1 6335 98 THE ROLE OF DNA METHYLATION IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS. DIABETES MELLITUS (DM) IS A CHRONIC CONDITION CHARACTERISED BY BETA CELL DYSFUNCTION AND PERSISTENT HYPERGLYCAEMIA. THE DISORDER CAN BE DUE TO THE ABSENCE OF ADEQUATE PANCREATIC INSULIN PRODUCTION OR A WEAK CELLULAR RESPONSE TO INSULIN SIGNALLING. AMONG THE THREE TYPES OF DM, NAMELY, TYPE 1 DM (T1DM), TYPE 2 DM (T2DM), AND GESTATIONAL DM (GDM); T2DM ACCOUNTS FOR ALMOST 90% OF DIABETES CASES WORLDWIDE.EPIGENETIC TRAITS ARE STABLY HERITABLE PHENOTYPES THAT RESULT FROM CERTAIN CHANGES THAT AFFECT GENE FUNCTION WITHOUT ALTERING THE GENE SEQUENCE. WHILE EPIGENETIC TRAITS ARE CONSIDERED REVERSIBLE MODIFICATIONS, THEY CAN BE INHERITED MITOTICALLY AND MEIOTICALLY. IN ADDITION, EPIGENETIC TRAITS CAN RANDOMLY ARISE IN RESPONSE TO ENVIRONMENTAL FACTORS OR CERTAIN GENETIC MUTATIONS OR LESIONS, SUCH AS THOSE AFFECTING THE ENZYMES THAT CATALYSE THE EPIGENETIC MODIFICATION. IN THIS REVIEW, WE FOCUS ON THE ROLE OF DNA METHYLATION, A TYPE OF EPIGENETIC MODIFICATION, IN THE PATHOGENESIS OF T2DM. 2020 2 776 40 CELL- AND TISSUE-SPECIFIC EPIGENETIC CHANGES ASSOCIATED WITH CHRONIC INFLAMMATION IN INSULIN RESISTANCE AND TYPE 2 DIABETES MELLITUS. TYPE 2 DIABETES MELLITUS (T2DM) IS A CHRONIC METABOLIC DISORDER CHARACTERIZED BY HYPERGLYCAEMIA, WHICH CAN CAUSE MICRO- AND MACROVASCULAR COMPLICATIONS. CHRONIC INFLAMMATION MAY BE THE CAUSE AND RESULT OF T2DM, AND ITS RELATED COMPLICATIONS AS AN IMBALANCE BETWEEN PRO- AND ANTI-INFLAMMATORY CYTOKINES CAN AFFECT IMMUNE FUNCTIONS. APART FROM GENETIC CHANGES OCCURRING WITHIN THE BODY RESULTING IN INFLAMMATION IN T2DM, EPIGENETIC MODIFICATIONS CAN MODIFY GENE EXPRESSION IN RESPONSE TO ENVIRONMENTAL CUES SUCH AS AN UNHEALTHY DIET, LACK OF EXERCISE AND OBESITY. THE MOST WIDELY STUDIED EPIGENETIC MODIFICATION, DNA METHYLATION (DNAM), REGULATES GENE EXPRESSION AND MAY MANIPULATE INFLAMMATORY GENES TO INCREASE OR DECREASE INFLAMMATION ASSOCIATED WITH T2DM. THIS REVIEW EXPLORES THE STUDIES RELATED TO EPIGENETIC CHANGES, MORE SPECIFICALLY DNAM, ASSOCIATED WITH CHRONIC INFLAMMATION IN T2DM, AT BOTH THE CELL AND TISSUE LEVELS. STUDYING EPIGENETIC ALTERATIONS DURING INFLAMMATORY RESPONSE, AS A RESULT OF GENETIC AND ENVIRONMENTAL SIGNALS, CREATES OPPORTUNITIES FOR THE DEVELOPMENT OF "EARLY DETECTION/RELATIVE RISK" TESTS TO AID IN PREVENTION OF T2DM. UNDERSTANDING INFLAMMATION IN T2DM AT THE GENE LEVEL IN INFLAMMATION-ASSOCIATED CELLS AND TISSUES MAY PROVIDE FURTHER INSIGHT FOR THE DEVELOPMENT OF SPECIFIC THERAPEUTIC TARGETS FOR THE DISORDER. 2018 3 3748 40 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 4 6341 26 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 2964 29 GENETIC AND EPIGENETIC MECHANISMS UNDERLYING ARSENIC-ASSOCIATED DIABETES MELLITUS: A PERSPECTIVE OF THE CURRENT EVIDENCE. CHRONIC EXPOSURE TO ARSENIC HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF DIABETES MELLITUS (DM), A DISEASE CHARACTERIZED BY HYPERGLYCEMIA RESULTING FROM DYSREGULATION OF GLUCOSE HOMEOSTASIS. THIS REVIEW SUMMARIZES FOUR MAJOR MECHANISMS BY WHICH ARSENIC INDUCES DIABETES, NAMELY INHIBITION OF INSULIN-DEPENDENT GLUCOSE UPTAKE, PANCREATIC BETA-CELL DAMAGE, PANCREATIC BETA-CELL DYSFUNCTION AND STIMULATION OF LIVER GLUCONEOGENESIS THAT ARE SUPPORTED BY BOTH IN VIVO AND IN VITRO STUDIES. ADDITIONALLY, THE ROLE OF POLYMORPHIC VARIANTS ASSOCIATED WITH ARSENIC TOXICITY AND DISEASE SUSCEPTIBILITY, AS WELL AS EPIGENETIC MODIFICATIONS ASSOCIATED WITH ARSENIC EXPOSURE, ARE CONSIDERED IN THE CONTEXT OF ARSENIC-ASSOCIATED DM. TAKEN TOGETHER, IN VITRO, IN VIVO AND HUMAN GENETIC/EPIGENETIC STUDIES SUPPORT THAT ARSENIC HAS THE POTENTIAL TO INDUCE DM PHENOTYPES AND IMPAIR KEY PATHWAYS INVOLVED IN THE REGULATION OF GLUCOSE HOMEOSTASIS. 2017 6 6607 35 TYPE 2 DIABETES MELLITUS AND CARDIOVASCULAR DISEASE: GENETIC AND EPIGENETIC LINKS. TYPE 2 DIABETES MELLITUS (DM) IS A COMMON METABOLIC DISORDER PREDISPOSING TO DIABETIC CARDIOMYOPATHY AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (CVD), WHICH COULD LEAD TO HEART FAILURE THROUGH A VARIETY OF MECHANISMS, INCLUDING MYOCARDIAL INFARCTION AND CHRONIC PRESSURE OVERLOAD. PATHOGENETIC MECHANISMS, MAINLY LINKED TO HYPERGLYCEMIA AND CHRONIC SUSTAINED HYPERINSULINEMIA, INCLUDE CHANGES IN METABOLIC PROFILES, INTRACELLULAR SIGNALING PATHWAYS, ENERGY PRODUCTION, REDOX STATUS, INCREASED SUSCEPTIBILITY TO ISCHEMIA, AND EXTRACELLULAR MATRIX REMODELING. THE CLOSE RELATIONSHIP BETWEEN TYPE 2 DM AND CVD HAS LED TO THE COMMON SOIL HYPOTHESIS, POSTULATING THAT BOTH CONDITIONS SHARE COMMON GENETIC AND ENVIRONMENTAL FACTORS INFLUENCING THIS ASSOCIATION. HOWEVER, ALTHOUGH THE COMMON RISK FACTORS OF BOTH CVD AND TYPE 2 DM, SUCH AS OBESITY, INSULIN RESISTANCE, DYSLIPIDEMIA, INFLAMMATION, AND THROMBOPHILIA, CAN BE IDENTIFIED IN THE MAJORITY OF AFFECTED PATIENTS, LESS IS KNOWN ABOUT HOW THESE FACTORS INFLUENCE BOTH CONDITIONS, SO THAT EFFORTS ARE STILL NEEDED FOR A MORE COMPREHENSIVE UNDERSTANDING OF THIS RELATIONSHIP. THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL BACKGROUNDS OF BOTH TYPE 2 DM AND CVD HAVE BEEN MORE RECENTLY STUDIED AND UPDATED. HOWEVER, THE UNDERLYING PATHOGENETIC MECHANISMS HAVE SELDOM BEEN INVESTIGATED WITHIN THE BROADER SHARED BACKGROUND, BUT RATHER STUDIED IN THE SPECIFIC CONTEXT OF TYPE 2 DM OR CVD, SEPARATELY. AS THE PRECISE PATHOPHYSIOLOGICAL LINKS BETWEEN TYPE 2 DM AND CVD ARE NOT ENTIRELY UNDERSTOOD AND MANY ASPECTS STILL REQUIRE ELUCIDATION, AN INTEGRATED DESCRIPTION OF THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL INFLUENCES INVOLVED IN THE CONCOMITANT DEVELOPMENT OF BOTH DISEASES IS OF PARAMOUNT IMPORTANCE TO SHED NEW LIGHT ON THE INTERLINKS BETWEEN TYPE 2 DM AND CVD. THIS REVIEW ADDRESSES THE CURRENT KNOWLEDGE OF OVERLAPPING GENETIC AND EPIGENETIC ASPECTS IN TYPE 2 DM AND CVD, INCLUDING MICRORNAS AND LONG NON-CODING RNAS, WHOSE ABNORMAL REGULATION HAS BEEN IMPLICATED IN BOTH DISEASE CONDITIONS, EITHER ETIOLOGICALLY OR AS CAUSE FOR THEIR PROGRESSION. UNDERSTANDING THE LINKS BETWEEN THESE DISORDERS MAY HELP TO DRIVE FUTURE RESEARCH TOWARD AN INTEGRATED PATHOPHYSIOLOGICAL APPROACH AND TO PROVIDE FUTURE DIRECTIONS IN THE FIELD. 2018 7 6067 37 THE DIABETES MELLITUS-ATHEROSCLEROSIS CONNECTION: THE ROLE OF LIPID AND GLUCOSE METABOLISM AND CHRONIC INFLAMMATION. DIABETES MELLITUS COMPRISES A GROUP OF CARBOHYDRATE METABOLISM DISORDERS THAT SHARE A COMMON MAIN FEATURE OF CHRONIC HYPERGLYCEMIA THAT RESULTS FROM DEFECTS OF INSULIN SECRETION, INSULIN ACTION, OR BOTH. INSULIN IS AN IMPORTANT ANABOLIC HORMONE, AND ITS DEFICIENCY LEADS TO VARIOUS METABOLIC ABNORMALITIES IN PROTEINS, LIPIDS, AND CARBOHYDRATES. ATHEROSCLEROSIS DEVELOPS AS A RESULT OF A MULTISTEP PROCESS ULTIMATELY LEADING TO CARDIOVASCULAR DISEASE ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY. ALTERATION OF LIPID METABOLISM IS A RISK FACTOR AND CHARACTERISTIC FEATURE OF ATHEROSCLEROSIS. POSSIBLE LINKS BETWEEN THE TWO CHRONIC DISORDERS DEPENDING ON ALTERED METABOLIC PATHWAYS HAVE BEEN INVESTIGATED IN NUMEROUS STUDIES. IT WAS SHOWN THAT BOTH TYPES OF DIABETES MELLITUS CAN ACTUALLY INDUCE ATHEROSCLEROSIS DEVELOPMENT OR FURTHER ACCELERATE ITS PROGRESSION. ELEVATED GLUCOSE LEVEL, DYSLIPIDEMIA, AND OTHER METABOLIC ALTERATIONS THAT ACCOMPANY THE DISEASE DEVELOPMENT ARE TIGHTLY INVOLVED IN THE PATHOGENESIS OF ATHEROSCLEROSIS AT ALMOST EVERY STEP OF THE ATHEROGENIC PROCESS. CHRONIC INFLAMMATION IS CURRENTLY CONSIDERED AS ONE OF THE KEY FACTORS IN ATHEROSCLEROSIS DEVELOPMENT AND IS PRESENT STARTING FROM THE EARLIEST STAGES OF THE PATHOLOGY INITIATION. IT MAY ALSO BE REGARDED AS ONE OF THE POSSIBLE LINKS BETWEEN ATHEROSCLEROSIS AND DIABETES MELLITUS. HOWEVER, THE DATA AVAILABLE SO FAR DO NOT ALLOW FOR DEVELOPING EFFECTIVE ANTI-INFLAMMATORY THERAPEUTIC STRATEGIES THAT WOULD STOP ATHEROSCLEROTIC LESION PROGRESSION OR INDUCE LESION REDUCTION. IN THIS REVIEW, WE SUMMARIZE THE MAIN ASPECTS OF DIABETES MELLITUS THAT POSSIBLY AFFECT THE ATHEROGENIC PROCESS AND ITS RELATIONSHIP WITH CHRONIC INFLAMMATION. WE ALSO DISCUSS THE ESTABLISHED PATHOPHYSIOLOGICAL FEATURES THAT LINK ATHEROSCLEROSIS AND DIABETES MELLITUS, SUCH AS OXIDATIVE STRESS, ALTERED PROTEIN KINASE SIGNALING, AND THE ROLE OF CERTAIN MIRNA AND EPIGENETIC MODIFICATIONS. 2020 8 4793 32 NUTRITIONAL FACTORS, DNA METHYLATION, AND RISK OF TYPE 2 DIABETES AND OBESITY: PERSPECTIVES AND CHALLENGES. A HEALTHY DIET IMPROVES LIFE EXPECTANCY AND HELPS TO PREVENT COMMON CHRONIC DISEASES SUCH AS TYPE 2 DIABETES (T2D) AND OBESITY. THE MECHANISMS DRIVING THESE EFFECTS ARE NOT FULLY UNDERSTOOD, BUT ARE LIKELY TO INVOLVE EPIGENETICS. EPIGENETIC MECHANISMS CONTROL GENE EXPRESSION, MAINTAINING THE DNA SEQUENCE, AND THEREFORE THE FULL GENOMIC INFORMATION INHERITED FROM OUR PARENTS, UNCHANGED. AN INTERESTING FEATURE OF EPIGENETIC CHANGES LIES IN THEIR DYNAMIC NATURE AND REVERSIBILITY. ACCORDINGLY, THEY ARE SUSCEPTIBLE TO CORRECTION THROUGH TARGETED INTERVENTIONS. HERE WE WILL REVIEW THE EVIDENCE SUPPORTING A ROLE FOR NUTRITIONAL FACTORS IN MEDIATING METABOLIC DISEASE RISK THROUGH DNA METHYLATION CHANGES. SPECIAL EMPHASIS WILL BE PLACED ON THE POTENTIAL OF USING DNA METHYLATION TRAITS AS BIOMARKERS TO PREDICT RISK OF OBESITY AND T2D AS WELL AS ON THEIR RESPONSE TO DIETARY AND PHARMACOLOGICAL (EPI-DRUG) INTERVENTIONS. 2019 9 2613 31 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 10 599 34 BETA-CELL DIFFERENTIATION STATUS IN TYPE 2 DIABETES. TYPE 2 DIABETES (T2D) AFFECTS 415 MILLION PEOPLE WORLDWIDE AND IS CHARACTERIZED BY CHRONIC HYPERGLYCAEMIA AND INSULIN RESISTANCE, PROGRESSING TO INSUFFICIENT INSULIN PRODUCTION, AS A RESULT OF BETA-CELL FAILURE. OVER TIME, CHRONIC HYPERGLYCAEMIA CAN ULTIMATELY LEAD TO LOSS OF BETA-CELL FUNCTION, LEAVING PATIENTS INSULIN-DEPENDENT. UNTIL RECENTLY THE LOSS OF BETA-CELL MASS SEEN IN T2D WAS CONSIDERED TO BE THE RESULT OF INCREASED RATES OF APOPTOSIS; HOWEVER, IT HAS BEEN PROPOSED THAT APOPTOSIS ALONE CANNOT ACCOUNT FOR THE EXTENT OF BETA-CELL MASS LOSS SEEN IN THE DISEASE, AND THAT A LOSS OF FUNCTION MAY ALSO OCCUR AS A RESULT OF CHANGES IN BETA-CELL DIFFERENTIATION STATUS. IN THE PRESENT REVIEW, WE CONSIDER CURRENT KNOWLEDGE OF DETERMINANTS OF BETA-CELL FATE IN THE CONTEXT OF UNDERSTANDING ITS RELEVANCE TO DISEASE PROCESS IN T2D, AND ALSO THE IMPACT OF A DIABETOGENIC ENVIRONMENT (HYPERGLYCAEMIA, HYPOXIA, INFLAMMATION AND DYSLIPIDAEMIA) ON THE EXPRESSION OF GENES INVOLVED IN MAINTENANCE OF BETA-CELL IDENTITY. WE DESCRIBE CURRENT KNOWLEDGE OF THE IMPACT OF THE DIABETIC MICROENVIRONMENT ON GENE REGULATORY PROCESSES SUCH ALTERNATIVE SPLICING, THE EXPRESSION OF DISALLOWED GENES AND EPIGENETIC MODIFICATIONS. ELUCIDATING THE MOLECULAR MECHANISMS THAT UNDERPIN CHANGES TO BETA-CELL DIFFERENTIATION STATUS AND THE CONCOMITANT BETA-CELL FAILURE OFFERS POTENTIAL TREATMENT TARGETS FOR THE FUTURE MANAGEMENT OF PATIENTS WITH T2D. 2016 11 2039 34 EPIGENETIC CHANGES UNDERLIE THE ASSOCIATION BETWEEN DIABETES MELLITUS AND ORAL DISEASES. PATIENTS WITH DIABETES MELLITUS (DM) SUFFER FROM ORAL COMPLICATIONS RELATED TO ORAL INFECTIONS, PERIODONTAL DISEASES, AND ENDODONTIC LESIONS. EMERGING EVIDENCE HAS REVEALED THE CONTRIBUTION OF THE EPIGENETIC PROCESS AS THE UNDERLYING MECHANISM OF DM COMPLICATIONS. DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING RNAS ARE EPIGENETIC REGULATORS THAT DIRECTLY AFFECT GENE EXPRESSION. THE PRESENT REVIEW ELABORATED ON THE ROLE OF EPIGENETIC DYSREGULATION IN THE ETIOLOGY OF DIABETES-RELATED PERIODONTAL AND ENDODONTIC DISEASES. THE NARRATIVE REVIEW STUDY WAS PREPARED USING DATABASES SUCH AS PUBMED, GOOGLE SCHOLAR, SCIENCE DIRECT, AND SCOPUS. THE FORMATION OF GLYCATION PRODUCTS AS A RESULT OF HYPERGLYCEMIC CONDITION INCREASES OXIDATIVE STRESS, AND ELEVATES CHRONIC INFLAMMATORY MEDIATORS THAT COULD IN TURN ADVERSELY CHANGE THE CELLULAR ENVIRONMENT AND ALTER THE EPIGENETIC STATUS. THIS PROCESS CONTRIBUTES TO THE ALTERATION OF REGULATORY GENES EXPRESSION, LEADING TO THE DEVELOPMENT OF DIABETES-INDUCED BONE COMPLICATIONS AND IMPAIRED ODONTOGENIC CAPACITY OF PULP. INDEED, EPIGENETIC MECHANISMS MEDIATE THE INTERACTION BETWEEN GENE EXPRESSION AND DM CELLULAR ENVIRONMENT. FURTHER INVESTIGATIONS ON EPIGENETIC FACTORS INVOLVED IN DM ORAL COMPLICATIONS MAY PROVIDE NOVEL THERAPEUTIC TARGETS. 2023 12 2009 27 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 2163 28 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 14 2549 33 EPIGENETICS IN OBESITY AND DIABETES MELLITUS: NEW INSIGHTS. A LONG-TERM COMPLICATION OF OBESITY IS THE DEVELOPMENT OF TYPE 2 DIABETES (T2D). PATIENTS WITH T2D HAVE BEEN DESCRIBED AS HAVING EPIGENETIC MODIFICATIONS. EPIGENETICS IS THE POST-TRANSCRIPTIONAL MODIFICATION OF DNA OR ASSOCIATED FACTORS CONTAINING GENETIC INFORMATION. THESE ENVIRONMENTALLY-INFLUENCED MODIFICATIONS, MAINTAINED DURING CELL DIVISION, CAUSE STABLE CHANGES IN GENE EXPRESSION. EPIGENETIC MODIFICATIONS OF T2D ARE DNA METHYLATION, ACETYLATION, UBIQUITYLATION, SUMOYLATION, AND PHOSPHORYLATION AT THE LYSINE RESIDUE AT THE AMINO TERMINUS OF HISTONES, AFFECTING DNA, HISTONES, AND NON-CODING RNA. DNA METHYLATION HAS BEEN SHOWN IN PANCREATIC ISLETS, ADIPOSE TISSUE, SKELETAL MUSCLE, AND THE LIVER. FURTHERMORE, EPIGENETIC CHANGES HAVE BEEN OBSERVED IN CHRONIC COMPLICATIONS OF T2D, SUCH AS DIABETIC NEPHROPATHY, DIABETIC RETINOPATHY, AND DIABETIC NEUROPATHY. RECENTLY, A NEW DRUG HAS BEEN DEVELOPED WHICH ACTS ON BROMODOMAINS AND EXTRATERMINAL (BET) DOMAIN PROTEINS, WHICH OPERATE LIKE EPIGENETIC READERS AND COMMUNICATE WITH CHROMATIN TO MAKE DNA ACCESSIBLE FOR TRANSCRIPTION BY INHIBITING THEM. THIS DRUG (APABETALONE) IS BEING STUDIED TO PREVENT MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PEOPLE WITH T2D, LOW HDL CHOLESTEROL, CHRONIC KIDNEY FAILURE, AND RECENT CORONARY EVENTS. THIS REVIEW AIMS TO DESCRIBE THE RELATIONSHIP BETWEEN OBESITY, LONG-TERM COMPLICATIONS SUCH AS T2D, AND EPIGENETIC MODIFICATIONS AND THEIR POSSIBLE TREATMENTS. 2023 15 2491 30 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 16 2190 34 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 17 1974 32 EPIGENETIC ALTERATIONS CAUSED BY NUTRITIONAL STRESS DURING FETAL PROGRAMMING OF THE ENDOCRINE PANCREAS. NUTRITION DURING CRITICAL PERIODS OF DEVELOPMENT IS ONE OF THE PIVOTAL FACTORS IN ESTABLISHING A LIFELONG HEALTHY METABOLISM. DIFFERENT NUTRITIONAL DEFICIENCIES SUCH AS A LOW AVAILABILITY OF PROTEINS IN THE MATERNAL DIET PRODUCE ALTERATIONS IN OFFSPRING THAT INCLUDE CHANGES IN INSULIN AND GLUCOSE METABOLISM, A DECREASE IN THE SIZE AND NUMBER OF CELLS OF PANCREATIC ISLETS OF LANGERHANS, AND PREMATURE AGEING OF THE SECRETORY FUNCTION OF PANCREATIC BETA CELLS. MOREOVER, IT HAS BEEN REPORTED THAT CHRONIC NUTRITIONAL STRESS IS ASSOCIATED WITH EPIGENETIC ALTERATIONS IN MECHANISMS OF GENE REGULATION DURING PANCREATIC DEVELOPMENT AND FUNCTION. THESE ALTERATIONS CAN LEAD TO DYSFUNCTIONAL STATES IN PANCREATIC BETA CELLS, WHICH IN THE LONG RUN ARE RESPONSIBLE FOR THE ONSET OF METABOLIC DISEASES LIKE TYPE 2 DIABETES. THE PRESENT REVIEW SUMMARIZES THE MOST IMPORTANT EVIDENCE IN RELATION TO THE PARTICIPATION OF EPIGENETIC MECHANISMS IN THE REGULATION OF GENE EXPRESSION DURING THE INTRAUTERINE PROGRAMMING OF THE ENDOCRINE PANCREAS IN ANIMAL MODELS. SUCH MECHANISMS INCLUDE DNA METHYLATION AS WELL AS MODIFICATIONS OF HISTONES AND MICRORNAS (MIRNAS). 2015 18 6812 33 [EPIGENETICS, INTERFACE BETWEEN ENVIRONMENT AND GENES: ROLE IN COMPLEX DISEASES]. EPIGENETICS IS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION OR CELLULAR PHENOTYPE CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE. EPIGENETICS IS ONE OF THE MAJOR MECHANISMS EXPLAINING THE "DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASES" (DOHAD). BESIDES GENETIC BACKGROUND INHERITED FROM PARENTS, WHICH CONFERS SUSCEPTIBILITY TO CERTAIN PATHOLOGIES, EPIGENETIC CHANGES CONSTITUTE THE MEMORY OF PREVIOUS EVENTS, EITHER POSITIVE OR NEGATIVE, ALONG THE LIFE CYCLE, INCLUDING AT THE IN UTERO STAGE. THE LATER EXPOSITION TO HOSTILE ENVIRONMENT MAY REVEAL SUCH SUSCEPTIBILITY, WITH THE DEVELOPMENT OF VARIOUS PATHOLOGIES, AMONG THEM NUMEROUS CHRONIC COMPLEX DISEASES. THE DEMONSTRATION OF SUCH A SEQUENCE OF EVENTS HAS BEEN SHOWN FOR METABOLIC DISEASES AS OBESITY, METABOLIC SYNDROME AND TYPE 2 DIABETES, CARDIOVASCULAR DISEASE AND CANCER. IN CONTRAST TO GENETIC PREDISPOSITION, WHICH IS IRREVERSIBLE, EPIGENETIC CHANGES ARE POTENTIALLY REVERSIBLE, THUS GIVING TARGETS NOT ONLY FOR PREVENTION, BUT POSSIBLY ALSO FOR THE TREATMENT OF CERTAIN COMPLEX DISEASES. 2012 19 2208 37 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 20 44 37 A COMPREHENSIVE REVIEW ON HIGH -FAT DIET-INDUCED DIABETES MELLITUS: AN EPIGENETIC VIEW. MODERN LIFESTYLE, GENETICS, NUTRITIONAL OVERLOAD THROUGH HIGH-FAT DIET ATTRIBUTED PREVALENCE AND DIABETES OUTCOMES WITH VARIOUS COMPLICATIONS PRIMARILY DUE TO OBESITY IN WHICH ENERGY-DENSE DIETS FREQUENTLY AFFECT METABOLIC HEALTH. ONE POSSIBLE ISSUE USUALLY ASSOCIATED WITH ELEVATED CHRONIC FAT INTAKE IS INSULIN RESISTANCE, AND HYPERGLYCEMIA CONSTITUTES AN IMPORTANT FUNCTION IN ALTERING THE CARBOHYDRATES AND LIPIDS METABOLISM. SIMILARLY, IN ASSESSING HUMAN SUSCEPTIBILITY TO WEIGHT GAIN AND OBESITY, GENETIC VARIATIONS PLAY A CENTRAL ROLE, CONTRIBUTING TO KEEN INTEREST IN IDENTIFYING THE POSSIBLE ROLE OF EPIGENETICS AS A MEDIATOR OF GENE-ENVIRONMENTAL INTERACTIONS INFLUENCING THE PRODUCTION OF TYPE 2 DIABETES MELLITUS AND ITS RELATED CONCERNS. EPIGENETIC MODIFICATIONS ASSOCIATED WITH THE ACCEPTANCE OF A SEDENTARY LIFESTYLE AND ENVIRONMENTAL STRESS FACTORS IN RESPONSE TO ENERGY INTAKE AND EXPENDITURE IMBALANCES COMPLEMENT GENETIC ALTERATIONS AND LEAD TO THE PRODUCTION AND ADVANCEMENT OF METABOLIC DISORDERS SUCH AS DIABETES AND OBESITY. METHYLATION OF DNA, HISTONE MODIFICATIONS, AND INCREASES IN THE EXPRESSION OF NON-CODING RNAS CAN RESULT IN REDUCED TRANSCRIPTIONAL ACTIVITY OF KEY BETA-CELL GENES THUS CREATING INSULIN RESISTANCE. EPIGENETICS CONTRIBUTE TO CHANGES IN THE EXPRESSION OF THE UNDERLYING INSULIN RESISTANCE AND INSUFFICIENCY GENE NETWORKS, ALONG WITH LOW-GRADE OBESITY-RELATED INFLAMMATION, INCREASED ROS GENERATION, AND DNA DAMAGE IN MULTIORGANS. THIS REVIEW FOCUSED ON EPIGENETIC MECHANISMS AND METABOLIC REGULATIONS ASSOCIATED WITH HIGH-FAT DIET (HFD)-INDUCED DIABETES MELLITUS. 2022