1 2009 86 EPIGENETIC BASIS OF DIABETIC VASCULOPATHY. TYPE 2 DIABETES MELLITUS (T2DM) CAUSES PERIPHERAL VASCULAR DISEASE BECAUSE OF WHICH SEVERAL BLOOD-BORNE FACTORS, INCLUDING VITAL NUTRIENTS FAIL TO REACH THE AFFECTED TISSUE. TISSUE EPIGENOME IS SENSITIVE TO CHRONIC HYPERGLYCEMIA AND IS KNOWN TO CAUSE PATHOGENESIS OF MICRO- AND MACROVASCULAR COMPLICATIONS. THESE VASCULAR COMPLICATIONS OF T2DM MAY PERPETUATE THE ONSET OF ORGAN DYSFUNCTION. THE BURDEN OF DIABETES IS PRIMARILY BECAUSE OF A WIDE RANGE OF COMPLICATIONS OF WHICH NONHEALING DIABETIC ULCERS REPRESENT A MAJOR COMPONENT. THUS, IT IS IMPERATIVE THAT CURRENT RESEARCH HELP RECOGNIZE MORE EFFECTIVE METHODS FOR THE DIAGNOSIS AND MANAGEMENT OF EARLY VASCULAR INJURIES. THIS REVIEW ADDRESSES THE SIGNIFICANCE OF EPIGENETIC PROCESSES SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS IN THE EVOLUTION OF MACROVASCULAR AND MICROVASCULAR COMPLICATIONS OF T2DM. 2022 2 4433 28 MOLECULAR COMPLEXITIES UNDERLYING THE VASCULAR COMPLICATIONS OF DIABETES MELLITUS - A COMPREHENSIVE REVIEW. DIABETES IS A CHRONIC DISEASE, CHARACTERIZED BY HYPERGLYCEMIA, WHICH REFERS TO THE ELEVATED LEVELS OF GLUCOSE IN THE BLOOD, DUE TO THE INABILITY OF THE BODY TO PRODUCE OR USE INSULIN EFFECTIVELY. CHRONIC HYPERGLYCEMIA LEVELS LEAD TO MACROVASCULAR AND MICROVASCULAR COMPLICATIONS. THE MACROVASCULAR COMPLICATIONS CONSIST OF PERIPHERAL ARTERY DISEASE (PAD), CARDIOVASCULAR DISEASES (CVD) AND CEREBROVASCULAR DISEASES, WHILE THE MICROVASCULAR COMPLICATIONS COMPRISE OF DIABETIC MICROANGIOPATHY, DIABETIC NEPHROPATHY, DIABETIC RETINOPATHY AND DIABETIC NEUROPATHY. VASCULAR ENDOTHELIAL DYSFUNCTION PLAYS A CRUCIAL ROLE IN MEDIATING BOTH MACROVASCULAR AND MICROVASCULAR COMPLICATIONS UNDER HYPERGLYCEMIC CONDITIONS. IN DIABETIC MICROVASCULATURE, THE INTRACELLULAR HYPERGLYCEMIA CAUSES DAMAGE TO THE VASCULAR ENDOTHELIUM THROUGH - (I) ACTIVATION OF FOUR BIOCHEMICAL PATHWAYS, NAMELY THE POLYOL PATHWAY, PROTEIN KINASE C (PKC) PATHWAY, ADVANCED GLYCATION END PRODUCTS (AGE) PATHWAY AND HEXOSAMINE PATHWAY, ALL OF WHICH COMMUTES GLUCOSE AND ITS INTERMEDIATES LEADING TO OVERPRODUCTION OF REACTIVE OXYGEN SPECIES, (II) DYSREGULATION OF GROWTH FACTORS AND CYTOKINES, (III) EPIGENETIC CHANGES WHICH CONCERN THE CHANGES IN DNA AS A RESPONSE TO INTRACELLULAR CHANGES, AND (IV) ABNORMALITIES IN NON-CODING RNAS, SPECIFICALLY MICRORNAS. THIS REVIEW WILL FOCUS ON GAINING AN UNDERSTANDING OF THE MOLECULAR COMPLEXITIES UNDERLYING THE VASCULAR COMPLICATIONS IN DIABETES MELLITUS, TO INCREASE OUR UNDERSTANDING TOWARDS THE DEVELOPMENT OF NEW MECHANISTIC THERAPEUTIC STRATEGIES TO PREVENT OR TREAT DIABETES-INDUCED VASCULAR COMPLICATIONS. 2020 3 2171 29 EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF DIABETIC FOOT ULCERS. THE INCIDENCE OF DIABETES MELLITUS, A CHRONIC METABOLIC DISEASE ASSOCIATED WITH BOTH PREDISPOSING GENETIC AND ENVIRONMENTAL FACTORS, IS INCREASING GLOBALLY. AS A RESULT, IT IS EXPECTED THAT THERE WILL ALSO BE AN INCREASING INCIDENCE OF DIABETIC COMPLICATIONS WHICH ARISE AS A RESULT OF POOR GLYCEMIC CONTROL. COMPLICATIONS INCLUDE CARDIOVASCULAR DISEASES, NEPHROPATHY, RETINOPATHY AND DIABETIC FOOT ULCERS. THE FINDINGS OF SEVERAL MAJOR CLINICAL TRIALS HAVE IDENTIFIED THAT DIABETIC COMPLICATIONS MAY ARISE EVEN AFTER MANY YEARS OF PROPER GLYCEMIC CONTROL. THIS HAS LED TO THE CONCEPT OF PERSISTENT EPIGENETIC CHANGES. VARIOUS EPIGENETIC MECHANISMS HAVE BEEN IDENTIFIED AS IMPORTANT CONTRIBUTORS TO THE PATHOGENESIS OF DIABETES AND DIABETIC COMPLICATIONS. THE AIM OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE PATHOBIOLOGY OF TYPE 2 DIABETES WITH AN EMPHASIS ON COMPLICATIONS, PARTICULARLY DIABETIC FOOT ULCERS. AN OVERVIEW OF EPIGENETIC MECHANISMS IS PROVIDED AND THE FOCUS IS ON THE EMERGING EVIDENCE FOR ABERRANT EPIGENETIC MECHANISMS IN DIABETIC FOOT ULCERS. 2012 4 1387 26 DIABETIC GUT MICROBIOTA DYSBIOSIS AS AN INFLAMMAGING AND IMMUNOSENESCENCE CONDITION THAT FOSTERS PROGRESSION OF RETINOPATHY AND NEPHROPATHY. THE INCREASED PREVALENCE OF TYPE 2 DIABETES MELLITUS (T2DM) AND LIFE EXPECTANCY OF DIABETIC PATIENTS FOSTERS THE WORLDWIDE PREVALENCE OF RETINOPATHY AND NEPHROPATHY, TWO MAJOR MICROVASCULAR COMPLICATIONS THAT HAVE BEEN DIFFICULT TO TREAT WITH CONTEMPORARY GLUCOSE-LOWERING MEDICATIONS. THE GUT MICROBIOTA (GM) HAS BECOME A LIVELY FIELD RESEARCH IN THE LAST YEARS; THERE IS A GROWING RECOGNITION THAT ALTERED INTESTINAL MICROBIOTA COMPOSITION AND FUNCTION CAN DIRECTLY IMPACT THE PHENOMENON OF AGEING AND AGE-RELATED DISORDERS. IN FACT, HUMAN GM, ENVISAGED AS A POTENTIAL SOURCE OF NOVEL THERAPEUTICS, STRONGLY MODULATES HOST IMMUNITY AND METABOLISM. IT IS NOW CLEAR THAT GUT DYSBIOSIS AND THEIR PRODUCTS (E.G. P-CRESYL SULFATE, TRIMETHYLAMINE?N?OXIDE) DICTATE A SECRETORY ASSOCIATED SENESCENCE PHENOTYPE AND CHRONIC LOW-GRADE INFLAMMATION, FEATURES SHARED IN THE PHYSIOLOGICAL PROCESS OF AGEING ("INFLAMMAGING") AS WELL AS IN T2DM ("METAFLAMMATION") AND IN ITS MICROVASCULAR COMPLICATIONS. THIS REVIEW PROVIDES AN IN-DEPTH LOOK ON THE CROSSTALK BETWEEN GM, HOST IMMUNITY AND METABOLISM. FURTHER, IT CHARACTERIZES HUMAN GM SIGNATURES OF ELDERLY AND T2DM PATIENTS. FINALLY, A COMPREHENSIVE SCRUTINY OF RECENT MOLECULAR FINDINGS (E.G. EPIGENETIC CHANGES) UNDERLYING CAUSAL RELATIONSHIPS BETWEEN GM DYSBIOSIS AND DIABETIC RETINOPATHY/NEPHROPATHY COMPLICATIONS IS PINPOINTED, WITH THE ULTIMATE GOAL TO UNRAVEL POTENTIAL PATHOPHYSIOLOGICAL MECHANISMS THAT MAY BE EXPLORED, IN A NEAR FUTURE, AS PERSONALIZED DISEASE-MODIFYING THERAPEUTIC APPROACHES. 2019 5 3909 26 LIFE AFTER PANCREAS TRANSPLANTATION: REVERSAL OF DIABETIC LESIONS. PURPOSE OF REVIEW: RECIPIENTS OF PANCREAS TRANSPLANTATION BEAR THE BURDEN OF CHRONIC COMPLICATIONS OF DIABETES, BOTH MICROVASCULAR AND MACROVASCULAR. PANCREAS TRANSPLANTATION PROVIDES THE MOST EFFECTIVE METHOD OF GLYCEMIC AND METABOLIC CONTROL. AS TRANSPLANTATION PROVIDES IMMEDIATE RELIEF FROM ACUTE COMPLICATIONS OF DIABETES, THE IMPACT OF A SUCCESSFUL TRANSPLANT ON LONG-TERM COMPLICATIONS IS THE FOCUS OF THIS REVIEW. RECENT FINDINGS: IT IS INCREASINGLY RECOGNIZED THAT A SUCCESSFUL PANCREAS TRANSPLANT MAY SLOW, STABILIZE, OR AMELIORATE THE PROGRESSION OF MACROVASCULAR AND MICROVASCULAR COMPLICATIONS OF DIABETES. NEW UNDERSTANDING OF THE GENETIC AND EPIGENETIC MECHANISMS AND PATHOPHYSIOLOGY OF DIABETIC COMPLICATIONS HAS PROVIDED NEW DATA POTENTIALLY USEFUL FOR PROSPECTIVELY STUDYING THE EFFECT OF PANCREAS TRANSPLANT ON CHRONIC COMPLICATIONS OF DIABETES. SUMMARY: EARLIER CORRECTION OF DIABETES BY PANCREAS TRANSPLANTATION DECREASES CHRONIC COMPLICATIONS. REFINEMENTS IN THE UNDERSTANDING OF THE TISSUE TARGETS OF DIABETES COMPLICATIONS AND NEW DIAGNOSTIC AND IMAGING TOOLS TO MEASURE THEM MAY PROVE USEFUL IN FURTHER STUDYING THE IMPACT OF PANCREAS TRANSPLANTATION ON CHRONIC COMPLICATIONS OF DIABETES. 2014 6 4459 33 MOLECULAR MECHANISMS OF DIABETIC VASCULAR COMPLICATIONS. DIABETIC COMPLICATIONS ARE THE MAJOR CAUSES OF MORBIDITY AND MORTALITY IN PATIENTS WITH DIABETES. MICROVASCULAR COMPLICATIONS INCLUDE RETINOPATHY, NEPHROPATHY AND NEUROPATHY, WHICH ARE LEADING CAUSES OF BLINDNESS, END-STAGE RENAL DISEASE AND VARIOUS PAINFUL NEUROPATHIES; WHEREAS MACROVASCULAR COMPLICATIONS INVOLVE ATHEROSCLEROSIS RELATED DISEASES, SUCH AS CORONARY ARTERY DISEASE, PERIPHERAL VASCULAR DISEASE AND STROKE. DIABETIC COMPLICATIONS ARE THE RESULT OF INTERACTIONS AMONG SYSTEMIC METABOLIC CHANGES, SUCH AS HYPERGLYCEMIA, LOCAL TISSUE RESPONSES TO TOXIC METABOLITES FROM GLUCOSE METABOLISM, AND GENETIC AND EPIGENETIC MODULATORS. CHRONIC HYPERGLYCEMIA IS RECOGNIZED AS A MAJOR INITIATOR OF DIABETIC COMPLICATIONS. MULTIPLE MOLECULAR MECHANISMS HAVE BEEN PROPOSED TO MEDIATE HYPERGLYCEMIA'S ADVERSE EFFECTS ON VASCULAR TISSUES. THESE INCLUDE INCREASED POLYOL PATHWAY, ACTIVATION OF THE DIACYLGLYCEROL/PROTEIN KINASE C PATHWAY, INCREASED OXIDATIVE STRESS, OVERPRODUCTION AND ACTION OF ADVANCED GLYCATION END PRODUCTS, AND INCREASED HEXOSAMINE PATHWAY. IN ADDITION, THE ALTERATIONS OF SIGNAL TRANSDUCTION PATHWAYS INDUCED BY HYPERGLYCEMIA OR TOXIC METABOLITES CAN ALSO LEAD TO CELLULAR DYSFUNCTIONS AND DAMAGE VASCULAR TISSUES BY ALTERING GENE EXPRESSION AND PROTEIN FUNCTION. LESS STUDIED THAN THE TOXIC MECHANISMS, HYPERGLYCEMIA MIGHT ALSO INHIBIT THE ENDOGENOUS VASCULAR PROTECTIVE FACTORS SUCH AS INSULIN, VASCULAR ENDOTHELIAL GROWTH FACTOR, PLATELET-DERIVED GROWTH FACTOR AND ACTIVATED PROTEIN C, WHICH PLAY IMPORTANT ROLES IN MAINTAINING VASCULAR HOMEOSTASIS. THUS, EFFECTIVE THERAPIES FOR DIABETIC COMPLICATIONS NEED TO INHIBIT MECHANISMS INDUCED BY HYPERGLYCEMIA'S TOXIC EFFECTS AND ALSO ENHANCE THE ENDOGENOUS PROTECTIVE FACTORS. THE PRESENT REVIEW SUMMARIZES THESE MULTIPLE BIOCHEMICAL PATHWAYS ACTIVATED BY HYPERGLYCEMIA AND THE POTENTIAL THERAPEUTIC INTERVENTIONS THAT MIGHT PREVENT DIABETIC COMPLICATIONS. (J DIABETES INVEST, DOI: 10.1111/J.2040-1124.2010.00018.X, 2010). 2010 7 1896 21 ENDOTHELIAL-TO-MESENCHYMAL TRANSITION: AN UNDERAPPRECIATED MEDIATOR OF DIABETIC COMPLICATIONS. DIABETES AND ITS COMPLICATIONS REPRESENT A GREAT BURDEN ON THE GLOBAL HEALTHCARE SYSTEM. DIABETIC COMPLICATIONS ARE FUNDAMENTALLY DISEASES OF THE VASCULATURE, WITH ENDOTHELIAL CELLS BEING THE CENTERPIECE OF EARLY HYPERGLYCEMIA-INDUCED CHANGES. ENDOTHELIAL-TO-MESENCHYMAL TRANSITION IS A TIGHTLY REGULATED PROCESS THAT RESULTS IN ENDOTHELIAL CELLS LOSING ENDOTHELIAL CHARACTERISTICS AND DEVELOPING MESENCHYMAL TRAITS. ALTHOUGH ENDOTHELIAL-TO-MESENCHYMAL TRANSITION HAS BEEN FOUND TO OCCUR WITHIN MOST OF THE MAJOR COMPLICATIONS OF DIABETES, IT HAS NOT BEEN A MAJOR FOCUS OF STUDY OR A COMMON TARGET IN THE TREATMENT OR PREVENTION OF DIABETIC COMPLICATIONS. IN THIS REVIEW WE SUMMARIZE THE IMPORTANCE OF ENDOTHELIAL-TO-MESENCHYMAL TRANSITION IN EACH MAJOR DIABETIC COMPLICATION, EXAMINE SPECIFIC MECHANISMS AT PLAY, AND HIGHLIGHT POTENTIAL MECHANISMS TO PREVENT ENDOTHELIAL-TO-MESENCHYMAL TRANSITION IN EACH OF THE MAJOR CHRONIC COMPLICATIONS OF DIABETES. 2023 8 2953 24 GENETIC AND EPIGENETIC EVENTS IN DIABETIC WOUND HEALING. THE PREVALENCE OF THE CHRONIC METABOLIC DISORDER, DIABETES MELLITUS, IS EXPECTED TO INCREASE IN THE COMING YEARS AND WORLDWIDE PANDEMIC LEVELS ARE PREDICTED. INEVITABLY, THIS WILL BE ACCOMPANIED BY AN INCREASE IN THE PREVALENCE OF DIABETIC COMPLICATIONS, INCLUDING DIABETIC FOOT ULCERS. AT PRESENT, TREATMENT OPTIONS FOR DIABETIC FOOT ULCERS ARE IN MANY CASES INSUFFICIENT, AND PROGRESSION OF THE CONDITION RESULTS IN THE REQUIREMENT FOR LIMB AMPUTATION IN A PROPORTION OF PATIENTS. TO IMPROVE THERAPY, AN INCREASE IN OUR UNDERSTANDING OF THE PATHOBIOLOGY OF DIABETIC COMPLICATIONS SUCH AS IMPAIRED WOUND HEALING IS NECESSARY. IN THIS REVIEW, RECENT ADVANCES IN MOLECULAR ASPECTS OF NORMAL AND IMPAIRED DIABETIC WOUND HEALING ARE DISCUSSED. FURTHERMORE, INVESTIGATIONS OF THE ROLE OF EPIGENETIC PROCESSES IN THE PATHOGENESIS OF IMPAIRED DIABETIC WOUND HEALING ARE NOW EMERGING. INDEED, EPIGENETIC CHANGES HAVE ALREADY BEEN IDENTIFIED AS KEY FACTORS IN DIABETES AND RELATED COMPLICATIONS AND THESE ARE OVERVIEWED IN THIS REVIEW. 2011 9 4195 30 METABOLIC MEMORY: MECHANISMS AND IMPLICATIONS FOR DIABETIC RETINOPATHY. CHRONIC HYPERGLYCEMIA OF DIABETES LEADS TO MICROVASCULAR COMPLICATIONS THAT SEVERELY IMPACT QUALITY OF LIFE. DIABETIC RETINOPATHY (DR) MAY BE THE MOST COMMON OF THESE AND IS A LEADING CAUSE OF VISUAL IMPAIRMENT AND BLINDNESS AMONG WORKING AGE ADULTS IN DEVELOPED NATIONS. MANY LARGE-SCALE TYPE 1 AND TYPE 2 DIABETES CLINICAL TRIALS HAVE DEMONSTRATED THAT EARLY INTENSIVE GLYCEMIC CONTROL CAN REDUCE THE INCIDENCE AND PROGRESSION OF MICRO AND MACROVASCULAR COMPLICATIONS. ON THE OTHER HAND, EPIDEMIOLOGICAL AND PROSPECTIVE DATA HAVE REVEALED THAT THE STRESSORS OF DIABETIC VASCULATURE PERSIST BEYOND THE POINT WHEN GLYCEMIC CONTROL HAS BEEN ACHIEVED. THESE KINDS OF PERSISTENT ADVERSE EFFECTS OF HYPERGLYCEMIA ON THE DEVELOPMENT AND PROGRESSION OF COMPLICATIONS HAS BEEN DEFINED AS "METABOLIC MEMORY", AND OXIDATIVE STRESS, ADVANCED GLYCATION END PRODUCTS AND EPIGENETIC CHANGES HAVE BEEN IMPLICATED IN THE PROCESS. RECENT STUDIES HAVE INDICATED THAT SUCH "HYPERGLYCEMIC MEMORY" MAY ALSO INFLUENCE DR, SUGGESTING THAT MANIPULATION OF HYPERGLYCEMIC MEMORY MAY PROVE A BENEFICIAL APPROACH TO PREVENTION AND TREATMENT. THIS REVIEW SUMMARIZES THE EVIDENCE FROM DR-RELATED CLINICAL TRIALS AND MECHANISTIC STUDIES TO INVESTIGATE THE SIGNIFICANCE OF METABOLIC MEMORY IN DR AND UNDERSTAND ITS POTENTIAL AS A TARGET OF MOLECULAR THERAPEUTICS AIMED AT REVERSING HYPERGLYCEMIC MEMORY. 2012 10 6648 29 UPDATE ON DIAGNOSIS, PATHOPHYSIOLOGY, AND MANAGEMENT OF DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD) IS A CHRONIC COMPLICATION OF DIABETES MELLITUS WHICH MAY EVENTUALLY LEAD TO END-STAGE KIDNEY DISEASE (ESKD). DESPITE IMPROVEMENTS IN GLYCAEMIC CONTROL AND BLOOD PRESSURE MANAGEMENT WITH RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) BLOCKADE, THE CURRENT THERAPY CANNOT COMPLETELY HALT DKD PROGRESSION TO ESKD IN SOME PATIENTS. DKD IS A HETEROGENEOUS DISEASE ENTITY IN TERMS OF ITS CLINICAL MANIFESTATIONS, HISTOPATHOLOGY AND THE RATE OF PROGRESSION, WHICH MAKES IT DIFFICULT TO DEVELOP EFFECTIVE THERAPEUTICS. IT WAS FORMERLY CONSIDERED THAT ALBUMINURIA PRECEDED KIDNEY FUNCTION DECLINE IN DKD, BUT RECENT EPIDEMIOLOGICAL STUDIES REVEALED THAT A DISTINCT GROUP OF PATIENTS PRESENTED KIDNEY DYSFUNCTION WITHOUT DEVELOPING ALBUMINURIA. OTHER COMORBIDITIES, SUCH AS HYPERTENSION, OBESITY AND GOUT, ALSO AFFECT THE CLINICAL COURSE OF DKD. THE PATHOPHYSIOLOGY OF DKD IS COMPLEX AND MULTIFACTORIAL, INVOLVING BOTH METABOLIC AND HAEMODYNAMIC FACTORS. THESE INDUCE ACTIVATION OF INTRACELLULAR SIGNALLING PATHWAYS, OXIDATIVE STRESS, HYPOXIA, DYSREGULATED AUTOPHAGY AND EPIGENETIC CHANGES, WHICH RESULT IN KIDNEY INFLAMMATION AND FIBROSIS. RECENTLY, TWO GROUPS OF ANTIDIABETIC DRUGS, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS AND GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS, WERE DEMONSTRATED TO PROVIDE RENOPROTECTION ON TOP OF THEIR GLUCOSE-LOWERING EFFECTS. SEVERAL OTHER THERAPEUTIC AGENTS ARE ALSO BEING DEVELOPED AND EVALUATED IN CLINICAL TRIALS. 2021 11 6357 26 THE ROLE OF HYPERGLYCAEMIA IN THE DEVELOPMENT OF DIABETIC CARDIOMYOPATHY. DIABETES MELLITUS IS A METABOLIC DISORDER WITH A CHRONIC HYPERGLYCAEMIC STATE. CARDIOVASCULAR DISEASES ARE THE PRIMARY CAUSE OF MORTALITY IN PATIENTS WITH DIABETES. INCREASING EVIDENCE SUPPORTS THE EXISTENCE OF DIABETIC CARDIOMYOPATHY, A CARDIAC DYSFUNCTION WITH IMPAIRED CARDIAC CONTRACTION AND RELAXATION, INDEPENDENT OF CORONARY AND/OR VALVULAR COMPLICATIONS. DIABETIC CARDIOMYOPATHY CAN LEAD TO HEART FAILURE. SEVERAL PRECLINICAL AND CLINICAL STUDIES HAVE AIMED TO DECIPHER THE UNDERLYING MECHANISMS OF DIABETIC CARDIOMYOPATHY. AMONG ALL THE CO-FACTORS, HYPERGLYCAEMIA SEEMS TO PLAY AN IMPORTANT ROLE IN THIS PATHOLOGY. HYPERGLYCAEMIA HAS BEEN SHOWN TO ALTER CARDIAC METABOLISM AND FUNCTION THROUGH SEVERAL DELETERIOUS MECHANISMS, SUCH AS OXIDATIVE STRESS, INFLAMMATION, ACCUMULATION OF ADVANCED GLYCATED END-PRODUCTS AND UPREGULATION OF THE HEXOSAMINE BIOSYNTHESIS PATHWAY. THESE MECHANISMS ARE RESPONSIBLE FOR THE ACTIVATION OF HYPERTROPHIC PATHWAYS, EPIGENETIC MODIFICATIONS, MITOCHONDRIAL DYSFUNCTION, CELL APOPTOSIS, FIBROSIS AND CALCIUM MISHANDLING, LEADING TO CARDIAC STIFFNESS, AS WELL AS CONTRACTILE AND RELAXATION DYSFUNCTION. THIS REVIEW AIMS TO DESCRIBE THE HYPERGLYCAEMIC-INDUCED ALTERATIONS THAT PARTICIPATE IN DIABETIC CARDIOMYOPATHY, AND THEIR CORRELATION WITH THE SEVERITY OF THE DISEASE AND PATIENT MORTALITY, AND TO PROVIDE AN OVERVIEW OF CARDIAC OUTCOMES OF GLUCOSE-LOWERING THERAPY. 2021 12 4971 28 PATHOPHYSIOLOGIC MECHANISMS IN DIABETIC KIDNEY DISEASE: A FOCUS ON CURRENT AND FUTURE THERAPEUTIC TARGETS. DIABETIC KIDNEY DISEASE (DKD) IS THE PRIMARY CAUSE OF CHRONIC KIDNEY DISEASE AROUND THE GLOBE AND IS ONE OF THE MAIN COMPLICATIONS IN PATIENTS WITH TYPE 1 AND 2 DIABETES. THE STANDARD TREATMENT FOR DKD IS DRUGS CONTROLLING HYPERGLYCEMIA AND HIGH BLOOD PRESSURE. RENIN ANGIOTENSIN ALDOSTERONE SYSTEM BLOCKADE AND SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITION HAVE YIELDED PROMISING RESULTS IN DKD, BUT MANY DIABETIC PATIENTS ON SUCH TREATMENTS NEVERTHELESS CONTINUE TO DEVELOP DKD, LEADING TO KIDNEY FAILURE AND CARDIOVASCULAR COMORBIDITIES. NEW THERAPEUTIC OPTIONS ARE URGENTLY REQUIRED. WE REVIEW HERE THE PROMISING THERAPEUTIC AVENUES BASED ON INSIGHTS INTO THE MECHANISMS OF DKD THAT HAVE RECENTLY EMERGED, INCLUDING MINERALOCORTICOID RECEPTOR ANTAGONISTS, SGLT2 INHIBITORS, GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST, ENDOTHELIN RECEPTOR A INHIBITION, ANTI-INFLAMMATORY AGENTS, AUTOPHAGY ACTIVATORS AND EPIGENETIC REMODELLING. THE INVOLVEMENT OF SEVERAL MOLECULAR MECHANISMS IN DKD PATHOGENESIS, TOGETHER WITH THE GENETIC AND EPIGENETIC VARIABILITY OF THIS CONDITION, MAKES IT DIFFICULT TO TARGET THIS HETEROGENEOUS PATIENT POPULATION WITH A SINGLE DRUG. PERSONALIZED MEDICINE, TAKING INTO ACCOUNT THE GENETIC AND MECHANISTIC VARIABILITY, MAY THEREFORE IMPROVE RENAL AND CARDIOVASCULAR PROTECTION IN DIABETIC PATIENTS WITH DKD. 2020 13 6409 22 THE SIGNALING OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE (CKD) IN WESTERN COUNTRIES. NOTABLY, IT HAS A RAPIDLY RISING PREVALENCE IN CHINA. THE PATIENTS, COMMONLY COMPLICATED WITH CARDIOVASCULAR DISEASES AND NEUROLOGIC DISORDERS, ARE AT HIGH RISK TO PROGRESS INTO END-STAGE RENAL DISEASE (ESRD) AND DEATH. HOWEVER, THE PATHOGENIC MECHANISMS OF DIABETIC NEPHROPATHY HAVE NOT BEEN DETERMINED. CELLULAR SENESCENCE, WHICH RECENTLY HAS GAINED BROAD ATTENTION, IS THOUGHT TO BE AN IMPORTANT PLAYER IN THE ONSET AND DEVELOPMENT OF DIABETIC NEPHROPATHY. IN THIS ISSUE, WE GENERALLY REVIEW THE MECHANISMS OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY, WHICH INVOLVE TELOMERE ATTRITION, DNA DAMAGE, EPIGENETIC ALTERATIONS, MITOCHONDRIAL DYSFUNCTION, LOSS OF KLOTHO, WNT/BETA-CATENIN SIGNALING ACTIVATION, PERSISTENT INFLAMMATION, AND ACCUMULATION OF UREMIC TOXINS. MOREOVER, WE HIGHLIGHT THE POTENTIAL THERAPEUTIC TARGETS OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY AND PROVIDE IMPORTANT CLUES FOR CLINICAL STRATEGIES. 2019 14 4137 25 MECHANISMS OF METABOLIC MEMORY AND RENAL HYPOXIA AS A THERAPEUTIC TARGET IN DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD) IS A WORLDWIDE PUBLIC HEALTH PROBLEM. THE DEFINITION OF DKD IS UNDER DISCUSSION. ALTHOUGH THE TERM DKD WAS ORIGINALLY DEFINED AS 'KIDNEY DISEASE SPECIFIC TO DIABETES,' DKD FREQUENTLY MEANS CHRONIC KIDNEY DISEASE WITH DIABETES MELLITUS AND INCLUDES NOT ONLY CLASSICAL DIABETIC NEPHROPATHY, BUT ALSO KIDNEY DYSFUNCTION AS A RESULT OF NEPHROSCLEROSIS AND OTHER CAUSES. METABOLIC MEMORY PLAYS A CRUCIAL ROLE IN THE PROGRESSION OF VARIOUS COMPLICATIONS OF DIABETES, INCLUDING DKD. THE MECHANISMS OF METABOLIC MEMORY IN DKD ARE SUPPOSED TO INCLUDE ADVANCED GLYCATION END-PRODUCTS, DEOXYRIBONUCLEIC ACID METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RIBONUCLEIC ACID INCLUDING MICRO RIBONUCLEIC ACID. REGARDLESS OF THE PRESENCE OF DIABETES MELLITUS, THE FINAL COMMON PATHWAY IN CHRONIC KIDNEY DISEASE IS CHRONIC KIDNEY HYPOXIA, WHICH INFLUENCES EPIGENETIC PROCESSES, INCLUDING DEOXYRIBONUCLEIC ACID METHYLATION, HISTONE MODIFICATION, AND CONFORMATIONAL CHANGES IN MICRO RIBONUCLEIC ACID AND CHROMATIN. THEREFORE, HYPOXIA AND OXIDATIVE STRESS ARE APPROPRIATE TARGETS OF THERAPIES AGAINST DKD. PROLYL HYDROXYLASE DOMAIN INHIBITOR ENHANCES THE DEFENSIVE MECHANISMS AGAINST HYPOXIA. BARDOXOLONE METHYL PROTECTS AGAINST OXIDATIVE STRESS, AND CAN EVEN REVERSE IMPAIRED RENAL FUNCTION; A PHASE 2 TRIAL WITH CONSIDERABLE ATTENTION TO HEART COMPLICATIONS IS CURRENTLY ONGOING IN JAPAN. 2017 15 2208 35 EPIGENETIC MODIFICATIONS AND NON-CODING RNA IN DIABETES-MELLITUS-INDUCED CORONARY ARTERY DISEASE: PATHOPHYSIOLOGICAL LINK AND NEW THERAPEUTIC FRONTIERS. DIABETES MELLITUS (DM) IS A GLUCOSE METABOLISM DISORDER CHARACTERIZED BY CHRONIC HYPERGLYCEMIA RESULTING FROM A DEFICIT OF INSULIN PRODUCTION AND/OR ACTION. DM AFFECTS MORE THAN 1 IN 10 ADULTS, AND IT IS ASSOCIATED WITH AN INCREASED RISK OF CARDIOVASCULAR MORBIDITY AND MORTALITY. CARDIOVASCULAR DISEASE (CVD) ACCOUNTS FOR TWO THIRDS OF THE OVERALL DEATHS IN DIABETIC PATIENTS, WITH CORONARY ARTERY DISEASE (CAD) AND ISCHEMIC CARDIOMYOPATHY AS THE MAIN CONTRIBUTORS. HYPERGLYCEMIC DAMAGE ON VASCULAR ENDOTHELIAL CELLS LEADING TO ENDOTHELIAL DYSFUNCTION REPRESENTS THE MAIN INITIATING FACTOR IN THE PATHOGENESIS OF DIABETIC VASCULAR COMPLICATIONS; HOWEVER, THE UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS ARE STILL NOT ENTIRELY UNDERSTOOD. THIS REVIEW ADDRESSES THE CURRENT KNOWLEDGE ON THE PATHOPHYSIOLOGICAL LINKS BETWEEN DM AND CAD WITH A FOCUS ON THE ROLE OF EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND NONCODING RNA CONTROL. INCREASED KNOWLEDGE OF EPIGENETIC MECHANISMS HAS CONTRIBUTED TO THE DEVELOPMENT OF NEW PHARMACOLOGICAL TREATMENTS ("EPIDRUGS") WITH EPIGENETIC TARGETS, ALTHOUGH THESE APPROACHES PRESENT SEVERAL CHALLENGES. SPECIFIC EPIGENETIC BIOMARKERS MAY ALSO BE USED TO PREDICT OR DETECT THE DEVELOPMENT AND PROGRESSION OF DIABETES COMPLICATIONS. FURTHER STUDIES ON DIABETES AND CAD EPIGENETICS ARE NEEDED IN ORDER TO IDENTIFY POSSIBLE NEW THERAPEUTIC TARGETS AND ADVANCE PERSONALIZED MEDICINE WITH THE PREDICTION OF INDIVIDUAL DRUG RESPONSES AND MINIMIZATION OF ADVERSE EFFECTS. 2022 16 465 29 ARE TARGETED THERAPIES FOR DIABETIC CARDIOMYOPATHY ON THE HORIZON? DIABETES INCREASES THE RISK OF HEART FAILURE APPROXIMATELY 2.5-FOLD, INDEPENDENT OF CORONARY ARTERY DISEASE AND OTHER COMORBIDITIES. THIS PROCESS, TERMED DIABETIC CARDIOMYOPATHY, IS CHARACTERIZED BY INITIAL IMPAIRMENT OF LEFT VENTRICULAR (LV) RELAXATION FOLLOWED BY LV CONTRACTILE DYSFUNCTION. POST-MORTEM EXAMINATION REVEALS THAT HUMAN DIASTOLIC DYSFUNCTION IS CLOSELY ASSOCIATED WITH LV DAMAGE, INCLUDING CARDIOMYOCYTE HYPERTROPHY, APOPTOSIS AND FIBROSIS, WITH IMPAIRED CORONARY MICROVASCULAR PERFUSION. THE PATHOPHYSIOLOGICAL MECHANISMS UNDERPINNING THE CHARACTERISTIC FEATURES OF DIABETIC CARDIOMYOPATHY REMAIN POORLY UNDERSTOOD, ALTHOUGH MULTIPLE FACTORS INCLUDING ALTERED LIPID METABOLISM, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, ENDOPLASMIC RETICULUM (ER) STRESS, INFLAMMATION, AS WELL AS EPIGENETIC CHANGES, ARE IMPLICATED. DESPITE A RECENT RISE IN RESEARCH INTERROGATING THESE MECHANISMS AND AN INCREASED UNDERSTANDING OF THE CLINICAL IMPORTANCE OF DIABETIC CARDIOMYOPATHY, THERE REMAINS A LACK OF SPECIFIC TREATMENT STRATEGIES. HOW THE CHRONIC METABOLIC DISTURBANCES OBSERVED IN DIABETES LEAD TO STRUCTURAL AND FUNCTIONAL CHANGES REMAINS A PERTINENT QUESTION, AND IT IS HOPED THAT RECENT ADVANCES, PARTICULARLY IN THE AREA OF EPIGENETICS, AMONG OTHERS, MAY PROVIDE SOME ANSWERS. THIS REVIEW HENCE EXPLORES THE TEMPORAL ONSET OF THE PATHOLOGICAL FEATURES OF DIABETIC CARDIOMYOPATHY, AND THEIR RELATIVE CONTRIBUTION TO THE RESULTANT DISEASE PHENOTYPE, AS WELL AS BOTH CURRENT AND POTENTIAL THERAPEUTIC OPTIONS. THE EMERGENCE OF GLUCOSE-OPTIMIZING AGENTS, NAMELY GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS AND SODIUM/GLUCOSE CO-TRANSPORTER (SGLT)2 INHIBITORS THAT CONFER BENEFITS ON CARDIOVASCULAR OUTCOMES, TOGETHER WITH NOVEL EXPERIMENTAL APPROACHES, HIGHLIGHT A NEW AND EXCITING ERA IN DIABETES RESEARCH, WHICH IS LIKELY TO RESULT IN MAJOR CLINICAL IMPACT. 2017 17 6341 30 THE ROLE OF EPIGENETIC MODIFICATIONS IN LATE COMPLICATIONS IN TYPE 1 DIABETES. TYPE 1 DIABETES IS A CHRONIC AUTOIMMUNE DISEASE IN WHICH THE DESTRUCTION OF PANCREATIC BETA CELLS LEADS TO HYPERGLYCEMIA. THE PREVENTION OF HYPERGLYCEMIA IS VERY IMPORTANT TO AVOID OR AT LEAST POSTPONE THE DEVELOPMENT OF MICRO- AND MACROVASCULAR COMPLICATIONS, ALSO KNOWN AS LATE COMPLICATIONS. THESE INCLUDE DIABETIC RETINOPATHY, CHRONIC RENAL FAILURE, DIABETIC NEUROPATHY, AND CARDIOVASCULAR DISEASES. THE IMPACT OF LONG-TERM HYPERGLYCEMIA HAS BEEN SHOWN TO PERSIST LONG AFTER THE NORMALIZATION OF BLOOD GLUCOSE LEVELS, A PHENOMENON KNOWN AS METABOLIC MEMORY. IT IS BELIEVED THAT EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS, PLAY AN IMPORTANT ROLE IN METABOLIC MEMORY. THE AIM OF THIS REVIEW IS TO ADDRESS THE IMPACT OF LONG-TERM HYPERGLYCEMIA ON EPIGENETIC MARKS IN LATE COMPLICATIONS OF TYPE 1 DIABETES. 2022 18 5363 20 RECENT ADVANCES IN DIABETIC KIDNEY DISEASES: FROM KIDNEY INJURY TO KIDNEY FIBROSIS. DIABETIC KIDNEY DISEASE (DKD) IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE. THE NATURAL HISTORY OF DKD INCLUDES GLOMERULAR HYPERFILTRATION, PROGRESSIVE ALBUMINURIA, DECLINING ESTIMATED GLOMERULAR FILTRATION RATE, AND, ULTIMATELY, KIDNEY FAILURE. IT IS KNOWN THAT DKD IS ASSOCIATED WITH METABOLIC CHANGES CAUSED BY HYPERGLYCEMIA, RESULTING IN GLOMERULAR HYPERTROPHY, GLOMERULOSCLEROSIS, AND TUBULOINTERSTITIAL INFLAMMATION AND FIBROSIS. HYPERGLYCEMIA IS ALSO KNOWN TO CAUSE PROGRAMMED EPIGENETIC MODIFICATION. HOWEVER, THE DETAILED MECHANISMS INVOLVED IN THE ONSET AND PROGRESSION OF DKD REMAIN ELUSIVE. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES REGARDING THE PATHOGENIC MECHANISMS INVOLVED IN DKD. 2021 19 4891 27 OXIDATIVE STRESS AND INFLAMMATORY MARKERS IN PREDIABETES AND DIABETES. PREDIABETES IS A STATE OF ELEVATED PLASMA GLUCOSE IN WHICH THE THRESHOLD FOR DIABETES HAS NOT YET BEEN REACHED AND CAN PREDISPOSE TO THE DEVELOPMENT OF TYPE 2 DIABETES AND CARDIOVASCULAR DISEASES. INSULIN RESISTANCE AND IMPAIRED BETA-CELL FUNCTION ARE OFTEN ALREADY PRESENT IN PREDIABETES. HYPERGLYCEMIA CAN UPREGULATE MARKERS OF CHRONIC INFLAMMATION AND CONTRIBUTE TO INCREASED REACTIVE OXYGEN SPECIES (ROS) GENERATION, WHICH ULTIMATELY CAUSE VASCULAR DYSFUNCTION. CONVERSELY, INCREASED OXIDATIVE STRESS AND INFLAMMATION CAN LEAD TO INSULIN RESISTANCE AND IMPAIRED INSULIN SECRETION. PROPER TREATMENT OF HYPERGLYCEMIA AND INHIBITION OF ROS OVERPRODUCTION IS CRUCIAL FOR DELAYING ONSET OF DIABETES AND FOR PREVENTION OF CARDIOVASCULAR COMPLICATIONS. THUS, IT IS IMPERATIVE TO DETERMINE THE MECHANISMS INVOLVED IN THE PROGRESSION FROM PREDIABETES TO DIABETES INCLUDING A CLARIFICATION OF HOW OLD AND NEW MEDICATIONS AFFECT OXIDATIVE AND IMMUNE MECHANISMS OF DIABETES. IN THIS REVIEW, WE DISCUSS THE RELATIONSHIP BETWEEN OXIDATIVE STRESS AND HYPERGLYCEMIA ALONG WITH LINKS BETWEEN INFLAMMATION AND PREDIABETES. ADDITIONALLY, THE EFFECTS OF HYPERGLYCEMIC MEMORY, MICROVESICLES, MICRO-RNA, AND EPIGENETIC REGULATION ON INFLAMMATION, OXIDATIVE STATE, AND GLYCEMIC CONTROL ARE HIGHLIGHTED. ADIPOSE TISSUE AND THEIR INFLUENCE ON CHRONIC INFLAMMATION ARE ALSO BRIEFLY REVIEWED. FINALLY, THE ROLE OF IMMUNE-TARGETED THERAPIES AND ANTI-DIABETIC MEDICATION ON GLYCEMIC CONTROL AND OXIDATIVE STRESS ARE DISCUSSED. 2019 20 5024 19 PERSONALIZED EPIGENETIC MANAGEMENT OF DIABETES. THE NOVEL GENOME-WIDE ASSAYS OF EPIGENETIC MARKS HAVE RESULTED IN A GREATER UNDERSTANDING OF HOW GENETICS AND THE ENVIRONMENT INTERACT IN THE DEVELOPMENT AND INHERITANCE OF DIABETES. CHRONIC HYPERGLYCEMIA INDUCES EPIGENETIC CHANGES IN MULTIPLE ORGANS, CONTRIBUTING TO DIABETIC COMPLICATIONS. SPECIFIC EPIGENETIC-MODIFYING COMPOUNDS HAVE BEEN DEVELOPED TO ERASE THESE MODIFICATIONS, POSSIBLY SLOWING DOWN THE ONSET OF DIABETES-RELATED COMPLICATIONS. THE CURRENT REVIEW IS AN UPDATE OF THE PREVIOUSLY PUBLISHED PAPER, DESCRIBING THE MOST RECENT ADVANCES IN THE EPIGENETICS OF DIABETES. 2017