1 1389 126 DIABETIC RETINOPATHY AND SYSTEMIC FACTORS. DIABETIC RETINOPATHY, AN OCULARDISEASE, IS GOVERNED BY SYSTEMIC AS WELL AS LOCAL OCULAR FACTORS. THESE INCLUDE PRIMARILY CHRONIC LEVELS OF BLOOD GLUCOSE. INDIVIDUALS WITH CHRONICALLY ELEVATED BLOOD GLUCOSE LEVELS HAVE SUBSTANTIALLY MORE, AND MORE SEVERE, RETINOPATHY THAN THOSE WITH LOWER BLOOD GLUCOSE LEVELS. THE RELATIONSHIP OF BLOOD GLUCOSE TO RETINOPATHY IS CONTINUOUS, WITH NO THRESHOLD ALTHOUGH INDIVIDUALS WITH HEMOGLOBIN A1C LEVELS (A MEASURE OF CHRONIC GLYCEMIA) <6.5%, GENERALLY DEVELOP LITTLE OR NO RETINOPATHY. BLOOD PRESSURE LEVELS HAVE BEEN CLAIMED TO INFLUENCE RETINOPATHY DEVELOPMENT AND PROGRESSION, BUT MULTIPLE CONTROLLED CLINICAL TRIALS OF ANTIHYPERTENSIVE AGENTS IN DIABETIC SUBJECTS HAVE PRODUCED ONLY WEAK EVIDENCE OF BENEFIT FROM BLOOD PRESSURE LOWERING ON THE INCIDENCE AND PROGRESSION OF DIABETIC RETINOPATHY. ELEVATED BLOOD LIPIDS SEEM TO PLAY A ROLE IN THE PROGRESSION OF RETINOPATHY, AND TWO TRIALS OF FENOFIBRATE, A LIPID-LOWERING AGENT THAT HAS NOT PROVED EFFECTIVE IN PREVENTING CARDIOVASCULAR DISEASE, HAVE SHOWN BENEFIT IN PREVENTING RETINOPATHY PROGRESSION. THE MECHANISM OF THIS EFFECT MAY NOT, HOWEVER, BE DIRECTLY RELATED TO THE REDUCTION IN BLOOD LIPIDS. FINALLY, THERE IS STRONG, BUT ONLY CIRCUMSTANTIAL, EVIDENCE FOR A GENETIC OR EPIGENETIC INFLUENCE ON THE PATHOGENESIS OF DIABETIC RETINOPATHY. DESPITE THE POWER OF LARGE-SCALE EPIDEMIOLOGIC STUDIES AND MODERN MOLECULAR BIOLOGICAL AND COMPUTATIONAL TECHNIQUES, THE GENE OR GENES, WHICH PREDISPOSE OR PROTECT AGAINST THE DEVELOPMENT AND PROGRESSION OF DIABETIC RETINOPATHY REMAIN ELUSIVE. 2015 2 4433 30 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 2210 33 EPIGENETIC MODIFICATIONS AND POTENTIAL NEW TREATMENT TARGETS IN DIABETIC RETINOPATHY. RETINOPATHY IS A DEBILITATING VASCULAR COMPLICATION OF DIABETES. AS WITH OTHER DIABETIC COMPLICATIONS, DIABETIC RETINOPATHY (DR) IS CHARACTERIZED BY THE METABOLIC MEMORY, WHICH HAS BEEN OBSERVED BOTH IN DR PATIENTS AND IN DR ANIMAL MODELS. EVIDENCES HAVE PROVIDED THAT AFTER A PERIOD OF POOR GLUCOSE CONTROL INSULIN OR DIABETES DRUG TREATMENT FAILS TO PREVENT THE DEVELOPMENT AND PROGRESSION OF DR EVEN WHEN GOOD GLYCEMIC CONTROL IS REINSTITUTED (GLUCOSE NORMALIZATION), SUGGESTING A METABOLIC MEMORY PHENOMENON. RECENT STUDIES ALSO UNDERLINE THE ROLE OF EPIGENETIC CHROMATIN MODIFICATIONS AS MEDIATORS OF THE METABOLIC MEMORY. INDEED, EPIGENETIC CHANGES MAY LEAD TO STABLE MODIFICATION OF GENE EXPRESSION, PARTICIPATING IN DR PATHOGENESIS. MOREOVER, INCREASING EVIDENCES SUGGEST THAT ENVIRONMENTAL FACTORS SUCH AS CHRONIC HYPERGLYCEMIA ARE IMPLICATED DR PROGRESSION AND MAY ALSO AFFECT THE EPIGENETIC STATE. HERE WE REVIEW RECENT FINDINGS DEMONSTRATING THE KEY ROLE OF EPIGENETICS IN THE PROGRESSION OF DR. FURTHER ELUCIDATION OF EPIGENETIC MECHANISMS, ACTING BOTH AT THE CIS- AND TRANS-CHROMATIN STRUCTURAL ELEMENTS, WILL YIELD NEW INSIGHTS INTO THE PATHOGENESIS OF DR AND WILL OPEN THE WAY FOR THE DISCOVERY OF NOVEL THERAPEUTIC TARGETS TO PREVENT DR PROGRESSION. 2014 4 4459 38 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 5 5392 28 REDOXISOME AND DIABETIC RETINOPATHY: PATHOPHYSIOLOGY AND THERAPEUTIC INTERVENTIONS. DIABETIC RETINOPATHY (DR) IS A CHRONIC MICROVASCULAR COMPLICATION OF DIABETES MELLITUS (DM). IT IS A WORLDWIDE GROWING EPIDEMIC DISEASE CONSIDERED TO BE THE LEADING CAUSE OF VISION-LOSS AND BLINDNESS IN PEOPLE WITH DM. REDOX REACTIONS OCCURRING AT THE EXTRA- AND INTRACELLULAR LEVELS ARE ESSENTIAL FOR THE MAINTENANCE OF CELLULAR HOMEOSTASIS. DYSREGULATION OF REDOX HOMEOSTASIS ARE IMPLICATED IN THE ONSET AND DEVELOPMENT OF DR. THIOREDOXIN1 (TRX1) AND THIOREDOXIN2 (TRX2) ARE CYTOPLASMIC AND MITOCHONDRIALLY LOCALIZED ANTIOXIDANT PROTEINS UBIQUITOUSLY EXPRESSED IN VARIOUS CELLS AND CONTROL CELLULAR REACTIVE OXYGEN SPECIES (ROS) BY REDUCING THE DISULFIDES INTO THIOL GROUPS. THIOREDOXIN-INTERACTING PROTEIN (TXNIP) BINDS TO TRX SYSTEM AND INHIBITS THE ACTIVE REDUCED FORM OF TRX THROUGH DISULFIDE EXCHANGE REACTION. RECENT STUDIES INDICATE THE ASSOCIATION OF TRX/TXNIP WITH REDOX SIGNAL TRANSDUCTION PATHWAYS INCLUDING ACTIVATION OF NOD-LIKE RECEPTOR PYRIN DOMAIN CONTAINING PROTEIN-3 (NLRP3) INFLAMMASOME, APOPTOSIS, AUTOPHAGY/MITOPHAGY, EPIGENETIC MODIFICATIONS IN A REDOX-DEPENDENT MANNER. THUS, IT IS IMPORTANT TO GAIN A MORE IN-DEPTH UNDERSTANDING ABOUT THE CELLULAR AND MOLECULAR MECHANISMS THAT LINKS REDOXISOME AND ER/MITOCHONDRIAL DYSFUNCTION TO DRIVE THE PROGRESSION OF DR. THE PURPOSE OF THIS REVIEW IS TO PROVIDE A MECHANISTIC UNDERSTANDING OF THE COMPLEX MOLECULAR MECHANISMS AND PATHOPHYSIOLOGICAL ROLES ASSOCIATED WITH REDOXISOME, THE TRX/TXNIP REDOX SIGNALING COMPLEX UNDER OXIDATIVE STRESS IN THE DEVELOPMENT OF DR. ALSO, THE MOLECULAR TARGETS OF FDA APPROVED DRUGS AND CLINICAL TRIALS IN ADDITION TO EFFECTIVE ANTIOXIDANT STRATEGIES FOR THE TREATMENT OF DIABETIC RETINOPATHY ARE REVIEWED. 2022 6 4195 37 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 7 1387 31 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 8 2171 38 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 9 2965 40 GENETIC AND EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF DIABETIC RETINOPATHY: A MOLECULAR LINK TO REGULATE GENE EXPRESSION. INTENSIFICATION IN THE FREQUENCY OF DIABETES AND THE ASSOCIATED VASCULAR COMPLICATIONS HAS BEEN A ROOT CAUSE OF BLINDNESS AND VISUAL IMPAIRMENT WORLDWIDE. ONE SUCH VASCULAR COMPLICATION WHICH HAS BEEN THE PROMINENT CAUSE OF BLINDNESS; RETINAL VASCULATURE, NEURONAL AND GLIAL ABNORMALITIES IS DIABETIC RETINOPATHY (DR), A CHRONIC COMPLICATED OUTCOME OF TYPE 1 AND TYPE 2 DIABETES. IT HAS ALSO BECOME CLEAR THAT "GENETIC" VARIATIONS IN POPULATION ALONE CAN'T EXPLAIN THE DEVELOPMENT AND PROGRESSION OF DIABETES AND ITS COMPLICATIONS INCLUDING DR. DR EXPERIENCES ENGAGEMENT OF FOREMOST MEDIATORS OF DIABETES SUCH AS HYPERGLYCEMIA, OXIDANT STRESS, AND INFLAMMATORY FACTORS THAT LEAD TO THE DYSREGULATION OF "EPIGENETIC" MECHANISMS INVOLVING HISTONE ACETYLATION AND HISTONE AND DNA METHYLATION, CHROMATIN REMODELING AND EXPRESSION OF A COMPLEX SET OF STRESS-REGULATED AND DISEASE-ASSOCIATED GENES. IN ADDITION, BOTH ELEVATED GLUCOSE CONCENTRATION AND INSULIN RESISTANCE LEAVE A ROBUST EFFECT ON EPIGENETIC REPROGRAMMING OF THE ENDOTHELIAL CELLS TOO, SINCE ENDOTHELIUM ASSOCIATED WITH THE EYE AIDS IN MAINTAINING THE VASCULAR HOMEOSTASIS. FURTHERMORE, SEVERAL STUDIES CONDUCTED ON THE DISEASE SUGGEST THAT THE MODIFICATIONS OF THE EPIGENOME MIGHT BE THE FUNDAMENTAL MECHANISM(S) FOR THE PROPOSED METABOLIC MEMORY' RESULTING INTO PROLONGED GENE EXPRESSION FOR INFLAMMATION AND CELLULAR DYSFUNCTION EVEN AFTER ATTAINING THE GLYCEMIC CONTROL IN DIABETICS. HENCEFORTH, THE PRESENT REVIEW FOCUSES ON THE ASPECTS OF GENETIC AND EPIGENETIC ALTERATIONS IN GENES SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR AND ALDOSE REDUCTASE CONSIDERED BEING ASSOCIATED WITH DR. IN ADDITION, WE DISCUSS BRIEFLY THE ROLE OF THE THIOREDOXIN-INTERACTING PROTEIN TXNIP, WHICH IS STRONGLY INDUCED BY HIGH GLUCOSE AND DIABETES, IN CELLULAR OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION POTENTIALLY LEADING TO CHROMATIN REMODELING AND OCULAR COMPLICATIONS OF DIABETES. THE IDENTIFICATION OF DISEASE-ASSOCIATED GENES AND THEIR EPIGENETIC REGULATIONS WILL LEAD TO POTENTIAL NEW DRUGS AND GENE THERAPIES AS WELL AS PERSONALIZED MEDICINE TO PREVENT OR SLOW DOWN THE PROGRESSION OF DR. 2016 10 6453 28 THIOREDOXIN INTERACTING PROTEIN (TXNIP) INDUCES INFLAMMATION THROUGH CHROMATIN MODIFICATION IN RETINAL CAPILLARY ENDOTHELIAL CELLS UNDER DIABETIC CONDITIONS. CHRONIC HYPERGLYCEMIA AND ACTIVATION OF RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE) ARE KNOWN RISK FACTORS FOR MICROVASCULAR DISEASE DEVELOPMENT IN DIABETIC RETINOPATHY. THIOREDOXIN-INTERACTING PROTEIN (TXNIP), AN ENDOGENOUS INHIBITOR OF ANTIOXIDANT THIOREDOXIN (TRX), PLAYS A CAUSATIVE ROLE IN DIABETES AND ITS VASCULAR COMPLICATIONS. HEREIN WE INVESTIGATE WHETHER HG AND RAGE INDUCE INFLAMMATION IN RAT RETINAL ENDOTHELIAL CELLS (EC) UNDER DIABETIC CONDITIONS IN CULTURE THROUGH TXNIP ACTIVATION AND WHETHER EPIGENETIC MECHANISMS PLAY A ROLE IN INFLAMMATORY GENE EXPRESSION. WE SHOW THAT RAGE ACTIVATION BY ITS LIGAND S100B OR HG TREATMENT OF RETINAL EC INDUCES THE EXPRESSION OF TXNIP AND INFLAMMATORY GENES SUCH AS COX2, VEGF-A, AND ICAM1. TXNIP SILENCING BY SIRNA IMPEDES RAGE AND HG EFFECTS WHILE STABLE OVER-EXPRESSION OF A CDNA FOR HUMAN TXNIP IN EC ELEVATES INFLAMMATION. P38 MAPK-NF-KAPPAB SIGNALING PATHWAY AND HISTONE H3 LYSINE (K) NINE MODIFICATIONS ARE INVOLVED IN TXNIP-INDUCED INFLAMMATION. CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAYS REVEAL THAT TXNIP OVER-EXPRESSION IN EC ABOLISHES H3K9 TRI-METHYLATION, A MARKER FOR GENE INACTIVATION, AND INCREASES H3K9 ACETYLATION, AN INDICATOR OF GENE INDUCTION, AT PROXIMAL COX2 PROMOTER BEARING THE NF-KAPPAB-BINDING SITE. THESE FINDINGS HAVE IMPORTANT IMPLICATIONS TOWARD UNDERSTANDING THE MOLECULAR MECHANISMS OF OCULAR INFLAMMATION AND ENDOTHELIAL DYSFUNCTION IN DIABETIC RETINOPATHY. 2009 11 6341 33 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 12 2009 23 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 13 5363 22 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 14 6575 33 TREATMENT OF DIABETIC KIDNEY DISEASE: CURRENT AND FUTURE. DIABETIC KIDNEY DISEASE (DKD) IS THE MAJOR CAUSE OF END-STAGE KIDNEY DISEASE. HOWEVER, ONLY RENIN-ANGIOTENSIN SYSTEM INHIBITOR WITH MULTIDISCIPLINARY TREATMENTS IS EFFECTIVE FOR DKD. IN 2019, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR SHOWED EFFICACY AGAINST DKD IN CANAGLIFLOZIN AND RENAL EVENTS IN DIABETES WITH ESTABLISHED NEPHROPATHY CLINICAL EVALUATION (CREDENCE) TRIAL, ADDING A NEW TREATMENT OPTION. HOWEVER, THE PROGRESSION OF DKD HAS NOT BEEN COMPLETELY CONTROLLED. THE PATIENTS WITH TRANSIENT EXPOSURE TO HYPERGLYCEMIA DEVELOP DIABETIC COMPLICATIONS, INCLUDING DKD, EVEN AFTER NORMALIZATION OF THEIR BLOOD GLUCOSE. TEMPORARY HYPERGLYCEMIA CAUSES ADVANCED GLYCATION END PRODUCT (AGE) ACCUMULATIONS AND EPIGENETIC CHANGES AS METABOLIC MEMORY. THE DRUGS THAT IMPROVE METABOLIC MEMORY ARE AWAITED, AND AGE INHIBITORS AND HISTONE MODIFICATION INHIBITORS ARE THE FOCUS OF CLINICAL AND BASIC RESEARCH. IN ADDITION, INCRETIN-RELATED DRUGS SHOWED A RENOPROTECTIVE ABILITY IN MANY CLINICAL TRIALS, AND THESE TRIALS WITH RENAL OUTCOME AS THEIR PRIMARY ENDPOINT ARE CURRENTLY ONGOING. HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITORS RECENTLY APPROVED FOR RENAL ANEMIA MAY BE RENOPROTECTIVE SINCE THEY IMPROVE TUBULOINTERSTITIAL HYPOXIA. FURTHERMORE, NF-E2-RELATED FACTOR 2 ACTIVATORS IMPROVED THE GLOMERULAR FILTRATION RATE OF DKD PATIENTS IN BARDOXOLONE METHYL TREATMENT: RENAL FUNCTION IN CHRONIC KIDNEY DISEASE/TYPE 2 DIABETES (BEAM) TRIAL AND PHASE II STUDY OF BARDOXOLONE METHYL IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES (TSUBAKI) TRIAL. THUS, FOLLOWING SGLT2 INHIBITOR, NUMEROUS NOVEL DRUGS COULD BE UTILIZED IN TREATING DKD. FUTURE STUDIES ARE EXPECTED TO PROVIDE NEW INSIGHTS. 2021 15 3909 27 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 16 4137 24 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 17 5546 32 ROLE OF EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF CHRONIC COMPLICATIONS OF DIABETES. THERE IS GROWING EVIDENCE THAT EPIGENETIC REGULATION OF GENE EXPRESSION INCLUDING POST-TRANSLATIONAL HISTONE MODIFICATIONS (PTHMS), DNA METHYLATION AND MICRORNA (MIRNA)-REGULATION OF MRNA TRANSLATION COULD PLAY A CRUCIAL ROLE IN THE DEVELOPMENT OF CHRONIC, DIABETIC COMPLICATIONS. HYPERGLYCEMIA CAN INDUCE AN ABNORMAL ACTION OF PTHMS AND DNA METHYLTRANSFERASES AS WELL AS ALTER THE LEVELS OF NUMEROUS MIRNAS IN ENDOTHELIAL CELLS, VASCULAR SMOOTH MUSCLE CELLS, CARDIOMYOCYTES, RETINA, AND RENAL CELLS. THESE EPIGENETIC ABNORMALITIES RESULT IN CHANGES IN THE EXPRESSION OF NUMEROUS GENES CONTRIBUTING TO EFFECTS SUCH AS DEVELOPMENT OF CHRONIC INFLAMMATION, IMPAIRED CLEARANCE OF REACTIVE OXYGEN SPECIES (ROS), ENDOTHELIAL CELL DYSFUNCTION AND/OR THE ACCUMULATION OF EXTRACELLULAR MATRIX IN THE KIDNEY, WHICH CAUSING THE DEVELOPMENT OF RETINOPATHY, NEPHROPATHY OR CARDIOMYOPATHY. SOME EPIGENETIC MODIFICATIONS, FOR EXAMPLE PTHMS AND DNA METHYLATION, BECOME IRREVERSIBLE OVER TIME. THEREFORE, THESE PROCESSES HAVE GAINED MUCH ATTENTION IN EXPLAINING THE LONG-LASTING DETRIMENTAL CONSEQUENCES OF HYPERGLYCAEMIA CAUSING THE DEVELOPMENT OF CHRONIC COMPLICATIONS EVEN AFTER IMPROVED GLYCAEMIC CONTROL IS ACHIEVED. OUR REVIEW SUGGESTS THAT THE TREATMENT OF CHRONIC COMPLICATIONS SHOULD FOCUS ON ERASING METABOLIC MEMORY BY TARGETING CHROMATIN MODIFICATION ENZYMES AND BY RESTORING MIRNA LEVELS. 2014 18 6357 31 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 19 2206 30 EPIGENETIC MODIFICATIONS AND DIABETIC RETINOPATHY. DIABETIC RETINOPATHY REMAINS ONE OF THE MOST DEBILITATING CHRONIC COMPLICATIONS, BUT DESPITE EXTENSIVE RESEARCH IN THE FIELD, THE EXACT MECHANISM(S) RESPONSIBLE FOR HOW RETINA IS DAMAGED IN DIABETES REMAINS AMBIGUOUS. MANY METABOLIC PATHWAYS HAVE BEEN IMPLICATED IN ITS DEVELOPMENT, AND GENES ASSOCIATED WITH THESE PATHWAYS ARE ALTERED. DIABETIC ENVIRONMENT ALSO FACILITATES EPIGENETICS MODIFICATIONS, WHICH CAN ALTER THE GENE EXPRESSION WITHOUT PERMANENT CHANGES IN DNA SEQUENCE. THE ROLE OF EPIGENETICS IN DIABETIC RETINOPATHY IS NOW AN EMERGING AREA, AND RECENT WORK HAS SHOWN THAT GENES ENCODING MITOCHONDRIAL SUPEROXIDE DISMUTASE (SOD2) AND MATRIX METALLOPROTEINASE-9 (MMP-9) ARE EPIGENETICALLY MODIFIED, ACTIVATES OF EPIGENETIC MODIFICATION ENZYMES, HISTONE LYSINE DEMETHYLASE 1 (LSD1), AND DNA METHYLTRANSFERASE ARE INCREASED, AND THE MICRO RNAS RESPONSIBLE FOR REGULATING NUCLEAR TRANSCRIPTIONAL FACTOR AND VEGF ARE UPREGULATED. WITH THE GROWING EVIDENCE OF EPIGENETIC MODIFICATIONS IN DIABETIC RETINOPATHY, BETTER UNDERSTANDING OF THESE MODIFICATIONS HAS POTENTIAL TO IDENTIFY NOVEL TARGETS TO INHIBIT THIS DEVASTATING DISEASE. FORTUNATELY, THE INHIBITORS AND MIMICS TARGETED TOWARDS HISTONE MODIFICATION, DNA METHYLATION, AND MIRNAS ARE NOW BEING TRIED FOR CANCER AND OTHER CHRONIC DISEASES, AND BETTER UNDERSTANDING OF THE ROLE OF EPIGENETICS IN DIABETIC RETINOPATHY WILL OPEN THE DOOR FOR THEIR POSSIBLE USE IN COMBATING THIS BLINDING DISEASE. 2013 20 6648 33 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