Biomarkers in Diabetes

Description

This handbook focuses specifically on biomarkers in diabetes and provides a comprehensive understanding of this field. Readers will gain deep insights into bioinformatics and network analysis of biomarkers in diabetes, and will learn about circulating biomarkers in body fluids and specific pathological features of diabetes. Various animal models in diabetes research are also presented. In addition, like the previous volumes in this large reference series, the book provides a comprehensive look at genetics, cellular, and histological variables. The goal of this handbook is to provide information on markers of this disease to facilitate diagnosis, introduce new technologies, and ultimately improve health. It is a must for researchers as well as advanced students and physicians in the field of diabetes and biomarker research and application. Preface Contents About the Editors Contributors Part I: General Aspects 1 Linking Variants of Hemoglobin A1C and Glycemic Status Introduction Overview of Genome-Wide Association Studies of HbA1c Functional Characterization of HbA1c-Associated Genetic Variants Glycemic-Related Genetic Variants Erythrocyte-Related Genetic Variants Unclassified Genetic Variants Erythrocyte-Related HbA1c Variants and Glycemic Status Screening G6PD: rs1050828 and rs76723693 HBB-rs334 G6PD-rs1050828 and HBB-rs334 Cumulative Effect of Erythrocyte-Related Genetic Variants Conclusion Applications to Other Diseases or Conditions Mini-Dictionary of Terms Key Facts of HbA1c Summary Points Reference 2 Treatment Regimes in Diabetes and Their Impact on Biomarkers Lipid Profile and T2DM Introduction to Lipids and T2DM The Relationship Between Obesity and Lipids The Relationship Between Lipids and T2DM Lipid Intermediates and Insulin Resistance Role of Exercise on Lipid Metabolism in T2DM Acute Effects of Exercise on Muscle Lipid Content Acute Effects of Exercise on Muscle Lipid Intermediates Chronic Effects of Exercise on Muscle Lipid Content Chronic Effects of Exercise on Muscle Lipid Intermediates Effect of Exercise on Liver Lipid Content Exercise Interventions and Classic Lipid Biomarkers Inflammatory Profile and T2DM Introduction to Inflammation and T2DM The Relationship Between Obesity and Inflammation The Relationship Between Inflammation and T2DM TNF-α and T2DM IL-6 and T2DM IL-1β and T2DM Anti-inflammatory Effects of Exercise Acute Effects of Exercise and Anti-inflammatory Mechanisms Chronic Effects of Exercise and Anti-inflammatory Mechanisms Exercise Interventions and Inflammatory Biomarkers Applications to Other Diseases or Conditions Conclusion Mini-Dictionary of Terms Key Facts on Exercise and the Lipid Profile Key Facts on Exercise and Inflammation Summary Points References Part II: Circulating and Body Fluid Biomarkers: Impact of Diabetes on Pathology 3 Resistin as a Biomarker and Applications to Prediabetes Introduction Diabetes Prediabetes: Definition and Related Diseases The Role of Adipokines at Energy Balance Resistin As a Biomarker at Different Types of Disease Resistin As a Biomarker in Cardiovascular Disorders Resistin As a Biomarker in Obesity Resistin As a Biomarker in Diabetes Resistin As a Biomarker in Cancer The Association Between Resistin and Prediabetes and Outcomes Conclusion Key Facts of Resistin Summary Points References 4 Altered Metabolome of Amino Acids Species: A Source of Signature Early Biomarkers of T2DM Introduction Diabetes Mellitus The Need for New Biomarkers for Diabetes Amino Acids in Metabolic Signaling and Insulin Resistance Altered Amino Acid Profiles in Insulin Resistance and Diabetes Amino Acids Metabolic Intermediates As Markers for Insulin Resistance and Diabetes Conclusions Applications to Prognosis, Other Diseases, or Conditions Mini Dictionary of Terms Key Facts of Amino acids Summary Points References 5 Components of the Purine Metabolism Pathways as Biomarkers for the Early Diagnosis of Diabetes Introduction Purine Metabolism Xanthine Oxidase Adenosine Metabolizing Enzymes, Inosine and Adenosine Inosine-5′-Monophosphate Dehydrogenase Uric Acid Conclusion Applications to Prognosis, Other Diseases or Conditions Mini-Dictionary of Terms Key Facts of Purine Enzymes and Related Metabolites Summary Points References 6 Serpin A12 (Vaspin) as a Serine Protease Inhibitor Introduction Type 2 Diabetes and the Importance of Biomarkers Vaspin as a Diabetes Biomarker Biochemical Characterization Main Sources of Vaspin Vaspin and Anti-Inflammatory Effects Glucose Intolerance and Vaspin Insulin Role and Vaspin Action Circulating Vaspin Level, Type 2 Diabetes, and Obesity Metabolic Syndrome (MetS) and Vaspin Applications to Prognosis, Other Diseases, and Conditions Conclusion Mini-Dictionary of Terms Key Facts of Type 2 Diabetes Summary Points References 7 Advanced Glycation End Products in Diabetes Introduction Advanced Glycation End Products (AGEs) AGE Receptors Effects of AGEs AGE Measurements Effects of AGEs in Diabetes Nephropathy in Diabetes Cardiomyopathy and Arterial Alterations in Diabetes Neuropathy in Diabetes Retinopathy in Diabetes Cancer and Diabetes Cross Talk Between AGEs and Oxidative Stress in Diabetes AGEs in Other Diseases Applications to Other Diseases or Conditions Mini Dictionary of Terms Key Facts of Diabetes: Where Advanced Glycation End Products Is the Topic Summary Points References 8 Markers of Liver Function and Insulin Resistance Introduction Applications to Diagnosis Mini-Dictionary of Terms Summary Points (5-10) Markers of Liver Function and Insulin Resistance Visceral Fat and Insulin Resistance NAFLD, IR Y T2DM Hepatokines DPP4 (Dipeptidyl Peptidase-4) Pharmacological DPP-4 Inhibitors Fetuin A (AHSG) Fetuin B Selenoprotein P LECT-2 Hepassocin, Also Called Hepatocyte-Derived Fibrinogen-Related Protein 1, HPS, and HFREP1 Pigment Epithelium-Derived Factor Tsukushi (TSK) Conclusions References 9 Biological Markers of Insulin Sensitivity Links with Dietary Antioxidant Introduction Applications to Diagnosis Mini Dictionary of Terms Key Facts of Insulin Sensitivity, Biomarkers, and Dietary Antioxidants Summary Points Markers of Liver Function and Insulin Resistance Insulin Sensitivity Adiponectin Adropin, Angiopoietin-lLike Protein 4 (ANGPTL4) DPP4, GLP-1 Fetuin-A and Fetuin-B FGF21 HMBG1, Myostatin Interleukins, Irisin, RBP4 Minerals in Insulin Resistance Sensitivity Calcium, Magnesium Chromiun, Selenium, Zinc Vitamins in Insulin Sensitivity Vitamin C, E Vitamin D, K, B Conclusions References 10 Serum Uric Acid and Metabolic Markers in Diabetes Introduction Metabolic Markers in Diabetes Uric Acid Uric Acid in Diabetes Pathophysiology Uric Acid as a Biomarker in Diabetes Serum Uric Acid as a Predictor of Diabetes Risk Serum Uric Acid, Blood Glucose Level, and HbA1c Uric Acid in Diabetic Complications Uric Acid in Macrovascular Complications Uric Acid in Microvascular Complications eGFR and Serum Uric Acid Levels Applications to Prognosis and Other Diseases or Conditions Applications to Prognosis Applications to Other Diseases or Conditions Mini-Dictionary of Terms Key Facts of Serum Uric Acid and Metabolic Markers in Diabetes: eGFR, HbA1c, and Beyond Key Facts of Uric Acid and Diabetes Key Facts of Uric Acid and Diabetic Complications Summary Points References 11 Urinary Interleukins and Kidney Damage in Diabetes Introduction Inflammation and Diabetic Kidney Disease Urinary Interleukins Interleukin 1 Interleukin 6 Interleukin 8 Interleukin 10 Interleukin 18 Potential Applications to Prognosis, Other Diseases, or Conditions Mini-dictionary of Terms Key Facts of Diabetes, Kidney Damage, and Urinary Interleukins Summary Points References 12 Serum Homocysteine as a Biomarker in Diabetes Introduction Homocysteine and Its Role in the Body Biosynthesis and Metabolism of Homocysteine Factors Causing Hyperhomocysteinemia Diabetes Mellitus Cellular Metabolism Disturbance and Micronutrient Status in Diabetes Mellitus Hyperhomocysteinemia and Diabetes Mellitus Cognitive Dysfunction in Diabetes Mellitus Cognitive Function Factors That Affect Cognitive Function Hyperhomocysteinemia and Cognitive Function Compliance in Diabetes Management and Cognitive Dysfunction Applications to Prognosis Mini-Dictionary of Terms Key Facts of Serum Homocysteine as a Biomarker in Diabetes: Links with Variables Such as Cognition Summary Points References 13 3-Hydroxyisobutyrate (3-HIB): Features and Links as a Biological Marker in Diabetes Introduction BCAA Catabolism in Adipose Tissue 3-HIB in Interorgan Metabolic Crosstalk 3-HIB Reflects Hepatic Fatty Acid Oxidation Conclusion and Future Perspectives Applications to Prognosis, Other Diseases, or Conditions Mini-Dictionary of Terms Key Facts of Diabetes Summary Points References 14 Proteomic Biomarkers: What They Are and How Type 2 Diabetes Mellitus Has Similarities with Other Diseases Introduction Proteomic Biomarkers and Type 2 Diabetes Mellitus Proteomics in Type 2 Diabetes Mellitus Complications Diabetic Retinopathy Diabetic Kidney Disease Diabetic Neuropathy and Chronic Wounds Proteomics in Type 2 Diabetes Mellitus and Other Diseases Type 2 Diabetes Mellitus and Obesity Type 2 Diabetes Mellitus and Cardiovascular Diseases Type 2 Diabetes Mellitus and Metabolic Diseases Type 2 Diabetes Mellitus and Pancreatic Cancer Type 2 Diabetes Mellitus and Neurologic Disorders Conclusion Applications to Prognosis and Other Diseases or Conditions Applications to Prognosis Applications to Other Diseases or Conditions Mini-Dictionary of Terms Key Factors of Proteomic Biomarkers in Diabetes Mellitus Summary Points References 15 Salivary C-Reactive Protein as a Biomarker and Implications for Diabetes Introduction Biomarkers of Type 2 Diabetes C-Reactive Protein and Pathogenesis Type 2 Diabetes and CRP Human Saliva as Diagnostic Fluid for Biomarkers Salivary Biomarkers in Type 2 Diabetes Identification of Diabetes-Associated Serum Proteins Found in Saliva Measurement of Diabetes-Related Serum Protein Markers in Saliva of Diabetic Patients Correlation of the CRP Levels in Saliva and Serum Diagnostic Methods of Salivary Biomarker Identification Enzyme-Linked Immunosorbent Assay (ELISA) Multiplex Analysis Other Detection Methods Applications to Prognosis, Other Diseases, or Conditions Mini-dictionary of Terms Key Facts of C-Reactive Protein Summary Points References 16 Assessing Insulin Sensitivity in People with Type 1 Diabetes Without Euglycemic-Hyperinsulinemic Clamps Introduction Euglycemic-Hyperinsulinemic Clamp Estimation of Insulin Sensitivity Estimation of GDR in Type 1 Diabetes Application to Prognosis and Other Diseases or Conditions Mini-Dictionary of Terms Key Facts Summary Points References 17 Serum Betatrophin: What It Shows and How It Alters in Gestational Diabetes Mellitus Gestational Diabetes Mellitus: Definition and Prevalence GDM Incidence GDM Risk Factors GDM Treatment Glucose Regulation During Healthy Pregnancy GDM Physiology The Adipose Tissue in the Pathophysiology of Gestational Diabetes Mellitus Betatrophin Betatrophin in Gestational Diabetes Mellitus Applications to Prognosis, Other Diseases or Conditions Applications to Prognosis Applications to Other Diseases or Conditions Mini Dictionary of Terms Key Facts of Betatrophin Summary Points References 18 Biomarkers in Disease: Diabetes Methods, Discoveries, and Applications Introduction Risk Prediction of Diabetes and the Role of Lipoproteins The Role of Large VLDL Particles (High Density of VLDL1 Particles) in Risk Prediction of Diabetes: Results from Clinical Studi... The Role of Large VLDL Particles (High Density of VLDL1 Particles) in Risk Prediction of Diabetes: Rationale Suggesting a Caus... The Role of VLDL Particles and Triglycerides in Risk Prediction of Diabetes: What is the Role of Genetics? The Role of Large VLDL Particles (High Density of VLDL1 Particles) in Risk Prediction of Diabetes: Genetics as a Fundamental P... Lipidomics as Tool to Study TRL Metabolism and the Risk of Diabetes Applications to Other Diseases or Conditions Mini-Dictionary of Terms Key Facts of Type 2 Diabetes and Hypertriglyceridemia Summary Points References 19 Correlations Between Renal Biomarkers and the Treatment Outcomes in Diabetes: Ophthalmic Aspects Introduction Correlations Between Renal Biomarkers and Diabetic Retinopathy Serum Creatinine and Estimated Glomerular Filtration Rate Albuminuria Erythropoietin Correlations Between Renal Biomarkers and Diabetic Macular Edema Serum Creatinine and Estimated Glomerular Filtration Rate Albuminuria Body Fluid Status Correlations Between Renal Biomarkers and Treatment Outcomes of Diabetic Macular Edema Serum Creatinine and Estimated Glomerular Filtration Rate Albuminuria Effects of Diabetic Nephropathy Treatment on Diabetic Retinopathy and Diabetic Macular Edema Glycemic Control Glucagon-Like Peptide-1 (GLP-1) Agonists Dipeptidyl Peptidase-4 (DPP-4) Inhibitors Sodium-Glucose Co-Transporter-2 (SGLT-2) Inhibitors Renal Replacement Therapy Kidney Transplantation Correlations Between Renal Biomarkers and Other Ocular Manifestations in Diabetes Diabetic Keratopathy and Corneal Nerve Degeneration Renal Biomarkers Versus Diabetic Keratopathy Effects of Renal Replacement Therapy or Kidney Transplantation on Diabetic Keratopathy Glaucoma in Diabetes Renal Biomarkers Versus Glaucoma in Diabetes Effects of Renal Replacement Therapy or Kidney Transplantation on Glaucoma Renal Biomarkers Versus Cataract in Diabetes Effects of Renal Replacement Therapy or Kidney Transplantation on Cataract Conclusions Applications of Renal Biomarkers to Prognosis Mini-dictionary of Terms Key Facts of Diabetic Retinopathy Key Facts of Diabetic Macular Edema Summary Points References 20 Serum Paraoxonase 1 as a Biomarker: Features and Applications in Type 2 Diabetes Mellitus Introduction Structure of PON1 Functions and Physiological Roles of PON1 PON1 Polymorphisms PON1 Polymorphisms in T2DM PON1 and T2DM Conclusions Application in Other Diseases or Conditions Mini-Dictionary of Terms Key Facts Summary Points References 21 The Ratio of Omega-6/Omega-3 Fatty Acid: Implications and Application as a Marker to Diabetes Introduction Fatty Acids General Metabolism of n-3 and n-6 PUFA PUFA Composition and Cell Membrane Role of PUFA in Cellular Function Diet and Polyunsaturated Fatty Acids Omega-6/Omega-3 Ratio Significance of Omega-6/Omega-3 Ratio in Type 2 Diabetes Mellitus Applications to Prognosis, Other Diseases, or Conditions Obesity Cardiovascular Diseases Cancer Pulmonary Disorders Skin Brain-Related Functions Autoimmune Disease Key Facts Summary References 22 Engulfment and Cell Motility Protein (ELMO)-1 as a Biomarker in Type II Diabetes Introduction A Genetic Variant of ELMO-1 as the Risk for DN in T2DM The Role of ELMO-1 in Diabetic Nephropathy, Studies in the Animal Model, and Cell Culture ELMO-1 in Circulation and Renal Tissue in Humans as a Potential Biomarker of DN in T2DM Application to Prognosis, Other Diseases or Condition Mini-Dictionary Key Facts Key Facts of Albuminuria Key Facts of ELMO-1 Protein Key Facts of ELMO-1 Genetic Variant rs741301 Summary Points References 23 Brain-Derived Neurotrophic Factor and Vascular Endothelial Growth Factor A: Biomarkers Potential in Diabetes Introduction Brain-Derived Neurotrophic Factor: Mechanisms of Action and Functions Vascular Endothelial Growth Factor A: Mechanisms of Action and Functions Diagnostic and Therapeutic Potential of Brain-Derived Neurotrophic Factor in Metabolic Disturbances of Type 2 Diabetes Mellitus Study of Serum Concentrations of BDNF in Human Populations Inflammation and Brain-Derived Neurotrophic Factor Diagnostic and Therapeutic Potential of Vascular Endothelial Growth Factor and Type 2 Diabetes Mellitus Type 1 Diabetes Mellitus and Growth Factors Serum BDNF and VEGFA as Biomarkers of Diabetes Complications Study of Serum Concentrations of BDNF and VEGFA in Human Populations in Diabetic Polyneuropathy Differences in Serum Levels of Neurotrophins in Diabetic Polyneuropathy in Type 1 and Type 2 Diabetes Mellitus Modulation of Neuropathic Pain by BDNF in Diabetic Neuropathy Central Nervous System Disturbances in DM: The Role of Growth Factors Applications to Prognosis, Other Diseases, or Conditions Key Facts of Brain-Derived Neurotrophic Factor and Vascular Endothelial Growth Factor A: Biomarkers´ Potential in Diabetes Mini-Dictionary of Terms Summary Points References 24 The Role of Glycated Albumin as a Biomarker of Glycemic Control in Diabetes and Chronic Kidney Disease Introduction Albumin Discovery and Structure Albumin Glycation Process Diabetes Mellitus (DM) Diabetes Mellitus and Glycation The Use of Glycated Albumin in Monitoring Metabolic Control Pitfalls of Conventional Measures of Glycemia Fructosamine and Glycated Albumin CKD and Diabetes HbA1c for Glycemic Control in CKD GA and Dialysis Challenges and Pitfalls in the Measurement of Glycated Albumin Conclusions, Limitations, and Recommendations Applications to Prognosis and Other Diseases and Conditions Key Facts of Glycated Albumin Mini-Dictionary of Terms Summary Points References Part III: Genetic, Molecular, and Cellular Variables 25 Epigenetics and 5-Hydroxymethylcytosines as a Biomarker in Type 2 Diabetes Introduction Novel Epigenetic Modifications beyond DNA Methylation Technical Advances Enable Discovery of Hydroxymethylation Biomarkers TAB-Seq oxBS-Seq The 5hmC as Novel Epigenetic Biomarkers for T2D Complications Vascular Complications Diabetic Retinopathy Diabetic Nephropathy Conclusions Applications to Prognosis Applications to Other Diseases or Conditions Mini-Dictionary of Terms Key Facts of Diabetic Complications Summary Points References 26 Adult Stem Cells as a Biomarker in Diabetes Introduction Why Adult Stem Cells Effect of Exercise on Endothelial Progenitor Cells (EPCs) Effects on EPC Age Is Another Major Factor Behind Reduction of EPC Numbers Effect of Novel Diabetes Medications on Endothelial Progenitor Cells (EPCs) Effect of HIV Medication Regimens on Endothelial Progenitor Cells (EPCs) Effects on Exercise on MSCs Conclusion Applications to Other Diseases or Conditions Mini-dictionary of Terms References 27 The Search for Immunological Biomarkers in Type 1 Diabetes Mellitus (T1DM) and Multiple Sclerosis (MS): Th40 Cells Provide ... Mini Dictionary of Terms Key Facts Summary Points References 28 Epigenetically Modified DNA Fragments Introduction Epigenetic Modifications Cell-Free DNA and Epigenetically Modified DNA Fragments Technologies for DNA Methylation Detection Differentially Methylated cfDNA as a Biomarker for β-Cell Death Advancing Technologies to Measure Differentially Methylated cfDNA Differentially Methylated cfDNA Beyond T1D Limitations to Measuring Differentially Methylated cfDNA as a Biomarker for β-Cell Death Applications to Prognosis, Other Diseases, or Conditions Mini-Dictionary of Terms Key Facts of Diabetes Key Facts of Cell-Free DNA (cfDNA) Summary Points References 29 Urinary Glucose Excretion as a Biomarker for Precision Medicine in Diabetes Introduction The Role of the Kidney in Glucose Homeostasis Physiology of Glucosuria Clinical Determinants of Urinary Glucose Excretion in the Diabetic State Sodium-Glucose Cotransporters and Glucosuria Mutations in the SGLT2 Gene and Urinary Glucose Excretion Common Variants of the SGLT2 Gene SLC5A2 and Diabetes-Related Phenotypes Association of SGLT2 Gene with Susceptibility to Type 2 Diabetes Mellitus Application to Prediction SLC5A2 rs9934336 Polymorphism as a Genetic Marker of Diabetes-Related Phenotypes Mini-Dictionary of Terms Key Facts of Urinary Glucose Excretion Summary Points References 30 Secreted Frizzled-Related Proteins 4 and 5: What They Are and Can They Be Used as a Biomarker in Gestational Diabetes Melli... Glucose Homeostasis During Pregnancy Gestational Diabetes Mellitus Adverse Pregnancy Outcomes GDM and Treatment Secreted Frizzled-Related Protein Family Secreted Frizzled-Related Protein Family During Pregnancy sFRP4 and sFRP5 in Glucose Homeostasis Biomarker for Gestational Diabetes Mellitus Applications to Prognosis Applications to Other Diseases or Conditions Mini-Dictionary of Terms Key Facts of Secreted Frizzled-Related Proteins 4 and 5: What They Are and Can They Be Used as a Biomarker in Gestational Diab... Key Facts of Gestational Diabetes Mellitus Key Facts of Secreted Frizzled-Related Proteins (sFRPs) Summary Points References 31 Insights into the World of MicroRNAs Introduction miRNA Biogenesis Circulating miRNAs Circulating miRNAs and Diabetes Circulating miRNAs and DR miR-1281 as a Novel Circulating Biomarker in Patients with DR Conclusions Key Facts of miRNAs Summary Points References 32 Genomic Ancestry as Biomarkers Introduction How to Determine Ethnicity? How to Assess Genetic Ancestry? Short Tandem Repeats (STRs) SNPs INDELs AIMs The Role of Ancestry in DR: What Do We Know so Far? Conclusions Applications to Other Diseases or Conditions Mini-Dictionary of Terms Key Facts of Genomic Ancestry as a Biomarker in Diabetic Retinopathy Summary Points References 33 Hp1-1 as a Genetic Marker in Diabetes: Measures, Applications, and Correlations Key Facts of Haptoglobin Phenotype Introduction Structure and Polymorphic Variants of Haptoglobin Biological Functions of Haptoglobin Correlations of Haptoglobin The Relationship Between the Haptoglobin Variant and Cardiovascular Disease The Relationship Between the Haptoglobin Variant and the Development of Diabetic Complications Relationship Between the Haptoglobin Variant and Neurodegenerative Diseases The Relationship Between the Haptoglobin Variant and the Development of Infection The Relationship Between the Haptoglobin Variant and the Development of Immune-Mediated Diseases Conclusion Summary Points References Part IV: Functional Variables, Physiological Variables, and Platforms 34 Day-by-Day Home Blood Pressure Monitoring as a Biomarker in Diabetes Introduction Diabetes and BPV Different Types of BPV and Related Evidence Day-by-Day HBPV and Target Organ Damage or CVD Current Status of DKD Association Between HBP, Day-by-Day HBPV, and DKD Association Between HBP Level and Albuminuria Association Between Day-by-Day Home BPV and Albuminuria Association Between HBP Level and eGFR Association Between Day-by-Day Home BPV and eGFR Perspectives on HBPM Conclusion Applications to Prognosis and Other Diseases or Conditions Applications to Prognosis Applications to Other Diseases or Conditions Mini-Dictionary of Terms (5-15 terms) Key Facts Summary Points References 35 Methods for Measuring Blood Pressure and Applications to Diabetes Introduction Diagnosis of Hypertension and Blood Pressure Measurement Office Blood Pressure Measurement Types of OBPM Devices for OBPM Number of Measurements per Occasion Blood Pressure Measurement Technique Twenty-Four-Hour Ambulatory Blood Pressure Monitoring (Table 1) Home Blood Pressure Monitoring (Table 2) Applications to Prognosis Applications to Other Diseases or Conditions Mini-Dictionary of Terms Key Facts of ``Methods for Measuring Blood Pressure and Applications to Diabetes: A Focus on Children, Adolescents, and Young ... Summary Points References 36 Carotid Bodies: Use of Chemosensitivity as a Biomarker in Prediabetes The Carotid Bodies Role of CB in Metabolic Diseases CB Dysfunction in Prediabetes and Type 2 Diabetes What Is the Trigger for CB Dysfunction in Metabolic Diseases? Insulin Leptin Evaluation of CB Chemosensitivity in Humans Evaluation of Hypertonicity of Peripheral Chemoreceptors Evaluation of Hyperreflexivity of Peripheral Chemoreceptors Biomarkers of Prediabetes Hyperinsulinemia and Obesity as Risk Factors for Prediabetes Early Diagnosis of Prediabetes Questionnaires and Scales Biochemical Markers CB Chemosensitivity as a Biomarker of Prediabetes Evaluation of CB Hypertonicity by the Dejours Test CBmeter: A New Medical Device for Early Detection of Prediabetes Future Perspectives Applications to Prognosis, Other Diseases, or Conditions Mini-Dictionary of Terms Key Facts of Carotid Bodies: Use of Chemosensitivity as a Biomarker in Prediabetes Summary Points References 37 Optical Coherence Tomography Angiography for Biomarker Indices in Diabetes Introduction Principles of Optical Coherence Tomography Angiography Visualization Methods of Optical Coherence Tomography Angiography Diabetic Retinopathy Optical Coherence Tomography Angiography Features of Diabetic Retinopathy Diabetic Eyes Without Clinical Retinopathy Correlation with Other Biomarkers of Diabetic Retinopathy Nonproliferative Diabetic Retinopathy Proliferative Diabetic Retinopathy Diabetic Macular Edema Applications to Prognosis and Other Diseases or Conditions Application to Diabetic Retinopathy Screening and Its Monitoring Application to Retinal Vascular Diseases Limitations of OCTA Mini-Dictionary of Terms Key Facts of Optical Coherence Tomography Angiography (OCTA) in Diabetic Retinopathy (DR) Summary Points References 38 Urinary Profiling with Liquid Chromatography-Mass Spectrometry Introduction Urine as Diagnosis Specimen Animal Model in Studying Human Disease Liquid Chromatography-Mass Spectrometry Application of Orthogonal Partial Least Squares Discriminant Analysis (OPLA-DA) to Prediabetes Diagnosis Benefits of Physical Activity and Dietary Control Proteomics Analysis of Urinary Proteins Common Protein Biomarkers for Diagnosis of Diabetes Application of Major Urinary Proteins and Histone H4 as Prediabetes Biomarker Proteins Conclusion Key Facts of Prediabetes Mini-Dictionary Terms Summary Points References 39 Physiologic Measures in Diabetes: QTc Prolongation Introduction ECG and the Myocardial Action Potential QT Interval Genetics of the QT Interval Early ECG Changes in Diabetes Glycemic Variability and the QT Interval QT Interval in Diabetes Mellitus QT Interval and Sudden Cardiac Death QT Interval and Atrial Fibrillation QT Dispersion Pathologic Q Waves: Diabetic Risk of Silent Myocardial Infarction REGARDS Study Applications to Prognosis and Other Diseases or Conditions Mini-Dictionary of Terms Key Facts of QT Interval Key Facts of Atrial Fibrillation Key Facts of Malignant Arrhythmias Key Facts of Sudden Cardiac Death Summary Points References 40 Biomarkers of Myocardial Fibrosis in Diabetes, Echocardiography, and Magnetic Resonance Imaging Introduction Heart Disease in Diabetes Heart Failure with Preserved Ejection Fraction Imaging Biomarkers of Myocardial Function in Diabetes and HFpEF Epidemiology of Diabetic Heart Disease Diabetic Cardiomyopathy Treatment of Diabetes in Relation to Cardiomyopathy Treatment of HFpEF Myocardial Fibrosis in Diabetes Cardiac Metabolism in Diabetes The Heart´s Interaction with the Peripheral Circulation The Myocardial Extracellular Volume Animal Models of Cardiac Fibrosis in Diabetes Magnetic Resonance Imaging of Fibrosis and the Extracellular Volume The Two CMR Techniques of Fibrosis Quantitation Tissue T1 Times Gadolinium Contrast Myocardial Blood Flow Determination with CMR Determination of the Extracellular Volume The Late Gadolinium Enhancement Technique CMR Determination of Fibrosis in Cardiomyopathies Ischemic Versus Non-ischemic Cardiomyopathy with LGE Extracellular Volume and Fibrosis in Diabetes by CMR Cardiac Fibrosis and Extracellular Volume in Patients with T2DM Relation of Cardiac Fibrosis to Markers of Diastolic Function Myocardial Blood Flow in T2DM The Relation of Fibrosis to Myocardial Blood Flow Looking to the Future Longitudinal Studies CMR for Screening of DM Patients? Validation of Serum Biomarkers of Fibrosis Applications to Prognosis Key Facts of Diabetic Cardiomyopathy Key Facts of Cardiac Magnetic Resonance Imaging of Fibrosis Mini-Dictionary of Terms Summary Points References 41 Measures of Endothelial Function in Type 2 Diabetes: A Focus on Non-circulatory Methods of Measurement Introduction Noncirculatory Measures of Endothelial Function Venous Occlusion Plethysmography (VOP) Flow-Mediated Dilatation Peripheral Artery Tonometry (PAT) Aortic Pulse Wave Velocity (PWV) Laser Doppler Flowmetry (LDF) Skin Autofluorescence (SAF) Applications to Diabetes Mini-dictionary of Terms Key Facts of Endothelial Dysfunction in Type 2 Diabetes Mellitus Summary Points References 42 Measures of Endothelial Function in Type 2 Diabetes: A Focus on Circulatory Biomarkers Introduction Circulatory Biomarkers as Measures of Endothelial Function Nitric Oxide Metabolites and Asymmetric Dimethylarginine (ADMA) High-Sensitivity C-Reactive Protein (hsCRP) Adhesion Molecules and Chemokines Endothelial Progenitor Cells (EPC) Endothelial Microparticles (EMP) Advanced Glycosylation End Products Endocan External Counterpulsation (ECP) Therapy on Measures of Endothelial Function Applications to Diabetes Mini-Dictionary of Terms Summary Points References Part V: Biomarkers in Specific Conditions or Scenarios of Diabetes 43 Biomarkers of Diabetes-Induced Nephropathy Introduction Overview of Pathogenesis of Diabetic Nephropathy Stages of Diabetic Nephropathy First Stage Second Stage Third Stage Fourth Stage Fifth Stage Conventional Biomarker of Diabetic Nephropathy New Biomarkers of Diabetic Nephropathy Biomarkers of Glomerular Damage Biomarkers of Tubular Damage Inflammatory Biomarkers Biomarkers of Oxidative Stress Associated with Diabetic Nephropathy Future Perspectives in the Diagnosis and Prognosis of Diabetic Nephropathy NADPH Oxidase MicroRNA (miRNAs) Proteomics Metabolomics Genomics Mini-Dictionary of Terms Key Facts of Biomarkers of Diabetes-Induced Nephropathy Summary Points References 44 Serum Vitamin D As a Biomarker in Diabetic: Applications and Associations with Retinopathy Introduction Vitamin D Deficiency Vitamin D and Diabetes Mellitus Vitamin D and Diabetic Retinopathy Development and Severity Diabetic Retinopathy Pathophysiology - Where Does Vitamin D Stand? Vitamin D Supplementation for DR Prevention - What Is the Current Evidence? Applications to Prognosis Conclusion Key Facts Mini Dictionary of Terms Summary Points References 45 Markers of Bacterial Translocation in Type 2 Diabetes Mellitus Introduction Gut Microbiome The Gut Barrier´s Defense Mechanisms The Gut Barrier Is Composed of Multiple Layers: (Fig. 1) Factors Affecting the Gut Barrier Integrity Mechanisms of Gut Barrier Disruption Consequences of Gut Barrier Disruption/Dysfunction Bacterial Translocation Markers of Bacterial Translocation Lipopolysaccharide (LPS) Bacteria and Bacterial DNA Other Bacterial Translocation Markers Applications to Other Diseases/Conditions Mini-Dictionary of Terms Key Facts Summary Points References 46 Serum Leptin as a Biomarker in Diabetes Diabetes Mellitus Complications of Diabetes Mellitus Insulin Resistance and β-Cell Function in Type 2 Diabetes Mellitus Diabetes Mellitus and Acromegaly Acromegaly Comorbidities Metabolic Complications Cardiovascular Disease Insulin Resistance and Leptin in Type 2 Diabetes Mellitus Leptin Resistance in Type 2 Diabetes Mellitus Leptin in Acromegaly Medical Therapy Applications to Prognosis Applications to Other Diseases or Conditions Mini-Dictionary of Terms Key Facts of Hyperinsulinemia Key Facts of Human Leptin Key Facts of Acromegaly Summary Points References 47 Vitreous Biomarkers: What They Are and How They May Be Used to Advance the Management of Diabetic Retinopathy Introduction Diabetic Retinopathy Pathogenesis and Pathophysiology Clinical Grading Clinical Management Assessing Local Molecular Biomarkers for DR Ocular Liquid Biopsy Sample Selection and Method of Analysis Vitreous Molecular Biomarkers of DR Cytokines Kinin-Kallikrein System (KKS) Complement System (CS) MicroRNA (miRNA) Metabolites Applications to Prognosis and Other Diseases and Conditions Key Facts of Vitreous Biomarkers in Diabetic Retinopathy (DR) Mini-Dictionary of Terms Summary Points References 48 Protein Pyrrole Adducts in Diabetes Mellitus Introduction Diabetic Distal Symmetrical Polyneuropathy DSPN: Central-Peripheral Distal Axonopathy DSPN Etiology and Pathogenesis Existing DSPN Biomarkers Protein Pyrrole Adducts Cross-Linking of γ-Diketone-Derived Pyrroles Cross-Linking of Protein Pyrrole Adduct: Links with DSPN Detection of Pyrrole Adducts Applications to Peripheral Neuropathy Occupational n-Hexane/2-Hexanone Neuropathy Diabetic Polyneuropathy Conclusions Mini-Dictionary of Terms Key Facts Summary Points References 49 Biomarkers in Gestational Diabetes Application to Prognosis, Other Diseases or Conditions Application to Prognosis Application to Other Diseases or Conditions Introduction Noncontinuous Versus Continuous Glucose Monitoring: Postprandial Versus Preprandial Glucose Monitoring: Updated Guidelines Conclusion Mini Dictionary of Terms Key Facts Summary Points References 50 Metabolomic Biomarkers, Metabolite Patterns, and Gestational Diabetes Mellitus Introduction Epidemiology, Etiology, and Consequences of Gestational Diabetes Mellitus Epidemiology Etiology Consequences Screening and Diagnosis Metabolic Heterogeneity Among GDM Cases Applications of Metabolomics in Gestational Diabetes Mellitus Prevention/Prediction Treatment/Prognosis Amino Acid Profile Amino Acids and Applications to GDM Treatment Amino Acids and Applications to GDM Prognosis Lipid Profile Lipids and Applications to GDM Treatment Lipids and Applications to GDM Prognosis Carbohydrates Future Directions Mini-Dictionary of Terms Key Facts of Gestational Diabetes Mellitus Summary Points References 51 Neuroinflammatory Biomarkers in Diabetic Encephalopathy: Linking Cholinergic and Cognitive Dysfunction Introduction Diabetes and Brain Neuroinflammation and Diabetes Mechanistic Insights Involved in Diabetes-Induced Neuroinflammation Cognitive Impairment and Neuroinflammation in Diabetic Animal Models Conclusion Application to Prognosis, Other Diseases, or Conditions Key Facts Mini Dictionary Summary Points References Part VI: Diet and Diabetes 52 Selenium and Risk of Diabetes Introduction Association Between Selenium and the Risk of T2DM Recent Updates on Clinical Studies Selenium and Gestational Diabetes Selenium and Diabetes Complications Potential Mechanisms of Action of Selenium on Glucose Homeostasis Conclusion Summary Points References Part VII: Models and Modeling in Diabetes 53 Models of Diabetes in Rats: A Focus on Diabetic Neuropathy and Biomarkers Introduction Rat Model of Diabetic Neuropathy Biomarkers of Diabetic Neuropathy in Rat Models Oxidative Stress Markers Adiponectin Immune Cells Glial Cells in Peripheral and Central Nervous Systems Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κB) Interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNF-α) Monocyte Chemoattractant Protein-1 (MCP-1) Cell Receptors Transient Receptor Potential Vanilloid-1 (TRPV1) N-Methyl-d-Aspartate Receptors (NMDARs) Gamma-Amino Butyric Acid (GABA) Receptors Enzyme-Related Markers Nicotinamide Adenine Dinucleotide Phosphate Oxidase (NOX) Heme Oxygenase-1 (HO-1) Other Protein Caveolin-1 (CAV-1) Conclusion Applications to Prognosis, Other Diseases or Conditions Mini-dictionary of Terms Key Facts Key Facts of Diabetic Neuropathy Key Facts of Rat Model of Diabetic Neuropathy Summary Points References 54 Biomarkers in Experimental Diabetes: Studies with Syzygium Cumini (L.) and Links with the Sulfonylurea 1 Receptor Introduction Pathophysiology of Diabetes Mellitus Clinically Used Biomarkers in Diabetes Mellitus Animal Models for Experimental Diabetes Experimental Models for Type 1 DM Experimental Models for Type 2 DM Experiments with Syzygium Cumini Fasting Blood Glucose (FBG) Serum Insulin and C Peptide Levels Glycosylated Hemoglobin (HbA1C) Homeostatic Model of Assessment (HOMA) Liver Glycogen Lipid Profile Adiponectin Glucagon-Like Peptide 1 (GLP 1) Markers of Oxidative Stress Inflammatory Biomarkers Histopathology of Islets of Pancreas PPARs (Peroxisome Proliferator-Activated Receptors) Hexokinase Biomarkers for Evaluating Molecular Mechanisms Molecular Docking Study of Syzygium Cumini extract Components on Sulfonylurea Receptor (SUR1) Applications to Prognosis Mini Dictionary of Terms Key Facts: Biomarkers in Experimental Diabetes: Studies with Syzygium Cumini (L.) and Links with the Sulfonylurea 1 Receptor Summary References Part VIII: Resources 55 Recommended Resources for Biomarkers in Diabetes: Methods, Discoveries, and Applications Introduction Resources Other Resources Summary Points References Index