1 2702 118 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 2 4185 36 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 3 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 4 948 27 CHRONIC METABOLIC DERANGEMENT-INDUCED COGNITIVE DEFICITS AND NEUROTOXICITY ARE ASSOCIATED WITH REST INACTIVATION. CHRONIC METABOLIC ALTERATIONS MAY REPRESENT A RISK FACTOR FOR THE DEVELOPMENT OF COGNITIVE IMPAIRMENT, DEMENTIA, OR NEURODEGENERATIVE DISEASES. HYPERGLYCEMIA AND OBESITY ARE KNOWN TO IMPRINT EPIGENETIC MARKERS THAT COMPROMISE THE PROPER EXPRESSION OF CELL SURVIVAL GENES. HERE, WE SHOWED THAT CHRONIC HYPERGLYCEMIA (60 DAYS) INDUCED BY A SINGLE INTRAPERITONEAL INJECTION OF STREPTOZOTOCIN COMPROMISED COGNITION BY REDUCING HIPPOCAMPAL ERK SIGNALING AND BY INDUCING NEUROTOXICITY IN RATS. THE MECHANISMS APPEAR TO BE LINKED TO REDUCED ACTIVE DNA DEMETHYLATION AND DIMINISHED EXPRESSION OF THE NEUROPROTECTIVE TRANSCRIPTION FACTOR REST. THE IMPACT OF THE RELATIONSHIP BETWEEN ADIPOSITY AND DNA HYPERMETHYLATION ON REST EXPRESSION WAS ALSO DEMONSTRATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN OBESE CHILDREN WITH REDUCED LEVELS OF BLOOD ASCORBATE. THE REVERSIBLE NATURE OF EPIGENETIC MODIFICATIONS AND THE COGNITIVE IMPAIRMENT REPORTED IN OBESE CHILDREN, ADOLESCENTS, AND ADULTS SUGGEST THAT THE CORRECTION OF THE ANTHROPOMETRY AND THE PERIPHERAL METABOLIC ALTERATIONS WOULD PROTECT BRAIN HOMEOSTASIS AND REDUCE THE RISK OF DEVELOPING NEURODEGENERATIVE DISEASES. 2019 5 2964 26 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 1974 30 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 7 3837 24 IONIZING RADIATION-INDUCED OXIDATIVE STRESS, EPIGENETIC CHANGES AND GENOMIC INSTABILITY: THE PIVOTAL ROLE OF MITOCHONDRIA. PURPOSE: TO REVIEW THE DATA CONCERNING THE ROLE OF ENDOGENOUSLY GENERATED REACTIVE OXYGEN SPECIES (ROS) IN THE NON-TARGETED IONIZING RADIATION (IR) EFFECTS AND IN DETERMINATION OF THE CELL POPULATION'S FATE, BOTH EARLY AFTER EXPOSURE AND AFTER MANY GENERATIONS. CONCLUSIONS: THE SHORT-TERM AS WELL AS CHRONIC OXIDATIVE STRESS RESPONSES MAINLY ARE PRODUCED DUE TO ROS GENERATION BY THE ELECTRON TRANSPORT CHAIN (ETC) OF THE MITOCHONDRIA AND BY THE CYTOPLASMIC NADPH OXIDASES. WHETHER THE INDUCTION OF THE OXIDATIVE STRESS AND ITS CONSEQUENCES OCCUR OR ARE HAMPERED IN A SINGLE CELL LARGELY DEPENDS ON THE INTERACTION BETWEEN THE NUCLEUS AND THE CELLULAR POPULATION OF SEVERAL HUNDRED OR THOUSANDS OF MITOCHONDRIA THAT ARE GENETICALLY HETEROGENEOUS. HIGH INTRA-MITOCHONDRIAL ROS LEVEL IS DAMAGING THE MITOCHONDRIAL (MT) DNA AND ITS MUTATIONS AFFECT THE EPIGENETIC CONTROL MECHANISMS OF THE NUCLEAR (N) DNA, BY DECREASING THE ACTIVITY OF METHYLTRANSFERASES AND THUS, CAUSING GLOBAL DNA HYPOMETHYLATION. THESE CHANGES ARE TRANSMITTED TO THE PROGENY OF THE IRRADIATED CELLS. THE CHRONIC OXIDATIVE STRESS IS THE MAIN CAUSE OF THE LATE POST-RADIATION EFFECTS, INCLUDING CANCER, AND THIS MAKES IT AN IMPORTANT ADVERSE EFFECT OF EXPOSURE TO IR AND A TARGET FOR RADIOLOGICAL PROTECTION. 2015 8 4974 23 PATHOPHYSIOLOGICAL MECHANISMS LEADING TO MUSCLE LOSS IN CHRONIC KIDNEY DISEASE. LOSS OF MUSCLE PROTEINS IS A DELETERIOUS CONSEQUENCE OF CHRONIC KIDNEY DISEASE (CKD) THAT CAUSES A DECREASE IN MUSCLE STRENGTH AND FUNCTION, AND CAN LEAD TO A REDUCTION IN QUALITY OF LIFE AND INCREASED RISK OF MORBIDITY AND MORTALITY. THE EFFECTIVENESS OF CURRENT TREATMENT STRATEGIES IN PREVENTING OR REVERSING MUSCLE PROTEIN LOSSES IS LIMITED. THE LIMITATIONS LARGELY STEM FROM THE SYSTEMIC NATURE OF DISEASES SUCH AS CKD, WHICH STIMULATE SKELETAL MUSCLE PROTEIN DEGRADATION PATHWAYS WHILE SIMULTANEOUSLY ACTIVATING MECHANISMS THAT IMPAIR MUSCLE PROTEIN SYNTHESIS AND REPAIR. STIMULI THAT INITIATE MUSCLE PROTEIN LOSS INCLUDE METABOLIC ACIDOSIS, INSULIN AND IGF1 RESISTANCE, CHANGES IN HORMONES, CYTOKINES, INFLAMMATORY PROCESSES AND DECREASED APPETITE. A GROWING BODY OF EVIDENCE SUGGESTS THAT SIGNALLING MOLECULES SECRETED FROM MUSCLE CAN ENTER THE CIRCULATION AND SUBSEQUENTLY INTERACT WITH RECIPIENT ORGANS, INCLUDING THE KIDNEYS, WHILE CONVERSELY, PATHOLOGICAL EVENTS IN THE KIDNEY CAN ADVERSELY INFLUENCE PROTEIN METABOLISM IN SKELETAL MUSCLE, DEMONSTRATING THE EXISTENCE OF CROSSTALK BETWEEN KIDNEY AND MUSCLE. TOGETHER, THESE SIGNALS, WHETHER DIRECT OR INDIRECT, INDUCE CHANGES IN THE LEVELS OF REGULATORY AND EFFECTOR PROTEINS VIA ALTERATIONS IN MRNAS, MICRORNAS AND CHROMATIN EPIGENETIC RESPONSES. ADVANCES IN OUR UNDERSTANDING OF THE SIGNALS AND PROCESSES THAT MEDIATE MUSCLE LOSS IN CKD AND OTHER MUSCLE WASTING CONDITIONS WILL SUPPORT THE FUTURE DEVELOPMENT OF THERAPEUTIC STRATEGIES TO REDUCE MUSCLE LOSS. 2022 9 6205 37 THE INFLUENCE OF PLANT EXTRACTS AND PHYTOCONSTITUENTS ON ANTIOXIDANT ENZYMES ACTIVITY AND GENE EXPRESSION IN THE PREVENTION AND TREATMENT OF IMPAIRED GLUCOSE HOMEOSTASIS AND DIABETES COMPLICATIONS. DIABETES IS A COMPLEX METABOLIC DISORDER RESULTING EITHER FROM INSULIN RESISTANCE OR AN IMPAIRED INSULIN SECRETION. PROLONGED ELEVATED BLOOD GLUCOSE CONCENTRATION, THE KEY CLINICAL SIGN OF DIABETES, INITIATES AN ENHANCEMENT OF REACTIVE OXYGEN SPECIES DERIVED FROM GLUCOSE AUTOXIDATION AND GLYCOSYLATION OF PROTEINS. CONSEQUENTLY, CHRONIC OXIDATIVE STRESS OVERWHELMS CELLULAR ENDOGENOUS ANTIOXIDANT DEFENSES AND LEADS TO THE ACUTE AND LONG-STANDING STRUCTURAL AND FUNCTIONAL CHANGES OF MACROMOLECULES RESULTING IN IMPAIRED CELLULAR FUNCTIONING, CELL DEATH AND ORGAN DYSFUNCTION. THE OXIDATIVE STRESS PROVOKED CHAIN OF PATHOLOGICAL EVENTS OVER TIME CAUSE DIABETIC COMPLICATIONS SUCH AS NEPHROPATHY, PERIPHERAL NEUROPATHY, CARDIOMYOPATHY, RETINOPATHY, HYPERTENSION, AND LIVER DISEASE. UNDER DIABETIC CONDITIONS, ACCOMPANYING GENOME/EPIGENOME AND METABOLITE MARKERS ALTERATIONS MAY ALSO AFFECT GLUCOSE HOMEOSTASIS, PANCREATIC BETA-CELLS, MUSCLE, LIVER, AND ADIPOSE TISSUE. BY PROVIDING DEEPER GENETIC/EPIGENETIC INSIGHT OF DIRECT OR INDIRECT DIETARY EFFECTS, NUTRIGENOMICS OFFERS A PROMISING OPPORTUNITY TO IMPROVE THE QUALITY OF LIFE OF DIABETIC PATIENTS. NATURAL PLANT EXTRACTS, OR THEIR NATURALLY OCCURRING COMPOUNDS, WERE SHOWN TO BE VERY PROFICIENT IN THE PREVENTION AND TREATMENT OF DIFFERENT PATHOLOGIES ASSOCIATED WITH OXIDATIVE STRESS INCLUDING DIABETES AND ITS COMPLICATIONS. CONSIDERING THAT FOOD INTAKE IS ONE OF THE CRUCIAL COMPONENTS IN DIABETES' PREVALENCE, PROGRESSION AND COMPLICATIONS, THIS REVIEW SUMMARIZES THE EFFECT OF THE MAJOR PLANT SECONDARY METABOLITE AND PHYTOCONSTITUENTS ON THE ANTIOXIDANT ENZYMES ACTIVITY AND GENE EXPRESSION UNDER DIABETIC CONDITIONS. 2021 10 3287 34 HIERARCHICAL AND CYBERNETIC NATURE OF BIOLOGIC SYSTEMS AND THEIR RELEVANCE TO HOMEOSTATIC ADAPTATION TO LOW-LEVEL EXPOSURES TO OXIDATIVE STRESS-INDUCING AGENTS. DURING EVOLUTION IN AN AEROBIC ENVIRONMENT, MULTICELLULAR ORGANISMS SURVIVED BY ADAPTIVE RESPONSES TO BOTH THE ENDOGENOUS OXIDATIVE METABOLISM IN THE CELLS OF THE ORGANISM AND THE CHEMICALS AND LOW-LEVEL RADIATION TO WHICH THEY HAD BEEN EXPOSED. THE DEFENSE REPERTOIRE EXISTS AT ALL LEVELS OF THE BIOLOGICAL HIERARCHY--FROM THE MOLECULAR AND BIOCHEMICAL LEVEL TO THE CELLULAR AND TISSUE LEVEL TO THE ORGAN AND ORGAN SYSTEM LEVEL. CELLS CONTAIN PREVENTIVE ANTIOXIDANTS TO SUPPRESS OXIDATIVE DAMAGE TO MEMBRANES. CELLS ALSO CONTAIN PROTEINS AND DNA; BUILT-IN REDUNDANCIES FOR DAMAGED MOLECULES AND ORGANELLES; TIGHTLY COUPLED REDOX SYSTEMS; POOLS OF REDUCTANTS; ANTIOXIDANTS; DNA REPAIR MECHANISMS AND SENSITIVE SENSOR MOLECULES SUCH AS NUCLEAR FACTOR KAPPA BETA; AND SIGNAL TRANSDUCTION MECHANISMS AFFECTING BOTH TRANSCRIPTION AND POST-TRANSLATIONAL MODIFICATION OF PROTEINS NEEDED TO COPE WITH OXIDATIVE STRESS. THE BIOLOGIC CONSEQUENCES OF THE LOW-LEVEL RADIATION THAT EXCEEDS THE BACKGROUND LEVEL OF OXIDATIVE DAMAGE COULD BE NECROSIS OR APOPTOSIS, CELL PROLIFERATION, OR CELL DIFFERENTIATION. THESE EFFECTS ARE TRIGGERED BY OXIDATIVE STRESS-INDUCED SIGNAL TRANSDUCTION MECHANISMS--AN EPIGENETIC, NOT GENOTOXIC, PROCESS. IF THE END POINTS OF CELL PROLIFERATION, DIFFERENTIATION, OR CELL DEATH ARE NOT SEEN AT FREQUENCIES ABOVE BACKGROUND LEVELS IN AN ORGANISM, IT IS UNLIKELY THAT LOW-LEVEL RADIATION WOULD PLAY A ROLE IN THE MULTISTEP PROCESSES OF CHRONIC DISEASES SUCH AS CANCER. THE MECHANISM LINKED TO HOMEOSTATIC REGULATION OF PROLIFERATION AND ADAPTIVE FUNCTIONS IN A MULTICELLULAR ORGANISM COULD PROVIDE PROTECTION OF ANY ONE CELL RECEIVING DEPOSITED ENERGY BY THE RADIATION TRACT THROUGH THE SHARING OF REDUCTANTS AND BY TRIGGERING APOPTOSIS OF TARGET STEM CELLS. EXAMPLES OF THE ROLE OF GAP JUNCTIONAL INTERCELLULAR COMMUNICATION IN THE ADAPTIVE RESPONSE OF CELLS AND THE BYSTANDER EFFECT ILLUSTRATE HOW THE INTERACTION OF CELLS CAN MODULATE THE EFFECT OF RADIATION ON THE SINGLE CELL. 1998 11 5252 30 PROGRAMMING AND REGULATION OF METABOLIC HOMEOSTASIS. EVIDENCE IS PRESENTED THAT THE RATE AND EQUILIBRIUM CONSTANTS IN MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION SET AND MAINTAIN METABOLIC HOMEOSTASIS IN EUKARYOTIC CELLS. THESE INTERNAL CONSTANTS DETERMINE THE ENERGY STATE ([ATP]/[ADP][PI]), AND THE ENERGY STATE MAINTAINS HOMEOSTASIS THROUGH A BIDIRECTIONAL SENSORY/SIGNALING CONTROL NETWORK THAT REACHES EVERY ASPECT OF CELLULAR METABOLISM. THE ENERGY STATE IS MAINTAINED WITH HIGH PRECISION (TO APPROXIMATELY 1 PART IN 10(10)), AND THE CONTROL SYSTEM CAN RESPOND TO TRANSIENT CHANGES IN ENERGY DEMAND (ATP UTILIZATION) OF MORE THAN 100 TIMES THE RESTING RATE. EPIGENETIC AND ENVIRONMENTAL FACTORS ARE ABLE TO "FINE-TUNE" THE PROGRAMMED SET POINT OVER A NARROW RANGE TO MEET THE SPECIAL NEEDS ASSOCIATED WITH CELL DIFFERENTIATION AND CHRONIC CHANGES IN METABOLIC REQUIREMENTS. THE RESULT IS ROBUST ACROSS-PLATFORM CONTROL OF METABOLISM, WHICH IS ESSENTIAL TO CELLULAR DIFFERENTIATION AND THE EVOLUTION OF COMPLEX ORGANISMS. A MODEL OF OXIDATIVE PHOSPHORYLATION IS PRESENTED, FOR WHICH THE STEADY-STATE RATE EXPRESSION HAS BEEN DERIVED AND COMPUTER PROGRAMMED. THE BEHAVIOR OF OXIDATIVE PHOSPHORYLATION PREDICTED BY THE MODEL IS SHOWN TO FIT THE EXPERIMENTAL DATA AVAILABLE FOR ISOLATED MITOCHONDRIA AS WELL AS FOR CELLS AND TISSUES. THIS INCLUDES MEASUREMENTS FROM SEVERAL DIFFERENT MAMMALIAN TISSUES AS WELL AS FROM INSECT FLIGHT MUSCLE AND PLANTS. THE RESPIRATORY CHAIN AND OXIDATIVE PHOSPHORYLATION IS REMARKABLY SIMILAR FOR ALL HIGHER PLANTS AND ANIMALS. THIS IS CONSISTENT WITH THE EFFICIENT SYNTHESIS OF ATP AND PRECISE CONTROL OF METABOLIC HOMEOSTASIS PROVIDED BY OXIDATIVE PHOSPHORYLATION BEING A KEY TO CELLULAR DIFFERENTIATION AND THE EVOLUTION OF STRUCTURES WITH SPECIALIZED FUNCTION. 2015 12 3836 32 IONIZING RADIATION POTENTIATES HIGH-FAT DIET-INDUCED INSULIN RESISTANCE AND REPROGRAMS SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS. EXPOSURE TO IONIZING RADIATION INCREASES THE RISK OF CHRONIC METABOLIC DISORDERS SUCH AS INSULIN RESISTANCE AND TYPE 2 DIABETES LATER IN LIFE. WE HYPOTHESIZED THAT IRRADIATION REPROGRAMS THE EPIGENOME OF METABOLIC PROGENITOR CELLS, WHICH COULD ACCOUNT FOR IMPAIRED METABOLISM AFTER CANCER TREATMENT. C57BL/6 MICE WERE TREATED WITH A SINGLE DOSE OF IRRADIATION AND SUBJECTED TO HIGH-FAT DIET (HFD). RNA SEQUENCING AND REDUCED REPRESENTATION BISULFITE SEQUENCING WERE USED TO CREATE TRANSCRIPTOMIC AND EPIGENOMIC PROFILES OF PREADIPOCYTES AND SKELETAL MUSCLE SATELLITE CELLS COLLECTED FROM IRRADIATED MICE. MICE SUBJECTED TO TOTAL BODY IRRADIATION SHOWED ALTERATIONS IN GLUCOSE METABOLISM AND, WHEN CHALLENGED WITH HFD, MARKED HYPERINSULINEMIA. INSULIN SIGNALING WAS CHRONICALLY DISRUPTED IN SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS COLLECTED FROM IRRADIATED MICE AND DIFFERENTIATED IN CULTURE. EPIGENOMIC PROFILING OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS FROM IRRADIATED ANIMALS REVEALED SUBSTANTIAL DNA METHYLATION CHANGES, NOTABLY FOR GENES REGULATING THE CELL CYCLE, GLUCOSE/LIPID METABOLISM, AND EXPRESSION OF EPIGENETIC MODIFIERS. OUR RESULTS SHOW THAT TOTAL BODY IRRADIATION ALTERS INTRACELLULAR SIGNALING AND EPIGENETIC PATHWAYS REGULATING CELL PROLIFERATION AND DIFFERENTIATION OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS AND PROVIDE A POSSIBLE MECHANISM BY WHICH IRRADIATION USED IN CANCER TREATMENT INCREASES THE RISK FOR METABOLIC DISEASE LATER IN LIFE. 2016 13 1900 29 ENERGY SENSING PATHWAYS: BRIDGING TYPE 2 DIABETES AND COLORECTAL CANCER? THE RECENTLY RAPID INCREASE OF OBESITY AND TYPE 2 DIABETES MELLITUS HAS CAUSED GREAT BURDEN TO OUR SOCIETY. A POSITIVE ASSOCIATION BETWEEN TYPE 2 DIABETES AND RISK OF COLORECTAL CANCER HAS BEEN REPORTED BY INCREASING EPIDEMIOLOGICAL STUDIES. THE MOLECULAR MECHANISM OF THIS CONNECTION REMAINS ELUSIVE. HOWEVER, TYPE 2 DIABETES MAY RESULT IN ABNORMAL CARBOHYDRATE AND LIPID METABOLISM, HIGH LEVELS OF CIRCULATING INSULIN, INSULIN GROWTH FACTOR-1, AND ADIPOCYTOKINES, AS WELL AS CHRONIC INFLAMMATION. ALL THESE FACTORS COULD LEAD TO THE ALTERATION OF ENERGY SENSING PATHWAYS SUCH AS THE AMP ACTIVATED KINASE (PRKA), MECHANISTIC (MAMMALIAN) TARGET OF RAPAMYCIN (MTOR), SIRT1, AND AUTOPHAGY SIGNALING PATHWAYS. THE RESULTED IMPAIRED SIRT1 AND AUTOPHAGY SIGNALING PATHWAY COULD INCREASE THE RISK OF GENE MUTATION AND CANCER GENESIS BY DECREASING GENETIC STABILITY AND DNA MISMATCH REPAIR. THE DYSREGULATED MTOR AND PRKA PATHWAY COULD REMODEL CELL METABOLISM DURING THE GROWTH AND METASTASIS OF CANCER IN ORDER FOR THE CANCER CELL TO SURVIVE THE UNFAVORABLE MICROENVIRONMENT SUCH AS HYPOXIA AND LOW BLOOD SUPPLY. MOREOVER, THESE PATHWAYS MAY BE COUPLING METABOLIC AND EPIGENETIC ALTERATIONS THAT ARE CENTRAL TO ONCOGENIC TRANSFORMATION. FURTHER RESEARCHES INCLUDING MOLECULAR PATHOLOGIC EPIDEMIOLOGIC STUDIES ARE WARRANTED TO BETTER ADDRESS THE PRECISE LINKS BETWEEN THESE TWO IMPORTANT DISEASES. 2017 14 2499 22 EPIGENETICS AND EXERCISE. EPIGENETICS CAN BE DEFINED AS 'THE STRUCTURAL ADAPTATION OF CHROMOSOMAL REGIONS SO AS TO REGISTER, SIGNAL, OR PERPETUATE ALTERED ACTIVITY STATES.' INCREASED TRANSCRIPTION OF KEY REGULATORY, METABOLIC, AND MYOGENIC GENES IS AN EARLY RESPONSE TO EXERCISE AND IS IMPORTANT IN MEDIATING SUBSEQUENT ADAPTATIONS IN SKELETAL MUSCLE. DNA HYPOMETHYLATION AND HISTONE HYPERACETYLATION ARE EMERGING AS IMPORTANT CRUCIAL EVENTS FOR INCREASED TRANSCRIPTION. THE COMPLEX INTERACTIONS BETWEEN MULTIPLE EPIGENETIC MODIFICATIONS AND THEIR REGULATION BY METABOLIC CHANGES AND SIGNALING EVENTS DURING EXERCISE, WITH IMPLICATIONS FOR ENHANCED UNDERSTANDING OF THE ACUTE AND CHRONIC ADAPTATIONS TO EXERCISE, ARE QUESTIONS FOR FURTHER INVESTIGATION. 2019 15 996 25 CHRONIC STRESS, EPIGENETICS, AND ADIPOSE TISSUE METABOLISM IN THE OBESE STATE. IN OBESITY, ENDOCRINE AND METABOLIC PERTURBATIONS, INCLUDING THOSE INDUCED BY CHRONIC ACTIVATION OF THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS, ARE ASSOCIATED WITH THE ACCUMULATION OF ADIPOSE TISSUE AND INFLAMMATION. SUCH CHANGES ARE ATTRIBUTABLE TO A COMBINATION OF GENETIC AND EPIGENETIC FACTORS THAT ARE INFLUENCED BY THE ENVIRONMENT AND EXACERBATED BY CHRONIC ACTIVATION OF THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS. STRESS EXPOSURE AT DIFFERENT LIFE STAGES CAN ALTER ADIPOSE TISSUE METABOLISM DIRECTLY THROUGH EPIGENETIC MODIFICATION OR INDIRECTLY THROUGH THE MANIPULATION OF HYPOTHALAMIC APPETITE REGULATION, AND THEREBY CONTRIBUTE TO ENDOCRINE CHANGES THAT FURTHER DISRUPT WHOLE-BODY ENERGY BALANCE. THIS REVIEW SYNTHESIZES CURRENT KNOWLEDGE, WITH AN EMPHASIS ON HUMAN CLINICAL TRIALS, TO DESCRIBE METABOLIC CHANGES IN ADIPOSE TISSUE AND ASSOCIATED ENDOCRINE, GENETIC AND EPIGENETIC CHANGES IN THE OBESE STATE. IN PARTICULAR, WE DISCUSS EPIGENETIC CHANGES INDUCED BY STRESS EXPOSURE AND THEIR CONTRIBUTION TO APPETITE AND ADIPOCYTE DYSFUNCTION, WHICH COLLECTIVELY PROMOTE THE PATHOGENESIS OF OBESITY. SUCH KNOWLEDGE IS CRITICAL FOR PROVIDING FUTURE DIRECTIONS OF METABOLISM RESEARCH AND TARGETS FOR TREATING METABOLIC DISORDERS. 2020 16 215 29 ACUTE AND LONG-TERM NUTRIENT-LED MODIFICATIONS OF GENE EXPRESSION: POTENTIAL ROLE OF SIRT1 AS A CENTRAL CO-ORDINATOR OF SHORT AND LONGER-TERM PROGRAMMING OF TISSUE FUNCTION. ENVIRONMENTAL FACTORS CAN INFLUENCE THE ACUTE AND LONGER-TERM RISKS OF DEVELOPING DISEASES, INCLUDING TYPE 2 DIABETES MELLITUS AND CARDIOVASCULAR DISEASE; HOWEVER, THE UNDERLYING MECHANISM REMAINS ELUSIVE. INCREASING EVIDENCE SUGGESTS THAT THESE EFFECTS CAN BE ACHIEVED BY MODIFICATION OF METABOLIC GENE EXPRESSION. THESE INCLUDE ACUTE CHANGES IN HISTONE METHYLATION, ACETYLATION, PHOSPHORYLATION, AND UBIQUITINATION AND LONGER-TERM DNA SILENCING ELICITED BY DNA METHYLATION. THUS, AN INCREASED RISK OF DISEASE MAY REFLECT ACUTE OR CHRONIC STABLE MODIFICATION OF GENES THAT REGULATE NUTRIENT HANDLING, LEADING TO ALTERED NUTRIENT UTILIZATION (INCREASED LIPID OXIDATION AT THE EXPENSE OF GLUCOSE UTILIZATION) AND/OR CHANGES IN THE BALANCE BETWEEN NUTRIENT STORAGE AND ENERGY PRODUCTION, THEREBY FAVORING THE DEVELOPMENT OF OBESITY. THE REVIEW ADDRESSES THE HYPOTHESIS THAT EARLY-LIFE EPIGENETIC PROGRAMMING OF GENE EXPRESSION COULD BE MIRRORED BY CHANGES IN ACUTE FUNCTION OF NUCLEAR RECEPTORS, IN PARTICULAR THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS, ACHIEVED BY ENZYMES THAT ARE MORE CONVENTIONALLY INVOLVED IN REGULATING DNA METHYLATION AND POST-TRANSCRIPTIONAL MODIFICATION OF HISTONES. EMPHASIS IS PLACED ON THE POTENTIAL IMPORTANCE OF THE PROTEIN DEACETYLASE SIRTUIN-1 AS A CENTRAL CO-ORDINATOR. 2010 17 1017 33 CIRCADIAN RHYTHMS IN LIVER PHYSIOLOGY AND LIVER DISEASES. IN MAMMALS, CIRCADIAN RHYTHMS FUNCTION TO COORDINATE A DIVERSE PANEL OF PHYSIOLOGICAL PROCESSES WITH ENVIRONMENTAL CONDITIONS SUCH AS FOOD AND LIGHT. AS THE DRIVING FORCE FOR CIRCADIAN RHYTHMICITY, THE MOLECULAR CLOCK IS A SELF-SUSTAINED TRANSCRIPTION-TRANSLATIONAL FEEDBACK LOOP SYSTEM CONSISTING OF TRANSCRIPTION FACTORS, EPIGENETIC MODULATORS, KINASES/PHOSPHATASES, AND UBIQUITIN E3 LIGASES. THE MOLECULAR CLOCK EXISTS NOT ONLY IN THE SUPRACHIASMATIC NUCLEI OF THE HYPOTHALAMUS BUT ALSO IN THE PERIPHERAL TISSUES TO REGULATE CELLULAR AND PHYSIOLOGICAL FUNCTION IN A TISSUE-SPECIFIC MANNER. THE CIRCADIAN CLOCK SYSTEM IN THE LIVER PLAYS IMPORTANT ROLES IN REGULATING METABOLISM AND ENERGY HOMEOSTASIS. CLOCK GENE MUTANT ANIMALS DISPLAY IMPAIRED GLUCOSE AND LIPID METABOLISM AND ARE SUSCEPTIBLE TO DIET-INDUCED OBESITY AND METABOLIC DYSFUNCTION, PROVIDING STRONG EVIDENCE FOR THE CONNECTION BETWEEN THE CIRCADIAN CLOCK AND METABOLIC HOMEOSTASIS. CIRCADIAN-CONTROLLED HEPATIC METABOLISM IS PARTIALLY ACHIEVED BY CONTROLLING THE EXPRESSION AND/OR ACTIVITY OF KEY METABOLIC ENZYMES, TRANSCRIPTION FACTORS, SIGNALING MOLECULES, AND TRANSPORTERS. RECIPROCALLY, INTRACELLULAR METABOLITES MODULATE THE MOLECULAR CLOCK ACTIVITY IN RESPONSE TO THE ENERGY STATUS. ALTHOUGH STILL AT THE EARLY STAGE, CIRCADIAN CLOCK DYSFUNCTION HAS BEEN IMPLICATED IN COMMON CHRONIC LIVER DISEASES. CIRCADIAN DYSREGULATION OF LIPID METABOLISM, DETOXIFICATION, REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, AND CELL-CYCLE CONTROL MIGHT CONTRIBUTE TO THE ONSET AND PROGRESSION OF LIVER STEATOSIS, FIBROSIS, AND EVEN CARCINOGENESIS. IN SUMMARY, THESE FINDINGS CALL FOR A COMPREHENSIVE STUDY OF THE FUNCTION AND MECHANISMS OF HEPATIC CIRCADIAN CLOCK TO GAIN BETTER UNDERSTANDING OF LIVER PHYSIOLOGY AND DISEASES. 2013 18 6527 27 TRANSCRIPTIONAL CONTROL OF MALADAPTIVE AND PROTECTIVE RESPONSES IN ALCOHOLICS: A ROLE OF THE NF-KAPPAB SYSTEM. ALCOHOL DEPENDENCE AND ASSOCIATED COGNITIVE IMPAIRMENT APPEAR TO RESULT FROM MALADAPTIVE NEUROPLASTICITY IN RESPONSE TO CHRONIC ALCOHOL CONSUMPTION, NEUROINFLAMMATION AND NEURODEGENERATION. THE INHERENT STABILITY OF BEHAVIORAL ALTERATIONS ASSOCIATED WITH THE ADDICTED STATE SUGGESTS THAT TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS ARE OPERATIVE. NF-KAPPAB TRANSCRIPTION FACTORS ARE REGULATORS OF SYNAPTIC PLASTICITY AND INFLAMMATION, AND RESPONSIVE TO A VARIETY OF STIMULI INCLUDING ALCOHOL. THESE FACTORS ARE ABUNDANT IN THE BRAIN WHERE THEY HAVE DIVERSE FUNCTIONS THAT DEPEND ON THE COMPOSITION OF THE NF-KAPPAB COMPLEX AND CELLULAR CONTEXT. IN NEURON CELL BODIES, NF-KAPPAB IS CONSTITUTIVELY ACTIVE, AND INVOLVED IN NEURONAL INJURY AND NEUROPROTECTION. HOWEVER, AT THE SYNAPSE, NF-KAPPAB IS PRESENT IN A LATENT FORM AND UPON ACTIVATION IS TRANSPORTED TO THE CELL NUCLEUS. IN GLIA, NF-KAPPAB IS INDUCIBLE AND REGULATES INFLAMMATORY PROCESSES THAT EXACERBATE ALCOHOL-INDUCED NEURODEGENERATION. ANIMAL STUDIES DEMONSTRATE THAT ACUTE ALCOHOL EXPOSURE TRANSIENTLY ACTIVATES NF-KAPPAB, WHICH INDUCES NEUROINFLAMMATORY RESPONSES AND NEURODEGENERATION. POSTMORTEM STUDIES OF BRAINS OF HUMAN ALCOHOLICS SUGGEST THAT REPEATED CYCLES OF ALCOHOL CONSUMPTION AND WITHDRAWAL CAUSE ADAPTIVE CHANGES IN THE NF-KAPPAB SYSTEM THAT MAY PERMIT THE SYSTEM TO BETTER TOLERATE EXCESSIVE STIMULATION. THIS TYPE OF TOLERANCE, ENSURING A LOW DEGREE OF RESPONSIVENESS TO APPLIED STIMULI, APPARENTLY DIFFERS FROM THAT IN THE IMMUNE SYSTEM, AND MAY REPRESENT A COMPENSATORY RESPONSE THAT PROTECTS BRAIN CELLS AGAINST ALCOHOL NEUROTOXICITY. THIS VIEW IS SUPPORTED BY FINDINGS SHOWING PREFERENTIAL DOWNREGULATION OF PRO-APOPTOTIC GENE EXPRESSION IN THE AFFECTED BRAIN AREAS IN HUMAN ALCOHOLICS. ALTHOUGH FURTHER VERIFICATION IS NEEDED, WE SPECULATE THAT NF-KAPPAB-DRIVEN NEUROINFLAMMATION AND DISRUPTION TO NEUROPLASTICITY PLAY A SIGNIFICANT ROLE IN REGULATING ALCOHOL DEPENDENCE AND COGNITIVE IMPAIRMENT. 2011 19 599 29 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 20 426 26 ANTI-DIABETIC FUNCTIONS OF SOY ISOFLAVONE GENISTEIN: MECHANISMS UNDERLYING ITS EFFECTS ON PANCREATIC BETA-CELL FUNCTION. TYPE 2 DIABETES IS A RESULT OF CHRONIC INSULIN RESISTANCE AND LOSS OF FUNCTIONAL PANCREATIC BETA-CELL MASS. STRATEGIES TO PRESERVE BETA-CELL MASS AND A GREATER UNDERSTANDING OF THE MECHANISMS UNDERLYING BETA-CELL TURNOVER ARE NEEDED TO PREVENT AND TREAT THIS DEVASTATING DISEASE. GENISTEIN, A NATURALLY OCCURRING SOY ISOFLAVONE, IS REPORTED TO HAVE NUMEROUS HEALTH BENEFITS ATTRIBUTED TO MULTIPLE BIOLOGICAL FUNCTIONS. OVER THE PAST 10 YEARS, NUMEROUS STUDIES HAVE DEMONSTRATED THAT GENISTEIN HAS ANTI-DIABETIC EFFECTS, IN PARTICULAR, DIRECT EFFECTS ON BETA-CELL PROLIFERATION, GLUCOSE-STIMULATED INSULIN SECRETION AND PROTECTION AGAINST APOPTOSIS, INDEPENDENT OF ITS FUNCTIONS AS AN ESTROGEN RECEPTOR AGONIST, ANTIOXIDANT, OR TYROSINE KINASE INHIBITOR. EFFECTS ARE STRUCTURE-SPECIFIC AND NOT COMMON TO ALL FLAVONOIDS. WHILE THERE ARE LIMITED DATA ON THE EFFECTS OF GENISTEIN CONSUMPTION IN HUMANS WITH DIABETES, THERE ARE A PLETHORA OF ANIMAL AND CELL-CULTURE STUDIES THAT DEMONSTRATE A DIRECT EFFECT OF GENISTEIN ON BETA-CELLS AT PHYSIOLOGICALLY RELEVANT CONCENTRATIONS (<10 MUM). THE EFFECTS APPEAR TO INVOLVE CAMP/PKA SIGNALING AND THERE ARE SOME STUDIES THAT SUGGEST AN EFFECT ON EPIGENETIC REGULATION OF GENE EXPRESSION. THIS REVIEW FOCUSES ON THE ANTI-DIABETIC EFFECTS OF GENISTEIN IN BOTH IN VITRO AND IN VIVO MODELS AND POTENTIAL MECHANISMS UNDERLYING ITS DIRECT EFFECTS ON BETA-CELLS. 2013