1 4263 147 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 2 3859 36 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 3 1974 40 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 4 1701 34 DYNAMIC IMMUNE/INFLAMMATION PRECISION MEDICINE: THE GOOD AND THE BAD INFLAMMATION IN INFECTION AND CANCER. NORMAL OR "GOOD" INFLAMMATION PROCESS STARTS FROM A LOCAL CELLULAR RESPONSE AGAINST INJURY OR ANY INFECTIOUS AGENT, WITH THE ACTIVATION OF NEUTROPHILS, MACROPHAGES, LANGERHANS CELLS, DENDRITIC CELLS, AND INNATE IMMUNE CELLS. CYTOKINES AND CHEMOKINES ARE PRODUCED TO AMPLIFY THE LOCAL INFLAMMATORY PROCESS FOLLOWED BY THE MIGRATION OF IMMUNE CELLS TO THE REGIONAL LYMPH NODES WHERE ADAPTIVE IMMUNE RESPONSE IS INITIATED. SYSTEMIC INFLAMMATION ENHANCES THE BIOLOGICAL RESPONSE TO MOBILIZE ADDITIONAL CELLS FROM CENTRAL AND PERIPHERAL IMMUNE/HEMATOPOIETIC SYSTEM. LOCAL MECHANISMS TO LIMIT INFLAMMATION ARE INITIATED AND LEAD TO HEALING. DURING THE NORMAL INFLAMMATORY PROCESS, THERE IS A BALANCE BETWEEN THE PRODUCTION OF INFLAMMATORY CHEMOKINES/CYTOKINES SUCH AS TUMOR NECROSIS FACTOR (TNF)-ALPHA, INTERLEUKIN (IL)-6 AND IL-1 AND THE PRODUCTION OF COMPOUNDS THAT LIMIT INFLAMMATION AND HAVE AN IMMUNE SUPPRESSIVE EFFECT, SUCH AS IL-10 AND TRANSFORMING FACTOR (TGF) BETA. IL-6 AND IL-6/SOLUBLE IL-6 RECEPTOR (R) COMPLEX STIMULATE LIVER CELLS TO PRODUCE INFLAMMATORY PROTEINS, WHICH REPRESENTS THE SYSTEMIC INFLAMMATION RESPONSE. THE MAGNITUDE AND THE DURATION OF THE SYSTEMIC INFLAMMATORY RESPONSE ARE LINKED TO THE CAUSE, UNDER GENETIC AND EPIGENETIC CONTROL. SIGNIFICANT INFLAMMATION AS SEEN IN SEPTIC SHOCK, IN SEVERE FORMS OF INFECTIONS OR IN CERTAIN ACTIVE CANCERS, REPRESENTS THE "BAD INFLAMMATION", CORRELATED WITH A POOR PROGNOSIS. IN ADDITION, THE PERSISTENCE OF A CHRONIC SMOLDERING INFLAMMATION MAY LEAD TO PATHOLOGICAL SITUATIONS WHICH ARE OBSERVED IN THE MAJORITY OF INFLAMMATORY, DEGENERATIVE, DYSMETABOLIC, OR DYSIMMUNE DISEASES AND CANCER. CHRONIC SMOLDERING INFLAMMATION IS A CROSS BETWEEN DIFFERENT PATHOLOGICAL SITUATIONS POSSIBLY LINKED. IN ADDITION, WITHIN THE TUMOR MICROENVIRONMENT, INFLAMMATORY PROCESS RESULTS FROM DIFFERENT CELLULAR MECHANISMS MODULATED BY METABOLIC AND VASCULAR CHANGES. ON THE CONTRARY, A LIMITED AND BALANCED INFLAMMATION INITIATES THE NORMAL IMMUNE RESPONSE, INCLUDING THE ADAPTIVE RESPONSE WHICH AMPLIFIES ANY IMMUNOTHERAPY, INCLUDING VACCINES. IMMUNE CHECKPOINT INHIBITORS AND CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS ARE ASSOCIATED WITH CYTOKINE RELEASE SYNDROME, A CLINICAL RISK LEADING TO THE USE OF ANTI-CYTOKINE DRUGS. NOWADAYS, IT IS TIME TO MONITOR THE DYNAMIC INFLAMMATORY PROCESS FOR A BETTER IMMUNE PRECISION MEDICINE IN BOTH INFECTIONS AND CANCER. 2021 5 2954 35 GENETIC AND EPIGENETIC FACTORS DETERMINING NAFLD RISK. BACKGROUND: HEPATIC STEATOSIS IS A COMMON CHRONIC LIVER DISEASE THAT CAN PROGRESS INTO MORE SEVERE STAGES OF NAFLD OR PROMOTE THE DEVELOPMENT OF LIFE-THREATENING SECONDARY DISEASES FOR SOME OF THOSE AFFECTED. THESE INCLUDE THE LIVER ITSELF (NONALCOHOLIC STEATOHEPATITIS OR NASH; FIBROSIS AND CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA) OR OTHER ORGANS SUCH AS THE VESSELS AND THE HEART (CARDIOVASCULAR DISEASE) OR THE ISLETS OF LANGERHANS (TYPE 2 DIABETES). IN ADDITION TO ELEVATED CALORIC INTAKE AND A SEDENTARY LIFESTYLE, GENETIC AND EPIGENETIC PREDISPOSITION CONTRIBUTE TO THE DEVELOPMENT OF NAFLD AND THE SECONDARY DISEASES. SCOPE OF REVIEW: WE PRESENT DATA FROM GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND FUNCTIONAL STUDIES IN RODENTS WHICH DESCRIBE POLYMORPHISMS IDENTIFIED IN GENES RELEVANT FOR THE DISEASE AS WELL AS CHANGES CAUSED BY ALTERED DNA METHYLATION AND GENE REGULATION VIA SPECIFIC MIRNAS. THE REVIEW ALSO PROVIDES INFORMATION ON THE CURRENT STATUS OF THE USE OF GENETIC AND EPIGENETIC FACTORS AS RISK MARKERS. MAJOR CONCLUSION: WITH OUR OVERVIEW WE PROVIDE AN INSIGHT INTO THE GENETIC AND EPIGENETIC LANDSCAPE OF NAFLD AND ARGUE ABOUT THE APPLICABILITY OF CURRENTLY DEFINED RISK SCORES FOR RISK STRATIFICATION AND CONCLUDE THAT FURTHER EFFORTS ARE NEEDED TO MAKE THE SCORES MORE USABLE AND MEANINGFUL. 2021 6 1302 29 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 7 6163 33 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 8 5250 35 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 9 6164 41 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 10 599 38 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 11 615 33 BIOACTIVE COMPONENTS AND POSSIBLE ACTIVITIES OF MEDICINAL MUSHROOMS IN ALLEVIATING THE PATHOGENESIS OF NONALCOHOLIC FATTY LIVER DISEASE (REVIEW). NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A GLOBAL DISEASE THAT IS CLOSELY ASSOCIATED WITH OBESITY, TYPE 2 DIABETES MELLITUS, AND CARDIOVASCULAR DISEASE. EXCESSIVE FAT ACCUMULATION, FATTY DEGENERATION, AND CHRONIC INFLAMMATION OF THE LIVER ACTIVATE THE PROGRESSION OF NAFLD FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS AND FURTHER TO LIVER FIBROSIS, CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. THE UNDERLYING MECHANISM FOR THE DEVELOPMENT AND PROGRESSION OF NAFLD IS COMPLEX AND A MULTIPLE-HIT HYPOTHESIS INCLUDING DIETARY, ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS HAS BEEN RAISED. INCREASED DE NOVO LIPOGENESIS, DECREASED LIPOLYSIS, AND INSULIN RESISTANCE ARE ASSOCIATED WITH THE DEVELOPMENT OF NAFLD. CURRENTLY, NO EFFECTIVE DRUG THERAPIES ARE APPROVED FOR THE TREATMENT OF NAFLD. SEVERAL MEDICINAL MUSHROOMS HAVE BEEN FOUND TO HAVE SIGNIFICANT WEIGHT CONTROL AND GUT MICROBE MODULATION ACTIVITIES AND ANTIHYPERTRIGLYCERIDEMIC, ANTIHYPERGLYCEMIC, ANTIOXIDANT, AND ANTI-INFLAMMATORY EFFECTS, WHICH MAY BE USEFUL TO PREVENT AND ATTENUATE THE DEVELOPMENT AND PROGRESSION OF NAFLD. THESE BENEFICIAL EFFECTS ARE ASSOCIATED WITH MUSHROOMS' BIOACTIVE COMPONENTS, SUCH AS POLYSACCHARIDES, DIETARY FIBERS, ANTIOXIDANTS, AND OTHER COMPOUNDS DERIVED FROM FRUITING BODIES, CULTURED MYCELIUM, AND/OR BROTH OF MEDICINAL MUSHROOMS. THIS ARTICLE PRESENTS AN OVERVIEW OF MULTIPLE ASPECTS OF NAFLD, INCLUDING THE EPIDEMIOLOGY, PATHOGENESIS, MANAGEMENT, AND TREATMENT. THE BIOACTIVE COMPONENTS AND POSSIBLE ACTIVITIES OF MEDICINAL MUSHROOMS IN ALLEVIATING THE PATHOGENESIS OF NAFLD ARE ALSO REVIEWED. 2021 12 4070 34 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 13 241 41 ADIPOCYTE, IMMUNE CELLS, AND MIRNA CROSSTALK: A NOVEL REGULATOR OF METABOLIC DYSFUNCTION AND OBESITY. OBESITY IS CHARACTERIZED AS A COMPLEX AND MULTIFACTORIAL EXCESS ACCRETION OF ADIPOSE TISSUE (AT) ACCOMPANIED WITH ALTERATIONS IN THE IMMUNE RESPONSE THAT AFFECTS VIRTUALLY ALL AGE AND SOCIOECONOMIC GROUPS AROUND THE GLOBE. THE ABNORMAL ACCUMULATION OF AT LEADS TO SEVERAL METABOLIC DISEASES, INCLUDING NONALCOHOLIC FATTY LIVER DISORDER (NAFLD), LOW-GRADE INFLAMMATION, TYPE 2 DIABETES MELLITUS (T2DM), CARDIOVASCULAR DISORDERS (CVDS), AND CANCER. AT IS AN ENDOCRINE ORGAN COMPOSED OF ADIPOCYTES AND IMMUNE CELLS, INCLUDING B-CELLS, T-CELLS AND MACROPHAGES. THESE IMMUNE CELLS SECRETE VARIOUS CYTOKINES AND CHEMOKINES AND CROSSTALK WITH ADIPOKINES TO MAINTAIN METABOLIC HOMEOSTASIS AND LOW-GRADE CHRONIC INFLAMMATION. A NOVEL FORM OF ADIPOKINES, MICRORNA (MIRS), IS EXPRESSED IN MANY DEVELOPING PERIPHERAL TISSUES, INCLUDING ATS, T-CELLS, AND MACROPHAGES, AND MODULATES THE IMMUNE RESPONSE. MIRS ARE ESSENTIAL FOR INSULIN RESISTANCE, MAINTAINING THE TUMOR MICROENVIRONMENT, AND OBESITY-ASSOCIATED INFLAMMATION (OAI). THE ABNORMAL REGULATION OF AT, T-CELLS, AND MACROPHAGE MIRS MAY CHANGE THE FUNCTION OF DIFFERENT ORGANS INCLUDING THE PANCREAS, HEART, LIVER, AND SKELETAL MUSCLE. SINCE OBESITY AND INFLAMMATION ARE CLOSELY ASSOCIATED, THE DYSREGULATED EXPRESSION OF MIRS IN INFLAMMATORY ADIPOCYTES, T-CELLS, AND MACROPHAGES SUGGEST THE IMPORTANCE OF MIRS IN OAI. THEREFORE, IN THIS REVIEW ARTICLE, WE HAVE ELABORATED THE ROLE OF MIRS AS EPIGENETIC REGULATORS AFFECTING ADIPOCYTE DIFFERENTIATION, IMMUNE RESPONSE, AT BROWNING, ADIPOGENESIS, LIPID METABOLISM, INSULIN RESISTANCE (IR), GLUCOSE HOMEOSTASIS, OBESITY, AND METABOLIC DISORDERS. FURTHER, WE WILL DISCUSS A SET OF ALTERED MIRS AS NOVEL BIOMARKERS FOR METABOLIC DISEASE PROGRESSION AND THERAPEUTIC TARGETS FOR OBESITY. 2021 14 4326 35 MICRORNAS IN THE PATHOGENESIS OF NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), OR, MORE ACCURATELY, METABOLIC ASSOCIATED FATTY LIVER DISEASE, ACCOUNTS FOR A LARGE PROPORTION OF CHRONIC LIVER DISORDERS WORLDWIDE AND IS CLOSELY ASSOCIATED WITH OTHER CONDITIONS SUCH AS CARDIOVASCULAR DISEASE, OBESITY, AND TYPE 2 DIABETES MELLITUS. NAFLD RANGES FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS (NASH) AND CAN PROGRESS TO CIRRHOSIS AND, EVENTUALLY, ALSO HEPATOCELLULAR CARCINOMA. THE MORBIDITY AND MORTALITY ASSOCIATED WITH NAFLD ARE INCREASING RAPIDLY YEAR ON YEAR. CONSEQUENTLY, THERE IS AN URGENT NEED TO UNDERSTAND THE ETIOLOGY AND PATHOGENESIS OF NAFLD AND IDENTIFY EFFECTIVE THERAPEUTIC TARGETS. MICRORNAS (MIRNAS), IMPORTANT EPIGENETIC FACTORS, HAVE RECENTLY BEEN PROPOSED TO PARTICIPATE IN NAFLD PATHOGENESIS. HERE, WE REVIEW THE ROLES OF MIRNAS IN LIPID METABOLISM, INFLAMMATION, APOPTOSIS, FIBROSIS, HEPATIC STELLATE CELL ACTIVATION, INSULIN RESISTANCE, AND OXIDATIVE STRESS, KEY FACTORS THAT CONTRIBUTE TO THE OCCURRENCE AND PROGRESSION OF NAFLD. ADDITIONALLY, WE SUMMARIZE THE ROLE OF MIRNA-ENRICHED EXTRACELLULAR VESICLES IN NAFLD. THESE MIRNAS MAY COMPRISE SUITABLE THERAPEUTIC TARGETS FOR THE TREATMENT OF THIS CONDITION. 2021 15 5190 33 PRENATAL CAUSES OF KIDNEY DISEASE. IT HAS RECENTLY BEEN INCREASINGLY RECOGNISED THAT DISTURBED INTRA-UTERINE DEVELOPMENT MAY IMPACT ON RENAL AND CARDIOVASCULAR RISK IN ADULT LIFE, E.G. ALBUMINURIA AND CHRONIC KIDNEY DISEASE, HYPERTENSION, TYPE 2 DIABETES OR CARDIOVASCULAR EVENTS. ACCORDING TO BARKER'S HYPOTHESIS, WHEN RESOURCES IN UTERO ARE RESTRICTED, THEIR ALLOCATION TO THE DEVELOPMENT OF THE KIDNEY AND PANCREATIC ISLETS IS RESTRICTED TO GUARANTEE APPROPRIATE DEVELOPMENT OF THE BRAIN AND HEART. THE UNDERLYING EPIGENETIC MECHANISMS INVOLVE MODIFICATION OF GENE EXPRESSION BY ALTERED DNA METHYLATION AND HISTONE ACETYLATION AS WELL AS BY ALLOCATION OF STEM CELLS. THE RESULT OF THIS TRADE-OFF BETWEEN THE BRAIN AND KIDNEY DURING ORGANOGENESIS IS A DIMINISHED NUMBER OF NEPHRONS ('NEPHRON UNDERDOSING') WHICH PREDISPOSES TO ALBUMINURIA AND RISK OF CHRONIC KIDNEY DISEASE, AS WELL AS HYPERTENSION. IN PARALLEL, CHANGED APPETITE CENTRES, INSULIN RESISTANCE AND BETA-CELL DEVELOPMENT PREDISPOSE TO OBESITY, METABOLIC SYNDROME AND TYPE 2 DIABETES AND THE RESULTING RENAL SEQUELAE. NUMEROUS FACTORS MAY TRIGGER INTRA-UTERINE RESTRICTION OF FETAL GROWTH, SUCH AS UTERINE UNDERPERFUSION, MATERNAL MALNUTRITION, HYPERGLYCAEMIA AND HYPERINSULINAEMIA OF THE MOTHER, SMOKING OR MEDICATIONS. 2009 16 4464 22 MOLECULAR MECHANISMS OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)/NONALCOHOLIC STEATOHEPATITIS (NASH). NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST COMMON CHRONIC LIVER DISEASES WORLDWIDE AND HAS GARNERED INCREASING ATTENTION IN RECENT DECADES. NAFLD IS CHARACTERIZED BY A WIDE RANGE OF LIVER CHANGES, FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS (NASH), CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. THE PATHOGENESIS OF NAFLD/NASH IS VERY COMPLICATED AND INVOLVES LIPID ACCUMULATION, INSULIN RESISTANCE, INFLAMMATION, AND FIBROGENESIS. IN ADDITION, NAFLD IS CLOSELY ASSOCIATED WITH COMPLICATIONS SUCH AS OBESITY, DYSLIPIDEMIA, AND TYPE 2 DIABETES. IN PARTICULAR, THE CLINICAL SPECTRUM, PATHOPHYSIOLOGY, AND THERAPEUTIC OPTIONS OF NAFLD SHARE MANY THINGS IN COMMON WITH DIABETES. INSULIN RESISTANCE IS AN UNDERLYING BASIS FOR THE PATHOGENESIS OF DIABETES AND NAFLD. THIS CHAPTER FOCUSES ON THE MOLECULAR MECHANISM INVOLVED IN THE PATHOGENESIS OF INSULIN RESISTANCE, DIABETES, AND NASH/NAFLD INCLUDING THOSE THAT DRIVE DISEASE PROGRESSION SUCH AS OXIDATIVE STRESS, GENETIC AND EPIGENETIC MECHANISMS, ADIPONECTIN, CYTOKINES, AND IMMUNE CELLS. 2021 17 6335 35 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 18 2178 34 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 19 3863 39 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 20 3817 34 INTRAUTERINE PROGRAMMING OF THE ENDOCRINE PANCREAS. EPIDEMIOLOGICAL STUDIES HAVE REVEALED STRONG RELATIONSHIPS BETWEEN POOR FOETAL GROWTH AND SUBSEQUENT DEVELOPMENT OF THE METABOLIC SYNDROME. PERSISTING EFFECTS OF EARLY MALNUTRITION BECOME TRANSLATED INTO PATHOLOGY, THEREBY DETERMINE CHRONIC RISK FOR DEVELOPING GLUCOSE INTOLERANCE AND DIABETES. THESE EPIDEMIOLOGICAL OBSERVATIONS IDENTIFY THE PHENOMENA OF FOETAL PROGRAMMING WITHOUT EXPLAINING THE UNDERLYING MECHANISMS THAT ESTABLISH THE CAUSAL LINK. ANIMAL MODELS HAVE BEEN ESTABLISHED AND STUDIES HAVE DEMONSTRATED THAT REDUCTION IN THE AVAILABILITY OF NUTRIENTS DURING FOETAL DEVELOPMENT PROGRAMS THE ENDOCRINE PANCREAS AND INSULIN-SENSITIVE TISSUES. WHATEVER THE TYPE OF FOETAL MALNUTRITION, WHETHER THERE ARE NOT ENOUGH CALORIES OR PROTEIN IN FOOD OR AFTER PLACENTAL DEFICIENCY, MALNOURISHED PUPS ARE BORN WITH A DEFECT IN THEIR BETA-CELL POPULATION THAT WILL NEVER COMPLETELY RECOVER, AND INSULIN-SENSITIVE TISSUES WILL BE DEFINITIVELY ALTERED. DESPITE THE SIMILAR ENDPOINT, DIFFERENT CELLULAR AND PHYSIOLOGICAL MECHANISMS ARE PROPOSED. HORMONES OPERATIVE DURING FOETAL LIFE LIKE INSULIN ITSELF, INSULIN-LIKE GROWTH FACTORS AND GLUCOCORTICOIDS, AS WELL AS SPECIFIC MOLECULES LIKE TAURINE, OR ISLET VASCULARIZATION WERE IMPLICATED AS POSSIBLE FACTORS AMPLIFYING THE DEFECT. THE MOLECULAR MECHANISMS RESPONSIBLE FOR INTRAUTERINE PROGRAMMING OF THE BETA CELLS ARE STILL ELUSIVE, BUT TWO HYPOTHESES RECENTLY EMERGED: THE FIRST ONE IMPLIES PROGRAMMING OF MITOCHONDRIA AND THE SECOND, EPIGENETIC REGULATION. 2007