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Effects of Prediabetes on the Progression of Cardiovascular Diseases: When Should We Care?

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 26871

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Special Issue Editors

Prof. Dr. Raffaele Marfella

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Guest Editor

Professore Ordinario Medicina Interna, Università degli studi della Campania, Luigi Vanvitelli, Caserta, Italy
Interests: coronary artery diseases; heart failure; diabetes; atherosclerosis
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Maria Luisa Balestrieri

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Guest Editor

Department of Biochemistry, Biophysics and General Pathology, School of Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Interests: aging; oxidative stress; nitric oxide; endothelial cells; endothelial progenitor cells; angiogenesis; inflammation; cell senescence; apoptosis; atherosclerosis; diabetes, endothelial dysfunction, sirtuins and cardiovascular disease; natural products; betaines; health; bioactive compounds; free radicals; antioxidants; ergothioneine; cell cycle; cancer-related biochemical pathways; cell proliferation; senescence; cancer cell death; epigenetic regulation; sirtuins and cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Prediabetes affects more than 38% of adults. Diagnosis of prediabetes is based on the presence of impaired fasting glucose, impaired glucose tolerance, and/or elevated HbA1c levels between 5.7% and 6.4%. The prediabetes state is not only a noteworthy risk factor for type 2 diabetes but is also a significant risk factor for macrovascular disease. Although some of the risk may be due to the progression to overt diabetes, an independent risk is still present in individuals who have not yet progressed to diabetes. Without any intervention, prediabetes often progresses to diabetes mellitus and is associated with increased risk of cardiovascular disease. Although indices of glycemia define clinical criteria for prediabetes, vascular dysfunction results not only from effects of hyperglycemia but also from vascular proinflammatory and metabolic consequences associated to increased adipose tissue in diverse anatomic locations. This issue on Molecular Endocrinology and Metabolism will focus on recent advances on “prediabetes and cardiovascular impairments: the double edge in atherosclerosis development and progression”, including new insights into the molecular mechanisms of plaque progression and rupture and their correlations with hard outcomes (i.e., mortality and cardiovascular events). In addition, we will investigate when and how start a therapeutic strategy to reduce the impact of prediabetes on cardiovascular mortality.

Prof. Dr. Raffaele Marfella
Prof. Dr. Maria Luisa Balestrieri
Guest Editors

Manuscript Submission Information

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Keywords

Prediabetes
Atherosclerosis
Coronary artery disease
Heart failure
miRNA
Long noncoding RNAs
Inflammation
Therapeutics

Published Papers (6 papers)

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Research

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12 pages, 2763 KiB

Open AccessArticle

Changes in Stress-Mediated Markers in a Human Cardiomyocyte Cell Line under Hyperglycemia

by Vikram Thakur, Narah Alcoreza, Jasmine Cazares and Munmun Chattopadhyay

Int. J. Mol. Sci. 2021, 22(19), 10802; https://doi.org/10.3390/ijms221910802 - 07 Oct 2021

Cited by 9 | Viewed by 2830

Abstract

Diabetes is a major risk factor for cardiovascular diseases, especially cardiomyopathy, a condition in which the smooth muscles of the heart become thick and rigid, affecting the functioning of cardiomyocytes, the contractile cells of the heart. Uncontrolled elevated glucose levels over time can result in oxidative stress, which could lead to inflammation and altered epigenetic mechanisms. In the current study, we investigated whether hyperglycemia can modify cardiac function by directly affecting these changes in cardiomyocytes. To evaluate the adverse effect of high glucose, we measured the levels of gap junction protein, connexin 43, which is responsible for modulating cardiac electric activities and Troponin I, a part of the troponin complex in the heart muscles, commonly used as cardiac markers of ischemic heart disease. AC16 human cardiomyocyte cells were used in this study. Under hyperglycemic conditions, these cells demonstrated altered levels of connexin 43 and Troponin-I after 24 h of exposure. We also examined hyperglycemia induced changes in epigenetic markers: H3K9me1, Sirtuin-1 (SIRT1), and histone deacetylase (HDAC)-2 as well as in inflammatory and stress-related mediators, such as heat shock protein (HSP)-60, receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)-4, high mobility group box (HMGB)-1 and CXC chemokine receptor (CXCR)-4. Cardiomyocytes exposed to 25mM glucose resulted in the downregulation of HSP60 and SIRT1 after 48 h. We further examined that hyperglycemia mediated the decrease in the gap junction protein CX43, as well as CXC chemokine receptor CXCR4 which may affect the physiological functions of the cardiomyocytes when exposed to high glucose for 24 and 48 h. Upregulated expression of DNA-binding nuclear protein HMGB1, along with changes in histone methylation marker H3K9me1 have demonstrated hyperglycemia-induced damage to cardiomyocyte at 24 h of exposure. Our study established that 24 to 48 h of hyperglycemic exposure could stimulate stress-mediated inflammatory mediators in cardiomyocytes in vitro. These stress-related changes in hyperglycemia-induced cardiomyocytes may further initiate an increase in injury markers which eventually could alter the epigenetic processes. Therefore, epigenetic and inflammatory mechanisms in conjunction with alterations in a downstream signaling pathway could have a direct effect on the functionality of the cardiomyocytes exposed to high glucose during short and long-term exposures. Full article

(This article belongs to the Special Issue Effects of Prediabetes on the Progression of Cardiovascular Diseases: When Should We Care?)

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11 pages, 2384 KiB

Open AccessArticle

Toxicity Induced by Cytokines, Glucose, and Lipids Increase Apoptosis and Hamper Insulin Secretion in the 1.1E7 Beta Cell-Line

by Antonia Diaz-Ganete, Aranzazu Quiroga-de-Castro, Rosa M. Mateos, Francisco Medina, Carmen Segundo and Alfonso M. Lechuga-Sancho

Int. J. Mol. Sci. 2021, 22(5), 2559; https://doi.org/10.3390/ijms22052559 - 04 Mar 2021

Cited by 5 | Viewed by 2495

Abstract

Basic research on types 1 and 2 diabetes mellitus require early stage studies using beta cells or cell lines, ideally of human origin and with preserved insulin secretion in response to glucose. The 1.1E7 cells are a hybrid cell line resulting from the electrofusion of dispersed human islets and PANC-1 cells, capable of secreting insulin in response to glucose, but their survival and function under toxic conditions remains untested. This characterization is the purpose of the present study. We treated these cells with a cytokine mix, high glucose, palmitate, and the latter two combined. Under these conditions, we measured cell viability and apoptosis (MTT, Caspase Glo and TUNEL assays, as well as caspase-8 and -9 levels by Western blotting), endoplasmic reticulum stress markers (EIF2AK3, HSPA4, EIF2a, and HSPA5) by real-time PCR, and insulin secretion with a glucose challenge. All of these stimuli (i) induce apoptosis and ER stress markers expression, (ii) reduce mRNA amounts of 2–5 components of genes involved in the insulin secretory pathway, and (iii) abrogate the insulin release capability of 1.1E7 cells in response to glucose. The most pronounced effects were observed with cytokines and with palmitate and high glucose combined. This characterization may well serve as the starting point for those choosing this cell line for future basic research on certain aspects of diabetes. Full article

(This article belongs to the Special Issue Effects of Prediabetes on the Progression of Cardiovascular Diseases: When Should We Care?)

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Review

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19 pages, 1480 KiB

Open AccessReview

Phenotyping the Prediabetic Population—A Closer Look at Intermediate Glucose Status and Cardiovascular Disease

by Elena Barbu, Mihaela-Roxana Popescu, Andreea-Catarina Popescu and Serban-Mihai Balanescu

Int. J. Mol. Sci. 2021, 22(13), 6864; https://doi.org/10.3390/ijms22136864 - 25 Jun 2021

Cited by 8 | Viewed by 3397

Abstract

Even though the new thresholds for defining prediabetes have been around for more than ten years, there is still controversy surrounding the precise characterization of this intermediate glucose metabolism status. The risk of developing diabetes and macro and microvascular disease linked to prediabetes is well known. Still, the prediabetic population is far from being homogenous, and phenotyping it into less heterogeneous groups might prove useful for long-term risk assessment, follow-up, and primary prevention. Unfortunately, the current definition of prediabetes is quite rigid and disregards the underlying pathophysiologic mechanisms and their potential metabolic progression towards overt disease. In addition, prediabetes is commonly associated with a cluster of risk factors that worsen the prognosis. These risk factors all revolve around a common denominator: inflammation. This review focuses on identifying the population that needs to be screened for prediabetes and the already declared prediabetic patients who are at a higher risk of cardiovascular disease and require closer monitoring. Full article

(This article belongs to the Special Issue Effects of Prediabetes on the Progression of Cardiovascular Diseases: When Should We Care?)

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39 pages, 1261 KiB

Open AccessReview

Diabetes and Cardiovascular Risk in Renal Transplant Patients

by Jacek Rysz, Beata Franczyk, Maciej Radek, Aleksandra Ciałkowska-Rysz and Anna Gluba-Brzózka

Int. J. Mol. Sci. 2021, 22(7), 3422; https://doi.org/10.3390/ijms22073422 - 26 Mar 2021

Cited by 14 | Viewed by 3918

Abstract

End-stage kidney disease (ESKD) is a main public health problem, the prevalence of which is continuously increasing worldwide. Due to adverse effects of renal replacement therapies, kidney transplantation seems to be the optimal form of therapy with significantly improved survival, quality of life and diminished overall costs compared with dialysis. However, post-transplant patients frequently suffer from post-transplant diabetes mellitus (PTDM) which an important risk factor for cardiovascular and cardiovascular-related deaths after transplantation. The management of post-transplant diabetes resembles that of diabetes in the general population as it is based on strict glycemic control as well as screening and treatment of common complications. Lifestyle interventions accompanied by the tailoring of immunosuppressive regimen may be of key importance to mitigate PTDM-associated complications in kidney transplant patients. More transplant-specific approach can include the exchange of tacrolimus with an alternative immunosuppressant (cyclosporine or mammalian target of rapamycin (mTOR) inhibitor), the decrease or cessation of corticosteroid therapy and caution in the prescribing of diuretics since they are independently connected with post-transplant diabetes. Early identification of high-risk patients for cardiovascular diseases enables timely introduction of appropriate therapeutic strategy and results in higher survival rates for patients with a transplanted kidney. Full article

(This article belongs to the Special Issue Effects of Prediabetes on the Progression of Cardiovascular Diseases: When Should We Care?)

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26 pages, 2103 KiB

Open AccessReview

Stress-Induced Hyperglycaemia in Non-Diabetic Patients with Acute Coronary Syndrome: From Molecular Mechanisms to New Therapeutic Perspectives

by Alessandro Bellis, Ciro Mauro, Emanuele Barbato, Antonio Ceriello, Antonio Cittadini and Carmine Morisco

Int. J. Mol. Sci. 2021, 22(2), 775; https://doi.org/10.3390/ijms22020775 - 14 Jan 2021

Cited by 24 | Viewed by 3121

Abstract

Stress-induced hyperglycaemia (SIH) at hospital admission for acute coronary syndrome is associated with poor outcome, especially in patients without known diabetes. Nevertheless, insulin treatment in these subjects was not correlated with the reduction of mortality. This is likely due to the fact that SIH in the context of an acute coronary syndrome, compared to that in known diabetes, represents an epiphenomenon of other pathological conditions, such as adrenergic and renin-angiotensin system over-activity, hyperglucagonaemia, increase of circulating free fatty acids and pancreatic beta-cell dysfunction, which are not completely reversed by insulin therapy and so worsen the prognosis. Thus, SIH may be considered not only as a biomarker of organ damage, but also as an indicator of a more complex therapeutic strategy in these subjects. The aim of this review is to analyse the molecular mechanisms by which SIH may favour a worse prognosis in non-diabetic patients with acute coronary syndrome and identify new therapeutic strategies, in addition to insulin therapy, for a more appropriate treatment and improved outcomes. Full article

(This article belongs to the Special Issue Effects of Prediabetes on the Progression of Cardiovascular Diseases: When Should We Care?)

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17 pages, 659 KiB

Open AccessReview

Prevention of Diabetes and Cardiovascular Disease in Obesity

by Lucia La Sala and Antonio E. Pontiroli

Int. J. Mol. Sci. 2020, 21(21), 8178; https://doi.org/10.3390/ijms21218178 - 31 Oct 2020

Cited by 70 | Viewed by 9905

Abstract

Obesity is one of the major risk factors for the development of both impaired glucose tolerance (IGT, or prediabetes) and type 2 diabetes (T2D), and its prevalence worldwide drives toward an increased rate of cardiovascular morbidity and mortality. Given the estimations of the World Health Organization (WHO) and the recommendation of the Diabetes Prevention Program (DPP), where IGT and diabetes are considered as risk factors for the development of cardiovascular complications and obesity, the development of diabetes should be treated because of its potential reversibility. In this view, several interventions such as diet, lifestyle changes, and pharmacological treatment are effective, including bariatric metabolic surgery (BMS), which is the most incisive way to efficiently lower body weight. In this review, we sought to summarize some of the major aspects linked to diabetes prevention in overweight/obesity, focusing on the use of surgery; we also attempted to elucidate molecular pathways involved in a variety of obesity-induced processes able to favor the progression of chronic diseases, such as diabetes and its complications. Full article

(This article belongs to the Special Issue Effects of Prediabetes on the Progression of Cardiovascular Diseases: When Should We Care?)

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