both miRNAs’ and lncRNAs’ utility in decelerating progressive nervous system impairment, including neurodegeneration in diabetic pathways. Full article

(This article belongs to the Special Issue Effects of Diabetes on Neurodegenerative and Neurovascular Changes)

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20 pages, 5467 KiB

Open AccessReview

Retinal Neurovascular Coupling in Diabetes

by Gerhard Garhöfer, Jacqueline Chua, Bingyao Tan, Damon Wong, Doreen Schmidl and Leopold Schmetterer

J. Clin. Med. 2020, 9(9), 2829; https://doi.org/10.3390/jcm9092829 - 1 Sep 2020

Cited by 30 | Viewed by 4464

Abstract

Neurovascular coupling, also termed functional hyperemia, is one of the physiological key mechanisms to adjust blood flow in a neural tissue in response to functional activity. In the retina, increased neural activity, such as that induced by visual stimulation, leads to the dilatation of retinal arterioles, which is accompanied by an immediate increase in retinal and optic nerve head blood flow. According to the current scientific view, functional hyperemia ensures the adequate supply of nutrients and metabolites in response to the increased metabolic demand of the neural tissue. Although the molecular mechanisms behind neurovascular coupling are not yet fully elucidated, there is compelling evidence that this regulation is impaired in a wide variety of neurodegenerative and vascular diseases. In particular, it has been shown that the breakdown of the functional hyperemic response is an early event in patients with diabetes. There is compelling evidence that alterations in neurovascular coupling precede visible signs of diabetic retinopathy. Based on these observations, it has been hypothesized that a breakdown of functional hyperemia may contribute to the retinal complications of diabetes such as diabetic retinopathy or macular edema. The present review summarizes the current evidence of impaired neurovascular coupling in patients with diabetes. In this context, the molecular mechanisms of functional hyperemia in health and disease will be covered. Finally, we will also discuss how neurovascular coupling may in future be used to monitor disease progression or risk stratification. Full article

(This article belongs to the Special Issue Effects of Diabetes on Neurodegenerative and Neurovascular Changes)

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24 pages, 1142 KiB

Open AccessReview

Early Biomarkers of Neurodegenerative and Neurovascular Disorders in Diabetes

by Aleksandra Gasecka, Dominika Siwik, Magdalena Gajewska, Miłosz J. Jaguszewski, Tomasz Mazurek, Krzysztof J. Filipiak, Marek Postuła and Ceren Eyileten

J. Clin. Med. 2020, 9(9), 2807; https://doi.org/10.3390/jcm9092807 - 30 Aug 2020

Cited by 50 | Viewed by 7444

Abstract

Diabetes mellitus (DM) is a common disease worldwide. There is a strong association between DM and neurovascular and neurodegenerative disorders. The first group mainly consists of diabetic retinopathy, diabetic neuropathy and stroke, whereas, the second group includes Alzheimer’s disease, Parkinson’s disease, mild cognitive impairment and dementia. The aforementioned diseases have a common pathophysiological background including insulin resistance, oxidative stress, atherosclerosis and vascular injury. The increasing prevalence of neurovascular and neurodegenerative disorders among diabetic patients has resulted in an urgent need to develop biomarkers for their prediction and/or early detection. The aim of this review is to present the potential application of the most promising biomarkers of diabetes-related neurodegenerative and neurovascular disorders, including amylin, β-amyloid, C-reactive protein (CRP), dopamine, gamma-glutamyl transferase (GGT), glycogen synthase kinase 3β, homocysteine, microRNAs (mi-RNAs), paraoxonase 1, phosphoinositide 3-kinases, tau protein and various growth factors. The most clinically promising biomarkers of neurovascular and neurodegenerative complications in DM are hsCRP, GGT, homocysteine and miRNAs. However, all biomarkers discussed in this review could become a part of the potential multi-biomarker screening panel for diabetic patients at risk of neurovascular and neurodegenerative complications. Full article

(This article belongs to the Special Issue Effects of Diabetes on Neurodegenerative and Neurovascular Changes)

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28 pages, 14669 KiB

Open AccessReview

Optical Coherence Tomography Angiography in Diabetes and Diabetic Retinopathy

by Jacqueline Chua, Ralene Sim, Bingyao Tan, Damon Wong, Xinwen Yao, Xinyu Liu, Daniel S. W. Ting, Doreen Schmidl, Marcus Ang, Gerhard Garhöfer and Leopold Schmetterer

J. Clin. Med. 2020, 9(6), 1723; https://doi.org/10.3390/jcm9061723 - 3 Jun 2020

Cited by 78 | Viewed by 7968

Abstract

Diabetic retinopathy (DR) is a common complication of diabetes mellitus that disrupts the retinal microvasculature and is a leading cause of vision loss globally. Recently, optical coherence tomography angiography (OCTA) has been developed to image the retinal microvasculature, by generating 3-dimensional images based on the motion contrast of circulating blood cells. OCTA offers numerous benefits over traditional fluorescein angiography in visualizing the retinal vasculature in that it is non-invasive and safer; while its depth-resolved ability makes it possible to visualize the finer capillaries of the retinal capillary plexuses and choriocapillaris. High-quality OCTA images have also enabled the visualization of features associated with DR, including microaneurysms and neovascularization and the quantification of alterations in retinal capillary and choriocapillaris, thereby suggesting a promising role for OCTA as an objective technology for accurate DR classification. Of interest is the potential of OCTA to examine the effect of DR on individual retinal layers, and to detect DR even before it is clinically detectable on fundus examination. We will focus the review on the clinical applicability of OCTA derived quantitative metrics that appear to be clinically relevant to the diagnosis, classification, and management of patients with diabetes or DR. Future studies with longitudinal design of multiethnic multicenter populations, as well as the inclusion of pertinent systemic information that may affect vascular changes, will improve our understanding on the benefit of OCTA biomarkers in the detection and progression of DR. Full article

(This article belongs to the Special Issue Effects of Diabetes on Neurodegenerative and Neurovascular Changes)

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25 pages, 1940 KiB

Open AccessReview

Link between Diabetes and Alzheimer’s Disease Due to the Shared Amyloid Aggregation and Deposition Involving Both Neurodegenerative Changes and Neurovascular Damages

by Gabriela Dumitrita Stanciu, Veronica Bild, Daniela Carmen Ababei, Razvan Nicolae Rusu, Alina Cobzaru, Luminita Paduraru and Delia Bulea

J. Clin. Med. 2020, 9(6), 1713; https://doi.org/10.3390/jcm9061713 - 3 Jun 2020

Cited by 64 | Viewed by 7220

Abstract

Diabetes and Alzheimer’s disease are two highly prevalent diseases among the aging population and have become major public health concerns in the 21st century, with a significant risk to each other. Both of these diseases are increasingly recognized to be multifactorial conditions. The terms “diabetes type 3” or “brain diabetes” have been proposed in recent years to provide a complete view of the potential common pathogenic mechanisms between these diseases. While insulin resistance or deficiency remains the salient hallmarks of diabetes, cognitive decline and non-cognitive abnormalities such as impairments in visuospatial function, attention, cognitive flexibility, and psychomotor speed are also present. Furthermore, amyloid aggregation and deposition may also be drivers for diabetes pathology. Here, we offer a brief appraisal of social impact and economic burden of these chronic diseases and provide insight into amyloidogenesis through considering recent advances of amyloid-β aggregates on diabetes pathology and islet amyloid polypeptide on Alzheimer’s disease. Exploring the detailed knowledge of molecular interaction between these two amyloidogenic proteins opens new opportunities for therapies and biomarker development. Full article

(This article belongs to the Special Issue Effects of Diabetes on Neurodegenerative and Neurovascular Changes)

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