1 6473 173 TO DO ONE AND TO GET MORE: PART II. DIABETES AND METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASES. TYPE 2 DIABETES MELLITUS (DM) IS CHARACTERIZED BY INABILITY OF FAULTY PANCREATIC BETA-CELLS TO SECRET A NORMAL AMOUNT OF INSULIN TO MAINTAIN NORMAL BODY CONSUMPTION, AND/OR PERIPHERAL TISSUE HAS A DECREASED SUSCEPTIBILITY TO INSULIN, RESULTING IN HYPERGLYCEMIA AND INSULIN RESISTANCE. SIMILAR TO OTHER CHRONIC SYSTEMIC INFLAMMATORY DISEASES, DM IS A RESULT FROM DYSREGULATED INTERACTIONS BETWEEN ETHNIC, GENETIC, EPIGENETIC, IMMUNOREGULATORY, HORMONAL, AND ENVIRONMENTAL FACTORS. THEREFORE, IT IS RATIONAL TO SUPPOSE THE CONCEPT AS "TO DO ONE AND TO GET MORE", WHILE USING ANTIDIABETIC AGENTS (ADA), A MAIN PHARMACOLOGIC AGENT FOR THE TREATMENT OF DM, CAN PROVIDE AN EXTRAGLYCEMIA EFFECT ON COMORBIDITIES OR CONCOMITTENT COMORBIDITIES TO DM. IN THIS REVIEW, BASED ON THE MUCH STRONG CORRELATION BETWEEN DM AND METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASES (MAFLD) SHOWN BY SIMILAR PATHOPHYSIOLOGICAL MECHANISMS AND A HIGH PREVALENCE OF DM IN MAFLD AND ITS VICE VERSA (A HIGH PREVALENCE OF MAFLD IN DM), IT IS POSSIBLE TO USE THE STRATEGY TO TARGET BOTH DISEASES SIMULTANEOUSLY. WE FOCUS ON A NEW CLASSIFICATION OF ADA, SUCH AS GLUCAGON-LIKE PEPTIDE-1 RECEPTOR (GLP1R) AGONIST AND SODIUM-GLUCOSE COTRANSPORTER-2 (SGLT-2) INHIBITORS TO SHOW THE POTENTIAL BENEFITS OF EXTRAGLYCEMIC EFFECT ON MAFLD. WE CONCLUDE THAT THE MANAGEMENT OF DM PATIENTS, ESPECIALLY FOR THOSE WHO NEED ADA AS ADJUVANT THERAPY SHOULD INCLUDE HEALTHY LIFESTYLE MODIFICATION TO OVERCOME THE METABOLIC SYNDROME, CONTRIBUTING TO THE URGENT NEED OF AN EFFECTIVE WEIGHT-REDUCTION STRATEGY. GLP1R AGONIST IS ONE OF EFFECTIVE BODY WEIGHT-LOWERING MEDICATIONS, WHICH MAY BE A BETTER CHOICE FOR DM COMPLICATED WITH MAFLD OR ITS-ASSOCIATED SEVERE FORM AS METABOLIC ASSOCIATED STEATOHEPATITIS (MASH), ALTHOUGH THE ROLE OF SGLT-2 INHIBITORS IS ALSO IMPRESSIVE. THE PRESCRIPTION OF THESE TWO CLASSES OF ADA MAY SATISFY THE CONCEPT "TO DO ONE AND TO GET MORE", BASED ON SUCCESSFUL SUGAR-LOWERING EFFECT FOR CONTROLLING DM AND EXTRAGLYCEMIA BENEFITS OF HEPATOPROTECTIVE ACTIVITY IN DM PATIENTS. 2022 2 6335 41 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 3 6607 51 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 4 3046 32 GENOME-WIDE ANALYSIS OF DNA METHYLATION IDENTIFIES S100A13 AS AN EPIGENETIC BIOMARKER IN INDIVIDUALS WITH CHRONIC (>/= 30 YEARS) TYPE 2 DIABETES WITHOUT DIABETIC RETINOPATHY. BACKGROUND: THIS STUDY AIMED TO DETERMINE THE EPIGENETIC BIOMARKERS OF DIABETIC RETINOPATHY (DR) IN SUBJECTS WITH TYPE 2 DIABETES MELLITUS (T2DM). THIS RETROSPECTIVE STUDY IS BASED ON THE SHANGHAI XINJING COMMUNITY PREVENTION AND TREATMENT ADMINISTRATIVE SYSTEM OF CHRONIC DISEASES. THE SUBJECTS ENROLLED HEREIN WERE T2DM PATIENTS WHO HAD UNDERGONE LONG-TERM FOLLOW-UP EVALUATION IN THE SYSTEM. TWO CONSECUTIVE STUDIES WERE CONDUCTED. IN THE DISCOVERY COHORT, AMONG 19 SUBJECTS WHO HAD DEVELOPED DR WITH A DM DURATION < 3 YEARS AND 21 SUBJECTS WITHOUT DR > 30 YEARS AFTER BEING DIAGNOSED WITH DM, AN INFINIUM HUMAN METHYLATION 850 BEADCHIP WAS USED TO IDENTIFY DIFFERENTIAL METHYLATION REGIONS (DMRS) AND DIFFERENTIAL METHYLATION SITES (DMSS). THE FUNCTION OF THE GENES WAS ASSESSED THROUGH KEGG ENRICHMENT ANALYSIS, GENE ONTOLOGY (GO) ANALYSIS, AND PATHWAY NETWORK ANALYSIS. IN THE REPLICATION COHORT, 87 DR PATIENTS WITH A SHORT DM DURATION AND 89 PATIENTS WITHOUT DR OVER A DM DURATION > 20 YEARS WERE COMPARED TO ASSESS THE ASSOCIATION BETWEEN DMSS AND DR UPON PYROSEQUENCING. RESULTS: A TOTAL OF 34 DMRS WERE IDENTIFIED. GENES CONTAINING DMSS WITH THE TOP 5 HIGHEST BETA VALUE DIFFERENCES BETWEEN DR AND NON-DR PARTICIPANTS WERE LOCATED ON CHROMOSOME 1 AND WERE PRESENT IN THE S100A13 GENE, WHICH WAS ASSOCIATED WITH 71 GO TERMS. TWO S100A13 GENE SITES, I.E., CG02873163 AND CG11343894, DISPLAYED A GOOD CORRELATION WITH DR ON PYROSEQUENCING. CONCLUSIONS: DMSS IN THE S100A13 GENE MAY BE POTENTIAL BIOMARKERS OF DR. 2020 5 2964 37 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 6648 48 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 7 2208 53 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 8 1308 43 DEFINING A RESEARCH AGENDA TO ADDRESS THE CONVERGING EPIDEMICS OF TUBERCULOSIS AND DIABETES: PART 2: UNDERLYING BIOLOGIC MECHANISMS. THERE IS GROWING INTEREST IN THE RE-EMERGING INTERACTION BETWEEN TYPE 2 DIABETES (DM) AND TB, BUT THE UNDERLYING BIOLOGIC MECHANISMS ARE POORLY UNDERSTOOD DESPITE THEIR POSSIBLE IMPLICATIONS IN CLINICAL MANAGEMENT. EXPERTS IN EPIDEMIOLOGIC, PUBLIC HEALTH, BASIC SCIENCE, AND CLINICAL STUDIES RECENTLY CONVENED AND IDENTIFIED RESEARCH PRIORITIES FOR ELUCIDATING THE UNDERLYING MECHANISMS FOR THE CO-OCCURRENCE OF TB AND DM. WE IDENTIFIED GAPS IN CURRENT KNOWLEDGE OF ALTERED IMMUNITY IN PATIENTS WITH DM DURING TB, WHERE MOST STUDIES SUGGEST AN UNDERPERFORMING INNATE IMMUNITY, BUT EXAGGERATED ADAPTIVE IMMUNITY TO MYCOBACTERIUM TUBERCULOSIS. VARIOUS MOLECULAR MECHANISMS AND PATHWAYS MAY UNDERLIE THESE OBSERVATIONS IN THE DM HOST. THESE INCLUDE SIGNALING INDUCED BY EXCESS ADVANCED GLYCATION END PRODUCTS AND THEIR RECEPTOR, HIGHER LEVELS OF REACTIVE OXIDATIVE SPECIES AND OXIDATIVE STRESS, EPIGENETIC CHANGES DUE TO CHRONIC HYPERGLYCEMIA, ALTERED NUCLEAR RECEPTORS, AND/OR DIFFERENCES IN CELL METABOLISM (IMMUNOMETABOLISM). STUDIES IN HUMANS AT DIFFERENT STAGES OF DM (NO DM, PRE-DM, AND DM) OR TB (LATENT OR ACTIVE TB) SHOULD BE COMPLEMENTED WITH FINDINGS IN ANIMAL MODELS, WHICH PROVIDE THE UNIQUE OPPORTUNITY TO STUDY EARLY EVENTS IN THE HOST-PATHOGEN INTERACTION. SUCH STUDIES COULD ALSO HELP IDENTIFY BIOMARKERS THAT WILL COMPLEMENT CLINICAL STUDIES IN ORDER TO TAILOR THE PREVENTION OF TB-DM, OR TO AVOID THE ADVERSE TB TREATMENT OUTCOMES THAT ARE MORE LIKELY IN THESE PATIENTS. SUCH STUDIES WILL ALSO INFORM NEW APPROACHES TO HOST-DIRECTED THERAPIES. 2017 9 1385 39 DIABETES IN CHILDHOOD CANCER SURVIVORS: EMERGING CONCEPTS IN PATHOPHYSIOLOGY AND FUTURE DIRECTIONS. WITH ADVANCEMENTS IN CANCER TREATMENT AND SUPPORTIVE CARE, THERE IS A GROWING POPULATION OF CHILDHOOD CANCER SURVIVORS WHO EXPERIENCE A SUBSTANTIAL BURDEN OF COMORBIDITIES RELATED TO HAVING RECEIVED CANCER TREATMENT AT A YOUNG AGE. DESPITE AN OVERALL REDUCTION IN THE INCIDENCE OF MOST CHRONIC HEALTH CONDITIONS IN CHILDHOOD CANCER SURVIVORS OVER THE PAST SEVERAL DECADES, THE CUMULATIVE INCIDENCE OF CERTAIN LATE EFFECTS, IN PARTICULAR DIABETES MELLITUS (DM), HAS INCREASED. THE IMPLICATIONS ARE SIGNIFICANT, BECAUSE DM IS A KEY RISK FACTOR FOR CARDIOVASCULAR DISEASE, A LEADING CAUSE OF PREMATURE DEATH IN CHILDHOOD CANCER SURVIVORS. THE UNDERLYING PATHOPHYSIOLOGY OF DM IN CANCER SURVIVORS IS MULTIFACTORIAL. DM DEVELOPS AT YOUNGER AGES IN SURVIVORS COMPARED TO CONTROLS, WHICH MAY REFLECT AN "ACCELERATED AGING" PHENOTYPE IN THESE INDIVIDUALS. THE TREATMENT-RELATED EXPOSURES (I.E., CHEMOTHERAPY, RADIATION) THAT INCREASE RISK FOR DM IN CHILDHOOD CANCER SURVIVORS MAY BE MORE THAN ADDITIVE WITH ESTABLISHED DM RISK FACTORS (E.G., OLDER AGE, OBESITY, RACE, AND ETHNICITY). EMERGING RESEARCH ALSO POINTS TO PARALLELS IN CELLULAR PROCESSES IMPLICATED IN AGING- AND CANCER TREATMENT-RELATED DM. STILL, THERE REMAINS MARKED INTER-INDIVIDUAL VARIABILITY REGARDING RISK OF DM THAT IS NOT EXPLAINED BY DEMOGRAPHIC AND THERAPEUTIC RISK FACTORS ALONE. RECENT STUDIES HAVE HIGHLIGHTED THE ROLE OF GERMLINE GENETIC RISK FACTORS AND EPIGENETIC MODIFICATIONS THAT ARE ASSOCIATED WITH RISK OF DM IN BOTH THE GENERAL AND ONCOLOGY POPULATIONS. THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF RECOGNIZED RISK FACTORS FOR DM IN CHILDHOOD CANCER SURVIVORS TO HELP INFORM TARGETED APPROACHES FOR DISEASE SCREENING, PREVENTION, AND TREATMENT. FURTHERMORE, IT HIGHLIGHTS THE EXISTING SCIENTIFIC GAPS IN UNDERSTANDING THE RELATIVE CONTRIBUTIONS OF INDIVIDUAL THERAPEUTIC EXPOSURES AND THE MECHANISMS BY WHICH THEY EXERT THEIR EFFECTS THAT UNIQUELY PREDISPOSE THIS POPULATION TO DM FOLLOWING CANCER TREATMENT. 2023 10 2039 39 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 11 6103 48 THE EMERGING ROLE OF HDACS: PATHOLOGY AND THERAPEUTIC TARGETS IN DIABETES MELLITUS. DIABETES MELLITUS (DM) IS ONE OF THE PRINCIPAL MANIFESTATIONS OF METABOLIC SYNDROME AND ITS PREVALENCE WITH MODERN LIFESTYLE IS INCREASING INCESSANTLY. CHRONIC HYPERGLYCEMIA CAN INDUCE SEVERAL VASCULAR COMPLICATIONS THAT WERE REFERRED TO BE THE MAJOR CAUSE OF MORBIDITY AND MORTALITY IN DM. ALTHOUGH SEVERAL THERAPEUTIC TARGETS HAVE BEEN IDENTIFIED AND ACCESSED CLINICALLY, THE IMMINENT RISK OF DM AND ITS PREVALENCE ARE STILL ASCENDING. SUBSTANTIAL PIECES OF EVIDENCE REVEALED THAT HISTONE DEACETYLASE (HDAC) ISOFORMS CAN REGULATE VARIOUS MOLECULAR ACTIVITIES IN DM VIA EPIGENETIC AND POST-TRANSLATIONAL REGULATION OF SEVERAL TRANSCRIPTION FACTORS. TO DATE, 18 HDAC ISOFORMS HAVE BEEN IDENTIFIED IN MAMMALS THAT WERE CATEGORIZED INTO FOUR DIFFERENT CLASSES. CLASSES I, II, AND IV ARE REGARDED AS CLASSICAL HDACS, WHICH OPERATE THROUGH A ZN-BASED MECHANISM. IN CONTRAST, CLASS III HDACS OR SIRTUINS DEPEND ON NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)) FOR THEIR MOLECULAR ACTIVITY. FUNCTIONALLY, MOST OF THE HDAC ISOFORMS CAN REGULATE BETA CELL FATE, INSULIN RELEASE, INSULIN EXPRESSION AND SIGNALING, AND GLUCOSE METABOLISM. MOREOVER, THE ROLES OF HDAC MEMBERS HAVE BEEN IMPLICATED IN THE REGULATION OF OXIDATIVE STRESS, INFLAMMATION, APOPTOSIS, FIBROSIS, AND OTHER PATHOLOGICAL EVENTS, WHICH SUBSTANTIALLY CONTRIBUTE TO DIABETES-RELATED VASCULAR DYSFUNCTIONS. THEREFORE, HDACS COULD SERVE AS THE POTENTIAL THERAPEUTIC TARGET IN DM TOWARDS DEVELOPING NOVEL INTERVENTION STRATEGIES. THIS REVIEW SHEDS LIGHT ON THE EMERGING ROLE OF HDACS/ISOFORMS IN DIABETIC PATHOPHYSIOLOGY AND EMPHASIZED THE SCOPE OF THEIR TARGETING IN DM FOR CONSTITUTING NOVEL INTERVENTIONAL STRATEGIES FOR METABOLIC DISORDERS/COMPLICATIONS. 2021 12 4433 40 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 13 4971 46 PATHOPHYSIOLOGIC MECHANISMS IN DIABETIC KIDNEY DISEASE: A FOCUS ON CURRENT AND FUTURE THERAPEUTIC TARGETS. DIABETIC KIDNEY DISEASE (DKD) IS THE PRIMARY CAUSE OF CHRONIC KIDNEY DISEASE AROUND THE GLOBE AND IS ONE OF THE MAIN COMPLICATIONS IN PATIENTS WITH TYPE 1 AND 2 DIABETES. THE STANDARD TREATMENT FOR DKD IS DRUGS CONTROLLING HYPERGLYCEMIA AND HIGH BLOOD PRESSURE. RENIN ANGIOTENSIN ALDOSTERONE SYSTEM BLOCKADE AND SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITION HAVE YIELDED PROMISING RESULTS IN DKD, BUT MANY DIABETIC PATIENTS ON SUCH TREATMENTS NEVERTHELESS CONTINUE TO DEVELOP DKD, LEADING TO KIDNEY FAILURE AND CARDIOVASCULAR COMORBIDITIES. NEW THERAPEUTIC OPTIONS ARE URGENTLY REQUIRED. WE REVIEW HERE THE PROMISING THERAPEUTIC AVENUES BASED ON INSIGHTS INTO THE MECHANISMS OF DKD THAT HAVE RECENTLY EMERGED, INCLUDING MINERALOCORTICOID RECEPTOR ANTAGONISTS, SGLT2 INHIBITORS, GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST, ENDOTHELIN RECEPTOR A INHIBITION, ANTI-INFLAMMATORY AGENTS, AUTOPHAGY ACTIVATORS AND EPIGENETIC REMODELLING. THE INVOLVEMENT OF SEVERAL MOLECULAR MECHANISMS IN DKD PATHOGENESIS, TOGETHER WITH THE GENETIC AND EPIGENETIC VARIABILITY OF THIS CONDITION, MAKES IT DIFFICULT TO TARGET THIS HETEROGENEOUS PATIENT POPULATION WITH A SINGLE DRUG. PERSONALIZED MEDICINE, TAKING INTO ACCOUNT THE GENETIC AND MECHANISTIC VARIABILITY, MAY THEREFORE IMPROVE RENAL AND CARDIOVASCULAR PROTECTION IN DIABETIC PATIENTS WITH DKD. 2020 14 2721 41 EXOSOMAL NON CODING RNAS AS A NOVEL TARGET FOR DIABETES MELLITUS AND ITS COMPLICATIONS. DIABETES MELLITUS (DM) IS A FIRST-LINE PRIORITY AMONG THE PROBLEMS FACING MEDICAL SCIENCE AND PUBLIC HEALTH IN ALMOST ALL COUNTRIES OF THE WORLD. THE MAIN PROBLEM OF DM IS THE HIGH INCIDENCE OF DAMAGE TO THE CARDIOVASCULAR SYSTEM, WHICH IN TURN LEADS TO DISEASES SUCH AS MYOCARDIAL INFARCTION, STROKE, GANGRENE OF THE LOWER EXTREMITIES, BLINDNESS AND CHRONIC RENAL FAILURE. AS A RESULT, THE STUDY OF THE MOLECULAR GENETIC MECHANISMS OF THE PATHOGENESIS OF DM IS OF CRITICAL IMPORTANCE FOR THE DEVELOPMENT OF NEW DIAGNOSTIC AND THERAPEUTIC STRATEGIES. MOLECULAR GENETIC ASPECTS OF THE ETIOLOGY AND PATHOGENESIS OF DIABETES MELLITUS ARE INTENSIVELY STUDIED IN WELL-KNOWN LABORATORIES AROUND THE WORLD. ONE OF THE STRATEGIES IN THIS DIRECTION IS TO STUDY THE ROLE OF EXOSOMES IN THE PATHOGENESIS OF DM. EXOSOMES ARE MICROSCOPIC EXTRACELLULAR VESICLES WITH A DIAMETER OF 30-100 NM, RELEASED INTO THE INTERCELLULAR SPACE BY CELLS OF VARIOUS TISSUES AND ORGANS. THE CONTENT OF EXOSOMES DEPENDS ON THE CELL TYPE AND INCLUDES MRNA, NON-CODING RNAS, DNA, AND SO ON. NON-CODING RNAS, A GROUP OF RNAS WITH LIMITED TRANSCRIPTIONAL ACTIVITY, HAVE BEEN DISCOVERED TO PLAY A SIGNIFICANT ROLE IN REGULATING GENE EXPRESSION THROUGH EPIGENETIC AND POSTTRANSCRIPTIONAL MODULATION, SUCH AS SILENCING OF MESSENGER RNA. ONE OF THE PROBLEMS OF USAGE EXOSOMES IN DM IS THE IDENTIFICATION OF THE CELLULAR ORIGIN OF EXOSOMES AND THE STANDARDIZATION OF PROTOCOLS FOR MOLECULAR GENETIC STUDIES IN CLINICAL LABORATORIES. IN ADDITION, THE QUESTION OF THE TARGET ORIENTATION OF EXOSOMES AND THEIR TARGETED ACTIVITY REQUIRES ADDITIONAL STUDY. SOLVING THESE AND OTHER PROBLEMS WILL MAKE IT POSSIBLE TO USE EXOSOMES FOR THE DIAGNOSIS AND DELIVERY OF DRUGS DIRECTLY TO TARGET CELLS IN DM. THIS STUDY PRESENTS AN ANALYSIS OF LITERATURE DATA ON THE ROLE OF EXOSOMES AND NCRNAS IN THE DEVELOPMENT AND PROGRESSION OF DM, AS WELL AS THE PROSPECTS FOR THE USE OF EXOSOMES IN CLINICAL PRACTICE IN THIS DISEASE. 2023 15 1302 31 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 16 5676 45 SHIFTS IN THE IMMUNOEPIGENOMIC LANDSCAPE OF MONOCYTES IN RESPONSE TO A DIABETES-SPECIFIC SOCIAL SUPPORT INTERVENTION: A PILOT STUDY AMONG NATIVE HAWAIIAN ADULTS WITH DIABETES. BACKGROUND: NATIVE HAWAIIANS ARE DISPROPORTIONATELY AFFECTED BY TYPE 2 DIABETES MELLITUS (DM), A CHRONIC METABOLIC, NON-COMMUNICABLE DISEASE CHARACTERIZED BY HYPERGLYCEMIA AND SYSTEMIC INFLAMMATION. UNRELENTING SYSTEMIC INFLAMMATION FREQUENTLY LEADS TO A CASCADE OF MULTIPLE COMORBIDITIES ASSOCIATED WITH DM, INCLUDING CARDIOVASCULAR DISEASE, MICROVASCULAR COMPLICATIONS, AND RENAL DYSFUNCTION. YET FEW STUDIES HAVE EXAMINED THE LINK BETWEEN CHRONIC INFLAMMATION AT A CELLULAR LEVEL AND ITS RELATIONSHIP TO STANDARD DM THERAPIES SUCH AS DIABETES-SPECIFIC LIFESTYLE AND SOCIAL SUPPORT EDUCATION, WELL RECOGNIZED AS THE CORNERSTONE OF CLINICAL STANDARDS OF DIABETES CARE. THIS PILOT STUDY WAS INITIATED TO EXPLORE THE ASSOCIATION OF MONOCYTE INFLAMMATION USING EPIGENETIC, IMMUNOLOGIC, AND CLINICAL MEASURES FOLLOWING A 3-MONTH DIABETES-SPECIFIC SOCIAL SUPPORT PROGRAM AMONG HIGH-RISK NATIVE HAWAIIAN ADULTS WITH DM. RESULTS: FROM A SAMPLE OF 16 NATIVE HAWAIIAN ADULTS WITH DM, MONOCYTES ENRICHED FROM PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) OF 8 INDIVIDUALS WERE RANDOMLY SELECTED FOR EPIGENOMIC ANALYSIS. USING THE ILLUMINA HUMANMETHYLATION450 BEADCHIP MICROARRAY, 1,061 DIFFERENTIALLY METHYLATED LOCI (DML) WERE IDENTIFIED IN MONOCYTES OF PARTICIPANTS AT BASELINE AND 3 MONTHS FOLLOWING A DM-SPECIFIC SOCIAL SUPPORT PROGRAM (DM-SSP). GENE ONTOLOGY ANALYSIS SHOWED THAT THESE DML WERE ENRICHED WITHIN GENES INVOLVED IN IMMUNE, METABOLIC, AND CARDIOMETABOLIC PATHWAYS, A SUBSET OF WHICH WERE ALSO SIGNIFICANTLY DIFFERENTIALLY EXPRESSED. EX VIVO ANALYSIS OF IMMUNE FUNCTION SHOWED IMPROVEMENT POST-DM-SSP COMPARED WITH BASELINE, CHARACTERIZED BY ATTENUATED INTERLEUKIN 1BETA AND IL-6 SECRETION FROM MONOCYTES. ALTERED CYTOKINE SECRETION IN RESPONSE TO THE DM-SSP WAS SIGNIFICANTLY ASSOCIATED WITH CHANGES IN THE METHYLATION AND GENE EXPRESSION STATES OF IMMUNE-RELATED GENES IN MONOCYTES BETWEEN INTERVENTION TIME POINTS. CONCLUSIONS: OUR PILOT STUDY PROVIDES PRELIMINARY EVIDENCE OF CHANGES TO INFLAMMATORY MONOCYTE ACTIVITY, POTENTIALLY DRIVEN BY EPIGENETIC MODIFICATIONS, 3 MONTHS FOLLOWING A DM-SPECIFIC SSP INTERVENTION. THESE NOVEL ALTERATIONS IN THE TRAJECTORY OF MONOCYTE INFLAMMATORY STATES WERE IDENTIFIED AT LOCI THAT REGULATE TRANSCRIPTION OF IMMUNE AND METABOLIC GENES IN HIGH-RISK NATIVE HAWAIIANS WITH DM, SUGGESTING A RELATIONSHIP BETWEEN IMPROVEMENTS IN PSYCHOSOCIAL BEHAVIORS AND SHIFTS IN THE IMMUNOEPIGENETIC PATTERNS FOLLOWING A DIABETES-SPECIFIC SSP. FURTHER RESEARCH IS WARRANTED TO INVESTIGATE HOW SOCIAL SUPPORT INFLUENCES SYSTEMIC INFLAMMATION VIA IMMUNOEPIGENETIC MODIFICATIONS IN CHRONIC INFLAMMATORY DISEASES SUCH AS DM. 2022 17 2009 33 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 18 6163 36 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 19 3859 38 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 20 4137 31 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