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- Herausgeber: John Wiley & Sons
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- Sprache: Englisch
Presents comprehensive coverage of the many microvascular complications of diabetes
Diabetes remains one of the main causes, in the western world, of legal blindness, end stage renal disease, and amputation, despite the implementation of tight glycemic control and the great progress in the management and care of our patients. This book provides a useful and handy tool to professionals and students in the field of diabetes and its microvascular complications by integrating information from clinical settings as well as from the frontlines of diabetic research. It provides readers with up-to-date diagnostic criteria, classifications, and therapeutic approaches. and recent discoveries on mechanisms of disease, experimental therapeutic agents, and biomarkers of disease.
Written by top experts in the field, Microvascular Disease in Diabetes offers in-depth chapters covering pathophysiology; the genetics of diabetic microvascular disease; and the epigenetics of diabetic microvascular disease. It then provides sections featuring both clinical and research information on diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, and diabetic foot. It also looks at coronary microvascular dysfunction and cerebral microvascular disease.
- Integrates new and accessible material on diabetic microvascular comorbidities
- Covers all relevant microvascular systems
- Provides a much-needed resource synthesizing research and clinical applications to treating microvascular complications of diabetes
- Presents current diagnostic criteria, classifications, and therapeutic approaches, as well as recent discoveries on the mechanisms of disease, experimental therapeutic agents, and biomarkers of disease
Assembled in an easily consultable manner, Microvascular Disease in Diabetes is an excellent text for investigators, clinicians, and students looking to improve their understanding of diabetic complications.
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Table of Contents
Cover
Foreword to: Microvascular Disease in Diabetes
Editor Biography
List of Contributors
1 Introduction
References
2 Pathophysiology
Introduction
Anatomo‐Physiology of Microvessels
Regulation of Microvascular Tone
Structural Changes in the Microcirculation
Functional Changes in the Microcirculation
References
3 Genetics of Diabetic Microvascular Disease
Introduction
Genetics of DKD
Genetics of Diabetic Retinopathy
Genetics of Diabetic Neuropathy
Future Directions
Conclusions
References
4 Epigenetics of Diabetic Microvascular Disease
Diabetic Complications Include Microvascular and Macrovascular Injury
The Diabetes Control and Complications Trial
/
Epidemiology of Diabetes Interventions and Complications
(
DCCT
/
EDIC
) Study in Type 1 Diabetic Patients, and the UKPDS Study in Type 2 Diabetic Patients, Support the Existence of the Hyperglycemic Memory Phenomenon
Models of Hyperglycemic Memory
The “Epigenetic Code”
miRNAs Contribute to the Control of Glucose Homeostasis and Are Dysregulated in Diabetes
Future Prospects
References
5 Diabetic Retinopathy – Clinical
Introduction
Epidemiology
Screening
Risk Factors
Clinical Patterns
Diabetic Macular Edema
(
DME
)
Conclusions
References
6 Diabetic Retinopathy – Research
Retina and Induction of Hyperglycemia
Hyperglycemia and Retinal Microvasculature
Hyperglycemia and Reactive Gliosis
Hyperglycemia and Neurodegeneration
Hyperglycemia and Inflammation
References
7 Diabetic Nephropathy – Clinical
Epidemiology
Natural History
Stages of DN
Morphologic Changes
Pathophysiology
Clinical Course
Treatment
Primary Prevention
Secondary Prevention
Tertiary Prevention
Perspectives
References
8 Diabetic Nephropathy – Research
Essential Hypertension and DN
Role of Genetics in the Pathogenesis of DN
Polyol Pathway and Non‐Enzymatic Glycation
Environment
Perspectives
Animal Models
DN in Induced Model of Type 1 Diabetes Mellitus
(
T1DM
)
DN in Spontaneous Model of T1DM
Non‐Obese Diabetic
(
NOD
) Mice
OVE26 Friend leukemia virus B
(
FVB
) Mice
DN in Spontaneous Models of T2DM
References
9 Diabetic Neuropathy – Clinical
Introduction
Classification of Diabetic Neuropathies
Screening for Neuropathy
Summary of Management of Diabetic Neuropathy
References
10 Diabetic Neuropathy – Research
Basic and Translational Research in Diabetic Neuropathy
Acknowledgments
References
11 Diabetic Foot – Clinical
Introduction and Size of the Problem
Pathogenesis of Diabetic Foot Complications
Prevention
Treatment
Treatment of Neuropathic Diabetic Foot Ulcers: Offloading
Treatment of PAD: Revascularization
Diabetic Foot Infections
(
DFIs
)
Wound Healing
References
12 Diabetic Foot – Research
Introduction
Anatomy of the Skin and Microcirculation
Structural Changes in the Microcirculation
Functional Changes in the Microcirculation
Functional Changes in the Diabetic Foot
Pathophysiology of Diabetic Wound Healing
Adjunctive Treatment Options
Future Therapeutic Perspectives
Conclusion
References
13 Coronary Microvascular Dysfunction in Diabetes – Clinical and Research
Introduction
Clinical Assessment of CMD
References
14 Cerebral Microvascular Disease in Diabetes – Clinical and Research
Introduction
Postmortem Studies of the Brain in Diabetes
Cerebral Small Vessel Disease on MRI
MRI‐Measured Cerebral Small Vessel Disease in Type 1 Diabetic Patients
Type 2 Diabetes and Cerebral Small Vessel Disease
Clinical Impact of Cerebral Small Vessel Disease in Diabetes
The Influence of Microvascular Disease on the Structure and Functioning of the Diabetic Brain
Conclusions and Future Directions
References
Index
End User License Agreement
List of Tables
Chapter 3
Table 3.1
Genome‐wide association study
(
GWAS
) on
diabetic kidney disease
(
Chapter 4
Table 4.1 miRNA‐mediated epigenetic regulation of metabolism.
Chapter 5
Table 5.1 Classification of the severity of
diabetic retinopathy
(
DR
) accordin...
Table 5.2 Classification of
diabetic macular edema
(
DME
) according to the main...
Chapter 8
Table 8.1 Renal impact of superimposed diabetes on different animal strains.
Chapter 9
Table 9.1 Forms of neuropathy.
Table 9.2 Common tests of autonomic function.
Chapter 11
Table 11.1 Risk classification system.
Table 11.2 The
diabetic foot infection
(
DFI
) classification by the Infectious ...
Chapter 13
Table 13.1 Coronary microvascular dysfunction develops from a combination of ...
List of Illustrations
Chapter 3
Figure 3.1 Genome‐wide association studies on diabetic retinopathy, and subs...
Chapter 4
Figure 4.1
Diabetes Control and Complications Trial
‐
Epidemiology of Diabetes
...
Figure 4.2 Major histone H3 and H4 post‐transcriptional alterations induced ...
Chapter 5
Figure 5.1 Multimodal imaging of non‐proliferative diabetic retinopathy (NPD...
Figure 5.2 Multimodal imaging of
proliferative diabetic retinopathy
(
PDR
). M...
Figure 5.3 Multimodal imaging of
diabetic macular edema
(
DME
). Microaneurysm...
Figure 5.4 Structural
optical coherence tomography
(
OCT
) of
diabetic macular
...
Chapter 9
Figure 9.1 Treatment of neuropathic pain.
Chapter 10
Figure 10.1 The majority of mitochondrial proteins are synthesized in the nu...
Figure 10.2
Glutamate transporter 1
(
GLT1
) and
glutamate aspartate transporte
...
Chapter 11
Figure 11.1 Illustration of ulcer due to repetitive stress.
Figure 11.2 Foot compartments [62].
Chapter 12
Figure 12.1 Schematic diagram of the microcirculation in human skin. (a) The...
Figure 12.2 Stimulation of the C‐nociceptive nerve fibers results in antidro...
Figure 12.3 Hemodynamic and metabolic actions of insulin. Insulin promotes a...
Figure 12.4 The complications of diabetes mellitus and how they result in im...
Chapter 13
Figure 13.1 Example of patient with microvascular angina detected by cardiac...
Figure 13.2 Illustrative example of the comprehensive non‐invasive diagnosti...
Chapter 14
Figure 14.1 Markers of cerebral small vessel disease on
magnetic resonance i
...
Figure 14.2 Panel A shows the results of a meta‐analysis of 10 studies in wh...
Figure 14.3 In this figure the results are demonstrated of a meta‐analysis o...
Guide
Cover
Table of Contents
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Microvascular Disease in Diabetes
Edited by Francesco Tecilazich, MD, PhD
Endocrinology and Metabolic Diseases,San Raffaele Hospital,Milan, Italy
This edition first published 2020© 2020 John Wiley & Sons, Inc.
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Library of Congress Cataloging‐in‐Publication Data
Names: Tecilazich, Francesco, 1976– editor.Title: Microvascular disease in diabetes / edited by Francesco Tecilazich.Description: Hoboken, NJ : Wiley‐Blackwell, 2020. | Includes bibliographical references and index.Identifiers: LCCN 2019032065 (print) | ISBN 9781119309604 (hardback) | ISBN 9781119309611 (adobe pdf) | ISBN 9781119309628 (epub)Subjects: MESH: Diabetic Angiopathies | Diabetes MellitusClassification: LCC RC660.4 (print) | LCC RC660.4 (ebook) | NLM WK 835 | DDC 616.4/62–dc23LC record available at https://lccn.loc.gov/2019032065LC ebook record available at https://lccn.loc.gov/2019032066
Cover Design: WileyCover Image: Multimodal retinal imaging of diabetic retinopathy. Courtesy of Bandello F. et al
To my Mother and Father,To Francesca and our children
Foreword to: Microvascular Disease in Diabetes
Edited by Francesco Tecilazich, MD, PhD
Division of Endocrinology and Metabolic Disease, San Raffaele Scientific Institute, Milan, Italy
Boston, Massachusetts is a big city with dozens of hospitals and research centers, but is a small town when it comes to the diabetes care and research community. When Francesco Tecilazich arrived in Boston in 2009 to work as a fellow with Aristidis Veves at the Joslin Diabetes Center, I was glad to welcome him to our community. I had known Francesco Tecilazich for many years, since 2003, when he was an endocrinology fellow and I was a visiting Professor for a year at the Divisione di Endocronologia, Universita di Verona, Verona, Italy. In Verona, we spent time between tasks to talk about the ins and outs of diabetes biomedicine and Italian cuisine. Likewise, in Boston, we met frequently to discuss these most essential and absorbing topics.
Over the years in Boston, understanding of the molecular, physiological, and pathological basis of microvascular disease in diabetes continued to grow. After working with Aristidis Veves, Francesco Tecilazich expanded his vision and moved across town to work with Maura Lorenzi at the Schepens Eye Research Institute. Thusly well‐trained and becoming a well‐renowned expert in diabetic microvascular disease, he returned to Italy to continue his work at the prestigious San Raffaele Scientific Institute, Milan, Italy. He has been busy. In this book, Microvascular Disease in Diabetes, Francesco Tecilazich has assembled an impressive team of expert authors, who together establish the current edge of biomedical scientific knowledge of microvascular disease in diabetes.
Diabetes mellitus continues to arise unabated worldwide. Much of this is type 2 diabetes, where macrovascular cardiovascular disease dominates morbidity and mortality, but microvascular complications also contribute to suffering. Type 1 diabetes also continues to arise alarmingly and unabated worldwide according to multiple surveillance reports. Unlike type 2 diabetes, the best type 1 diabetes prevention strategies are not well understood, despite ongoing major efforts. In type 1 diabetes, microvascular complications dominate morbidity and mortality, with macrovascular cardiovascular disease contributing to suffering in later life. Furthermore, strategies to reduce cardiovascular disease morbidity and mortality are becoming well developed, with clear roles for blood pressure and LDL cholesterol reduction, and evolving roles for older therapies like aspirin and newer therapies like GLP1 mimetics and SGLT2 inhibitors. Strategies to reduce microvascular disease morbidity and mortality include scrupulous glycemic and blood pressure control but are otherwise less well developed and need the kind of knowledge contained here.
With diabetes increasing globally, the urgency to better understand and control the microvascular complications of diabetes increases apace. Microvascular Disease in Diabetes squarely addresses this need. An impressive collection of chapters by international experts provides in‐depth reviews of the state of the science. First, the basics: the pathophysiology, genetics, and epigenetics of microvascular disease in diabetes. Then, the major disease areas: diabetic retinopathy, nephropathy, and neuropathy undergo detailed scrutiny. These major areas are helpfully divided into separate clinical and research chapters. Then, the defiantly stubborn, multi‐pathogenic problem of the diabetic foot gets its own clinical and research chapters. Finally, new insights into coronary and cerebral microvascular dysfunction in diabetes round out the last two chapters.
At the end of Microvascular Disease in Diabetes, the reader will be thoroughly up to date on current knowledge in this field. However, the reader will also be well‐warned that every area of investigation covered in this book is “hot” and moving fast, with new knowledge arising at a regular pace. And so, at the end of this book the reader will be also prepared for the future. I can’t really say it better than Andrea Giustina and Stefano Frara, writing in the book’s Introduction: “This thorough and comprehensive book integrates new and accessible material on diabetic microvascular comorbidities. It will help investigators, clinicians, and students to improve their understanding, providing additional knowledge, assembled in an easily consultable manner, on pathogenesis, diagnosis, research, and cure of microvascular complications.”
Well said! With that, reader, enjoy and learn.
James B. Meigs MD MPH, FAHA
Professor of Medicine, Harvard Medical School
Physician, Massachusetts General Hospital
Director, MGH Division of Clinical Research Clinical Effectiveness Research Unit
Associate Member, Broad Institute
Division of General Internal Medicine
Massachusetts General Hospital
100 Cambridge St 16th Floor
Boston MA 02114
+1‐617‐724‐3203
Editor Biography
Dr. Francesco Tecilazich received his MD and PhD at the University of Trieste Medical School in Italy. Once he completed his residency and clinical fellowship in endocrinology and metabolic disease at the University of Verona Medical School in Italy, his training and career goal has been to become an expert in the study and management of diabetes and its complications and contribute to lessening their impact. He first worked on diabetic neuropathy and impaired wound healing under the mentorship of Dr. Aristides Veves at the Joslin‐Beth Israel Deaconess Medical Center, Harvard Medical School, in Boston (USA). He then sought training in diabetic retinopathy, this time wishing to master bench research while continuing clinical and translational investigation. This combination of interests brought Dr. Tecilazich to join Dr. Mara Lorenzi’s laboratory at the Schepens Eye Research Institute, Harvard Medical School in Boston (USA). After completing a senior post‐doctoral fellowship, he was promoted to the faculty position of Investigator at the Schepens Eye Research Institute‐Massachusetts Eye and Ear Infirmary, and Instructor in the Department of Ophthalmology, Harvard Medical School. He next returned to Italy at the IRCCS San Raffaele Hospital in Milan where he resumed clinical responsibilities as an endocrinologist in the Division of Endocrinology and Metabolic Diseases, and continues his research activities on the mechanisms of protection of microvessels against diabetes, and on the search for predictors of diabetic microvascular complications.
List of Contributors
Emanuela Aragona, MDClinical FellowDepartment of OphthalmologyUniversity Vita‐Salute and San Raffaele Scientific InstituteMilan, Italy
Francesco Bandello, MDProfessor and ChairmanDepartment of OphthalmologyUniversity Vita‐Salute and San Raffaele Scientific InstituteMilan, Italy
Krish Chandrasekaran, PhDResearch ScientistDepartment of NeurologyUniversity of Maryland School of MedicineBaltimore, MD, USA
Carol Forsblom, BM, DMScSenior Scientist, Folkhälsan Institute of Genetics, Folkhälsan Research Center Helsinki, FinlandAbdominal Center, Nephrology University of Helsinki and Helsinki University Hospital, Helsinki, FinlandResearch Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki Helsinki, Finland
Stefano Frara, MDAssistant Professor of EndocrinologyDivision of Endocrinology and Metabolic DiseasesIRCCS San Raffaele Scientific Institute Università Vita‐Salute San RaffaeleMilan, Italy
Guglielmo Gallone, MDClinical FellowCardiothoracic and Vascular DepartmentIRCCS San Raffaele Hospital and Vita‐Salute San Raffaele UniversityMilan, Italy
Georgios Theocharidis, PhDPostdoctoral Research Fellow,Beth Israel Deaconess Medical CenterHarvard Medical SchoolBoston, MA,USA
Christopher H. Gibbons, MD, MMScDirectorHarvard Medical SchoolBoston, MA,USA
Andrea Giustina, MDProfessor of EndocrinologyDivision of Endocrinology and Metabolic DiseasesIRCCS San Raffaele Scientific InstituteUniversità Vita‐Salute San RaffaeleMilan, Italy
Gopalan Gnanaguru, PhDInvestigator, Massachusetts Eye and Ear Infirmary – Department of OphthalmologyHarvard Medical SchoolBoston, MA,USA
Richard G. IJzerman, MD, PhDPrincipal InvestigatorDiabetes Center Amsterdam/Department of Internal MedicineAmsterdam University Medical CentersFree UniversityAmsterdam, The Netherlands
Rosangela Lattanzio, MDHead, Medical Retina ServiceDepartment of OphthalmologyUniversity Vita‐Salute and San Raffaele Scientific InstituteMilan, Italy
Silvia Maestroni, PhDResearch FellowDivision of ImmunologyDiabetes Research Institute (DRI)IRCCS San Raffaele Scientific InstituteMilan, Italy
Marco Magnoni, MDAdjunct Professor of CardiologyCardiothoracic and Vascular DepartmentIRCCS San Raffaele Hospital and Vita‐Salute San Raffaele UniversityMilan, Italy
Alessandro Marchese, MDClinical FellowDepartment of OphthalmologyUniversity Vita‐Salute and San Raffaele Scientific InstituteMilan, Italy
Francesco Moroni, MDClinical FellowCardiothoracic and Vascular DepartmentIRCCS San Raffaele Hospital and Vita‐Salute San Raffaele UniversityMilan, Italy
Cristian Nicoletti, MDChief, Diabetic Foot ClinicPederzoli HospitalVerona, Italy
Luciano Pirola, PhDResearcherCarMeN Institute – INSERM Unit 1060, South Lyon Medical Faculty, Lyon 1 University, Lyon, France
James W. Russell, MD MS FACP FRCPProfessor Department of Neurology, Anatomy and NeurobiologyUniversity of Maryland School of MedicineDirector Neuromuscular DivisionDirector Peripheral Neuropathy CenterCo‐Director Maryland ALS Association Center of ExcellenceInvestigator VA Maryland Medical CenterBaltimore, MD, USA
Niina Sandholm, DScSenior ResearcherFolkhälsan Institute of Genetics Folkhälsan Research Center Helsinki, FinlandAbdominal Center, Nephrology University of Helsinki and Helsinki University Hospital, Helsinki, FinlandResearch Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki Helsinki, Finland
Francesco Tecilazich, MD, PhDPrincipal InvestigatorDivision of Endocrinology and Metabolic DiseaseSan Raffaele Scientific InstituteMilan, Italy
Eelco van Duinkerken, PhDResearch FellowCenter for Epilepsy, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro RJ, BrazilDepartment of Medical Psychology Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam The NetherlandsDiabetes Center Amsterdam/Department of Internal Medicine Amsterdam University Medical Centers Free University, Amsterdam The Netherlands
Aristidis Veves, MD, DSc,Professor of SurgeryDirector, Rongxiang Xu, MD, Center for Regenerative TherapeuticsBoston, MA, USAHarvard Medical SchoolResearch DirectorJoslin‐Beth Israel Deaconess Foot Center and Microcirculation Lab,Boston, MA, USA
Gianpaolo Zerbini, MD, PhDGroup Leader, Complications of DiabetesDivision of ImmunologyDiabetes Research InstituteIRCCS San Raffaele Scientific InstituteMilan, Italy
Lindsay A. Zilliox, MD, MSAssistant Professor of NeurologyDepartment of NeurologyUniversity of Maryland School of MedicineBaltimore, MD, USAMaryland VA Healthcare SystemBaltimore, MD, USA
1Introduction
Andrea Giustina and Stefano Frara
IRCCS San Raffaele Scientific Institute, Università Vita‐Salute San Raffaele, Milan, Italy
The American Diabetes Association (ADA) stated in 2017 that diabetes is a complex, chronic illness requiring continuous medical care with multifactorial risk‐reduction strategies beyond glycemic control, including continuous patient self‐management education and support as critical issues to prevent acute complications and reduce the risk of long‐term complications [1]. At the same time, the International Diabetes Federation (IDF) defined diabetes as a pandemic disease and the major cause of cardiovascular (CV) disease (CVD), chronic renal disease, blindness, and amputation. In 2017, 425 million people were affected by diabetes worldwide [2].
One of the main priorities agreed on at the 2013 United Nations high‐level meeting on non‐communicable diseases (NCDs) was to halt the number of people living with diabetes as in 2010 [3]. Despite these efforts, the number of diabetic patients is expected to continue growing, reaching 629 million in 2045, regardless of country of residence, sex, race, social, or income levels [2]. Data from the NCD Risk Factor Collaboration (NCD‐RisC) showed that the global age‐standardized prevalence of diabetes between 1980 and 2014, rose from 4% to 9% in men, and from 5% to 8% in women. [4].
Despite a multitude of investigators around the world working extensively on a cure for diabetes, using different approaches, from islet transplantation to stem‐cell therapies, progress is slower than anticipated, and a definitive cure is currently not available and actually still far in the future. Indeed, diabetes is a plague due to the increased risk of multiple micro‐ and macrovascular conditions, dementia, cancers, and infectious diseases. Notably, people with diabetes are supposed to have double the risk of CVD as compared with sex‐, age‐, and body mass index (BMI)‐matched people with no glycemic derangements [5].
Even if women have historically poorer risk factor profiles, they usually receive lesser CV care compared with men, despite no differences in the safety and effectiveness of medication between women and men [6]. It is noteworthy that women with diabetes have a 44% greater risk of coronary artery disease as defined by the presence of angina, heart failure, and/or myocardial infarction [7], and a 27% greater risk of stroke than men [8], independent of sex differences and other major risk factors. Interestingly, the increased risk of microvascular chronic complications in diabetes has been shown to be a “phenomenon with a memory”. The first evidence was reported in a study from Dr. Lorenzi's group in the 1980s in which the authors elegantly showed that the microvascular changes induced by hyperglycemia persisted after restoration of normoglycemia [9]. Indeed, on the one hand, these observations have been replicated in humans within the Diabetes Control and Complications Trial (DCCT) 30‐years follow‐up study [10], and on the other hand, these observations represent the foundation of the study of the alterations induced by diabetes to the epigenome [11]. Therefore, in this complex clinical setting, the prevention of the chronic complications of diabetes is one of the main therapeutic goals. Currently, the only available approach to achieve this goal is an adequate management of blood glucose levels, and good control of blood pressure, cholesterol, triglycerides, and body weight through balanced diet and lifestyle changes [12]. Noteworthily, therapeutic patient education is now considered a crucial element in the treatment and prevention of diabetes: several trials have shown that education is able to improve clinical, lifestyle, and psycho‐social outcomes, but so far they have not clarified the ideal characteristics of a comprehensive patient education program in clinical practice [13, 14].
In the past, microvascular disease was thought to affect the smallest blood vessels after a long history of diabetes, while stroke and heart attacks were considered classical manifestations of macrovascular disease [15]. In 2000, the first edition of the Diabetes Atlas well described microvascular complications as abnormally thick but weak walls of the vessels, leading to bleeding, leaked proteins, and the slowing of the flow of blood through the body. Diabetic retinopathy (RD), nephropathy, neuropathy, and food lesions (up to amputations) were considered the peculiar manifestations of this condition [15]. However, in the past decade, increasing evidence has been published indicating that functional and structural abnormalities of the coronary microvascular district cause myocardial perfusion impairment and, finally, ischemia [16]. Hyperglycemia causes microvascular dysfunction, modifying several physiological pathways, such as NO and arachidonic acid metabolism, and, consequently, generating increased oxidative stress [17]. At early stages, patients with subclinical levels of diabetes‐induced myocardial changes (atherosclerotic changes of coronary arteries and microvascular endothelial dysfunction) are usually asymptomatic. Therefore, if not precociously detected, the disease may advance rapidly, leading to heart failure and death [18].
Intriguingly, hallmark studies such as the DCCT/EDIC (Epidemiology of Diabetes Interventions and Complications) and the ACCORD‐MIND (Action to Control Cardiovascular Risk in Diabetes – Memory in Diabetes), have demonstrated a link between diabetes and cognitive dysfunction [19, 20]. In addition, other more recent cohort studies highlighted a strong correlation between both type 1 and type 2 diabetes and the development of dementia, especially of vascular origin [21, 22]. The hypothesis of an association between cognitive impairment and microvascular derangement has been finally confirmed by the observations of a solid correlation between RD, the most frequent microvascular complication, and poor neurocognitive performance in patients with diabetes [23–26], with alterations of both gray and white matter structure [27, 28]. It has been proposed that inflammation may also play a key pathophysiological role in this clinical context. Indeed, it is well known that diabetes is associated with high levels of pro‐inflammatory cytokines; accordingly, high levels of inflammatory markers in the cerebrospinal fluid and in the circulation have been related to both RD and cognitive impairment [29, 30].
This thorough and comprehensive book integrates new and accessible material on diabetic microvascular comorbidities. It will helps investigators, clinicians, and students to improve their understanding, providing additional knowledge, assembled in an easily consultable manner, on pathogenesis, diagnosis, research, and cure of microvascular complications.
References
1
American Diabetes Association (2017). Standards of medical care in diabetes – 2017.
Diabetes Care
40 (Suppl.1): S1–S135.
2
International Diabetes Federation (2017).
IDF Diabetes Atlas
, 8e. Brussels: IDF.
3
World Health Organization (2013).
Global Action Plan for the Preservation and Control of NCDs 2013–2020
. Geneva: WHO
https://apps.who.int/iris/bitstream/handle/10665/94384/9789241506236_eng.pdf;jsessionid=CC8EBCE1881FCEE6413320FB422CD388?sequence=1
(accessed July 1, 2019).
4
NCD Risk Factor Collaboration (NCD‐RisC) (2016). Worldwide trends in diabetes since 1980: a pooled analysis of 751 population‐based studies with 4.4 million participants.
Lancet
387: 1513–1530.
5
Emerging Risk Factor Collaboration, Sarwar, N., Gao, P. et al. (2010). Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta‐analysis of 102 prospective studies.
Lancet
375: 2215–2222.
6
Hyun, K.K., Redfern, J., Patel, A. et al. (2017). Gender inequalities in cardiovascular risk factor assessment and management in primary healthcare.
Heart
103: 492–498.
7
Peters, S.A., Huxley, R.R., and Woodward, M. (2014). Diabetes as a risk factor for incident coronary heart disease in women compared with men and meta‐analysis of 64 cohorts, including 858,507 individuals and 28,203 coronary events.
Diabetologia
57: 1542–1551.
8
Peters, S.A., Huxley, R.R., and Woodward, M. (2014). Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta‐analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes.
Lancet
383: 1973–1980.
9
Roy, S., Sala, R., Cagliero, E., and Lorenzi, M. (1990). Overexpression of fibronectin induced by diabetes or high glucose: phenomenon with a memory.
Proc. Natl. Acad. Sci. U. S. A.
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2Pathophysiology
Francesco Tecilazich
Division of Endocrinology and Metabolic Disease, San Raffaele Scientific Institute, Milan, Italy
Introduction
A conspicuous portion of the pathologies of aging and many manifestations of the complications of diabetes are consequences of microvascular dysfunction or damage. Diabetes induces functional and structural changes in the microvessels; these changes occur through multiple mechanisms and at multiple levels, and have damaging consequences for the tissues.
In human diabetes a long latency period (12–15 years) precedes the appearance of microvascular disease; symmetrically, in rodents, microvascular disease does not become detectable until at least 6 months after the induction of diabetes [1], despite sustained hyperglycemia. This does not necessarily imply, but is consistent with, the presence of systems for protection or repair that are activated and efficient at early stages of diabetes and may lose efficacy at later times. Therefore, the natural history of diabetic microvascular disease could incorporate an early phase of active vascular repair; to date however, there is no systematic evidence for this.
Anatomo‐Physiology of Microvessels
Capillaries consist of endothelium surrounded by basement membrane, with the adjunction of ascent capillaries. Arterioles consist of, from the lumen outwards: endothelium (intima), internal elastic lamina (IEL), smooth muscle (media), and finally loose connective tissue (adventitia). Venules consist of endothelium surrounded by the basement membrane and pericytes. Finally, lymphatic vessels consist of endothelium surrounded by elastic fibers and a lax basement membrane.
The endothelium is a diaphanous monolayer of cells. It constitutes the inner layer lining of the blood vessels, is in direct contact with the circulating blood, and is an important autocrine and paracrine regulator of vascular function. Therefore, the endothelium represents a critical interface between blood and peripheral tissues. Endothelial cells (ECs) synthesize and release on the one hand vasodilating factors such as nitric oxide (NO), the prostacyclin PGI2 – a cyclooxygenase‐dependent metabolite of arachidonic acid, member of the prostanoid group of eicosanoids [2] –, and endothelium‐derived hyperpolarizing factor (EDHF), which induces smooth muscle cell relaxation via hyperpolarization [3]. On the other hand, ECs synthesize and release vasoconstricting factors such as endothelin‐1 (ET‐1), prostaglandins, and angiotensin II (ANG‐II).
Smooth muscle surrounds the endothelium, and represents “the muscle behind vascular biology” as it is the effector of vascular constriction and dilation. The smooth muscle is formed by layers of small, spindle‐shaped mononucleated cells, known as vascular smooth muscle cells (VSMCs). The number of VSMC layers varies according to the location and size of the vessel: many in elastic arteries, as few as one in resistance arteries [4]. The layers of VSMCs are separated by sheets of elastic laminae, and the IEL separates the endothelium from the smooth muscle [5]. Gap junctions are intercellular connectors that allow various molecules, ions, and electrical impulses to directly pass between neighboring cells in the vessels, as throughout the whole body. “Homo” gap junctions connect same cell types (EC–EC and VSMC–VSMC); “Hetero” gap junctions – also known as myoendothelial gap junctions (MEGJs) – connect different cell types (EC–VSMC). The diffusion of vasodilation is facilitated via the transmission of membrane hyperpolarization occurring via gap junctions; this phenomenon is known as “spreading vasodilation.”
Pericytes are a heterogeneous, tissue‐specific, and multipotent population of mural cells present in all vascular beds. Pericytes play a critical role in supporting and stabilizing the microvasculature, and regulate multiple aspects of vascular homeostasis, such as regulation of blood flow, angiogenesis, and vascular permeability [6].
Regulation of Microvascular Tone
Endothelial‐Dependent Vasodilation
A seminal discovery in vascular physiology was the finding by Furchgott and Zawadzki that arterial vasodilation was dependent on an intact endothelium and on the release of endothelium‐derived relaxing factor (EDRF) [7] – this molecule was later identified as NO. In ECs, NO synthase – in the presence of oxygen, NADPH, and other co‐factors – catalyzes the oxidation of the amino acid L‐arginine to form L‐citrulline and NO. NO is a gas that easily diffuses across the cell membrane to the adjacent VSMCs where it leads to a cascade of events (see below), resulting in VSMC relaxation and dilation of the vessel. As described above, ECs secrete other vasodilatatory mediators; however, NO is the main agent.
Endothelial‐Independent Vasodilation
VSMCs represent the final effectors of the vasodilating process, determined by relaxation of VSMCs, which is mainly achieved through three mechanisms: (i) the NO activation of soluble guanylate cyclase with subsequent formation of cyclic guanosine monophosphate (cGMP), which in turn activates protein kinase G, causing phosphorylation of myosin light‐chain phosphatase and therefore inactivation of myosin light‐chain kinase, which ultimately leads to the dephosphorylation of the myosin light chain; (ii) the PGI2 activation of the prostacyclin (IP) receptor leads to cyclic adenosine monophosphate (cAMP)‐mediated activation of protein kinase A (PKA), which in turn determines VSMC relaxation by reducing on the one hand intracellular Ca2+, via its extrusion through pumps on the cell surface and on the sarcoplasmic reticulum, and on the other hand by inducing VSMC hyperpolarization, via activation of K+ channels; and (iii) the EDHF‐mediated transmission of hyperpolarization from ECs to VSMCs through gap junctions and/or the release of diffusible factors.
Nerve Axon Reflex (NARV)
Under normal conditions, the ability to increase blood flow to the skin depends on the existence of an intact neurogenic vascular response; typically, this response is equal to one‐third of the maximal vasodilatory capacity. This protective hyperemic response, also known as Lewis's triple flare response or the NARV begins with stimulation of C‐nociceptive nerve fibers, leading to antidromic stimulation of the adjacent C fibers. The activated C fibers then secrete neuropeptides such as substance P, calcitonin gene‐related peptide, and histamine, causing vasodilation and increased blood flow to the injured tissues.
Myogenic Response
Bayliss in 1902 was the first to describe the myogenic response reporting that “the muscular coat of the arteries reacts, like smooth muscle in other situations, to a stretching force by contraction” and “these reactions are independent of the central nervous system, and are of myogenic nature” [8]. This intrinsic behavior of smooth muscle is independent of neural, metabolic, and hormonal influences [9]. The myogenic response is a complex event, highly regulated by an interplay of signaling mechanisms, and subtle effects of diabetes can interfere at more than one level. The myogenic response to pressure of resistance arteries entails that the VSMCs sense the pressure change, depolarize the membrane potential, and activate voltage‐dependent calcium channels in the plasma membrane, so that an influx of extracellular calcium can activate the machinery responsible for actin–myosin cross‐bridge cycling and VSMC contraction. While the myogenic response is an intrinsic property of the VSMCs, the events leading to constriction and its final intensity can further be modulated by a number of influences, some enhancing vasoconstriction (e.g. the activity of Rho‐kinase pathway), some antagonizing it (e.g. endothelial NO) [10, 11].
Functional Hyperemia
There is another mechanism of vessel reactivity elicited in the retina: the reduced dilation of retinal vessels to a light stimulus. A flickering source of illumination generates an increased metabolic demand of the neural retina, and the neural–glial elements of the retina trigger vasodilation to increase the blood flow and the provision of oxygen and nutrients to the retina. Of note, the retina does not present sympathetic innervation; therefore, this phenomenon cannot be attributed to Lewis's triple flare response as in the NARV (see above).
Venoarteriolar Response (VAR)
The VAR is the constriction of small arteries attributed to myogenic mechanisms associated with the changes in pressure. The VAR owes its name to the fact that stretch receptors in small veins cause signals that constrict the “upstream” arterioles [12]. The response does not occur through adrenergic mechanisms; rather, it is likely due to myogenic mechanisms associated with the changes in pressure [12].
Structural Changes in the Microcirculation
Structurally, the most notable changes induced by diabetes in the microvessels involve the decreased number and size of capillaries [13], and the increased thickness of the basement membrane [14, 15]. The extent of these alterations is related to glycemic control [16]. Thickening of the basement membrane has detrimental consequences on numerous cellular functions, such as vascular permeability; cellular adhesion, proliferation, differentiation, and gene expression; impaired exchange of nutrients; migration of activated leukocytes in the interstitium; and altered elastic properties of the vessel walls [17]. All these events eventually lead to vascular dysfunction.
Functional Changes in the Microcirculation
In the simplest terms, functional changes are the inability of the microvessels to modify their caliber in response to local stimuli; they can be the result of different conditions, such as: endothelial dysfunction, smooth muscle cell dysfunction, impairment of the nerve axon reflex, defective myogenic reflex, and reduced functional hyperemia.
Under normal physiological circumstances, the mechanisms leading to vasodilatation and vasoconstriction are balanced, so vascular tone and permeability, and the balance between coagulation and fibrinolysis, are finely regulated. Meanwhile, in the case of endothelial dysfunction, this balance is altered predisposing the onset and progression of atherosclerosis. Endothelial dysfunction is associated with decreased NO availability, either through loss of NO production or through loss of NO biological activity [18]. The significance of endothelial dysfunction for the micro‐ and macrocirculation and the variety of proposed mechanisms affecting normal function will be discussed in further detail.
Endothelial Dysfunction
Endothelium‐dependent vasodilation is impaired in diabetes, irrespective of the presence or absence of long‐term complications [19–23]. The endothelium has been shown to be dysfunctional in adolescents with type 1 diabetes, a population that is generally spared from the vascular complications of diabetes [24]. This finding suggests that endothelial dysfunction is present before the development of vascular complications and may play an important role in their development. Endothelial function in diabetes has been shown to be associated with total cholesterol, red cell folate, blood glucose, and duration of diabetes [25–27]. Extensive research effort has focused on the relationship of diabetes and vascular disease; it is currently well established that changes in the endothelial function precede the development of diabetes, and are already present in the prediabetic stage. It is also of interest that endothelial dysfunction is associated with insulin resistance in non‐diabetic subjects, suggesting a cause–effect relationship of these two conditions [23].
A study conducted in Dr. Veves' unit found that the vasodilatatory response to ACh was reduced in patients with diabetes complicated by neuropathy alone, neuropathy and vascular disease, and patients with Charcot neuroarthropathy; meanwhile, no difference was found between patients with diabetes not complicated by neuropathy and the healthy controls. In addition, Dr. Veves' group also found that the vasodilatory response was not diminished in subjects with neuropathy and vascular disease compared with subjects with neuropathy alone. Altogether, these data suggested for the first time the fundamental role played by the peripheral nervous system in regulating microcirculation [28].
Impairment in the microcirculation was also found to be present in the absence of large vessel disease. These findings implied that the main reason for reduced microvascular reactivity was the presence of neuropathy, as indicated by the fact that no other abnormalities were found in the non‐neuropathic diabetic patients. Further support for this claim is provided by the findings that the coexistence of neuropathy and vascular disease did not result in a greater decrease in endothelium‐dependent vasodilation than that due to neuropathy alone.
VSMC Dysfunction
Data on endothelium‐independent vasodilation function in complicated and non‐complicated diabetes is controversial [29–33]. Studies by Dr. Veves' group suggested that endothelium‐independent vasodilation is decreased in patients with diabetes [28]. Using laser Doppler imaging, measurements of vasodilatory response to iontophoresis of sodium nitroprusside – a NO donor – on VSMC function has been shown to be significantly reduced in diabetic patients with vascular disease, suggesting that the endothelium‐independent response may be spared. Since ACh stimulates the production of NO, it was surmised that an impaired NO production was responsible for the impaired vasodilatory response observed.
NARV Impairment
Nerve dysfunction contributes to the diminished vasodilatatory response observed in diabetes. Measurements in patients with a diabetic neuropathic foot have shown that this neurovascular response is impaired, leading to a significant reduction in blood flow under conditions of stress. It has been postulated that the observed reduction in the NARV in diabetic neuropathy is related to both impaired C‐nociceptive fiber function and impaired ability of the microvasculature to respond to vasomodulators secreted by these fibers [34]. Evidence for this vasodilatatory impairment related to the presence of diabetic neuropathy is provided by studies in Dr. Veves' lab. In diabetic patients with neuropathy, neuropathy, and peripheral vascular disease, and with Charcot arthropathy, the iontophoretic response to ACh in skin areas adjacent to this substance but not in direct contact with it was significantly reduced compared with patients with uncomplicated diabetes and to healthy subjects (a phenomenon called indirect response) [35].
The impairment in axon‐related vascular reactivity is believed to further aggravate the diabetic microcirculatory abnormalities, leading to a vicious cycle [28].
Defective Myogenic Response
According to Poiseuille's law, blood flow is related to the fourth power of the vessel radius. Thus, arteries that do not constrict normally when perfusion pressure increases allow a larger fraction of pressure and flow to reach the capillaries. The pathogenic consequences intrinsic to a defective myogenic response to pressure can also explain why systemic hypertension is the primary co‐pathogenic factor for both diabetic retinopathy and nephropathy. As demonstrated by Rassam, Patel, and Kohne [36], while control subjects constricted their retinal arteries in response to all increments in systemic blood pressure induced experimentally, T1D patients failed to constrict their arteries even at the smallest increment in blood pressure, and manifested large increases in retinal blood flow, especially when very hyperglycemic [36]. For nephropathy, the defective myogenic response of the glomerular afferent arteriole is known to contribute to hyperfiltration and to further worsen hyperfiltration when systemic hypertension develops [37, 38]. In animal models of diabetes an impaired myogenic response to pressure is reported in several vessels, from the ophthalmic arteries [39] to the arterioles of the cremaster muscle [40, 41], to the cerebral [42, 43] and coronary [43] arteries.
Although a defective myogenic response in T1D patients and animal models has been known for many years as a feature of the loss of vascular autoregulation, the appreciation that it can represent an early event is very recent. The reason is that only with the removal of the great equalizer (severe hyperglycemia), has it become possible to capture early individual differences in the path to complications, retinopathy in particular. In the early 1990s most if not all T1D patients had increased retinal blood flow at steady state [44]. In contrast, contemporary T1D patients with or without early retinopathy have absolutely normal retinal hemodynamics at steady state [45–47]. It was only upon the application of a challenge that Dr. Lorenzi identified patients with an abnormal myogenic response. The challenge was a simple change from the sitting to the supine position, which causes an increase in retinal perfusion pressure. In response to the postural challenge approximately 50% of T1D patients without clinical retinopathy manifested lack of arterial constriction in response to the increased perfusion pressure, i.e., a defective myogenic response [46]. When considering that a simple change in position from sitting to reclining, or physical exercise [48, 49], augments perfusion pressure in the eye, it is evident that an insufficient myogenic response will place the retinal capillaries at risk many times a day, every day.
Our group has recently defined more precisely the potential role of the defective myogenic response, as an accelerator of microvascular disease in the retina. We observed that the abnormality (i) tended to predict the appearance of retinopathy, (ii) was not required for the development of retinopathy, and (iii) was associated with accelerated onset of retinopathy [45].
Reduced Functional Hyperemia
Some T1D patients present reduced dilation of retinal vessels to a light stimulus. The reduced dilation tends to be more pronounced in TD1 patients with retinopathy, but also occurs in TD1 patients without clinical retinopathy, thus representing an early abnormality [50, 51]. Studies by Dr. Schmetterer's group indicate that the reduced arterial dilation in T1D is not due to decreased reactivity of the retinal arterial smooth muscle cells (SMCs), as the response to a direct vasodilator was normal [52]. Nor is it due to neural retina dysfunction, as the abnormal dilation occurs in the presence of normal pattern electroretinogram [51]. This abnormality has never been investigated with prospective follow‐up studies, and the presentations of results have not included individual data to learn whether the abnormality is present in all patients or is more pronounced in some patients than in others.
Endothelial Dysfunction
Endothelial dysfunction is expressed as increased smooth muscle growth, vasoconstriction, impaired coagulation, thrombosis, and atherosclerosis. The main causes of endothelial dysfunction in diabetes have been postulated to include hyperglycemia, insulin resistance, and inflammation as possible mediators of abnormal endothelium‐dependent responses.
Role of the Immune System and Leukostasis
The dysregulation of the immune system in diabetes is responsible for the activation of the inflammatory response, which in turn generates oxidative stress and increases insulin resistance, thereby favoring the development of microvascular complications. For example, the expression of ICAM‐1, a molecule that mediates the adhesion of leukocytes to the endothelium via binding to LFA‐1, is increased in diabetes and has been proposed to be a key factor in the onset and progression of diabetic nephropathy, to the extent that inhibition of ICAM‐1 has been reported to slow the progression of nephropathy in diabetic animals [53, 54].
Interestingly, in animal models of diabetes, one of the earliest initial findings in microvascular disease is represented by an increased number of leukocytes firmly adherent to the microvessels. This phenomenon, known as diabetic leukostasis and interpreted as a detrimental event for a long time, [55] is constituted by two principal cellular components: monocytes and granulocytes [56]. Our group has recently demonstrated that a discrete subpopulation of monocytes, called patrolling monocytes (PMo), coincide substantially with diabetic leukostasis (Tecilazich and Lorenzi, unpublished). PMo are characterized by a distinct phenotype as they crawl on the endothelium at a speed that is up to 1000 times slower than the typical leukocyte rolling; [57] present a peculiar anti‐inflammatory biosynthetic profile [58]; and exert protective and healing actions in different tissues and contexts [59–61]. Studies in our unit clearly indicate that the reduction of leukostasis by removal of PMo in transgenic mice profoundly exacerbates the microvascular pathology seen in diabetes. Moreover, our studies on the transcriptome of these cells show that PMo respond to diabetes by activating an anti‐inflammatory, anti‐apoptotic, and vasculo‐protective program (Tecilazich and Lorenzi, unpublished). This finding is striking as other immune cells respond to diabetes in the opposite fashion [62–65]. Altogether, our data support the hypothesis that PMo dampen the stress induced by diabetes on the microvessels, and that ultimately leads to diabetic microvascular disease. Quite interestingly, the role of monocytes in the progression of diabetic microvascular disease has been suggested based on the findings that inhibition of CCL‐2 improved diabetic nephropathy [66, 67]; however, CCL‐2 is expressed on inflammatory monocytes, but not on PMo.
Further investigation is needed to validate this protective system, and hopefully to ascertain from this – and/or from other endogenous systems – the types of molecular actions that protect the vessels in early diabetes; and thus be enabled to mimic, complement, or leverage such actions via exogenous interventions over the duration of diabetes.
Role of Hyperglycemia
Hyperglycemia causes endothelial dysfunction primarily through the induction of oxidative stress. The molecular mechanisms involved in this process include the enhanced activation of protein kinase C (PKC); synthesis of vasoconstrictor prostanoids; activation of poly (ADP‐ribose) polymerase (PARP); generation of oxygen‐derived free radicals; synthesis of endothelin‐1 (ET‐1); induction of the polyol pathway; and generation of advanced glycosylated end products (AGEs). An additional mechanism is the reduction of the Na+–K+ ATPase activity.
AGEs
When proteins are exposed to hyperglycemic environments, a non‐enzymatic reaction (Maillard) determines the formation of Shiff bases that can be rearranged through non‐enzymatic glycosylation to form Amadori products, and eventually AGEs. AGEs contribute substantially to the increased vascular permeability of diabetes by altering protein structure and function, by modifying the extracellular matrix's structure, and by triggering inflammation. The blockade of a specific receptor for AGE (RAGE) reverses diabetes‐mediated vascular hyperpermeability [68], and limits the generation of reactive oxygen species (ROS). Interestingly, the relationship between ROS and AGEs is bidirectional as the inhibition of ROS prevents the generation of AGEs, suggesting that the autoxidative process plays an important role in the complex reaction cascade leading to AGE.
Polyol Pathway
Aldose‐reductase (AR) – a key factor in the polyol pathway – normally inactivates aldehydes by reducing them to alcohols. In the presence of intracellular hyperglycemia, glucose enters the polyol pathway: AR reduces glucose to sorbitol, an organic osmolyte, utilizing the cofactor NADPH; subsequently, sorbitol dehydrogenase oxidizes sorbitol to fructose. The result of excess polyol pathway activation is: increased sorbitol (which causes osmotic stress), increased fructose (which is a very potent glycation agent), increased ROS (see below), and decreased intracellular antioxidants NO and glutathione – this is the result of the consumption of NADPH, cofactor in the synthesis of sorbitol, NO, and glutathione [69]. The accumulation of sorbitol also causes the depletion of other osmolytes, like myo‐inositol and taurine [70], leading to vascular dysfunction and to nerve conduction defects [71]. In fact, the depletion of myo‐inositol impairs the phosphoinositide metabolism and decreases phosphoinositide‐derived diacylglycerols, which impairs neural PKC activation, with subsequent reduction of Na+–K + ‐ATPase activity [72]. Finally, the increased activity of AR plays a critical role also in the downstream activation of MAPK (mitogen‐activated protein kinase) [73], PARP [74], and NF‐κB [73].
More than 32 randomized controlled trials have tested the efficacy of AR inhibitors (ARIs), such as ranirestat and epalrestat, in the treatment of diabetic neuropathy. A meta‐analysis involving 879 ARI‐treated and 909 control (placebo or no treatment) participants, showed no overall significant difference in the treatment of diabetic polyneuropathy between the groups [75].
Oxidative Stress
Oxygen‐derived free radicals – such as superoxide and other ROS – are physiologically produced in the vascular cells by NADPH oxidase, xanthine oxidase, the mitochondrial electron transport chain, uncoupled endothelial NOS, and arachidonic acid metabolism pathways. Oxidative stress is generated when the production of oxygen‐derived free radicals exceeds the buffering capacity of available antioxidant defense systems. Diabetes promotes oxidative stress on the one hand by increasing lipid peroxidation products and protein carbonylation, and on the other hand by decreasing antioxidant efficiency through decreased activity of superoxide dismutases, catalases, glutathione peroxidase, and thioredoxin. Oxidative stress in turn induces cell dysfunction or death through the degeneration of biological macromolecules: nucleic acids, lipids, and proteins. Vitamin E is a potent free radical scavenger, and its effect on vessels has been tested at low and high doses: at low doses (400 IU/day) it has no effect on cardiovascular outcomes in patients with diabetes [76]. An initial promising study using high doses (1800 IU/day) showed normalized hemodynamic abnormalities – suggesting that administration of antioxidants could potentially reduce diabetic vascular complications [77] –; subsequent studies unfortunately did not replicate this finding [78], and some studies actually suggested an association of high‐dose Vitamin E with worsening of vascular reactivity
PKC
The PKCs are a superfamily of cytoplasmic serine/threonine kinases, ubiquitously expressed, involved in a wide range of intracellular signaling, such as: oxidant, inflammatory, mitogenic, and angiogenic. There are 10 PKC isoforms, grouped as classic, novel, and atypical: the most consistently associated with diabetic microvascular disease are PKC α, β, and δ; whereas PKC ε has been suggested to play a protective role in the kidney [79], and has been recently associated with hepatic insulin resistance [80]. In vessels, PKC regulates proliferation, neovascularization, permeability, and contractility; the production of extracellular matrix, the synthesis of cytokines, the activation of cytosolic phospholipase A2, and the inhibition of the Na+–K+‐ATPase pump. The effects of pharmacological inhibition of PKC‐β overactivation with the bisindolylmaleimide ruboxistaurin (RBX) were tested in diabetic animals, in whom they improved renal, retinal, and neural function [81–84]. The effects of RBX have been tested in patients with proliferative retinopathy, leading to decreased incidence of vision loss [85]; in patients with late‐stage nephropathy, leading to decreased incidence of end‐stage renal disease [86]; and in patients with severe peripheral neuropathy, in whom it led to significantly decreased symptoms of neuropathy, even though it failed to achieve the primary end point [87].
Transforming Growth Factor (TGF)‐β
TGF‐β is a cytokine that plays important roles in the maintenance of vascular homeostasis by regulating the production of extracellular matrix, the replication and survival of ECs, the interactions of ECs and pericytes, and the remodeling of vessels. In addition TGF‐β has been shown to be involved in the pathogenesis of disease, such as Marfan and other vasculopathies. In experimentally diabetic animals, Tgf‐β synthesis is increased in the kidney [88] and the retinal vessels [89]; furthermore, treatment with anti‐Tgf‐β antibodies prevents nephropathy [88]. Altogether, these observations have proposed TGF‐β is a contributor to, if not a master‐mediator of, diabetic microvascular disease. However, data on the role of TGF in vascular disease are conflicting. Recent work from our unit indicates that, in diabetes, the retinal vessels become dependent on an increase in TGF‐β signaling to maintain their integrity [90]. Our results are consistent with findings of other groups that used different approaches in different contexts [91–93]. It is noteworthy that TGF is known to be a negative regulator of lymphocytes, and to exert anti‐inflammatory actions on mono‐macrophagic immune cells.
Hexosamine Pathway
The first step of the glycolytic pathway is the conversion of glucose‐6 phosphate to fructose‐6 phosphate. In the presence of intracellular hyperglycemia, not all the fructose‐6 phosphate enters the glycolytic pathway; some in fact is diverted to the hexosamine pathway, where it is first converted to glucosamine‐6 phosphate, with the concomitant conversion of glutamine to glutamate (a reaction catalyzed by glutamine:fructose‐6 phosphate amidotransferase; GFAT), subsequently glucosamine‐6 phosphate is converted to uridine diphosphate N‐acetyl glucosamine (UDP‐GlcNAc). UDP‐GlcNAc – a high‐energy sugar nucleotide donor – can glycosylate lipids and proteins, can induce the generation of other UDP sugars, or can induce O‐GlcNAc modifications of nucleocytoplasmic proteins (e.g. transcription factors, signaling components, and metabolic enzymes) [94], thereby altering gene expression profiles of cells exposed to high glucose.
PARP
PARP is a nuclear enzyme that responds to oxidative DNA damage by activating an inefficient cellular metabolic cycle, often leading to cell necrosis. Activation of PARP is associated with changes in microvascular reactivity; in addition, PARP's activation – besides being related to endothelial dysfunction in patients with diabetes – has been observed also in healthy patients at risk of developing diabetes [95]. These findings overall suggest that changes in the microcirculation due to PARP activation may begin in the prediabetic state.
