1 4195 122 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 2 2210 46 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 3 2965 49 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 4 6341 37 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 5 5997 44 THE "METABOLIC MEMORY" THEORY AND THE EARLY TREATMENT OF HYPERGLYCEMIA IN PREVENTION OF DIABETIC COMPLICATIONS. SEVERAL EPIDEMIOLOGICAL AND PROSPECTIVE STUDIES SUGGEST THAT AN EARLY INTENSIVE CONTROL OF HYPERGLYCAEMIA IS ABLE TO DECREASE THE RISK OF DIABETIC MICRO- AND MACRO-VASCULAR COMPLICATIONS. A GROWING BODY OF EXPERIMENTAL EVIDENCE SUPPORTS THE CONCEPT THAT THE RISK FOR DIABETES COMPLICATIONS MAY BE LINKED TO OXIDATIVE STRESS, NON-ENZYMATIC GLYCATION OF PROTEINS, EPIGENETIC CHANGES, AND CHRONIC INFLAMMATION, LAYING THE FOUNDATION FOR THE "METABOLIC MEMORY" THEORY. FROM A CLINICAL POINT OF VIEW, THIS THEORY SUPPORTS THE NEED FOR A VERY EARLY AGGRESSIVE TREATMENT, WITH THE GOAL OF NORMALIZING METABOLIC CONTROL AS SOON AS POSSIBLE. IT MAY ALSO PROVE BENEFICIAL TO INTRODUCE THERAPEUTIC AGENTS THAT ARE ABLE TO REDUCE REACTIVE SPECIES AND GLYCATION, IN ADDITION TO PRESENTING BETTER CONTROL OF GLUCOSE LEVELS IN PATIENTS WITH DIABETES, IN ORDER TO MINIMIZE LONG-TERM DIABETES COMPLICATIONS. IN THIS REVIEW, WE EVALUATE THE EFFECT OF GLUCOSE INTAKE AND METABOLISM IN THE LIGHT OF THIS THEORY. 2017 6 2163 42 EPIGENETIC MECHANISMS IN DIABETIC VASCULAR COMPLICATIONS. THERE HAS BEEN A RAPID INCREASE IN THE INCIDENCE OF DIABETES AS WELL THE ASSOCIATED VASCULAR COMPLICATIONS. BOTH GENETIC AND ENVIRONMENTAL FACTORS HAVE BEEN IMPLICATED IN THESE PATHOLOGIES. INCREASING EVIDENCE SUGGESTS THAT EPIGENETIC FACTORS PLAY A KEY ROLE IN THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT. ACTIONS OF MAJOR PATHOLOGICAL MEDIATORS OF DIABETES AND ITS COMPLICATIONS SUCH AS HYPERGLYCAEMIA, OXIDANT STRESS, AND INFLAMMATORY FACTORS CAN LEAD TO DYSREGULATED EPIGENETIC MECHANISMS THAT AFFECT CHROMATIN STRUCTURE AND GENE EXPRESSION. FURTHERMORE, PERSISTENCE OF THIS ALTERED STATE OF THE EPIGENOME MAY BE THE UNDERLYING MECHANISM CONTRIBUTING TO A 'METABOLIC MEMORY' THAT RESULTS IN CHRONIC INFLAMMATION AND VASCULAR DYSFUNCTION IN DIABETES EVEN AFTER ACHIEVING GLYCAEMIC CONTROL. FURTHER EXAMINATION OF EPIGENETIC MECHANISMS BY ALSO TAKING ADVANTAGE OF RECENTLY DEVELOPED NEXT-GENERATION SEQUENCING TECHNOLOGIES CAN PROVIDE NOVEL INSIGHTS INTO THE PATHOLOGY OF DIABETES AND ITS COMPLICATIONS AND LEAD TO THE DISCOVERY OF MUCH NEEDED NEW DRUG TARGETS FOR THESE DISEASES. IN THIS REVIEW, WE HIGHLIGHT THE ROLE OF EPIGENETICS IN DIABETES AND ITS VASCULAR COMPLICATIONS, AND RECENT TECHNOLOGICAL ADVANCES THAT HAVE SIGNIFICANTLY ACCELERATED THE FIELD. 2011 7 2613 51 EPIGENETICS: DECIPHERING ITS ROLE IN DIABETES AND ITS CHRONIC COMPLICATIONS. 1. INCREASING EVIDENCE SUGGESTS THAT EPIGENETIC FACTORS MIGHT REGULATE THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT, AND AFFECT HUMAN DISEASES, SUCH AS DIABETES AND ITS COMPLICATIONS. 2. CLINICAL TRIALS HAVE UNDERSCORED THE LONG LASTING BENEFICIAL EFFECTS OF STRICT GLYCAEMIC CONTROL FOR REDUCING THE PROGRESSION OF DIABETIC COMPLICATIONS. THEY HAVE ALSO SHOWN THAT DIABETIC COMPLICATIONS, SUCH AS DIABETIC NEPHROPATHY, A CHRONIC KIDNEY DISORDER, CAN CONTINUE EVEN AFTER BLOOD GLUCOSE NORMALIZATION, SUGGESTING A METABOLIC MEMORY OF THE PRIOR GLYCAEMIC STATE. 3. DYSREGULATION OF EPIGENETIC POST-TRANSCRIPTIONAL MODIFICATIONS OF HISTONES IN CHROMATIN, INCLUDING HISTONE LYSINE METHYLATION, HAS BEEN IMPLICATED IN ABERRANT GENE REGULATION ASSOCIATED WITH THE PATHOLOGY OF DIABETES AND ITS COMPLICATIONS. GENOME-WIDE STUDIES HAVE SHOWN CELL-TYPE SPECIFIC CHANGES IN HISTONE METHYLATION PATTERNS UNDER DIABETIC CONDITIONS. IN ADDITION, STUDIES IN VASCULAR CELLS HAVE SHOWN LONG LASTING CHANGES IN EPIGENETIC MODIFICATIONS AT KEY INFLAMMATORY GENE PROMOTERS AFTER PRIOR EXPOSURE TO DIABETIC CONDITIONS, SUGGESTING A POSSIBLE MECHANISM FOR METABOLIC MEMORY. 4. RECENT STUDIES HAVE SHOWN ROLES FOR HISTONE METHYLATION, DNA METHYLATION, AS WELL AS MICRORNA IN DIABETIC NEPHROPATHY. WHETHER THESE EPIGENETIC FACTORS PLAY A ROLE IN METABOLIC MEMORY OF DIABETIC KIDNEY DISEASE IS LESS WELL UNDERSTOOD. 5. THE INCIDENCE OF DIABETES IS GROWING RAPIDLY, AS ALSO THE COST OF TREATING THE RESULTING COMPLICATIONS. A BETTER UNDERSTANDING OF METABOLIC MEMORY AND THE POTENTIAL INVOLVEMENT OF EPIGENETIC MECHANISMS IN THIS PHENOMENON COULD ENABLE THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS FOR THE TREATMENT AND/OR PREVENTION OF SUSTAINED DIABETIC COMPLICATIONS. 2011 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 2190 45 EPIGENETIC MECHANISMS. THE INCIDENCE OF DIABETES AND RELATED COMPLICATIONS LIKE NEPHROPATHY IS GROWING RAPIDLY AND HAS BECOME A MAJOR HEALTH CARE ISSUE. CHANGES IN THE ENVIRONMENT AND NUTRITIONAL HABITS HAVE BEEN IMPLICATED AS MAJOR PLAYERS. FURTHERMORE, IT IS BECOMING INCREASINGLY CLEAR THAT EPIGENETIC FACTORS MAY MODULATE THE CONNECTIONS BETWEEN GENES AND THE ENVIRONMENT. WHILE DIABETES IN ITSELF IS TREATABLE TO A LARGE EXTENT, IT IS STILL ASSOCIATED WITH SIGNIFICANTLY INCREASED RISK FOR COMPLICATIONS INCLUDING CHRONIC KIDNEY AND CARDIOVASCULAR DISEASES. CURRENT TREATMENTS HAVE ADDED PREVENTATIVE APPROACHES SO AS TO AVOID FUTURE DIABETIC COMPLICATIONS. UNFORTUNATELY, DIABETIC PATIENTS ARE OFTEN PLAGUED WITH THE CONTINUED DEVELOPMENT OF VARIOUS COMPLICATIONS EVEN AFTER ACHIEVING GLUCOSE CONTROL. THIS HAS BEEN SUGGESTED TO BE ATTRIBUTABLE TO A MYSTERIOUS PHENOMENON TERMED 'METABOLIC MEMORY' OF THE PRIOR GLYCEMIC STATE. RECENT STUDIES HAVE SUGGESTED THAT EPIGENETIC CHANGES TO CHROMATIN CAN AFFECT GENE EXPRESSION IN RESPONSE TO VARIOUS STIMULI, AND CHANGES IN KEY BIOCHEMICAL PATHWAYS AND EPIGENETIC HISTONE AND DNA METHYLATION PATTERNS IN CHROMATIN HAVE BEEN OBSERVED IN A DIABETIC MILIEU. THESE ACCUMULATING DATA SUGGEST THAT METABOLIC OR HYPERGLYCEMIC MEMORY MAY BE DUE TO EPIGENETIC CHANGES IN SPECIFIC TARGET TISSUES ALTERING GENE EXPRESSION WITHOUT CHANGING THE GENETIC CODE ITSELF. WHILE THE GENETICS OF DIABETES HAS LONG BEEN THE FOCUS OF SCIENTIFIC RESEARCH, MUCH LESS IS KNOWN ABOUT THE ROLE OF EPIGENETICS AND THE RELATED MOLECULAR PATHWAYS THAT MIGHT AFFECT THE DEVELOPMENT OF DIABETES AND THE ASSOCIATED COMPLICATIONS. FURTHER STUDIES OF EPIGENETIC MECHANISMS ARE THEREFORE TIMELY AND COULD PROVIDE VALUABLE NEW INSIGHTS INTO THE PATHOLOGY OF DIABETIC COMPLICATIONS AND ALSO UNCOVER MUCH NEEDED NEW THERAPEUTIC TARGETS. 2011 10 2028 45 EPIGENETIC CHANGES IN DIABETES. DIABETES IS A MULTIFACTORIAL DISEASE WITH NUMEROUS PATHWAYS INFLUENCING ITS PROGRESSION AND RECENT OBSERVATIONS SUGGEST THAT THE COMPLEXITY OF THE DISEASE CANNOT BE ENTIRELY ACCOUNTED FOR BY GENETIC PREDISPOSITION. A COMPELLING ARGUMENT FOR AN EPIGENETIC COMPONENT IS RAPIDLY EMERGING. EPIGENETIC PROCESSES AT THE CHROMATIN TEMPLATE SIGNIFICANTLY SENSITIZE TRANSCRIPTIONAL AND PHENOTYPIC OUTCOMES TO ENVIRONMENTAL SIGNALING INFORMATION INCLUDING METABOLIC STATE, NUTRITIONAL REQUIREMENTS AND HISTORY. EPIGENETIC MECHANISMS IMPACT GENE EXPRESSION THAT COULD PREDISPOSE INDIVIDUALS TO THE DIABETIC PHENOTYPE DURING INTRAUTERINE AND EARLY POSTNATAL DEVELOPMENT, AS WELL AS THROUGHOUT ADULT LIFE. FURTHERMORE, EPIGENETIC CHANGES COULD ACCOUNT FOR THE ACCELERATED RATES OF CHRONIC AND PERSISTENT MICROVASCULAR AND MACROVASCULAR COMPLICATIONS ASSOCIATED WITH DIABETES. EPIDEMIOLOGICAL AND EXPERIMENTAL ANIMAL STUDIES IDENTIFIED POOR GLYCEMIC CONTROL AS A MAJOR CONTRIBUTOR TO THE DEVELOPMENT OF DIABETIC COMPLICATIONS AND HIGHLIGHT THE REQUIREMENT FOR EARLY INTERVENTION. EARLY EXPOSURE TO HYPERGLYCEMIA CAN DRIVE THE DEVELOPMENT OF COMPLICATIONS THAT MANIFEST LATE IN THE PROGRESSION OF THE DISEASE AND PERSIST DESPITE IMPROVED GLYCEMIC CONTROL, INDICATING A MEMORY OF THE METABOLIC INSULT. UNDERSTANDING THE MOLECULAR EVENTS THAT UNDERLIE THESE TRANSCRIPTIONAL CHANGES WILL SIGNIFICANTLY CONTRIBUTE TO NOVEL THERAPEUTIC INTERVENTIONS TO PREVENT, REVERSE OR RETARD THE DELETERIOUS EFFECTS OF THE DIABETIC MILIEU. 2013 11 5024 23 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 12 4193 42 METABOLIC MEMORY AND DIABETIC NEPHROPATHY: BENEFICIAL EFFECTS OF NATURAL EPIGENETIC MODIFIERS. NEPHROPATHY IS ONE OF THE MOST FREQUENT COMPLICATIONS OF CHRONIC DIABETES. THE MAIN REASON FOR NEPHROPATHY DESPITE BEING HYPERGLYCEMIA, BUT IT PROGRESSES EVEN AFTER GOOD GLYCEMIC CONTROL HAS BEEN ACHIEVED IN DIABETIC PATIENTS. THE EFFECTS OF PRIOR EXPOSURE TO HIGH BLOOD GLUCOSE CONDITIONS DEPEND UPON THE SEVERITY AND DURATION OF THIS EXPOSURE, INDICATING A "METABOLIC MEMORY" PHENOMENON. HYPERGLYCEMIA NOT ONLY INCREASES OXIDATIVE STRESS BUT IS ALSO ALLEGED TO START SEVERAL BIOCHEMICAL ANOMALIES AND ALTER GENE EXPRESSION ASSOCIATED WITH METABOLIC HOMEOSTASIS. HIGH GLUCOSE LEVELS INDUCE EPIGENETIC MODIFICATIONS THAT ALTER GENE EXPRESSION WITHOUT CHANGING DNA SEQUENCES. THESE EPIGENETIC MODIFICATIONS HAVE SHOWN TO BE REVERSIBLE AND HAVE THE POTENTIAL TO CEASE ADVERSE EFFECTS IF GOOD GLYCEMIC CONTROL IS ACHIEVED FROM INITIATION OF DIABETES. HOWEVER, IF GOOD GLYCEMIC CONTROL IS NOT ACHIEVED FOR MONTHS, THESE MODIFICATIONS STAND FIRM TO REVERSALS. THERAPIES AND DRUGS HAVE BEEN IN USE TO PREVENT EPIGENETIC MODIFICATIONS AND OXIDATIVE STRESS, WHICH ALSO HELPED IN AMELIORATING DIABETIC NEPHROPATHY. BUT THESE SYNTHETIC DRUGS ARE LOADED WITH SIDE EFFECTS LIKE INCREASED BODY WEIGHT, KIDNEY DYSFUNCTION ETC. SO PHYTOCHEMICALS ARE EMERGING AS ALTERNATIVES AND MANY OF THEM HAVE ALREADY BEEN USED TO TREAT NEPHROPATHY. BUT STILL, THERE IS RIGOROUS NEED TO EVALUATE PHYTOCHEMICALS WHICH CAN REGULATE EPIGENETIC EVENTS AND HAVE THE POTENTIAL TO DECELERATE THE FURTHER PROGRESSION OF THESE LIFE-THREATENING DISEASES. IN THIS REVIEW ARTICLE WE DISCUSS THE POTENTIAL EPIGENETIC MODIFIERS FROM PLANTS THAT CAN ERASE METABOLIC MEMORY AND CAN THUS BE PROTECTIVE AGAINST DIABETIC NEPHROPATHY. 2020 13 4192 39 METABOLIC MEMORY AND CHRONIC DIABETES COMPLICATIONS: POTENTIAL ROLE FOR EPIGENETIC MECHANISMS. RECENT ESTIMATES INDICATE THAT DIABETES MELLITUS CURRENTLY AFFECTS MORE THAN 10 % OF THE WORLD'S POPULATION. EVIDENCE FROM BOTH THE LABORATORY AND LARGE SCALE CLINICAL TRIALS HAS REVEALED THAT PROLONGED HYPERGLYCEMIA INDUCES CHRONIC COMPLICATIONS WHICH PERSIST AND PROGRESS UNIMPEDED EVEN WHEN GLYCEMIC CONTROL IS PHARMACEUTICALLY ACHIEVED VIA THE PHENOMENON OF METABOLIC MEMORY. THE EPIGENOME IS COMPRISED OF ALL CHROMATIN MODIFICATIONS INCLUDING POST TRANSLATIONAL HISTONE MODIFICATION, EXPRESSION CONTROL VIA MIRNAS AND THE METHYLATION OF CYTOSINE WITHIN DNA. MODIFICATIONS OF THESE EPIGENETIC MARKS NOT ONLY ALLOW CELLS AND ORGANISMS TO QUICKLY RESPOND TO CHANGING ENVIRONMENTAL STIMULI BUT ALSO CONFER THE ABILITY OF THE CELL TO "MEMORIZE" THESE ENCOUNTERS. AS SUCH, THESE PROCESSES HAVE GAINED MUCH ATTENTION AS POTENTIAL MOLECULAR MECHANISMS UNDERLYING METABOLIC MEMORY AND CHRONIC DIABETIC COMPLICATIONS. HERE WE PRESENT A REVIEW OF THE VERY RECENT LITERATURE PUBLISHED PERTAINING TO THIS SUBJECT. 2012 14 3156 50 GLYCEMIC MEMORIES AND THE EPIGENETIC COMPONENT OF DIABETIC NEPHROPATHY. A STRONG CASE FOR THE DEREGULATION OF EPIGENETIC CHROMATIN MODIFICATIONS IN THE DEVELOPMENT AND PROGRESSION OF VARIOUS CHRONIC COMPLICATIONS OF DIABETES HAS EMERGED FROM RECENT EXPERIMENTAL OBSERVATIONS. CLINICAL TRIALS OF TYPE 1 AND TYPE 2 DIABETES PATIENTS HIGHLIGHT THE IMPORTANCE OF EARLY AND INTENSIVE TREATMENT AND THE PROLONGED DAMAGE OF HYPERGLYCEMIA ON ORGANS SUCH AS THE KIDNEY. THE FUNCTIONAL RELATIONSHIP BETWEEN THE REGULATION OF CHROMATIN ARCHITECTURE AND PERSISTENT GENE EXPRESSION CHANGES CONFERRED BY PRIOR HYPERGLYCEMIA REPRESENTS AN IMPORTANT AVENUE OF INVESTIGATION FOR EXPLAINING DIABETIC NEPHROPATHY. WHILE SEVERAL STUDIES IMPLICATE EPIGENETIC CHANGES AT THE CHROMATIN TEMPLATE IN THE DEREGULATED GENE EXPRESSION ASSOCIATED WITH DIABETIC NEPHROPATHY, THE MOLECULAR DETERMINANTS OF METABOLIC MEMORY IN RENAL CELLS REMAIN POORLY UNDERSTOOD. THERE IS NOW STRONG EVIDENCE FROM EXPERIMENTAL ANIMALS AND CELL CULTURE OF PERSISTENT GLUCOSE-DRIVEN CHANGES IN VASCULAR ENDOTHELIAL GENE EXPRESSION THAT MAY ALSO HAVE RELEVANCE FOR THE MICROVASCULATURE OF THE KIDNEY. EXPLORATION OF EPIGENETIC MECHANISMS UNDERLYING THE HYPERGLYCEMIC CUE MEDIATING PERSISTENT TRANSCRIPTIONAL CHANGES IN RENAL CELLS HOLDS NOVEL THERAPEUTIC POTENTIAL FOR DIABETIC NEPHROPATHY. 2013 15 3435 52 HYPERGLYCEMIA AND VASCULAR METABOLIC MEMORY: TRUTH OR FICTION? PREVENTION OF LONG-TERM COMPLICATIONS REMAINS THE MAIN CHALLENGE IN THE TREATMENT OF DIABETES. A STRONG RELATIONSHIP BETWEEN GLUCOSE CONTROL AND DEVELOPMENT OF COMPLICATIONS IS APPARENT IN ALL EPIDEMIOLOGIC STUDIES. YET, INTERVENTION TRIALS HAVE YIELDED QUESTIONABLE RESULTS, PARTICULARLY WHEN INTENSIVE TREATMENT WAS INTRODUCED IN PATIENTS WITH LONG-STANDING DIABETES. IT HAS BEEN POSTULATED THAT IN THESE SUBJECTS, PRIOR EXPOSURE TO CHRONIC HYPERGLYCEMIA MAY HAVE GENERATED A NEGATIVE "METABOLIC MEMORY," PREVENTING FULL EXERTION OF THE BENEFICIAL EFFECTS OF ANY SUBSEQUENT IMPROVEMENT OF GLUCOSE CONTROL. THIS PHENOMENON HAS BEEN REPLICATED IN ANIMAL MODELS AND IT RECOGNIZES A MOLECULAR BASIS IN THE ROLE OF OXIDATIVE STRESS, ADVANCED GLYCATION PROCESSES, AND EPIGENETIC MECHANISMS ACCOUNTING FOR SELF-PERPETUATING MODIFICATIONS OF GENE EXPRESSION. CONVERSELY, EARLY INTERVENTION IN BOTH TYPE 1 AND TYPE 2 DIABETES HAS PROVEN THAT GOOD GLYCEMIC CONTROL REDUCES THE RISK OF DEVELOPMENT AND PROGRESSION OF COMPLICATIONS WITH A BENEFICIAL EFFECT THAT EXTENDS WELL BEYOND THE DURATION OF NEAR-NORMOGLYCEMIA. THIS HAS BROUGHT UP THE CONCEPT OF "METABOLIC LEGACY," AN ADVANTAGE HANDED DOWN BY EARLY AND EFFECTIVE IMPLEMENTATION OF TREATMENTS DESIGNED TO REDUCE BLOOD GLUCOSE LEVELS AS SAFELY AS POSSIBLE ALONG WITH MULTIFACTORIAL INTERVENTION OF ALL CARDIOVASCULAR RISK FACTORS. THE EVIDENCE, NATURE, AND CLINICAL IMPLICATION OF THESE CONCEPTS ARE REVIEWED. 2013 16 2491 37 EPIGENETICS AND CARDIOVASCULAR DISEASE IN DIABETES. TYPE 2 DIABETES HAS BECOME A MAJOR HEALTH ISSUE WORLDWIDE. CHRONIC HYPERGLYCEMIA INDUCES A LOW-GRADE INFLAMMATION THAT, ON TOP OF OTHER MECHANISMS, LEADS TO ENDOTHELIAL DYSFUNCTION. MOUNTING EVIDENCE SUGGESTS THAT DNA METHYLATION, POST-TRANSLATIONAL MODIFICATIONS OF HISTONES, AND LONG NON-CODING RNAS PLAY AN IMPORTANT ROLE IN THE INITIATION, MAINTENANCE, AND PROGRESSION OF BOTH MACRO- AND MICRO-VASCULAR COMPLICATIONS OF DIABETES. LONG-TERM EXPOSURE TO HYPERGLYCEMIA INDUCES EPIGENETIC CHANGES THAT COULD BECOME IRREVERSIBLE, A PHENOMENON KNOWN AS THE 'METABOLIC MEMORY.' WHETHER EPIGENETIC-BASED THERAPIES COULD BE USED TO SLOW OR LIMIT THE PROGRESSION OF CARDIOVASCULAR DISEASE REMAINS UNCLEAR. WHILE NON-CODING RNAS ARE CURRENTLY INVESTIGATED AS POTENTIAL BIOMARKERS THAT PREDICT DIABETIC CARDIOVASCULAR DISEASE INCIDENCE AND PROGRESSION, THEIR THERAPEUTIC ROLE IS ONLY HYPOTHETICAL. IN THIS REVIEW, WE HIGHLIGHT THE LATEST FINDINGS IN EXPERIMENTAL AND CLINICAL STUDIES RELEVANT TO EPIGENETICS AND CARDIOVASCULAR DISEASE IN DIABETES. 2015 17 3909 37 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 18 2009 30 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 19 3748 43 INSIGHTS INTO THE ROLE OF DNA METHYLATION AND PROTEIN MISFOLDING IN DIABETES MELLITUS. BACKGROUND: DIABETES MELLITUS IS A METABOLIC DISORDER THAT IS CHARACTERIZED BY IMPAIRED GLUCOSE TOLERANCE RESULTING FROM DEFECTS IN INSULIN SECRETION, INSULIN ACTION, OR BOTH. EPIGENETIC MODIFICATIONS, WHICH ARE DEFINED AS INHERITED CHANGES IN GENE EXPRESSION THAT OCCUR WITHOUT CHANGES IN GENE SEQUENCE, ARE INVOLVED IN THE ETIOLOGY OF DIABETES. METHODS: IN THIS REVIEW, WE FOCUSED ON THE ROLE OF DNA METHYLATION AND PROTEIN MISFOLDING AND THEIR CONTRIBUTION TO THE DEVELOPMENT OF BOTH TYPE 1 AND TYPE 2 DIABETES MELLITUS. RESULTS: CHANGES IN DNA METHYLATION IN PARTICULAR ARE HIGHLY ASSOCIATED WITH THE DEVELOPMENT OF DIABETES. PROTEIN FUNCTION IS DEPENDENT ON THEIR PROPER FOLDING IN THE ENDOPLASMIC RETICULUM. DEFECTIVE PROTEIN FOLDING AND CONSEQUENTLY THEIR FUNCTIONS HAVE ALSO BEEN REPORTED TO PLAY A ROLE. EARLY TREATMENT OF DIABETES HAS PROVEN TO BE OF GREAT BENEFIT, AS EVEN TRANSIENT HYPERGLYCEMIA MAY LEAD TO PATHOLOGICAL EFFECTS AND COMPLICATIONS LATER ON. THIS HAS BEEN EXPLAINED BY THE THEORY OF THE DEVELOPMENT OF A METABOLIC MEMORY IN DIABETES. THE BASIS FOR THIS METABOLIC MEMORY WAS ATTRIBUTED TO OXIDATIVE STRESS, CHRONIC INFLAMMATION, NON-ENZYMATIC GLYCATION OF PROTEINS AND IMPORTANTLY, EPIGENETIC CHANGES. THIS HIGHLIGHTS THE IMPORTANCE OF LINKING NEW THERAPEUTICS TARGETING EPIGENETIC MECHANISMS WITH TRADITIONAL ANTIDIABETIC DRUGS. CONCLUSION: ALTHOUGH NEW DATA IS EVOLVING ON THE RELATION BETWEEN DNA METHYLATION, PROTEIN MISFOLDING, AND THE ETIOLOGY OF DIABETES, MORE STUDIES ARE REQUIRED FOR DEVELOPING NEW RELEVANT DIAGNOSTICS AND THERAPEUTICS. 2019 20 125 35 A SYSTEMS BIOLOGY OVERVIEW ON HUMAN DIABETIC NEPHROPATHY: FROM GENETIC SUSCEPTIBILITY TO POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL MODIFICATIONS. DIABETIC NEPHROPATHY (DN), A MICROVASCULAR COMPLICATION OCCURRING IN APPROXIMATELY 20-40% OF PATIENTS WITH TYPE 2 DIABETES MELLITUS (T2DM), IS CHARACTERIZED BY THE PROGRESSIVE IMPAIRMENT OF GLOMERULAR FILTRATION AND THE DEVELOPMENT OF KIMMELSTIEL-WILSON LESIONS LEADING TO END-STAGE RENAL FAILURE (ESRD). THE CAUSES AND MOLECULAR MECHANISMS MEDIATING THE ONSET OF T2DM CHRONIC COMPLICATIONS ARE YET SKETCHY AND IT IS NOT CLEAR WHY DISEASE PROGRESSION OCCURS ONLY IN SOME PATIENTS. WE PERFORMED A SYSTEMATIC ANALYSIS OF THE MOST RELEVANT STUDIES INVESTIGATING GENETIC SUSCEPTIBILITY AND SPECIFIC TRANSCRIPTOMIC, EPIGENETIC, PROTEOMIC, AND METABOLOMIC PATTERNS IN ORDER TO SUMMARIZE THE MOST SIGNIFICANT TRAITS ASSOCIATED WITH THE DISEASE ONSET AND PROGRESSION. THE PICTURE THAT EMERGES IS COMPLEX AND FASCINATING AS IT INCLUDES THE REGULATION/DYSREGULATION OF NUMEROUS BIOLOGICAL PROCESSES, CONVERGING TOWARD THE ACTIVATION OF INFLAMMATORY PROCESSES, OXIDATIVE STRESS, REMODELING OF CELLULAR FUNCTION AND MORPHOLOGY, AND DISTURBANCE OF METABOLIC PATHWAYS. THE GROWING INTEREST IN THE CHARACTERIZATION OF PROTEIN POST-TRANSLATIONAL MODIFICATIONS AND THE IMPORTANCE OF HANDLING LARGE DATASETS USING A SYSTEMS BIOLOGY APPROACH ARE ALSO DISCUSSED. 2016