1 3859 138 ISLET STRUCTURE AND FUNCTION IN THE GK RAT. TYPE 2 DIABETES MELLITUS (T2D) ARISES WHEN THE ENDOCRINE PANCREAS FAILS TO SECRETE SUFFICIENT INSULIN TO COPE WITH THE METABOLIC DEMAND BECAUSE OF BETA-CELL SECRETORY DYSFUNCTION AND/OR DECREASED BETA-CELL MASS. DEFINING THE NATURE OF THE PANCREATIC ISLET DEFECTS PRESENT IN T2D HAS BEEN DIFFICULT, IN PART BECAUSE HUMAN ISLETS ARE INACCESSIBLE FOR DIRECT STUDY. THIS REVIEW IS AIMED TO ILLUSTRATE TO WHAT EXTENT THE GOTO-KAKIZAKI RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2D, HAS PROVED TO BE A VALUABLE TOOL OFFERING SUFFICIENT COMMONALITIES TO STUDY THIS ASPECT. A COMPREHENSIVE COMPENDIUM OF THE MULTIPLE FUNCTIONAL GK ISLET ABNORMALITIES SO FAR IDENTIFIED IS PROPOSED IN THIS PERSPECTIVE. THE PATHOGENESIS OF DEFECTIVE BETA-CELL NUMBER AND FUNCTION IN THE GK MODEL IS ALSO DISCUSSED. IT IS PROPOSED THAT THE DEVELOPMENT OF T2D IN THE GK MODEL RESULTS FROM THE COMPLEX INTERACTION OF MULTIPLE EVENTS: (I) SEVERAL SUSCEPTIBILITY LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS (DISTINCT LOCI ENCODING IMPAIRMENT OF BETA-CELL METABOLISM AND INSULIN EXOCYTOSIS, BUT NO QUANTITATIVE TRAIT LOCUS FOR DECREASED BETA-CELL MASS); (II) GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE OFFSPRING PANCREAS (DECREASED BETA-CELL NEOGENESIS AND PROLIFERATION) TRANSMITTED OVER GENERATIONS; AND (III) LOSS OF BETA-CELL DIFFERENTIATION RELATED TO CHRONIC EXPOSURE TO HYPERGLYCAEMIA/HYPERLIPIDAEMIA, ISLET INFLAMMATION, ISLET OXIDATIVE STRESS, ISLET FIBROSIS AND PERTURBED ISLET VASCULATURE. 2010 2 1302 65 DEFECTIVE FUNCTIONAL BETA-CELL MASS AND TYPE 2 DIABETES IN THE GOTO-KAKIZAKI RAT MODEL. INCREASING EVIDENCE INDICATES THAT DECREASED FUNCTIONAL BETA-CELL MASS IS THE HALLMARK OF TYPE 2 DIABETES MELLITUS. THEREFORE, THE DEBATE FOCUSES ON THE POSSIBLE MECHANISMS RESPONSIBLE FOR ABNORMAL ISLET MICROENVIRONMENT, DECREASED BETA-CELL NUMBER, IMPAIRED BETA-CELL FUNCTION AND THEIR MULTIFACTORIAL ETIOLOGIES. THE INFORMATION AVAILABLE ON THE GOTO-KAKIZAKI/PAR RAT LINE, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS TYPE 2 DIABETES MELLITUS, ARE REVIEWED IN SUCH A PERSPECTIVE. WE PROPOSE THAT THE DEFECTIVE BETA-CELL MASS AND FUNCTION IN THE GOTO-KAKIZAKI/PAR MODEL REFLECT THE COMPLEX INTERACTIONS OF MULTIPLE PATHOGENIC PLAYERS, INCLUDING SEVERAL INDEPENDENT LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS (BUT NOT DECREASED BETA-CELL MASS), GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE PANCREAS (DECREASED BETA-CELL NEOGENESIS), WHICH IS TRANSMITTED TO THE NEXT GENERATION, AND LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA, INFLAMMATORY MEDIATORS, OXIDATIVE STRESS AND PERTURBED ISLET MICROARCHITECTURE. 2007 3 6163 84 THE GK RAT BETA-CELL: A PROTOTYPE FOR THE DISEASED HUMAN BETA-CELL IN TYPE 2 DIABETES? INCREASING EVIDENCE INDICATES THAT DECREASED FUNCTIONAL BETA-CELL MASS IS THE HALLMARK OF TYPE 2 DIABETES (T2D) MELLITUS. NOWADAYS, THE DEBATE FOCUSES ON THE POSSIBLE MECHANISMS RESPONSIBLE FOR ABNORMAL ISLET MICROENVIRONMENT, DECREASED BETA-CELL NUMBER, IMPAIRED BETA-CELL FUNCTION, AND THEIR MULTIFACTORIAL AETIOLOGIES. THIS REVIEW IS AIMED TO ILLUSTRATE TO WHAT EXTEND THE GOTO-KAKIZAKI RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2D, HAS PROVED BE A VALUABLE TOOL OFFERING SUFFICIENT COMMONALITIES TO STUDY THESE ASPECTS. WE PROPOSE THAT THE DEFECTIVE BETA-CELL MASS AND FUNCTION IN THE GK MODEL REFLECT THE COMPLEX INTERACTIONS OF MULTIPLE PATHOGENIC PLAYERS: (I) SEVERAL INDEPENDENT LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS (BUT NOT DECREASED BETA-CELL MASS); (II) GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE PANCREAS (DECREASED BETA-CELL NEOGENESIS AND/OR PROLIFERATION) WHICH IS TRANSMITTED TO THE NEXT GENERATION; AND (III) LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA/HYPERLIPIDEMIA, INFLAMMATORY MEDIATORS, OXIDATIVE STRESS AND TO PERTURBED ISLET MICROARCHITECTURE. 2009 4 6164 115 THE GK RAT: A PROTOTYPE FOR THE STUDY OF NON-OVERWEIGHT TYPE 2 DIABETES. TYPE 2 DIABETES MELLITUS (T2D) ARISES WHEN THE ENDOCRINE PANCREAS FAILS TO SECRETE SUFFICIENT INSULIN TO COPE WITH THE METABOLIC DEMAND BECAUSE OF BETA-CELL SECRETORY DYSFUNCTION AND/OR DECREASED BETA-CELL MASS. DEFINING THE NATURE OF THE PANCREATIC ISLET DEFECTS PRESENT IN T2D HAS BEEN DIFFICULT, IN PART BECAUSE HUMAN ISLETS ARE INACCESSIBLE FOR DIRECT STUDY. THIS REVIEW IS AIMED TO ILLUSTRATE TO WHAT EXTENT THE GOTO KAKIZAKI RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2D, HAS PROVED TO BE A VALUABLE TOOL OFFERING SUFFICIENT COMMONALITIES TO STUDY THIS ASPECT. A COMPREHENSIVE COMPENDIUM OF THE MULTIPLE FUNCTIONAL GK ABNORMALITIES SO FAR IDENTIFIED IS PROPOSED IN THIS PERSPECTIVE, TOGETHER WITH THEIR TIME-COURSE AND INTERACTIONS. A SPECIAL FOCUS IS GIVEN TOWARD THE PATHOGENESIS OF DEFECTIVE BETA-CELL NUMBER AND FUNCTION IN THE GK MODEL. IT IS PROPOSED THAT THE DEVELOPMENT OF T2D IN THE GK MODEL RESULTS FROM THE COMPLEX INTERACTION OF MULTIPLE EVENTS: (1) SEVERAL SUSCEPTIBILITY LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS; (2) GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE OFFSPRING PANCREAS AND THE MAJOR INSULIN TARGET TISSUES; AND (3) ENVIRONMENTALLY INDUCED LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA/HYPERLIPIDEMIA, INFLAMMATION, AND OXIDATIVE STRESS. 2012 5 5250 64 PROGRAMMED DISORDERS OF BETA-CELL DEVELOPMENT AND FUNCTION AS ONE CAUSE FOR TYPE 2 DIABETES? THE GK RAT PARADIGM. NOW THAT THE REDUCTION IN BETA-MASS HAS BEEN CLEARLY ESTABLISHED IN HUMANS WITH TYPE 2 DIABETES MELLITUS (T2DM) 1-4, THE DEBATE FOCUSES ON THE POSSIBLE MECHANISMS RESPONSIBLE FOR DECREASED BETA-CELL NUMBER AND IMPAIRED BETA-CELL FUNCTION AND THEIR MULTIFACTORIAL ETIOLOGY. APPROPRIATE INBRED RODENT MODELS ARE ESSENTIAL TOOLS FOR IDENTIFICATION OF GENES AND ENVIRONMENTAL FACTORS THAT INCREASE THE RISK OF ABNORMAL BETA-CELL FUNCTION AND OF T2DM. THE INFORMATION AVAILABLE IN THE GOTO-KAKIZAKI (GK) RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2DM, ARE REVIEWED IN SUCH A PERSPECTIVE. WE PROPOSE THAT THE DEFECTIVE BETA-CELL MASS AND FUNCTION IN THE GK MODEL REFLECT THE COMPLEX INTERACTIONS OF THREE PATHOGENIC PLAYERS: (1) SEVERAL INDEPENDENT LOCI CONTAINING GENES CAUSING IMPAIRED INSULIN SECRETION; (2) GESTATIONAL METABOLIC IMPAIRMENT INDUCING A PROGRAMMING OF ENDOCRINE PANCREAS (DECREASED BETA-CELL NEOGENESIS) WHICH IS TRANSMITTED TO THE NEXT GENERATION; AND (3) SECONDARY (ACQUIRED) LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA (GLUCOTOXICITY). AN IMPORTANT MESSAGE IS THAT THE 'HERITABLE' DETERMINANTS OF T2DM ARE NOT SIMPLY DEPENDANT ON GENETIC FACTORS, BUT PROBABLY INVOLVE TRANSGENERATIONAL EPIGENETIC RESPONSES. 2005 6 599 37 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 7 3863 32 IT'S WHAT AND WHEN YOU EAT: AN OVERVIEW OF TRANSCRIPTIONAL AND EPIGENETIC RESPONSES TO DIETARY PERTURBATIONS IN PANCREATIC ISLETS. OUR EVER-CHANGING MODERN ENVIRONMENT IS A SIGNIFICANT CONTRIBUTOR TO THE INCREASED PREVALENCE OF MANY CHRONIC DISEASES, AND PARTICULARLY, TYPE 2 DIABETES MELLITUS (T2DM). ALTHOUGH THE MODERN ERA HAS USHERED IN NUMEROUS CHANGES TO OUR DAILY LIVING CONDITIONS, CHANGES IN "WHAT" AND "WHEN" WE EAT APPEAR TO DISPROPORTIONATELY FUEL THE RISE OF T2DM. THE PANCREATIC ISLET IS A KEY BIOLOGICAL CONTROLLER OF AN ORGANISM'S GLUCOSE HOMEOSTASIS AND THUS PLAYS AN OUTSIZED ROLE TO COORDINATE THE RESPONSE TO ENVIRONMENTAL FACTORS TO PRESERVE EUGLYCEMIA THROUGH A DELICATE BALANCE OF ENDOCRINE OUTPUTS. BOTH SUCCESSFUL AND FAILED ADAPTATION TO DYNAMIC ENVIRONMENTAL STIMULI HAS BEEN POSTULATED TO OCCUR DUE TO CHANGES IN THE TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF PATHWAYS ASSOCIATED WITH ISLET SECRETORY FUNCTION AND SURVIVAL. THEREFORE, IN THIS REVIEW WE EXAMINED AND EVALUATED THE CURRENT EVIDENCE ELUCIDATING THE KEY EPIGENETIC MECHANISMS AND TRANSCRIPTIONAL PROGRAMS UNDERLYING THE ISLET'S COORDINATED RESPONSE TO THE INTERACTION BETWEEN THE TIMING AND THE COMPOSITION OF DIETARY NUTRIENTS COMMON TO MODERN LIFESTYLES. WITH THE EXPLOSION OF NEXT GENERATION SEQUENCING, ALONG WITH THE DEVELOPMENT OF NOVEL INFORMATIC AND -OMIC APPROACHES, FUTURE WORK WILL CONTINUE TO UNRAVEL THE ENVIRONMENTAL-EPIGENETIC RELATIONSHIP IN ISLET BIOLOGY WITH THE GOAL OF IDENTIFYING TRANSCRIPTIONAL AND EPIGENETIC TARGETS ASSOCIATED WITH ISLET PERTURBATIONS IN T2DM. 2022 8 4263 36 MICRO(RNA) MANAGEMENT AND MISMANAGEMENT OF THE ISLET. PANCREATIC BETA-CELLS LOCATED WITHIN THE ISLETS OF LANGERHANS PLAY A CENTRAL ROLE IN METABOLIC CONTROL. THE MAIN FUNCTION OF THESE CELLS IS TO PRODUCE AND SECRETE INSULIN IN RESPONSE TO A RISE IN CIRCULATING LEVELS OF GLUCOSE AND OTHER NUTRIENTS. THE RELEASE OF INSUFFICIENT INSULIN TO COVER THE ORGANISM NEEDS RESULTS IN CHRONIC HYPERGLYCEMIA AND DIABETES DEVELOPMENT. BETA-CELLS INSURE A HIGHLY SPECIALIZED TASK AND TO EFFICIENTLY ACCOMPLISH THEIR FUNCTION THEY NEED TO EXPRESS A SPECIFIC SET OF GENES. MICRORNAS (MIRNAS) ARE SMALL NONCODING RNAS AND KEY REGULATORS OF GENE EXPRESSION. INDEED, BY PARTIALLY PAIRING TO SPECIFIC SEQUENCES IN THE 3' UNTRANSLATED REGIONS OF TARGET MRNAS, EACH OF THEM CAN CONTROL THE TRANSLATION OF HUNDREDS OF TRANSCRIPTS. IN THIS REVIEW, WE FOCUS ON FEW KEY MIRNAS CONTROLLING ISLET FUNCTION AND DISCUSS: THEIR DIFFERENTIAL EXPRESSION IN TYPE 2 DIABETES (T2D), THEIR REGULATION BY GENETIC AND ENVIRONMENTAL FACTORS, AND THEIR THERAPEUTIC POTENTIAL. GENETIC AND EPIGENETIC CHANGES OR PROLONGED EXPOSURE TO HYPERGLYCEMIA AND/OR HYPERLIPIDEMIA CAN AFFECT THE BETA-CELL MIRNA EXPRESSION PROFILE, RESULTING IN IMPAIRED BETA-CELL FUNCTION AND SURVIVAL LEADING TO THE DEVELOPMENT OF T2D. EXPERIMENTAL APPROACHES PERMITTING TO CORRECT THE LEVEL OF MISEXPRESSED MIRNAS HAVE BEEN SHOWN TO PREVENT OR TREAT T2D IN ANIMAL MODELS, SUGGESTING THAT THESE SMALL RNAS MAY BECOME INTERESTING THERAPEUTIC TARGETS. HOWEVER, TRANSLATION OF THESE EXPERIMENTAL FINDINGS TO THE CLINICS WILL NECESSITATE THE DEVELOPMENT OF INNOVATIVE STRATEGIES ALLOWING SAFE AND SPECIFIC DELIVERY OF COMPOUNDS MODULATING THE LEVEL OF THE RELEVANT MIRNAS TO THE BETA-CELLS. 2020 9 6608 36 TYPE I INTERFERONS AS KEY PLAYERS IN PANCREATIC BETA-CELL DYSFUNCTION IN TYPE 1 DIABETES. TYPE 1 DIABETES (T1D) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY PANCREATIC ISLET INFLAMMATION (INSULITIS) AND SPECIFIC PANCREATIC BETA-CELL DESTRUCTION BY AN IMMUNE ATTACK. ALTHOUGH THE PRECISE UNDERLYING MECHANISMS LEADING TO THE AUTOIMMUNE ASSAULT REMAIN POORLY UNDERSTOOD, IT IS WELL ACCEPTED THAT INSULITIS TAKES PLACE IN THE CONTEXT OF A CONFLICTING DIALOGUE BETWEEN PANCREATIC BETA-CELLS AND THE IMMUNE CELLS. MOREOVER, BOTH HOST GENETIC BACKGROUND (I.E., CANDIDATE GENES) AND ENVIRONMENTAL FACTORS (E.G., VIRAL INFECTIONS) CONTRIBUTE TO THIS INADEQUATE DIALOGUE. ACCUMULATING EVIDENCE INDICATES THAT TYPE I INTERFERONS (IFNS), CYTOKINES THAT ARE CRUCIAL FOR BOTH INNATE AND ADAPTIVE IMMUNE RESPONSES, ACT AS KEY LINKS BETWEEN ENVIRONMENTAL AND GENETIC RISK FACTORS IN THE DEVELOPMENT OF T1D. THIS CHAPTER SUMMARIZES SOME RELEVANT PATHWAYS INVOLVED IN BETA-CELL DYSFUNCTION AND DEATH, AND BRIEFLY REVIEWS HOW ENTEROVIRAL INFECTIONS AND GENETIC SUSCEPTIBILITY CAN IMPACT INSULITIS. MOREOVER, WE PRESENT THE CURRENT EVIDENCE SHOWING THAT, IN BETA-CELLS, TYPE I IFN SIGNALING PATHWAY ACTIVATION LEADS TO SEVERAL OUTCOMES, SUCH AS LONG-LASTING MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS I HYPEREXPRESSION, ENDOPLASMIC RETICULUM (ER) STRESS, EPIGENETIC CHANGES, AND INDUCTION OF POSTTRANSCRIPTIONAL AS WELL AS POSTTRANSLATIONAL MODIFICATIONS. MHC CLASS I OVEREXPRESSION, WHEN COMBINED WITH ER STRESS AND POSTTRANSCRIPTIONAL/POSTTRANSLATIONAL MODIFICATIONS, MIGHT LEAD TO SUSTAINED NEOANTIGEN PRESENTATION TO IMMUNE SYSTEM AND BETA-CELL APOPTOSIS. THIS KNOWLEDGE SUPPORTS THE CONCEPT THAT TYPE I IFNS ARE IMPLICATED IN THE EARLY STAGES OF T1D PATHOGENESIS. FINALLY, WE HIGHLIGHT THE PROMISING THERAPEUTIC AVENUES FOR T1D TREATMENT DIRECTED AT TYPE I IFN SIGNALING PATHWAY. 2021 10 6093 36 THE EFFECTS OF HIGH GLUCOSE EXPOSURE ON GLOBAL GENE EXPRESSION AND DNA METHYLATION IN HUMAN PANCREATIC ISLETS. BACKGROUND: TYPE 2 DIABETES (T2D) IS A COMPLEX DISEASE CHARACTERISED BY CHRONIC HYPERGLYCAEMIA. THE EFFECTS OF ELEVATED GLUCOSE ON GLOBAL GENE EXPRESSION IN COMBINATION WITH DNA METHYLATION PATTERNS HAVE NOT YET BEEN STUDIED IN HUMAN PANCREATIC ISLETS. OUR AIM WAS TO STUDY THE IMPACT OF 48 H EXPOSURE TO HIGH (19 MM) VERSUS CONTROL (5.6 MM) GLUCOSE LEVELS ON GLUCOSE-STIMULATED INSULIN SECRETION, GENE EXPRESSION AND DNA METHYLATION IN HUMAN PANCREATIC ISLETS. RESULTS: WHILE ISLETS KEPT AT 5.6 MM GLUCOSE SECRETED SIGNIFICANTLY MORE INSULIN IN RESPONSE TO SHORT TERM GLUCOSE-STIMULATION (P = 0.0067), ISLETS EXPOSED TO HIGH GLUCOSE FOR 48 H WERE DESENSITISED AND UNRESPONSIVE TO SHORT TERM GLUCOSE-STIMULATION WITH RESPECT TO INSULIN SECRETION (P = 0.32). MOREOVER, THE EXPOSURE OF HUMAN ISLETS TO 19 MM GLUCOSE RESULTED IN SIGNIFICANTLY ALTERED EXPRESSION OF EIGHT GENES (FDR<5%), WITH FIVE OF THESE (GLRA1, RASD1, VAC14, SLCO5A1, CHRNA5) ALSO EXHIBITING CHANGES IN DNA METHYLATION (P < 0.05). A GENE SET ENRICHMENT ANALYSIS OF THE EXPRESSION DATA SHOWED SIGNIFICANT ENRICHMENT OF E.G. TGF-BETA SIGNALLING PATHWAY, NOTCH SIGNALLING PATHWAY AND SNARE INTERACTIONS IN VESICULAR TRANSPORT; THESE PATHWAYS ARE OF RELEVANCE FOR ISLET FUNCTION AND POSSIBLY ALSO DIABETES. WE ALSO FOUND INCREASED DNA METHYLATION OF CPG SITES ANNOTATED TO PDX1 IN HUMAN ISLETS EXPOSED TO 19 MM GLUCOSE FOR 48 H. FINALLY, WE COULD FUNCTIONALLY VALIDATE A ROLE FOR GLRA1 IN INSULIN SECRETION. CONCLUSION: OUR DATA DEMONSTRATE THAT HIGH GLUCOSE LEVELS AFFECT HUMAN PANCREATIC ISLET GENE EXPRESSION AND SEVERAL OF THESE GENES ALSO EXHIBIT EPIGENETIC CHANGES. THIS MIGHT CONTRIBUTE TO THE IMPAIRED INSULIN SECRETION SEEN IN T2D. 2018 11 2178 28 EPIGENETIC MECHANISMS OF MACROPHAGE ACTIVATION IN TYPE 2 DIABETES. THE ALARMING RISE OF OBESITY AND TYPE 2 DIABETES (T2D) HAS PUT A TREMENDOUS STRAIN ON GLOBAL HEALTHCARE SYSTEMS. OVER THE PAST DECADE EXTENSIVE RESEARCH HAS FOCUSED ON THE ROLE OF MACROPHAGES AS KEY MEDIATORS OF INFLAMMATION IN T2D. THE INFLAMMATORY ENVIRONMENT IN THE OBESE ADIPOSE TISSUE AND PANCREATIC BETA-CELL ISLETS CREATES AND PERPETUATES IMBALANCED INFLAMMATORY MACROPHAGE ACTIVATION. CONSEQUENCES OF THIS CHRONIC LOW-GRADE INFLAMMATION INCLUDE INSULIN RESISTANCE IN THE ADIPOSE TISSUE AND PANCREATIC BETA-CELL DYSFUNCTION. RECENTLY, THE EMERGING FIELD OF EPIGENETICS HAS PROVIDED NEW INSIGHTS INTO THE PATHOGENESIS OF T2D, WHILE ALSO AFFORDING POTENTIAL NEW OPPORTUNITIES FOR TREATMENT. IN MACROPHAGES, EPIGENETIC MECHANISMS ARE INCREASINGLY BEING RECOGNIZED AS CRUCIAL CONTROLLERS OF THEIR PHENOTYPE. HERE, WE FIRST DESCRIBE THE ROLE OF MACROPHAGES IN T2D. THEN WE ELABORATE ON EPIGENETIC MECHANISMS THAT REGULATE MACROPHAGE ACTIVATION, THEREBY FOCUSING ON T2D. NEXT, WE HIGHLIGHT HOW DIABETIC CONDITIONS SUCH AS HYPERLIPIDEMIA AND HYPERGLYCEMIA COULD INDUCE EPIGENETIC CHANGES THAT PROMOTE AN INFLAMMATORY MACROPHAGE PHENOTYPE. IN CONCLUSION WE DISCUSS POSSIBLE THERAPEUTIC INTERVENTIONS BY TARGETING MACROPHAGE EPIGENETICS AND SPECULATE ON FUTURE RESEARCH DIRECTIONS. 2017 12 4070 37 MATERNAL DIABETES, PROGRAMMING OF BETA-CELL DISORDERS AND INTERGENERATIONAL RISK OF TYPE 2 DIABETES. A SUBSTANTIAL BODY OF EVIDENCE SUGGESTS THAT AN ABNORMAL INTRA-UTERINE MILIEU ELICITED BY MATERNAL METABOLIC DISTURBANCES AS DIVERSE AS MALNUTRITION, PLACENTAL INSUFFICIENCY, DIABETES AND OBESITY MAY BE ABLE TO PROGRAMME SUSCEPTIBILITY OF THE FOETUS TO LATER DEVELOP CHRONIC DEGENERATIVE DISEASES SUCH AS OBESITY, HYPERTENSION, CARDIOVASCULAR DISEASES AND TYPE 2 DIABETES (T2D). AS INSULIN-PRODUCING CELLS HAVE BEEN PLACED CENTRE STAGE IN THE DEVELOPMENT OF T2D, THIS REVIEW EXAMINES DEVELOPMENTAL PROGRAMMING OF THE BETA-CELL MASS (BCM) IN VARIOUS RODENT MODELS OF MATERNAL PROTEIN RESTRICTION, CALORIE RESTRICTION, OVERNUTRITION AND DIABETES. THE MAIN MESSAGE IS THAT WHATEVER THE INITIAL MATERNAL INSULT (F0 GENERATION) AND WHETHER ALONE OR IN COMBINATION, IT GIVES RISE TO THE SAME PROGRAMMED BCM OUTCOME IN THE DAUGHTER GENERATION (F1). THE ALTERED BCM PHENOTYPE IN F1 FEMALES PROHIBITS NORMAL BCM ADAPTATION DURING PREGNANCY AND, THUS, DIABETES (GESTATIONAL DIABETES) ENSUES. THIS GESTATIONAL DIABETES IS THEN PASSED FROM ONE GENERATION (F1) TO THE NEXT (F2, F3 AND SO ON). THIS REVIEW HIGHLIGHTS A NUMBER OF STUDIES THAT HAVE IDENTIFIED EPIGENETIC MECHANISMS THAT MAY CONTRIBUTE TO ALTERED BCM DEVELOPMENT AND BETA-CELL FAILURE, AS OBSERVED IN DIABETES. IN ADDITION TO THEIR ROLE IN INSTILLING THE PROGRAMMED DEFECT, THESE NON-GENOMIC MECHANISMS MAY ALSO BE INVOLVED IN ITS INTERGENERATIONAL TRANSMISSION. 2014 13 2702 26 EXCITOTOXICITY AND OVERNUTRITION ADDITIVELY IMPAIR METABOLIC FUNCTION AND IDENTITY OF PANCREATIC BETA-CELLS. A SUSTAINED INCREASE IN INTRACELLULAR CA(2+) CONCENTRATION (REFERRED TO HEREAFTER AS EXCITOTOXICITY), BROUGHT ON BY CHRONIC METABOLIC STRESS, MAY CONTRIBUTE TO PANCREATIC BETA-CELL FAILURE. TO DETERMINE THE ADDITIVE EFFECTS OF EXCITOTOXICITY AND OVERNUTRITION ON BETA-CELL FUNCTION AND GENE EXPRESSION, WE ANALYZED THE IMPACT OF A HIGH-FAT DIET (HFD) ON ABCC8 KNOCKOUT MICE. EXCITOTOXICITY CAUSED BETA-CELLS TO BE MORE SUSCEPTIBLE TO HFD-INDUCED IMPAIRMENT OF GLUCOSE HOMEOSTASIS, AND THESE EFFECTS WERE MITIGATED BY VERAPAMIL, A CA(2+) CHANNEL BLOCKER. EXCITOTOXICITY, OVERNUTRITION, AND THE COMBINATION OF BOTH STRESSES CAUSED SIMILAR BUT DISTINCT ALTERATIONS IN THE BETA-CELL TRANSCRIPTOME, INCLUDING ADDITIVE INCREASES IN GENES ASSOCIATED WITH MITOCHONDRIAL ENERGY METABOLISM, FATTY ACID BETA-OXIDATION, AND MITOCHONDRIAL BIOGENESIS AND THEIR KEY REGULATOR PPARGC1A OVERNUTRITION WORSENED EXCITOTOXICITY-INDUCED MITOCHONDRIAL DYSFUNCTION, INCREASING METABOLIC INFLEXIBILITY AND MITOCHONDRIAL DAMAGE. IN ADDITION, EXCITOTOXICITY AND OVERNUTRITION, INDIVIDUALLY AND TOGETHER, IMPAIRED BOTH BETA-CELL FUNCTION AND IDENTITY BY REDUCING EXPRESSION OF GENES IMPORTANT FOR INSULIN SECRETION, CELL POLARITY, CELL JUNCTION, CILIA, CYTOSKELETON, VESICULAR TRAFFICKING, AND REGULATION OF BETA-CELL EPIGENETIC AND TRANSCRIPTIONAL PROGRAM. SEX HAD AN IMPACT ON ALL BETA-CELL RESPONSES, WITH MALE ANIMALS EXHIBITING GREATER METABOLIC STRESS-INDUCED IMPAIRMENTS THAN FEMALES. TOGETHER, THESE FINDINGS INDICATE THAT A SUSTAINED INCREASE IN INTRACELLULAR CA(2+), BY ALTERING MITOCHONDRIAL FUNCTION AND IMPAIRING BETA-CELL IDENTITY, AUGMENTS OVERNUTRITION-INDUCED BETA-CELL FAILURE. 2020 14 1837 36 EFFECTS OF PALMITATE ON GENOME-WIDE MRNA EXPRESSION AND DNA METHYLATION PATTERNS IN HUMAN PANCREATIC ISLETS. BACKGROUND: CIRCULATING FREE FATTY ACIDS ARE OFTEN ELEVATED IN PATIENTS WITH TYPE 2 DIABETES (T2D) AND OBESE INDIVIDUALS. CHRONIC EXPOSURE TO HIGH LEVELS OF SATURATED FATTY ACIDS HAS DETRIMENTAL EFFECTS ON ISLET FUNCTION AND INSULIN SECRETION. ALTERED GENE EXPRESSION AND EPIGENETICS MAY CONTRIBUTE TO T2D AND OBESITY. HOWEVER, THERE IS LIMITED INFORMATION ON WHETHER FATTY ACIDS ALTER THE GENOME-WIDE TRANSCRIPTOME PROFILE IN CONJUNCTION WITH DNA METHYLATION PATTERNS IN HUMAN PANCREATIC ISLETS. TO DISSECT THE MOLECULAR MECHANISMS LINKING LIPOTOXICITY TO IMPAIRED INSULIN SECRETION, WE INVESTIGATED THE EFFECTS OF A 48 H PALMITATE TREATMENT IN VITRO ON GENOME-WIDE MRNA EXPRESSION AND DNA METHYLATION PATTERNS IN HUMAN PANCREATIC ISLETS. METHODS: GENOME-WIDE MRNA EXPRESSION WAS ANALYZED USING AFFYMETRIX GENECHIP((R)) HUMAN GENE 1.0 ST WHOLE TRANSCRIPT-BASED ARRAY (N = 13) AND GENOME-WIDE DNA METHYLATION WAS ANALYZED USING INFINIUM HUMANMETHYLATION450K BEADCHIP (N = 13) IN HUMAN PANCREATIC ISLETS EXPOSED TO PALMITATE OR CONTROL MEDIA FOR 48 H. A NON-PARAMETRIC PAIRED WILCOXON STATISTICAL TEST WAS USED TO ANALYZE MRNA EXPRESSION. APOPTOSIS WAS MEASURED USING APO-ONE((R)) HOMOGENEOUS CASPASE-3/7 ASSAY (N = 4). RESULTS: WHILE GLUCOSE-STIMULATED INSULIN SECRETION WAS DECREASED, THERE WAS NO SIGNIFICANT EFFECT ON APOPTOSIS IN HUMAN ISLETS EXPOSED TO PALMITATE. WE IDENTIFIED 1,860 DIFFERENTIALLY EXPRESSED GENES IN PALMITATE-TREATED HUMAN ISLETS. THESE INCLUDE CANDIDATE GENES FOR T2D, SUCH AS TCF7L2, GLIS3, HNF1B AND SLC30A8. ADDITIONALLY, GENES IN GLYCOLYSIS/GLUCONEOGENESIS, PYRUVATE METABOLISM, FATTY ACID METABOLISM, GLUTATHIONE METABOLISM AND ONE CARBON POOL BY FOLATE WERE DIFFERENTIALLY EXPRESSED IN PALMITATE-TREATED HUMAN ISLETS. PALMITATE TREATMENT ALTERED THE GLOBAL DNA METHYLATION LEVEL AND DNA METHYLATION LEVELS OF CPG ISLAND SHELVES AND SHORES, 5'UTR, 3'UTR AND GENE BODY REGIONS IN HUMAN ISLETS. MOREOVER, 290 GENES WITH DIFFERENTIAL EXPRESSION HAD A CORRESPONDING CHANGE IN DNA METHYLATION, FOR EXAMPLE, TCF7L2 AND GLIS3. IMPORTANTLY, OUT OF THE GENES DIFFERENTIALLY EXPRESSED DUE TO PALMITATE TREATMENT IN HUMAN ISLETS, 67 WERE ALSO ASSOCIATED WITH BMI AND 37 WERE DIFFERENTIALLY EXPRESSED IN ISLETS FROM T2D PATIENTS. CONCLUSION: OUR STUDY DEMONSTRATES THAT PALMITATE TREATMENT OF HUMAN PANCREATIC ISLETS GIVES RISE TO EPIGENETIC MODIFICATIONS THAT TOGETHER WITH ALTERED GENE EXPRESSION MAY CONTRIBUTE TO IMPAIRED INSULIN SECRETION AND T2D. 2014 15 6606 36 TYPE 2 DIABETES ACROSS GENERATIONS: FROM PATHOPHYSIOLOGY TO PREVENTION AND MANAGEMENT. TYPE 2 DIABETES IS NOW A PANDEMIC AND SHOWS NO SIGNS OF ABATEMENT. IN THIS SEMINAR WE REVIEW THE PATHOPHYSIOLOGY OF THIS DISORDER, WITH PARTICULAR ATTENTION TO EPIDEMIOLOGY, GENETICS, EPIGENETICS, AND MOLECULAR CELL BIOLOGY. EVIDENCE IS EMERGING THAT A SUBSTANTIAL PART OF DIABETES SUSCEPTIBILITY IS ACQUIRED EARLY IN LIFE, PROBABLY OWING TO FETAL OR NEONATAL PROGRAMMING VIA EPIGENETIC PHENOMENA. MATERNAL AND EARLY CHILDHOOD HEALTH MIGHT, THEREFORE, BE CRUCIAL TO THE DEVELOPMENT OF EFFECTIVE PREVENTION STRATEGIES. DIABETES DEVELOPS BECAUSE OF INADEQUATE ISLET BETA-CELL AND ADIPOSE-TISSUE RESPONSES TO CHRONIC FUEL EXCESS, WHICH RESULTS IN SO-CALLED NUTRIENT SPILLOVER, INSULIN RESISTANCE, AND METABOLIC STRESS. THE LATTER DAMAGES MULTIPLE ORGANS. INSULIN RESISTANCE, WHILE FORCING BETA CELLS TO WORK HARDER, MIGHT ALSO HAVE AN IMPORTANT DEFENSIVE ROLE AGAINST NUTRIENT-RELATED TOXIC EFFECTS IN TISSUES SUCH AS THE HEART. REVERSAL OF OVERNUTRITION, HEALING OF THE BETA CELLS, AND LESSENING OF ADIPOSE TISSUE DEFECTS SHOULD BE TREATMENT PRIORITIES. 2011 16 4185 30 METABOLIC ADAPTIONS/REPROGRAMMING IN ISLET BETA-CELLS IN RESPONSE TO PHYSIOLOGICAL STIMULATORS-WHAT ARE THE CONSEQUENCES. IRREVERSIBLE PANCREATIC BETA-CELL DAMAGE MAY BE A RESULT OF CHRONIC EXPOSURE TO SUPRAPHYSIOLOGICAL GLUCOSE OR LIPID CONCENTRATIONS OR CHRONIC EXPOSURE TO THERAPEUTIC ANTI-DIABETIC DRUGS. THE BETA-CELLS ARE ABLE TO RESPOND TO BLOOD GLUCOSE IN A NARROW CONCENTRATION RANGE AND RELEASE INSULIN IN RESPONSE, FOLLOWING ACTIVATION OF METABOLIC PATHWAYS SUCH AS GLYCOLYSIS AND THE TCA CYCLE. THE BETA-CELL CANNOT PROTECT ITSELF FROM GLUCOSE TOXICITY BY BLOCKING GLUCOSE UPTAKE, BUT INDEED RELIES ON ALTERNATIVE METABOLIC PROTECTION MECHANISMS TO AVOID DYSFUNCTION AND DEATH. ALTERATION OF NORMAL METABOLIC PATHWAY FUNCTION OCCURS AS A COUNTER REGULATORY RESPONSE TO HIGH NUTRIENT, INFLAMMATORY FACTOR, HORMONE OR THERAPEUTIC DRUG CONCENTRATIONS. METABOLIC REPROGRAMMING IS A TERM WIDELY USED TO DESCRIBE A CHANGE IN REGULATION OF VARIOUS METABOLIC ENZYMES AND TRANSPORTERS, USUALLY ASSOCIATED WITH CELL GROWTH AND PROLIFERATION AND MAY INVOLVE RESHAPING EPIGENETIC RESPONSES, IN PARTICULAR THE ACETYLATION AND METHYLATION OF HISTONE PROTEINS AND DNA. OTHER METABOLIC MODIFICATIONS SUCH AS MALONYLATION, SUCCINYLATION, HYDROXYBUTYRYLATION, ADP-RIBOSYLATION, AND LACTYLATION, MAY IMPACT REGULATORY PROCESSES, MANY OF WHICH NEED TO BE INVESTIGATED IN DETAIL TO CONTRIBUTE TO CURRENT ADVANCES IN METABOLISM. BY DESCRIBING MULTIPLE MECHANISMS OF METABOLIC ADAPTION THAT ARE AVAILABLE TO THE BETA-CELL ACROSS ITS LIFESPAN, WE HOPE TO IDENTIFY SITES FOR METABOLIC REPROGRAMMING MECHANISMS, MOST OF WHICH ARE INCOMPLETELY DESCRIBED OR UNDERSTOOD. MANY OF THESE MECHANISMS ARE RELATED TO PROMINENT ANTIOXIDANT RESPONSES. HERE, WE HAVE ATTEMPTED TO DESCRIBE THE KEY BETA-CELL METABOLIC ADAPTIONS AND CHANGES WHICH ARE REQUIRED FOR SURVIVAL AND FUNCTION IN VARIOUS PHYSIOLOGICAL, PATHOLOGICAL AND PHARMACOLOGICAL CONDITIONS. 2022 17 5293 28 PROTEASOMAL DEGRADATION OF THE HISTONE ACETYL TRANSFERASE P300 CONTRIBUTES TO BETA-CELL INJURY IN A DIABETES ENVIRONMENT. IN TYPE 2 DIABETES, AMYLOID OLIGOMERS, CHRONIC HYPERGLYCEMIA, LIPOTOXICITY, AND PRO-INFLAMMATORY CYTOKINES ARE DETRIMENTAL TO BETA-CELLS, CAUSING APOPTOSIS AND IMPAIRED INSULIN SECRETION. THE HISTONE ACETYL TRANSFERASE P300, INVOLVED IN REMODELING OF CHROMATIN STRUCTURE BY EPIGENETIC MECHANISMS, IS A KEY UBIQUITOUS ACTIVATOR OF THE TRANSCRIPTIONAL MACHINERY. IN THIS STUDY, WE REPORT THAT LOSS OF P300 ACETYL TRANSFERASE ACTIVITY AND EXPRESSION LEADS TO BETA-CELL APOPTOSIS, AND MOST IMPORTANTLY, THAT STRESS SITUATIONS KNOWN TO BE ASSOCIATED WITH DIABETES ALTER P300 LEVELS AND FUNCTIONAL INTEGRITY. WE FOUND THAT PROTEASOMAL DEGRADATION IS THE MECHANISM SUBSERVING P300 LOSS IN BETA-CELLS EXPOSED TO HYPERGLYCEMIA OR PRO-INFLAMMATORY CYTOKINES. WE ALSO REPORT THAT MELATONIN, A HORMONE PRODUCED IN THE PINEAL GLAND AND KNOWN TO PLAY KEY ROLES IN BETA-CELL HEALTH, PRESERVES P300 LEVELS ALTERED BY THESE TOXIC CONDITIONS. COLLECTIVELY, THESE DATA IMPLY AN IMPORTANT ROLE FOR P300 IN THE PATHOPHYSIOLOGY OF DIABETES. 2018 18 4582 29 N-TERMINAL BET BROMODOMAIN INHIBITORS DISRUPT A BRD4-P65 INTERACTION AND REDUCE INDUCIBLE NITRIC OXIDE SYNTHASE TRANSCRIPTION IN PANCREATIC BETA-CELLS. CHRONIC INFLAMMATION OF PANCREATIC ISLETS IS A KEY DRIVER OF BETA-CELL DAMAGE THAT CAN LEAD TO AUTOREACTIVITY AND THE EVENTUAL ONSET OF AUTOIMMUNE DIABETES (T1D). IN THE ISLET, ELEVATED LEVELS OF PROINFLAMMATORY CYTOKINES INDUCE THE TRANSCRIPTION OF THE INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) GENE, NOS2, ULTIMATELY RESULTING IN INCREASED NITRIC OXIDE (NO). EXCESSIVE OR PROLONGED EXPOSURE TO NO CAUSES BETA-CELL DYSFUNCTION AND FAILURE ASSOCIATED WITH DEFECTS IN MITOCHONDRIAL RESPIRATION. RECENT STUDIES SHOWED THAT INHIBITION OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) FAMILY OF PROTEINS, A DRUGGABLE CLASS OF EPIGENETIC READER PROTEINS, PREVENTS THE ONSET AND PROGRESSION OF T1D IN THE NON-OBESE DIABETIC MOUSE MODEL. WE HYPOTHESIZED THAT BET PROTEINS CO-ACTIVATE TRANSCRIPTION OF CYTOKINE-INDUCED INFLAMMATORY GENE TARGETS IN BETA-CELLS AND THAT SELECTIVE, CHEMOTHERAPEUTIC INHIBITION OF BET BROMODOMAINS COULD REDUCE SUCH TRANSCRIPTION. HERE, WE INVESTIGATED THE ABILITY OF BET BROMODOMAIN SMALL MOLECULE INHIBITORS TO REDUCE THE BETA-CELL RESPONSE TO THE PROINFLAMMATORY CYTOKINE INTERLEUKIN 1 BETA (IL-1BETA). BET BROMODOMAIN INHIBITION ATTENUATED IL-1BETA-INDUCED TRANSCRIPTION OF THE INFLAMMATORY MEDIATOR NOS2 AND CONSEQUENT INOS PROTEIN AND NO PRODUCTION. REDUCED NOS2 TRANSCRIPTION IS CONSISTENT WITH INHIBITION OF NF-KAPPAB FACILITATED BY DISRUPTING THE INTERACTION OF A SINGLE BET FAMILY MEMBER, BRD4, WITH THE NF-KAPPAB SUBUNIT, P65. USING RECENTLY REPORTED SELECTIVE INHIBITORS OF THE FIRST AND SECOND BET BROMODOMAINS, INHIBITION OF ONLY THE FIRST BROMODOMAIN WAS NECESSARY TO REDUCE THE INTERACTION OF BRD4 WITH P65 IN BETA-CELLS. MOREOVER, INHIBITION OF THE FIRST BROMODOMAIN WAS SUFFICIENT TO MITIGATE IL-1BETA-DRIVEN DECREASES IN MITOCHONDRIAL OXYGEN CONSUMPTION RATES AND BETA-CELL VIABILITY. BY IDENTIFYING A ROLE FOR THE INTERACTION BETWEEN BRD4 AND P65 IN CONTROLLING THE RESPONSE OF BETA-CELLS TO PROINFLAMMATORY CYTOKINES, WE PROVIDE MECHANISTIC INFORMATION ON HOW BET BROMODOMAIN INHIBITION CAN DECREASE INFLAMMATION. THESE STUDIES ALSO SUPPORT THE POTENTIAL THERAPEUTIC APPLICATION OF MORE SELECTIVE BET BROMODOMAIN INHIBITORS IN ATTENUATING BETA-CELL INFLAMMATION. 2022 19 6335 30 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 20 4737 24 NOVEL EPIGENETIC-SENSITIVE CLINICAL CHALLENGES BOTH IN TYPE 1 AND TYPE 2 DIABETES. BACKGROUND: EPIGENETICS MODULATED TISSUE-SPECIFIC GENE EXPRESSION DURING THE ONSET OF TYPE 1 AND TYPE 2 DIABETES AND THEIR COMPLICATIONS. METHODS: WE SEARCHED THE PUBMED RECENT STUDIES ABOUT THE MAIN EPIGENETIC TAGS INVOLVED IN TYPE 1 AND TYPE 2 DIABETES ONSET AND THEIR CLINICAL COMPLICATIONS. PUBMED STUDIES ABOUT THE EPIGENETIC TAGS INVOLVED IN TYPE 1 AND 2 DIABETES ONSET WAS SEARCHED. RESULTS: THE EPIGENETIC METHYLATION MAPS OF CORD BLOOD SAMPLES HIGHLIGHTED DIFFERENCES IN THE METHYLATION STATUS OF CPG SITES WITHIN THE MHC GENES BETWEEN CARRIERS OF DIABETES TYPE 1 DR3-DQ2 AND DR4-DQ8 RISK HAPLOTYPES. BETA CELL-DERIVED UNMETHYLATED INS DNA SHOWED THE DECLINE OF BETA-CELL MASS PRESERVING INSULIN SECRETION. DIFFERENTIALLY METHYLATED REGIONS IN PANCREATIC ISLETS FROM TYPE 2 DIABETES COVERED PDX1, TCF7L2, AND ADCY5 PROMOTERS DURING ISLET DYSFUNCTION. THE RECRUITMENT OF SET7 AND SUV39H1 HISTONE METHYLTRANSFERASES AND LSD-1 LYSINE-SPECIFIC DEMETHYLASE-1 AT NF-KBETA-P65 PROMOTER IN VASCULAR CELLS WAS INVOLVED IN CORONARY HEART DISEASE. NEUTROPHIL EXTRACELLULAR TRAP, ACTIVATED BY PROTEIN ARGININE DEIMINASE-4, IMPAIRED WOUND HEALING FROM DIABETIC FOOT ULCERS. MIR-199A-3P OVER-EXPRESSION INDUCED COAGULATIVE CASCADE, SWELLING AND PAIN BY A DOWN-REGULATION OF SERPIN-E2 IN DIABETIC PERIPHERAL NEUROPATHY. A DNA HYPO-METHYLATION AND HISTONE HYPER-ACETYLATION AT MIOX PROMOTER LED AN OVEREXPRESSION OF ROS, FIBRONECTIN, HIF-1ALPHA, AND NOX-4 ASSOCIATED WITH DIABETIC TUBULOPATHY. A HYPO-METHYLATION OF H3K4 AT SOD2 PROMOTER BY LSD-1 INCREASED ROS CAUSING DIABETIC RETINOPATHY. CONCLUSIONS: EPIGENETICS PLAYED A RELEVANT ROLE IN PREVENTION, DIAGNOSIS, AND TREATMENT OF DIABETES. 2018