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Cardiovascular Risk in Diabetes Mellitus: Mechanisms, Drugs, and Other Therapies

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

Deadline for manuscript submissions: closed (10 May 2023) | Viewed by 29869

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Special Issue Editors

Dr. Francesco Prattichizzo

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Guest Editor

IRCCS MultiMedica, 20138 Milan, Italy
Interests: type 2 diabetes; diabetes complications; cardiovascular diseases; diabetes therapy; diabetes risk factors; low-grade inflammation; miRNAs; extracellular vesicles
Special Issues, Collections and Topics in MDPI journals

Dr. Giulia Matacchione

E-Mail Website
Guest Editor

Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, 60126 Ancona, Italy
Interests: aging; cellular senescence; age-related diseases; circulating biomarkers; immunosenescence; inflammaging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Patients with both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have a decreased life expectancy, mainly due to an increased incidence of cardiovascular (CV) diseases compared with people without these conditions. As demonstrated in specific trials, CV disease risk is attenuated, but not completely suppressed, by proper control of multiple risk factors (i.e., glucose, lipids, and blood pressure). Thus, diabetes might have an intrinsic, residual CV risk that is not fully addressed by available therapies. Emerging evidence suggests that a large range of molecular mechanisms and risk factors could explain such residual CV risk.

In parallel, cardiovascular outcome trials (CVOTs) have disclosed a protective effect against CV and other complications for two recently introduced classes of glucose-lowering drugs (i.e., SGLT-2 inhibitors and GLP-1 receptor agonists). Of note, this effect is likely independent of their ability to lower glucose levels, further stressing the fact that additional research is needed to decipher the mechanisms driving the development of diabetes complications and the molecular underpinnings of the benefit provided by these novel drugs.

Observational studies and pilot clinical trials suggest also that natural compounds might reduce the risk of developing T2DM complications (e.g., lipoic acid and diabetic neuropathy). Natural compounds can target specific pathways relevant for diabetes complications but can also eventually affect glucose homeostasis and lipid metabolism through a variety of mechanisms (i.e., inhibition/reduction of glucose, cholesterol and triglyceride transporters; stimulation of insulin secretion; reduction of serum cholesterol and triglycerides). Thus, they might represent an additional and alternative option to reduce the CV risk of patients with diabetes, especially those with intermediate/low risk.

In this special issue, we seek for contributions exploring the effect of old and novel molecular mechanisms to the development of diabetes complications, particularly the CV ones. Clinical studies assessing the relevance of non-canonical risk factors to the development of CV diseases in patients with diabetes are also welcomed, as long as they explore also an associated molecular mechanism. Finally, studies exploring the underpinnings of the effect of glucose-lowering drugs (old or novel) are also of great interest. Manuscripts dealing with T2DM are a priority while papers on T1DM are also encouraged, as long as they deal with the development of CV complications. Original research papers, short-communications, and reviews, both narrative and systematic, are all eligible pieces for this special issue. Meta-analyses focusing only on clinical outcomes are not within the scope of this special issue.

Dr. Francesco Prattichizzo
Dr. Giulia Matacchione
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

diabetes
cardiovascular diseases
diabetes complications
atherosclerosis
glycemic control
lipids
blood pressure
SGLT-2 inhibitors
GLP-1 receptor agonists
natural compounds
low-grade inflammation
molecular mechanisms of atherosclerosis

Published Papers (9 papers)

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Research

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25 pages, 4697 KiB

Open AccessArticle

Dysregulation of Gene Expression of Key Signaling Mediators in PBMCs from People with Type 2 Diabetes Mellitus

by Nilofer Qureshi, Julia Desousa, Adeela Z. Siddiqui, Betty M. Drees, David C. Morrison and Asaf A. Qureshi

Int. J. Mol. Sci. 2023, 24(3), 2732; https://doi.org/10.3390/ijms24032732 - 1 Feb 2023

Cited by 1 | Viewed by 2162

Abstract

Diabetes is currently the fifth leading cause of death by disease in the USA. The underlying mechanisms for type 2 Diabetes Mellitus (DM2) and the enhanced susceptibility of such patients to inflammatory disorders and infections remain to be fully defined. We have recently shown that peripheral blood mononuclear cells (PBMCs) from non-diabetic people upregulate expression of inflammatory genes in response to proteasome modulators, such as bacterial lipopolysaccharide (LPS) and soybean lectin (LEC); in contrast, resveratrol (RES) downregulates this response. We hypothesized that LPS and LEC will also elicit a similar upregulation of gene expression of key signaling mediators in (PBMCs) from people with type 2 diabetes (PwD2, with chronic inflammation) ex vivo. Unexpectedly, using next generation sequencing (NGS), we show for the first time, that PBMCs from PwD2 failed to elicit a robust LPS- and LEC-induced gene expression of proteasome subunit LMP7 (PSMB8) and mediators of T cell signaling that were observed in non-diabetic controls. These repressed genes included: PSMB8, PSMB9, interferon-γ, interferon-λ, signal-transducer-and-activator-of-transcription-1 (STAT1), human leukocyte antigen (HLA DQB1, HLA DQA1) molecules, interleukin 12A, tumor necrosis factor-α, transporter associated with antigen processing 1 (TAP1), and several others, which showed a markedly weak upregulation with toxins in PBMCs from PwD2, as compared to those from non-diabetics. Resveratrol (proteasome inhibitor) further downregulated the gene expression of these inflammatory mediators in PBMCs from PwD2. These results might explain why PwD2 may be susceptible to infectious disease. LPS and toxins may be leading to inflammation, insulin resistance, and thus, metabolic changes in the host cells. Full article

(This article belongs to the Special Issue Cardiovascular Risk in Diabetes Mellitus: Mechanisms, Drugs, and Other Therapies)

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12 pages, 2239 KiB

Open AccessArticle

Identification of Myocardial Insulin Resistance by Using Liver Tests: A Simple Approach for Clinical Practice

by José Raúl Herance, Queralt Martín-Saladich, Mayra Alejandra Velásquez, Cristina Hernandez, Carolina Aparicio, Clara Ramirez-Serra, Roser Ferrer, Marina Giralt-Arnaiz, Miguel Ángel González-Ballester, Juan M. Pericàs, Joan Castell-Conesa, Santiago Aguadé-Bruix and Rafael Simó

Int. J. Mol. Sci. 2022, 23(15), 8783; https://doi.org/10.3390/ijms23158783 - 7 Aug 2022

Cited by 2 | Viewed by 1918

Abstract

Background: We report that myocardial insulin resistance (mIR) occurs in around 60% of patients with type 2 diabetes (T2D) and was associated with higher cardiovascular risk in comparison with patients with insulin-sensitive myocardium (mIS). These two phenotypes (mIR vs. mIS) can only be assessed using time-consuming and expensive methods. The aim of the present study is to search a simple and reliable surrogate to identify both phenotypes. Methods: Forty-seven patients with T2D underwent myocardial [18F]FDG PET/CT at baseline and after a hyperinsulinemic–euglycemic clamp (HEC) to determine mIR were prospectively recruited. Biochemical assessments were performed before and after the HEC. Baseline hepatic steatosis index and index of hepatic fibrosis (FIB-4) were calculated. Furthermore, liver stiffness measurement was performed using transient elastography. Results: The best model to predict the presence of mIR was the combination of transaminases, protein levels, FIB-4 score and HOMA (AUC = 0.95; sensibility: 0.81; specificity: 0.95). We observed significantly higher levels of fibrosis in patients with mIR than in those with mIS (p = 0.034). In addition, we found that patients with mIR presented a reduced glucose uptake by the liver in comparison with patients with mIS. Conclusions: The combination of HOMA, protein, transaminases and FIB-4 is a simple and reliable tool for identifying mIR in patients with T2D. This information will be useful to improve the stratification of cardiovascular risk in T2D. Full article

(This article belongs to the Special Issue Cardiovascular Risk in Diabetes Mellitus: Mechanisms, Drugs, and Other Therapies)

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Review

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48 pages, 23415 KiB

Open AccessReview

Brain Dopamine–Clock Interactions Regulate Cardiometabolic Physiology: Mechanisms of the Observed Cardioprotective Effects of Circadian-Timed Bromocriptine-QR Therapy in Type 2 Diabetes Subjects

by Anthony H. Cincotta

Int. J. Mol. Sci. 2023, 24(17), 13255; https://doi.org/10.3390/ijms241713255 - 26 Aug 2023

Cited by 4 | Viewed by 4068

Abstract

Despite enormous global efforts within clinical research and medical practice to reduce cardiovascular disease(s) (CVD), it still remains the leading cause of death worldwide. While genetic factors clearly contribute to CVD etiology, the preponderance of epidemiological data indicate that a major common denominator among diverse ethnic populations from around the world contributing to CVD is the composite of Western lifestyle cofactors, particularly Western diets (high saturated fat/simple sugar [particularly high fructose and sucrose and to a lesser extent glucose] diets), psychosocial stress, depression, and altered sleep/wake architecture. Such Western lifestyle cofactors are potent drivers for the increased risk of metabolic syndrome and its attendant downstream CVD. The central nervous system (CNS) evolved to respond to and anticipate changes in the external (and internal) environment to adapt survival mechanisms to perceived stresses (challenges to normal biological function), including the aforementioned Western lifestyle cofactors. Within the CNS of vertebrates in the wild, the biological clock circuitry surveils the environment and has evolved mechanisms for the induction of the obese, insulin-resistant state as a survival mechanism against an anticipated ensuing season of low/no food availability. The peripheral tissues utilize fat as an energy source under muscle insulin resistance, while increased hepatic insulin resistance more readily supplies glucose to the brain. This neural clock function also orchestrates the reversal of the obese, insulin-resistant condition when the low food availability season ends. The circadian neural network that produces these seasonal shifts in metabolism is also responsive to Western lifestyle stressors that drive the CNS clock into survival mode. A major component of this natural or Western lifestyle stressor-induced CNS clock neurophysiological shift potentiating the obese, insulin-resistant state is a diminution of the circadian peak of dopaminergic input activity to the pacemaker clock center, suprachiasmatic nucleus. Pharmacologically preventing this loss of circadian peak dopaminergic activity both prevents and reverses existing metabolic syndrome in a wide variety of animal models of the disorder, including high fat-fed animals. Clinically, across a variety of different study designs, circadian-timed bromocriptine-QR (quick release) (a unique formulation of micronized bromocriptine—a dopamine D2 receptor agonist) therapy of type 2 diabetes subjects improved hyperglycemia, hyperlipidemia, hypertension, immune sterile inflammation, and/or adverse cardiovascular event rate. The present review details the seminal circadian science investigations delineating important roles for CNS circadian peak dopaminergic activity in the regulation of peripheral fuel metabolism and cardiovascular biology and also summarizes the clinical study findings of bromocriptine-QR therapy on cardiometabolic outcomes in type 2 diabetes subjects. Full article

(This article belongs to the Special Issue Cardiovascular Risk in Diabetes Mellitus: Mechanisms, Drugs, and Other Therapies)

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27 pages, 1224 KiB

Open AccessReview

Human Placental Lactogen in Relation to Maternal Metabolic Health and Fetal Outcomes: A Systematic Review and Meta-Analysis

by Kate Rassie, Rinky Giri, Anju E. Joham, Helena Teede and Aya Mousa

Int. J. Mol. Sci. 2022, 23(24), 15621; https://doi.org/10.3390/ijms232415621 - 9 Dec 2022

Cited by 10 | Viewed by 3330

Abstract

Human placental lactogen (hPL) is a placental hormone which appears to have key metabolic functions in pregnancy. Preclinical studies have putatively linked hPL to maternal and fetal outcomes, yet—despite human observational data spanning several decades—evidence on the role and importance of this hormone remains disparate and conflicting. We aimed to explore (via systematic review and meta-analysis) the relationship between hPL levels, maternal pre-existing and gestational metabolic conditions, and fetal growth. MEDLINE via OVID, CINAHL plus, and Embase were searched from inception through 9 May 2022. Eligible studies included women who were pregnant or up to 12 months post-partum, and reported at least one endogenous maternal serum hPL level during pregnancy in relation to pre-specified metabolic outcomes. Two independent reviewers extracted data. Meta-analysis was conducted where possible; for other outcomes narrative synthesis was performed. 35 studies met eligibility criteria. No relationship was noted between hPL and gestational diabetes status. In type 1 diabetes mellitus, hPL levels appeared lower in early pregnancy (possibly reflecting delayed placental development) and higher in late pregnancy (possibly reflecting increased placental mass). Limited data were found in other pre-existing metabolic conditions. Levels of hPL appear to be positively related to placental mass and infant birthweight in pregnancies affected by maternal diabetes. The relationship between hPL, a purported pregnancy metabolic hormone, and maternal metabolism in human pregnancy is complex and remains unclear. This antenatal biomarker may offer value, but future studies in well-defined contemporary populations are required. Full article

(This article belongs to the Special Issue Cardiovascular Risk in Diabetes Mellitus: Mechanisms, Drugs, and Other Therapies)

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14 pages, 721 KiB

Open AccessReview

Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms

by Rosalba La Grotta, Chiara Frigé, Giulia Matacchione, Fabiola Olivieri, Paola de Candia, Antonio Ceriello and Francesco Prattichizzo

Int. J. Mol. Sci. 2022, 23(20), 12325; https://doi.org/10.3390/ijms232012325 - 14 Oct 2022

Cited by 12 | Viewed by 4967

Abstract

Caloric restriction promotes longevity in multiple animal models. Compounds modulating nutrient-sensing pathways have been suggested to reproduce part of the beneficial effect of caloric restriction on aging. However, none of the commonly studied caloric restriction mimetics actually produce a decrease in calories. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) are a class of drugs which lower glucose by promoting its elimination through urine, thus inducing a net loss of calories. This effect promotes a metabolic shift at the systemic level, fostering ketones and fatty acids utilization as glucose-alternative substrates, and is accompanied by a modulation of major nutrient-sensing pathways held to drive aging, e.g., mTOR and the inflammasome, overall resembling major features of caloric restriction. In addition, preliminary experimental data suggest that SGLT-2i might also have intrinsic activities independent of their systemic effects, such as the inhibition of cellular senescence. Consistently, evidence from both preclinical and clinical studies have also suggested a marked ability of SGLT-2i to ameliorate low-grade inflammation in humans, a relevant driver of aging commonly referred to as inflammaging. Considering also the amount of data from clinical trials, observational studies, and meta-analyses suggesting a tangible effect on age-related outcomes, such as cardiovascular diseases, heart failure, kidney disease, and all-cause mortality also in patients without diabetes, here we propose a framework where at least part of the benefit provided by SGLT-2i is mediated by their ability to blunt the drivers of aging. To support this postulate, we synthesize available data relative to the effect of this class on: 1- animal models of healthspan and lifespan; 2- selected molecular pillars of aging in preclinical models; 3- biomarkers of aging and especially inflammaging in humans; and 4- COVID-19-related outcomes. The burden of evidence might prompt the design of studies testing the potential employment of this class as anti-aging drugs. Full article

(This article belongs to the Special Issue Cardiovascular Risk in Diabetes Mellitus: Mechanisms, Drugs, and Other Therapies)

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58 pages, 1256 KiB

Open AccessReview

Dietary Risk Factors and Eating Behaviors in Peripheral Arterial Disease (PAD)

by Andrea Leonardo Cecchini, Federico Biscetti, Maria Margherita Rando, Elisabetta Nardella, Giovanni Pecorini, Luis H. Eraso, Paul J. Dimuzio, Antonio Gasbarrini, Massimo Massetti and Andrea Flex

Int. J. Mol. Sci. 2022, 23(18), 10814; https://doi.org/10.3390/ijms231810814 - 16 Sep 2022

Cited by 9 | Viewed by 5132

Abstract

Dietary risk factors play a fundamental role in the prevention and progression of atherosclerosis and PAD (Peripheral Arterial Disease). The impact of nutrition, however, defined as the process of taking in food and using it for growth, metabolism and repair, remains undefined with regard to PAD. This article describes the interplay between nutrition and the development/progression of PAD. We reviewed 688 articles, including key articles, narrative and systematic reviews, meta-analyses and clinical studies. We analyzed the interaction between nutrition and PAD predictors, and subsequently created four descriptive tables to summarize the relationship between PAD, dietary risk factors and outcomes. We comprehensively reviewed the role of well-studied diets (Mediterranean, vegetarian/vegan, low-carbohydrate ketogenic and intermittent fasting diet) and prevalent eating behaviors (emotional and binge eating, night eating and sleeping disorders, anorexia, bulimia, skipping meals, home cooking and fast/ultra-processed food consumption) on the traditional risk factors of PAD. Moreover, we analyzed the interplay between PAD and nutritional status, nutrients, dietary patterns and eating habits. Dietary patterns and eating disorders affect the development and progression of PAD, as well as its disabling complications including major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Nutrition and dietary risk factor modification are important targets to reduce the risk of PAD as well as the subsequent development of MACE and MALE. Full article

(This article belongs to the Special Issue Cardiovascular Risk in Diabetes Mellitus: Mechanisms, Drugs, and Other Therapies)

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17 pages, 1989 KiB

Open AccessReview

Atherosclerosis Burdens in Diabetes Mellitus: Assessment by PET Imaging

by Poul F. Høilund-Carlsen, Reza Piri, Per Lav Madsen, Mona-Elisabeth Revheim, Thomas J. Werner, Abass Alavi, Oke Gerke and Michael Sturek

Int. J. Mol. Sci. 2022, 23(18), 10268; https://doi.org/10.3390/ijms231810268 - 6 Sep 2022

Cited by 7 | Viewed by 2194

Abstract

Arteriosclerosis and its sequelae are the most common cause of death in diabetic patients and one of the reasons why diabetes has entered the top 10 causes of death worldwide, fatalities having doubled since 2000. The literature in the field claims almost unanimously that arteriosclerosis is more frequent or develops more rapidly in diabetic than non-diabetic subjects, and that the disease is caused by arterial inflammation, the control of which should therefore be the goal of therapeutic efforts. These views are mostly based on indirect methodologies, including studies of artery wall thickness or stiffness, or on conventional CT-based imaging used to demonstrate tissue changes occurring late in the disease process. In contrast, imaging with positron emission tomography and computed tomography (PET/CT) applying the tracers ¹⁸F-fluorodeoxyglucose (FDG) or ¹⁸F-sodium fluoride (NaF) mirrors arterial wall inflammation and microcalcification, respectively, early in the course of the disease, potentially enabling in vivo insight into molecular processes. The present review provides an overview of the literature from the more than 20 and 10 years, respectively, that these two tracers have been used for the study of atherosclerosis, with emphasis on what new information they have provided in relation to diabetes and which questions remain insufficiently elucidated. Full article

(This article belongs to the Special Issue Cardiovascular Risk in Diabetes Mellitus: Mechanisms, Drugs, and Other Therapies)

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20 pages, 1187 KiB

Open AccessReview

The Contribution of Wnt Signaling to Vascular Complications in Type 2 Diabetes Mellitus

by Raquel Sanabria-de la Torre, Cristina García-Fontana, Sheila González-Salvatierra, Francisco Andújar-Vera, Luis Martínez-Heredia, Beatriz García-Fontana and Manuel Muñoz-Torres

Int. J. Mol. Sci. 2022, 23(13), 6995; https://doi.org/10.3390/ijms23136995 - 23 Jun 2022

Cited by 7 | Viewed by 2704

Abstract

Vascular complications are the leading cause of morbidity and mortality among patients with type 2 diabetes mellitus (T2DM). These vascular abnormalities result in a chronic hyperglycemic state, which influences many signaling molecular pathways that initially lead to increased oxidative stress, increased inflammation, and endothelial dysfunction, leading to both microvascular and macrovascular complications. Endothelial dysfunction represents the initial stage in both types of vascular complications; it represents “mandatory damage” in the development of microvascular complications and only “introductory damage” in the development of macrovascular complications. Increasing scientific evidence has revealed an important role of the Wnt pathway in the pathophysiology of the vascular wall. It is well known that the Wnt pathway is altered in patients with T2DM. This review aims to be an update of the current literature related to the Wnt pathway molecules that are altered in patients with T2DM, which may also be the cause of damage to the vasculature. Both microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular complications (coronary artery disease, cerebrovascular disease, and peripheral arterial disease) are analyzed. This review aims to concisely concentrate all the evidence to facilitate the view on the vascular involvement of the Wnt pathway and its components by highlighting the importance of exploring possible therapeutic strategy for patients with T2DM who develop vascular pathologies. Full article

(This article belongs to the Special Issue Cardiovascular Risk in Diabetes Mellitus: Mechanisms, Drugs, and Other Therapies)

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15 pages, 751 KiB

Open AccessReview

Advanced Glycations End Products in the Skin as Biomarkers of Cardiovascular Risk in Type 2 Diabetes

by Alejandra Planas, Olga Simó-Servat, Cristina Hernández and Rafael Simó

Int. J. Mol. Sci. 2022, 23(11), 6234; https://doi.org/10.3390/ijms23116234 - 2 Jun 2022

Cited by 5 | Viewed by 2310

Abstract

The incidence and prevalence of diabetes are increasing worldwide, and cardiovascular disease (CVD) is the leading cause of death among subjects with type 2 diabetes (T2D). The assessment and stratification of cardiovascular risk in subjects with T2D is a challenge. Advanced glycation end products are heterogeneous molecules produced by non-enzymatic glycation of proteins, lipids, or nucleic acids. Accumulation of advanced glycation end products is increased in subjects with T2D and is considered to be one of the major pathogenic mechanism in developing complications in diabetes. Skin AGEs could be assessed by skin autofluorescence. This method has been validated and related to the presence of micro and macroangiopathy in individuals with type 2 diabetes. In this context, the aim of this review is to critically summarize current knowledge and scientific evidence on the relationship between skin AGEs and CVD in subjects with type 2 diabetes, with a brief reference to other diabetes-related complications. Full article

(This article belongs to the Special Issue Cardiovascular Risk in Diabetes Mellitus: Mechanisms, Drugs, and Other Therapies)

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