{
  "question": [
    "What are the genetic bases for the varying efficacy of diabetes treatments among individuals?",
    "Explain Protective Genetic Factors Against Diabetes in Elderly Populations",
    "Explain Effect of Lifestyle Modifications on Aging-Associated Diabetes Risk",
    "Explain The Role of Longevity Genes in Protecting Against Diabetes",
    "What are the types of diabetes"
  ],
  "answer": [
    "The varying efficacy of diabetes treatments among individuals can be attributed to genetic variants present in drug receptors or drug metabolizers, such as OCT genes, KCNJ11, ABCC8, and CYP2C9. These genetic variants can influence the metabolism, transportation, and therapeutic mechanisms of antidiabetic drugs, leading to differences in drug disposition, glycemic response, tolerability, and incidence of adverse effects. Additionally, gene-gene, gene-environment, and gene-treatment interactions may also contribute to the variation in disease progression and response to therapy.",
    "Studies have shown that foreign genetic admixture can have a protective effect against diabetes. For instance, the prevalence of Type 2 Diabetes (T2D) in elderly Nauruans was reported to be 83% in full-blooded islanders but only 17% in those with foreign genetic admixture. This suggests that foreign genotypes can reduce the risk of diabetes. Similar findings have been reported in Pima Indians and other Native American populations.",
    "Lifestyle modifications, including increased physical activity, dietary changes, and weight reduction, have been shown to significantly reduce the risk of Type 2 Diabetes (T2D), which is often associated with aging. Regular physical activity improves insulin sensitivity, reducing the stress on insulin-producing cells. Dietary changes, particularly those reducing the intake of processed carbohydrates, energy-rich foods, and animal fats, can also lower T2D risk. Weight loss can directly improve insulin secretion and sensitivity. However, these lifestyle changes require not only individual efforts but also changes in social, built, and food environments.",
    "The background text does not provide information on the role of longevity genes in protecting against diabetes.",
    "The types of diabetes include Type 1 diabetes, Type 2 diabetes, gestational diabetes, and diabetes due to specific causes such as genetic defects causing deficient insulin secretion or action, diseases of the pancreas, and use of certain drugs. There are also subtypes of adult-onset diabetes identified as severe autoimmune diabetes, severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes, and mild age-related diabetes."
  ],
  "contexts": [
    [
      "Genetics and pharmacogenomicsWe are at the dawn of the age of pharmacogenomics and personalized medicine and ever closer to achieving the \"$1,000 genome. \"What does this mean for diabetes?Forward genetic approaches (i.e., starting from phenotype and identifying the genetic cause) to dissecting mendelian forms of diabetes have been hugely successful in identifying a small subset of diabetic patients in whom rare, highly penetrant mutations of a single gene cause their diabetes (13).While common variants of these genes that make a small contribution to polygenic diabetes may also exist (13), the variants causing monogenic diabetes have limited utility in pharmacogenetics due to their low allele frequency.The vast majority of type 2 diabetes patients have polygenetic forms of the disease that typically also require a permissive environment (e.g., obesity, sedentary lifestyle, advancing age, etc.) to be penetrant.Each locus contributes a small amount of risk (odds ratios typically ranging from 1.1- to 1.5-fold), so large cohorts are needed to identify the at-risk alleles.Some of the loci identified to date include transcription factor 7-like 2 (TCF7L2) (14), calpain 10 (CAPN10) (15), peroxisome proliferator-activated receptor  (PPARG) (16), and potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) (17).However, the pace of gene identification is increasing due to the availability of large-scale databases of genetic variation and advances in genotyping technology.A recent genome-wide study identified solute carrier family 30, member 8 (SLC30A8), a  cell Zn transporter, and two other genomic regions as additional diabetes risk loci (18).",
      "With further progress in unravelling the pathogenic roles of genes and epigenomic phenomena in type 2 diabetes, pharmacogenomic and pharmacoepigenomic studies might eventually yield treatment choices that can be personalised for individual patients.",
      "Pharmacogenomics of Type 2 DiabetesWith the advent of GWAS, studies on the roles of inherited and acquired genetic variations in drug response have undergone an evolution from pharmacogenetics into pharmacogenomics, with a shift from the focus on individual candidate genes to GWAS [147].Clinically, it is often observed that even patients who receive similar antidiabetic regimens demonstrate large variability in drug disposition, glycemic response, tolerability, and incidence of adverse effects [148].This interindividual variability can be attributed to specific gene polymorphisms involved in the metabolism, transportation, and therapeutic mechanisms of oral antidiabetic drugs.Pharmacogenomics is on the agenda to explore feasible genetic testing to predict treatment outcome, so that appropriate steps could be taken to treat type 2 diabetes more efficiently.",
      "Future directionsDelays in identifying genetic variants that are robustly associated with differences in individual predisposition to the complications of diabetes, have constrained progress towards a mechanistic understanding of these conditions.Some approaches to overcome these limitations are outlined in Figure 4.",
      "Genomics of T2DDiet, lifestyle, environment, and even genetic variation influence an individual's response to disease therapy.Like GWAS which identify genetic variants conferring risk for a disease, studies have been carried out for identifying genetic variants responsible for patient differences in drug response.Pharmacogenomics in diabetes focuses on the study of gene polymorphisms which influence an individual's response to antidiabetic drugs.Such genetic variants influence the pharmacodynamics and/or pharmacokinetics of the drug, thus affecting its efficacy or toxicity in an individual.The difference in response to treatments and therapies across individuals on account of these factors strengthens the case for personalized medicine in diabetes.Genetics & genomics of T2D Genome-wide association studies (GWAS) have been helpful in identifying a large number of genetic variants conferring risk to T2D.However, only close to 10% heritability is explained by these variants.Other genetic variants, particularly those which are rare but with significant effects need to be identified. Genetic variability is responsible for the difference in response to antidiabetic drugs seen across individuals.",
      "The aim of this study was to summarize current knowledge and provide perspectives on the relationships between human genetic variants, type 2 diabetes, antidiabetic treatment, and disease progression.Type 2 diabetes is a complex disease with clear-cut diagnostic criteria and treatment guidelines.Yet, the interindividual response to therapy and slope of disease progression varies markedly among patients with type 2 diabetes.Gene-gene, gene-environment, and gene-treatment interactions may explain some of the variation in disease progression.Several genetic variants have been suggested to be associated with response to antidiabetic drugs.Some are present in drug receptors or drug metabolizers (OCT genes, KCNJ11, ABCC8, and CYP2C9).Numerous type 2 diabetes risk variants have been identified, but genetic risk score models applying these variants have failed to identify 'disease progressors' among patients with diabetes.Although genetic risk scores are based on a few known loci and only explain a fraction of the heritability of type 2 diabetes, it seems that the genes responsible for the development of diabetes may not be the same driving disease progression after the diagnosis has been made.Pharmacogenetic interactions explain some of the interindividual variation in responses to antidiabetic treatment and may provide the foundation for future genotype-based treatment standards.Pharmacogenetics and Genomics 25:475-484Diabetes progression is a multifactorial process; however, pharmacogenetics seems to play an important role in understanding the different phenotypes and progression rates among diabetic patients.Genetic variants associated with decreased effect of a certain drug might explain why some individuals are more likely to experience glycemic deterioration on a given treatment.In the following sections, different genetic variants and their impact on treatment efficacy and outcome will be addressed.The aim of this study was to summarize current knowledge and provide perspectives on the relationships between human genetic variants, type 2 diabetes, antidiabetic treatment, and disease progression.Type 2 diabetes is a complex disease with clear-cut diagnostic criteria and treatment guidelines.Yet, the interindividual response to therapy and slope of disease progression varies markedly among patients with type 2 diabetes.Gene-gene, gene-environment, and gene-treatment interactions may explain some of the variation in disease progression.Several genetic variants have been suggested to be associated with response to antidiabetic drugs.Some are present in drug receptors or drug metabolizers (OCT genes, KCNJ11, ABCC8, and CYP2C9).Numerous type 2 diabetes risk variants have been identified, but genetic risk score models applying these variants have failed to identify 'disease progressors' among patients with diabetes.Although genetic risk scores are based on a few known loci and only explain a fraction of the heritability of type 2 diabetes, it seems that the genes responsible for the development of diabetes may not be the same driving disease progression after the diagnosis has been made.Pharmacogenetic interactions explain some of the interindividual variation in responses to antidiabetic treatment and may provide the foundation for future genotype-based treatment standards.Pharmacogenetics and Genomics 25:475-484To date, a number of genetic variants have been identified to be associated with response to antidiabetic drugs.Of these, some variants are present in either drug receptors or drug metabolizers as for OCT genes, KCNJ11, ABCC8, and CYP2C9.Other variants are known T2D susceptibility variants such as TCF7L2.To identify variants of importance for antiglycemic drug response, GWAS in large cohorts of patients with diabetes with detailed measures of pharmacotherapy are lacking.The pharmacologic management of patients with diabetes often involves drug classes other than antidiabetics.Pharmacogenetic studies on statin and antihypertensive treatment have reported several genetic variants associated with treatment response and adverse drug reactions [101,102].It therefore seems natural to conclude that the future perspectives in pharmacogenetics is to conduct genetic studies in large cohorts with wellphenotyped individuals, thorough data collection on baseline treatment, concomitant treatment, adherence to therapy as well as data collection on comorbidity and additional disease diagnoses.These types of pharmacogenetic studies may provide unique opportunities for future genotype-based treatment standards and may help in delaying or changing the slope of disease progression among patients with T2D.",
      "Genetic determinants of diabetes and metabolic syndromes.",
      "Thus, specific answers are lacking as to the genetic basis for type 2 diabetes.Still, speculations can be made about what eventually will be found.It is almost certain the genetic basis for type 2 diabetes and other common metabolic diseases will be extremely complex-that a predisposition for the disease will require several genetic hits as opposed to just one.Also, it is generally assumed there will be many susceptibility genes for type 2 diabetes, with enormous variability in different families and ethnic groups.Not known is whether there will be a common form of type 2 diabetes, with any one or even a few susceptibility genes accounting for a sizeable percentage of affected persons.As such, identifying diabetes genes will be slow and difficult.",
      "Ta rge ted T r e atmen t a nd Pr e v en t ion4][75] In monogenic forms of diabetes, at least, genetic testing already drives the choice of therapy.For example, in patients who have maturity-onset diabetes of the young due to mutations in the gene encoding glucokinase (GCK), the hyperglycemia is mild and stable, the risk of complications is low, and dietary management is often sufficient.In contrast, in patients who have maturity-onset diabetes of the young due to mutations in HNF1A, the disease follows a more aggressive course, with a greater risk of severe complications, but is particularly responsive to the hypoglycemic effects of sulfonylureas. 62,73Most children with neonatal diabetes have mutations in KCNJ11 or ABCC8, adjacent genes that jointly encode the beta-cell ATP-sensitive potassium channel that mediates glucose-stimulated insulin secretion and is the target of sulfonylureas.In such children, treatment with sulfonylureas has proved more effective and convenient than the lifelong insulin therapy previously considered the default option. 74,75n children with severe obesity due to profound leptin deficiency, exogenous leptin therapy is lifesaving. 76s yet, there are insufficient genetic data to support management decisions for common forms of type 2 diabetes and obesity. 77Although the TCF7L2 genotype is associated with variation in the response to sulfonylurea treatment, 78 the effect is too modest to guide the care of individual patients.For the time being, the contribution of genetic information to therapy is most likely to come through the drug-discovery pipeline.Information from genetic studies could be used to identify new targets for pharmaceutical intervention that have validated effects on physiological characteristics, to provide information about new and existing targets (e.g., clues about the long-term safety of pathway intervention), 32 and to characterize high-risk groups to enable more efficient clinical trials of agents designed to reduce the progression of type 2 diabetes or obesity or the risk of complications.",
      "Type 2 DiabetesWhile a subset of genetic variants are linked to both type 1 and type 2 diabetes (42,43), the two diseases have a largely distinct genetic basis, which could be leveraged toward classification of diabetes (44).Genome-wide association studies have identified more than 130 genetic variants associated with type 2 diabetes, glucose levels, or insulin levels; however, these variants explain less than 15% of disease heritability (45)(46)(47).There are many possibilities for explaining the majority of type 2 diabetes heritability, including disease heterogeneity, gene-gene interactions, and epigenetics.Most type 2 variants are in noncoding genomic regions.Some variants, such as those in KCNQ1, show strong parent-of-origin effects (48).It is possible that children of mothers carrying KCNQ1 are born with a reduced functional b-cell mass and thereby are less able to increase their insulin secretion when exposed to insulin resistance (49).Another area of particular interest has been the search for rare variants protecting from type 2 diabetes, such as loss-of-function mutations in SLC30A8 (50), which could offer potential new drug targets for type 2 diabetes.Research GapsAfter consideration of the known genetic associations with diabetes risk, consensus developed that the field is not yet at a place where genetics has provided actionable information to guide treatment decisions, with a few notable exceptions, namely in MODY.The experts agreed there is a need to use the increasingly accessible and affordable technologies to further refine our understanding of how genetic variations affect the rate of progression of diabetes and its complications.The expert committee also highlighted the importance of determining categorical phenotypic subtypes of diabetes in order to link specific genetic associations to these phenotypic subtypes.These types of information are necessary to develop the tools to predict response to-and side effects of-therapeutic approaches for diabetes in patient populations.",
      "Genome-wide association (GWAS) and sequencing studies are providing new insights into the genetic basis of type 2 diabetes (T2D) and the inter-individual variation in glycemic traits, including levels of glucose, insulin, proinsulin and hemoglobin A1c (HbA1c).At the end of 2011, established loci (P < 5  10 8 ) totaled 55 for T2D and 32 for glycemic traits.Since then, most new loci have been detected by analyzing common [minor allele frequency (MAF)>0.05]variants in increasingly large sample sizes from populations around the world, and in trans-ancestry studies that successfully combine data from diverse populations.Most recently, advances in sequencing have led to the discovery of four loci for T2D or glycemic traits based on low-frequency (0.005 < MAF  0.05) variants, and additional low-frequency, potentially functional variants have been identified at GWAS loci.Established published loci now total 88 for T2D and 83 for one or more glycemic traits, and many additional loci likely remain to be discovered.Future studies will build on these successes by identifying additional loci and by determining the pathogenic effects of the underlying variants and genes.",
      "Together, the findings from these studies were among the first to demonstrate that the genetic etiology of hyperglycemia may modulate response to hypoglycemia agents.Such results yielded strong implications for patient management and paved the way toward elucidating additional genetic factors that might influence drug response in the treatment of T2D.",
      "Anumber of studies have implicated a genetic basis for type 2 diabetes (1).The discovery of monogenic forms of the disease underscored the phenotypic and genotypic heterogeneity, although monogenic forms account for only a few percent of the disease (1).Defining the genetic basis of the far more common polygenic form of the disease presents more difficulties (2,3).Nevertheless, some interesting results have recently emerged.A genome scan of Hispanic-American families (330 affected sib-pairs [ASPs]) found linkage to chromosome 2q37 (logarithm of odds [LOD] 4.15) (4), and the causative gene has been recently reported (5).A number of other genome scans in various racial groups have identified other putative susceptibility loci (6 -8).The largest genome-wide scan for type 2 diabetes loci reported to date studied 477 Finnish families (716 ASPs) and found evidence for linkage to chromosome 20q12-13.1(LOD 2.06 at D20S107) (9).Interestingly, similar results have been reported by at least three other groups (10 -12).",
      "Because more than one genetic mutation contributes to T1D, the differences that occur between individuals of different backgrounds (for instance, race and locality) may need to be considered in the design of treatments.Personalized medicine is about the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or in their response to a specific treatment (Blau and Liakopoulou, 2013;Timmeman, 2013).This will allow for a more accurate diagnosis per individual, and design of specific treatment plans including gene therapy.",
      "Genetic predisposition to diabetes mellitus type 2: will large collaborative efforts be able to overcome the geneticist's nightmare?"
    ],
    [
      "If an environmental contributor is near ubiquitous and the geneticpredisposition common as well, interventions are most sensibly weighted towardsenvironmental risk factor modification. Even here, though, there is room for further research, since the etiopathogenesisof type 2 diabetes may not be as well understood as some suggest. Specifically,Chaufan implies that dietary intervention to prevent prenatal programmingleading to susceptibility to develop type 2 diabetes (the fetal origins of adult onsetdisease hypothesis) is as evidence-based as dietary management of the adult diabetic state. However, many questions remain in this area.",
      "In the bivariate analysis, there was a tendency of probands to be protected from diabetes when the father lived through a year or years of a surfeit of food during his SGP (OR 0.14, P=0.06).The same experience for the grandfather tended to be followed by a higher risk for the probands dying from diabetes, according to the bivariate analysis (OR 2.34, P=0.09).In the multivariable analysis, a father's exposure to a surfeit of food during his SGP tended to protect the proband from diabetes (OR 0.13, c.i. 0.02 -1.07, P=0.06).However, if the paternal grandfather was exposed to a surfeit of food during his SGP, then the proband had an over-mortality in diabetes (OR 4.1, c.i. 1.33 -12.93,P=0.01) when age at death and the effects of possible overeating among parents and grandparents during their respective SGP were taken into account.",
      "EnvironmentThe second factor in Figure 1 is environmental aspects.An important concept is the diabetes genotype typically causes only a predisposition for glucose intolerance (note the terminology susceptibility gene was used in the preceding paragraphs).Whether one develops the diabetes phenotype depends on environmental factors, some obvious in how they act, others less so.For instance, the Nurses Health Survey showed positive associations between obesity and lack of physical activity in the development of type 2 diabetes (as expected), but also protection by not smoking and moderate alcohol intake (14).Already discussed, many studies have shown an association between TV watching, high calorie diets, and lack of physical activity with risk of diabetes, i.e., our modern lifestyle, so it is not surprising that there is an explosion in the incidence of diabetes worldwide.",
      "Evidence from genetic admixture Some of the clearest data come from studies of genetic admixture.The prevalence of T2D in elderly Nauruans was reported to be 83% in full-blooded islanders but only 17% in those with (unsuspected) foreign genetic admixture. 15Since there were no apparent cultural dierences between the groups, this indicated a protective eect of foreign genotypes on diabetes risk.Similar ndings have been reported in Pima Indians 16 and other Native American populations. 17",
      "IntroductionClustering in families implicates a genetic component of diabetic nephropathy, but so far the specific genes underlying diabetic nephropathy remain largely unknown [1,2].Family studies have furthermore revealed that parental type 2 diabetes mellitus is associated with diabetic nephropathy in offspring with type 1 diabetes mellitus [3,4].A positive family history of type 2 diabetes mellitus has also been associated with cardiovascular disease [5] as well as markers of cardiovascular disease [6] in offspring with type 1 diabetes mellitus.Genetic variants or single-nucleotide polymorphisms (SNPs) predisposing to type 2 diabetes mellitus in the Finnish population have recently been identified in large-scale, genome-wide association studies [7,8].The question thus arises of whether these SNPs, which predispose to type 2 diabetes mellitus, also predispose to diabetic nephropathy and related complications in patients with type 1 diabetes mellitus.We therefore assessed the impact of a set of SNPs known to influence susceptibility to type 2 diabetes mellitus on diabetic nephropathy as well as diabetic retinopathy and cardiovascular disease in patients with type 1 diabetes mellitus.",
      "Family and twin studies indicate that a substantial fraction of susceptibility to type 1 diabetes is attributable to genetic factors.These and other epidemiologic studies also implicate environmental factors as important triggers.Although the specific environmental factors that contribute to immune-mediated diabetes remain unknown, several of the relevant genetic factors have been identified using two main approaches: genome-wide linkage analysis and candidate gene association studies.This article reviews the epidemiology of type 1 diabetes, the relative merits of linkage and association studies, and the results achieved so far using these two approaches.Prospects for the future of type 1 diabetes genetics research are considered.Type 1 diabetes has unusual epidemiological features related to genderType 1 diabetes also displays unusual patterns of inheritance that may yield insights into etiology and provide clues to the best methods for analyzing genetic studies.The risk to the offspring is generally greater from a mother or father who was diagnosed at an early age (again suggesting that early-onset cases are more heavily genetically 'loaded').However, the risk of diabetes is approximately two to four times higher for a child whose father has type 1 diabetes than one whose mother is affected [see (52,53) and references therein].This parental difference is largely due to a low risk for offspring of mothers who were diagnosed at a later age (53).The difference could be explained by at least three different factors.First, the risk alleles could only be active when transmitted by the father (such as is seen in imprinting, where only one of the parental alleles is expressed).Alternatively, a maternal environmental factor during pregnancy could be protective.However, it is difficult to see how this protective effect would be restricted to mothers diagnosed at a later age, especially since the protective effect was unrelated to the mother's duration of diabetes or even diabetic status at delivery (53).Finally, mothers who are diagnosed at a later age could represent more 'environmental' cases of diabetes, and thus be less likely to pass on risk genes to their offspring.Family and twin studies indicate that a substantial fraction of susceptibility to type 1 diabetes is attributable to genetic factors.These and other epidemiologic studies also implicate environmental factors as important triggers.Although the specific environmental factors that contribute to immune-mediated diabetes remain unknown, several of the relevant genetic factors have been identified using two main approaches: genome-wide linkage analysis and candidate gene association studies.This article reviews the epidemiology of type 1 diabetes, the relative merits of linkage and association studies, and the results achieved so far using these two approaches.Prospects for the future of type 1 diabetes genetics research are considered.",
      "CONCLUSIONThe greatest genetic risk (both increased risk, susceptible, and decreased risk, protective) for type 1 diabetes is conferred by specific alleles, genotypes, and haplotypes of the HLA class II (and class I) genes.There are currently about 50 non-HLA region loci that also affect the type 1 diabetes risk.Many of the assumed functions of the non-HLA genes of interest suggest that variants at these loci act in concert on the adaptive and innate immune systems to initiate, magnify, and perpetuate -cell destruction.The clues that genetic studies provide will eventually help lead us to identify how -cell destruction is influenced by environmental factors.While there is extensive overlap between type 1 diabetes and other immune-mediated diseases, it appears that type 1 and type 2 diabetes are genetically distinct entities.These observations may suggest ways to help identify causal gene(s) and, ultimately, a set of disease-associated variants defined on specific haplotypes.Unlike other complex human diseases, relatively little familial clustering remains to be explained for type 1 diabetes.The remaining missing heritability for type 1 diabetes is likely to be explained by as yet unmapped common variants, rare variants, structural polymorphisms, and gene-gene and/or gene-environmental interactions, in which we can expect epigenetic effects to play a role.The examination of the type 1 diabetes genes and their pathways may reveal the earliest pathogenic mechanisms that result in the engagement of the innate and adaptive immune systems to produce massive -cell destruction and clinical disease.The resources established by the international T1DGC are available to the research community and provide a basis for future discovery of genes that regulate the earliest events in type 1 diabetes etiology-potential targets for intervention or biomarkers for monitoring the effects and outcomes of potential therapeutic agents.",
      "Genome-wide search for genes affecting the age at diagnosis of type 1 diabetes.Genes affecting type 1 diabetes diagnosis age / A. Syreeni et al.Genome-wide search for genes affecting the age at diagnosis of type 1 diabetes.",
      "Type 1 DiabetesThe higher type 1 diabetes prevalence observed in relatives implies a genetic risk, and the degree of genetic identity with the proband correlates with risk (22)(23)(24)(25)(26). Gene variants in one major locus, human leukocyte antigen (HLA) (27), confer 50-60% of the genetic risk by affecting HLA protein binding to antigenic peptides and antigen presentation to T cells (28).Approximately 50 additional genes individually contribute smaller effects (25,29).These contributors include gene variants that modulate immune regulation and tolerance (30)(31)(32)(33), variants that modify viral responses (34,35), and variants that influence responses to environmental signals and endocrine function (36), as well as some that are expressed in pancreatic b-cells (37).Genetic influences on the triggering of islet autoimmunity and disease progression are being defined in relatives (38,39).Together, these gene variants explain ;80% of type 1 diabetes heritability.Epigenetic (40), gene expression, and regulatory RNA profiles (36) may vary over time and reflect disease activity, providing a dynamic readout of risk.",
      "Genetic factors have an important role in the development of diabetes, with some forms of the disease resulting from mutations in a single gene.Others are multifactorial in origin.The monogenic forms of diabetes account for approximately 5% of cases and are caused by mutations in genes encoding insulin 3 , the insulin receptor 4 , the glycolytic enzyme glucokinase 5 , and the transcription factors hepatocyte nuclear factor-1 (HNF-1), HNF-1, HNF-4, insulin promoter factor-1 and NeuroD1/BETA2 (refs  6-10).Mutations in maternally inherited mitochondrial genes can also cause diabetes, often in association with hearing loss 11 .",
      "Genetics of Diabetic Complications in HumansEpidemiologic studies have clearly established that only a subgroup of individuals with diabetes are at risk of nephropathy (2).To identify genetic determinants and candidate genes that confer susceptibility or progression for DNP in individuals with type 1 and type 2 diabetes, the National Institutes of Health established the ongoing Family Investigation of Nephropathy and Diabetes study consortium.The Family Investigation of Nephropathy and Diabetes is using Mapping by Admixture Linkage Disequilibrium and traditional affected and discordant sibling pair and relative pair analyses.Previous linkage analysis studies led to the mapping of several susceptibility loci for DNP on specific regions on chromosomes 3, 7, 9, 12, and 20 (14,15).",
      "However, these efforts to sift individuals into discrete subtypes of disease would appear to run counter to the evidence that points to a complex, graded, architecture of risk, one that is consistent with a multifactorial etiology, composed of genetic predisposition dominated by multiple common variants of modest effect, and pervasive exposures contributing to risk.In one recent study, Ahlqvist et al. () used basic clinical information from patients with newly diagnosed adult-onset diabetes to define five subtypes of late-onset diabetes: an autoimmune form (covering TD and other related clinical entities), two severe forms (one dominated by insulin deficiency, the other by insulin resistance), and two milder forms (termed \"obesityrelated\" and \"age-related\" diabetes).Whereas the genetic clusters that form the basis of pPS are defined at the level of the variants, these clinical subtypes are defined at the level of the individual and based on biomarkers and clinical data gathered at a specific point in the progression of an individual from health to disease.The latter is likely to limit their relevance to those who have not yet developed disease, and/or those who are on treatment.",
      "Studies [71][72][73][74] in Mexican and Asian populations have identified several mutations associated with type 2 diabetes in young people.The high prevalence of type 2 diabetes in the parents of young people diagnosed with type 2 diabetes could reflect a stronger genetic predisposition, even when monogenic diabetes is excluded.This hypothesis suggests that efforts to define genes that cause type 2 diabetes by linkage might be more powerful if focused on young adults with diabetes, raising the question of whether type 2 diabetes in older populations has a relatively smaller genetic contribution and a stronger environmental contribution. 66",
      "We found that the presence or absence of parental diabetes and the genotype score were independently associated with the risk of diabetes.This suggests that family history as a risk factor for diabetes conveys more than heritable genetic information; it probably includes nongenetic familial behaviors and norms.The lower relative risks for diabetes associated with observed parental diabetes as compared with those associated with self-reported family history (approximately 1.8 vs. approximately 2.2) support the contention that family history contains more risk information than is implied by inheritance of the diabetes phenotype alone.One of the limitations of our study is that the 18 SNPs we included are probably insufficient to account for the familial risk of diabetes.They account for a minority of diabetes heritability, and the SNP array platforms from which they were chosen capture only approximately 80% of common variants in Europeans.In addition, we have not considered structural variants that might confer a risk of diabetes.It is possible that the addition of rare risk alleles with large effects, or a much larger number of common risk alleles with small individual effects, could improve discrimination. 36Indeed, as many as 500 loci may underlie the genetic risk of type 2 diabetes. 16Also, we did not study interactions among genes or between genes and the environment that might alter the genetic risk in exposed persons.As more diabetes risk variants become known, their incorporation into the genotype score may explain more of the genetic risk implied by parental diabetes.Phenotypic Risk Factors and Definitions of DiabetesEach examination consisted of a medical history taking, physical examination, and collection of a fasting blood sample. 21In the sixth examination cycle (1995 through 1998), participants completed a self-administered questionnaire that asked about family history of disease.We defined a positive selfreported family history of diabetes as a report that one or both parents had diabetes; this definition is more than 56% sensitive and 97% specific for confirmed parental diabetes. 22Parental diabetes was confirmed by means of direct observation of the original cohort, over the course of 46 years of observation after their enrollment in the Framingham Heart Study, at the end of which time the mean age of surviving parents was 83 years.We considered diabetes to be present in a parent when medication was prescribed to control the diabetes or when the casual plasma glucose level was 11.1 mmol per liter or higher or 200.0 mg per deciliter or higher at any examination.We defined diabetes to be present in an offspring when treatment was prescribed to control the diabetes or when the fasting plasma glucose level was 7.0 mmol per liter or higher or 126.0 mg per deciliter or higher at any examination.More than 99% of the cases of diabetes among the participants in the Framingham Offspring Study are type 2 diabetes. 6",
      "Genetics is one example of the 'other risk factors' involved in the pathogenesis of DR.Twin and epidemiological studies have strongly suggested a genetic component in the etiology of DR (6 -10), with heritability scores ranging from 27 to 52% in both type 1 and type 2 diabetes (7 -10).There is an increased risk of severe DR among family members of DR subjects (8,9) and in siblings of affected subjects (8,9).Furthermore, several studies have also shown a discrepant rate of the prevalence of DR among different racial ethnic groups in the US population, with a significantly higher prevalence observed among Hispanic, African-American and Chinese-American when compared with Caucasian populations (11).While these differences may partially be attributed to lifestyle factors, evidence from familial aggregation, ethnic differences and heritability clearly supports a genetic contribution in the etiology of DR."
    ],
    [
      "Together, these clinical trials demonstrate that diet and lifestyle modification is highly effective in preventing type 2 diabetes in different ethnic and racial groups.There is an urgent need to translate the findings from these trials into clinical and public health practice.Emphasis should be placed on early adoption of healthy habits in pediatric populations because these practices track through to adulthood.Physical activityNumerous epidemiologic studies show that increased physical activity reduces risk of diabetes, whereas sedentary behaviors increase risk.In the NHS (26), each 2-h/day increment of time spent watching television (TV) was associated with a 14% increase in diabetes risk.Each 2-h/day increment of standing or walking around at home was associated with a 12% reduction in risk.Each 1-h/day increment of brisk walking was associated with a 34% reduction in risk (Fig. 3).These results indicate a continuum in the relationship between physical activity levels and diabetes risk.Among sedentary behaviors (TV watching, sitting at work, and other sitting), prolonged TV watching was associated with the highest risk.Accumulating evidence strongly demonstrates that the majority of type 2 diabetes cases can be prevented through diet and lifestyle modification.However, the adoption of a healthy diet and lifestyle requires not only individual behavioral changes, but also changes in our food, built, and social environments.Public health strategies that target the obesogenic environment are critical.Translating clinical and epidemiologic findings into practice requires fundamental shifts in public policies and health systems.To curb the diabetes epidemic, primary prevention through the promotion of a healthy diet and lifestyle should be a global public policy priority.",
      "An obvious conclusion is a manipulation of lifestyle provides an opportunity to reverse the diabetes trend.Stated another way, we cannot change our genetic make-up, but we can alter environmental factors.Indeed, many studies have shown that diet and exercise slow the onset of diabetes in persons with IGT (2,17,18).Also, low glycemic index diets have been shown to promote weight loss along with having metabolic benefits in persons with type 2 diabetes (19).The difficulty, of course, is trying to get people to change their habits.",
      "In conclusion, evidence from epidemiological studies and RCTs demonstrate that lifestyle modifi cation comprising higher levels of PA and prudent food consumption may be eff ective in obesity and T2DM prevention.The positive eff ect of lifestyle on body weight seems somewhat transient, whereas the eff ect on T2DM is sustained for longer periods.Furthermore, lifestyle modifi cation appears to have an eff ect on diabetes risk independently of body weight and even of weight loss.As already pointed out in several of the T2DM prevention studies the reduction in diabetes risk has been paralleled by substantial weight loss and weight reduction has been considered to have major importance for diabetes prevention ( Knowler et 1998 ).Hence, lifestyle modifi cation seems to have an eff ect on T2DM not only through reduction in body weight, but also through improvement in insulin sensitivity, blood glucose control and lipid profi le.Whereas there is convincing evidence that lifestyle changes can prevent T2DM in randomized controlled studies, so far little is known whether a lifestyle intervention could also modify cardiovascular morbidity and mortality.The 20-year follow-up results from the Chinese Da Qing diabetes prevention study showed a non-signifi cant 17 % reduction in cardiovascular mortality in the combined (diet and/or PA) intervention group vs. controls ( Li et al., 2008 ).Similarly, lifestyle intervention in the Finnish DPS was not found to reduce signifi cantly cardiovascular mortality during the fi rst 10 years of follow-up ( Uusitupa et al., 2009 ).However, this study was not initially designed to examine the eff ect of lifestyle intervention on total mortality or cardiovascular morbidity, and therefore the statistical power may not have been suffi cient to detect small diff erences in cardiovascular events between the 2 groups.Besides, a longer follow-up period might be needed to answer this question.In the Malm Preventive trial with a 12-year follow-up of men with IGT total and cardiovascular mortality were lower among participants in the lifestyle intervention group, however, these results should be considered with caution due to the non-randomized design of the study ( Eriksson and Lindgarde, 1998 ).Recent fi ndings of bariatric surgery treatment of very obese subjects showed that weight loss indeed may reduce not only T2DM risk but also total mortality ( Sjstrm et al., 2007 ).Further investigations are needed to clarify whether prevention of T2DM by lifestyle modifi cation is associated with cardiovascular disease prevention; until then decisions have to be made on the basis of the best available information.Evidence from randomized controlled trailsThe effi cacy of lifestyle changes in obesity and T2DM prevention has been established in numerous randomized controlled trails (RCTs).Several of them may, however, be considered of major importance due to their large sample sizes (i.e., 458-3234 individuals) and long-term duration (i.e., 3-6 years).The Chinese Da Qing diabetes prevention study was the fi rst to investigate the eff ect of 6-year lifestyle change on body weight and diabetes incidence in individuals with impaired glucose tolerance (IGT) ( Pan et al., 1997 ).Pan and co-workers (1997) reported 42 % reduction in diabetes incidence, although no signifi cant diff erence in body weight was present.Similar results were found in the Finnish Diabetes Prevention Study (DPS) and the US Diabetes Prevention Program (DPP).DPS and DPP independently reported reduction in diabetes incidence of 58 % accompanied by significant reduction in body weight (5-7 %) as a result of the lifestyle modifi cation ( Knowler et al., 2002 ;Tuomilehto et al., 2001 ).These fi ndings were also confi rmed in Japanese and Indian populations, reporting 67.4 % and 28.5 % reduction in diabetes incidence, respectively ( Kosaka et 2011) reported signifi cant reduction in body weight and diabetes incidence at 1, as well as, at 3 years during a lifestyle modifi cation program carried out in a primary healthcare setting among subjects with IGT.All large-scale interventions have been successful in preventing T2DM during the active intervention period.Remarkably when the eff ectiveness of the lifestyle modifi cation programs was assessed on the long-term after discontinuation of the intervention, diabetes risk still remained substantially reduced.In the Finnish DPS, for instance, at extended follow-up 3 years after the 4-year intervention period a substantial reduction in body weight and T2DM incidence was still present ( Lindstrom et al., This document was downloaded for personal use only.Unauthorized distribution is strictly prohibited.",
      "Because lifestyle changes to reduce bodyweight have always been an important therapy for type 2 diabetes, investigators of Look AHEAD trial 156 examined the eff ect of weight reduction (achieved by an intensive lifestyle intervention) on cardiovascular events.Despite diff erential weight loss for more than 10 years and improvements in many cardiovascular risk factors (including blood pressure and lipids), lifestyle change did not reduce cardiovascular events compared with diabetes support and education (control group).This fi nding might have been because large proportions of participants in both groups received medical treatment for these risk factors.However, participants in the group receiving Glucokinase Reduce hepatic production of glucoseTable 1: Selected therapeutic targets of largely untested mechanisms for type 2 diabetesintensive lifestyle intervention who had a history of a cardiovascular event at baseline had a tendency for an increased risk of a subsequent cardiovascular event; 156 a similar fi nding was reported in ACCORD. 144Several other fi ndings from Look AHEAD are worthy of comment.First, participants in the weight-loss group were more likely to achieve either partial or complete remission of diabetes, 157 had better glucose control needing fewer glucose-lowering drugs (including insulin), and were more likely to achieve a glycated haemoglobin A 1c measurement of less than 7% (53 mmol/mol) than were those in the control group. 158However, despite weight loss and addition of drugs, patients in the treatment group had similar progression of diabetes to that of the control group-ie, with continuous increases in glycated haemoglobin A 1c . 156Second, lifestyle change slowed progression of nephropathy.Third, other health outcomes associated with better quality of life-eg, sleep apnoea 159 and mobility 160 -improved.Thus, intensive lifestyle change in patients with type 2 diabetes has benefi ts, but unfortunately not for cardiovascular outcomes, which remain the major cause of premature mortality in type 2 diabetes.",
      "INTRODUCTIONIntensive lifestyle interventions (eg, promoting increased physical activity and weight loss) can be effective in decreasing the incidence of type 2 diabetes mellitus (T2DM). 1 However, healthcare resources are limited, and participants in interventions to prevent diabetes should be prioritized.Identification of individuals at high risk of T2DM could facilitate the targeting of prevention efforts to those who could benefit from them and reduce the cost of preventing T2DM.",
      "Epidemiological studies examining the associations between lifestyle behaviors and diabetes risk have reached similar conclusions as the clinical trials described above.For example, the 14-year follow-up University of Pennsylvania Alumni Health Study [52] (n = 5,990 men aged 39-68 years) showed PA (leisure time physical activity [LTPA] expressed in kcal expended per week through walking, stair climbing, and sports) was inversely associated with the incidence of T2D.Incidence rates declined as energy expenditure rose from 500 through 3,500 kcal/week.The age-adjusted relative risk ratio (RR) of T2D was reduced by about 6% for each 500 kcal increment increase in PA energy expenditure.There are two major factors that underlie these alarming projections.The first is T2D is associated with age, and Western populations are aging rapidly.The second major explanation is our lifestyles have changed dramatically in recent years.Epidemiological studies have identified strong T2D risk relationships for obesity, sedentary behavior [2][3][4], and diets rich in energy [5], processed carbohydrates [6], and animal fats [7].Collectively, these lifestyle factors impede the actions of insulin and raise hepatic glucose production, which can result in the diminution of endogenous insulin production and T2D.The strongest evidence for a causal relationship between adverse lifestyle behaviors and T2D comes from randomized controlled trials that show intensive lifestyle interventions involving structured exercise regimes which promote habitual physical activity (PA) and have a major beneficial impact on diabetes incidence in high-risk individuals [8,9].Practical ApplicationsAs we have described in this chapter, an abundance of evidence supports the protective effects of health lifestyle behaviors on type 2 diabetes risk.However, populationwide programs of intensive lifestyle interventions are probably unrealistic owing to the costs involved in running such trials and the difficulties in recruiting participants and motivating them to adhere to the interventions.It may be more feasible to identify individuals at high risk of diabetes who, because of their genetic characteristics, are likely to respond well to exercise interventions, as an example, and target these persons.This does not of course mean that healthy lifestyle behaviors would be discouraged in the remainder of the population, but one might prioritize other, more effective, preventive strategies in these individuals while continuing to promote the virtues of active lifestyles.The benefits to this approach might include reduced overall costs and greater preventive success.Moreover, because those who receive the intervention are likely to respond well and by consequence maintain motivation, attrition rates may diminish and adherence improve.The actualization of this perspective will first require robust empirical evidence, most likely emerging from the combination of epidemiology for hypothesis generation and clinical trials to test those hypotheses and provide evidence of causality.",
      "Type 2 diabetes can be prevented or delayed by lifestyle modification, including increased physical activity, beneficial dietary changes, and weight reduction (22,44).However, only Model adjusted for age, gender, group, baseline value of moderate-to-vigorous physical activity, and baseline values and changes in body weight and in intakes of energy and energy-adjusted saturated fat and fiber. *The median (range) of each tertile of change in moderate-to-vigorous physical activity is shown.Adjusted interaction between moderate-to-vigorous physical activity (3 groups) and the polymorphism (2 groups) on the risk of developing type 2 diabetes.a few studies have investigated the effects of such lifestyle interventions on insulin sensitivity and insulin secretion in persons with IGT (21,46).On the basis of the 4-yr follow-up study of the DPS with repeated frequently sampled intravenous glucose tolerance test (FSIGT), insulin sensitivity improved along with lifestyle changes, while insulin secretion remained virtually unchanged (46).Most other data also indicate that physical activity, diet, and weight loss primarily increase insulin sensitivity.Insulin resistance and the associated glycemic stress may exhaust -cells and impair their function.Regular physical activity may diminish glycemic stress by improving insulin sensitivity of target tissues (18).While the mechanisms of improved -cell function in response to lifestyle interventions are still largely unknown, several studies suggest that physical activity (5,11), diet (19,26), weight loss (45), or their combination (21) may directly improve the first-phase insulin secretion that is an indicator of the -cell function.GENETIC FACTORS AND LIFESTYLE interact in the development of type 2 diabetes.Physical activity, favorable dietary changes, and weight reduction were essential components of a success-ful lifestyle intervention in two large randomized controlled trials on the prevention of type 2 diabetes in high-risk individuals with impaired glucose tolerance (IGT), including the Finnish Diabetes Prevention Study (DPS) (44) and the Diabetes Prevention Program (DPP) (22).In the DPS, increased physical activity was associated with a decreased risk of type 2 diabetes independently of changes in diet and body weight.The individuals who increased their physical activity most (i.e., were in the upper third of the change) were 66% less likely to develop type 2 diabetes than those in the lower third (24).",
      "The worldwide explosion of the rates of diabetes and other metabolic diseases in the last few decades cannot be fully explained only by changes in the prevalence of classical lifestyle-related risk factors, such as physical inactivity and poor diet.For this reason, it has been recently proposed that other \"nontraditional\" risk factors could contribute to the diabetes epidemics.In particular, an increasing number of reports indicate that chronic exposure to and accumulation of a low concentration of environmental pollutants (especially the so-called persistent organic pollutants (POPs)) within the body might be associated with diabetogenesis.In this review, the epidemiological evidence suggesting a relationship between dioxin and other POPs exposure and diabetes incidence will be summarized, and some recent developments on the possible underlying mechanisms, with particular reference to dioxin, will be presented and discussed.The worldwide explosion of the rates of diabetes and other metabolic diseases in the last few decades cannot be fully explained only by changes in the prevalence of classical lifestyle-related risk factors, such as physical inactivity and poor diet.For this reason, it has been recently proposed that other \"nontraditional\" risk factors could contribute to the diabetes epidemics.In particular, an increasing number of reports indicate that chronic exposure to and accumulation of a low concentration of environmental pollutants (especially the so-called persistent organic pollutants (POPs)) within the body might be associated with diabetogenesis.In this review, the epidemiological evidence suggesting a relationship between dioxin and other POPs exposure and diabetes incidence will be summarized, and some recent developments on the possible underlying mechanisms, with particular reference to dioxin, will be presented and discussed.",
      "Lifestyle modification including exercise, nutrition and behavioral changes is the cornerstone to prevent and treat type 2 diabetes.Oral antidiabetic medicationeither as single agent or combination therapyis frequently required to maintain metabolic control, as assessed by monitoring of glycated hemoglobin A 1C (HbA 1C ) levels.Eventually, a significant proportion of patients with type 2 diabetes require the exogenous administration of insulin [40].",
      "Diet and lifestyle factorsDiet and lifestyle modification is an important aspect of T2DM prevention.Major clinical trials have demonstrated that intensive lifestyle interventions can lower the incidence of diabetes mellitus by 58% compared with control groups 55 .Trials have also shown that these interventions are more effective than pharmacological interventions 55 .Landmark clinical trials, such as the Diabetes Prevention Program in multi-ethnic Americans 55 , the Finnish Diabetes Prevention Study 56 and the Da Qing IGT and Diabetes Study in China 57 , have demonstrated that many cases of T2DM could be prevented through lifestyle interventions focused on increasing physical activity and adopting a healthy diet.Nevertheless, when lifestyle interventions are not feasible, pharmacological therapy can be considered as a strategy to prevent the development of T2DM.For example, metformin reduced the incidence of T2DM by 31% over an average follow-up period of 2.8 years among high-risk individuals from the USA who did not have diabetes mellitus 55 .Similarly, metformin reduced T2DM risk in clinical trials in India and China 58 .",
      "Multiple interventions in adults with T2D have been evaluated for risk reduction and prevention, both in the short and the long term.A recent systematic review (69) reported that after active interventions lasting from 6 months to .6 years, relative risk reduction achieved from lifestyle interventions (39%) was similar to that attained from use of drugs (36%); however, only lifestyle interventions had a sustained reduction in risk once the intervention period had ended.Analysis of the postintervention follow-up period (;7 years) revealed a risk reduction of 28% with lifestyle modification compared with a nonsignificant risk reduction of 5% from drug interventions."
    ],
    [
      "Researchers are expanding our understanding of genetic risk factors for diabetes through ongoing discoveries.Genetic variants associated with increased susceptibility to type 2 diabetes, a disease that affects more than 200 million people worldwide, have been identified (NHGRI & NIDDK, 2007).Such discoveries accelerate efforts to understand genetic contributions to chronic illness, as well as facilitate greater investigation of how these genetic factors interact with each other and with lifestyle factors.Ultimately, once the association of these variants with diabetes are confirmed, genetic tests may be utilized to identify (even before escalating blood sugars) those individuals, like Vanessa, who may be able to delay or prevent diabetes with healthy lifestyle decisions and behaviors.Information to assist nurses in this challenge is available in a toolkit \"Your Game Plan for Preventing Type 2 Diabetes\" (Your Game Plan, n.d.).Would you have known whether or not genetic testing was available for Vanessa?If you had said no to this question but could have explained the progress currently being made in understanding diabetes, Vanessa would have had access to the best care possible today.",
      "Recent gene discovery efforts have provided further evidence to support such assertions.Though, at this point, the identity of some of the genes mechanistically responsible for the association signals uncovered remains uncertain, it remains possible to determine, through studies of healthy populations, whether the type 2 diabetes-susceptibility variants themselves are mediating their effects through disruption of -cell function or insulin action.With the exception of FTO (known to influence type 2 diabetes risk through a primary effect on adiposity) and PPARG (long implicated in insulin action), all confirmed susceptibility alleles appear to exert their predominant effect on diabetes pathogenesis through abrogation of -cell function (or mass) (62,74 -77).It would be wrong to extrapolate too far: the known variants account for only a small proportion of overall genetic risk, and the focus on lean type 2 diabetes cases, which has characterized several of the genome-wide association (GWA) studies (58,59), may have generated a bias toward detection of variants detrimental to -cell performance.Nonetheless, the picture that emerges is one where alterations of -cell function seem to be playing the predominant role with respect to the inherited component of disease predisposition.",
      "In briefGardner et al. queried the genomes of over 400,000 individuals and identified novel genes associated with type 2 diabetes risk.The biological function of these genes highlights potentially new therapeutic avenues for treatment of type 2 diabetes.",
      "Ta rge ted T r e atmen t a nd Pr e v en t ion4][75] In monogenic forms of diabetes, at least, genetic testing already drives the choice of therapy.For example, in patients who have maturity-onset diabetes of the young due to mutations in the gene encoding glucokinase (GCK), the hyperglycemia is mild and stable, the risk of complications is low, and dietary management is often sufficient.In contrast, in patients who have maturity-onset diabetes of the young due to mutations in HNF1A, the disease follows a more aggressive course, with a greater risk of severe complications, but is particularly responsive to the hypoglycemic effects of sulfonylureas. 62,73Most children with neonatal diabetes have mutations in KCNJ11 or ABCC8, adjacent genes that jointly encode the beta-cell ATP-sensitive potassium channel that mediates glucose-stimulated insulin secretion and is the target of sulfonylureas.In such children, treatment with sulfonylureas has proved more effective and convenient than the lifelong insulin therapy previously considered the default option. 74,75n children with severe obesity due to profound leptin deficiency, exogenous leptin therapy is lifesaving. 76s yet, there are insufficient genetic data to support management decisions for common forms of type 2 diabetes and obesity. 77Although the TCF7L2 genotype is associated with variation in the response to sulfonylurea treatment, 78 the effect is too modest to guide the care of individual patients.For the time being, the contribution of genetic information to therapy is most likely to come through the drug-discovery pipeline.Information from genetic studies could be used to identify new targets for pharmaceutical intervention that have validated effects on physiological characteristics, to provide information about new and existing targets (e.g., clues about the long-term safety of pathway intervention), 32 and to characterize high-risk groups to enable more efficient clinical trials of agents designed to reduce the progression of type 2 diabetes or obesity or the risk of complications.From Gene t ic s t o Biol o gyAn improved understanding of pathophysiology achieved through genetic discovery provides new opportunities for treatment, diagnosis, and monitoring.Studies of risk variants for type 2 diabetes in healthy populations have shown that most variants act through perturbation of insulin secretion rather than insulin action, establishing inherited abnormalities of beta-cell function or mass (or both) as critical components of the progression to type 2 diabetes (Fig. 3). 22,50  Type 2 diabetes results when pancreatic beta cells are unable to secrete sufficient insulin to maintain normoglycemia, typically in the context of increasing peripheral insulin resistance.The beta-cell abnormalities fundamental to type 2 diabetes are thought to include both reduced beta-cell mass and disruptions of beta-cell function.Insulin resistance can be the consequence of obesity or of obesity-independent abnormalities in the responses of muscle, fat, or liver to insulin.Examples of susceptibility variants that, given current evidence, are likely to influence predisposition to type 2 diabetes by means of each of these mechanisms are shown.For type 2 diabetes and obesity, the discovery of causal genes (Fig. 1 and 2) has followed three main waves.The first wave consisted of family-based linkage analyses (see the Glossary) and focused candidate-gene studies.These proved effective in identifying genes responsible for extreme forms of early-onset disease segregating as single-gene (mendelian) disorders.Genes underlying several distinct, familial forms of nonautoimmune diabetes -including maturity-onset diabetes of the young, mitochondrial diabetes with deafness, and neonatal diabetes -were characterized (see the review by Waterfield and Gloyn 3 ).Similar approaches revealed mutations in genes responsible for rare forms of severe childhood obesity, including the genes encoding leptin, the leptin receptor, and proopiomelanocortin (see the review by O'Rahilly 4 ).These discoveries have provided insights into processes critical for the maintenance of normal glucose homeostasis and energy balance and clues to the inner workings of the pancreatic beta cell and hypothalamus.For many families, this information has led to improved diagnostic and therapeutic options (described in more detail below).",
      "Gene-lifestyle interaction studies supporting the protective role of diet, exercise or combined lifestyle interventions in individuals genetically susceptible to obesity and type 2 diabetes.This document was downloaded for personal use only.Unauthorized distribution is strictly prohibited.",
      "INTRODUCTIONDiabetes is a common, chronic disease that profoundly impacts health and longevity.Susceptibility is influenced by inheritance, and there has been substantial progress in identifying genes which, when mutated, influence individual risk of disease.Through study of common and rare forms, both polygenic and monogenic, diabetes genetics encompasses many pressing issues in human genetic research.",
      "Advances in technology and analytical approaches have identifi ed genes linked with type 2 diabetes.With use of candidate-gene approaches, PPARG was the fi rst gene identifi ed. 18Subsequently, mostly with use of genomewide association studies, more than 50 gene loci have been linked with type 2 diabetes. 19Furthermore, 53 loci have been linked with concentrations of insulin and glucose (however, not always with both fasting and 2 h concentrations of glucose), of which 33 are also associated with type 2 diabetes. 19,20Although some loci are associated with obesity and insulin resistance, most are linked with -cell function. 21Gene products for most of these loci have not been defi nitively identifi ed.Together, these genes do not explain much of the genetic basis of type 2 diabetes; the use of genotype risk scores only slightly improves prediction of subsequent diabetes compared with more frequently used clinical risk factors. 22,23side from obvious increases in caloric intake and decreased energy expenditure, other environmental factors seem to be important.Nutrient composition, specifi cally increased amounts of dietary fat (particularly saturated fat), are important to development of obesity, insulin resistance, -cell dysfunction, and glucose intolerance. 24Furthermore, an ageing-associated reduction in the responsiveness of  cells to carbohydrate partly underlies the fall in glucose tolerance with ageing. 25he in-utero environment, established partly by the mother's body size, could produce epigenetic and geneexpression changes that aff ect the risk of development of obesity and type 2 diabetes for the off spring. 26Recent Figure 1: Feedback loop between islet  cells and insulin-sensitive tissues (A) Insulin interacts in the liver to suppress glucose production, and in muscle and adipose tissue to stimulate uptake of glucose, aminoacids, and fatty acids.The amount of insulin released to maintain normal glucose homoeostasis is established by prevailing insulin sensitivity.This feedback is probably mediated through neuronal and humoral mechanisms, but exact mediators are still not known. (B) When insulin resistance develops in insulin-sensitive tissues, feedback to  cells ensures that the cells increase insulin output to maintain normal glucose tolerance. (C) When  cells are incapable of increasing insulin output in the presence of insulin resistance, the result is development of increased glucose concentrations, which initially manifests as impaired glucose tolerance.Because -cell dysfunction progresses, further elevations in glycaemia occur and diabetes is the eventual result.",
      "The availability of detailed information on gene  environment interactions may enhance our understanding of the molecular basis of T2D, elucidate the mechanisms through which lifestyle exposures influence diabetes risk, and possibly help to refine strategies for diabetes prevention or treatment.The ultimate hope is genetics might one day be used in primary care to inform the targeting of interventions that comprise exercise regimes and other lifestyle therapies for individuals most likely to respond well to them.",
      "Although the number of disease conditions for which the biomedical literature reports positive indications of genetic contributions increases weekly, diabetes has enjoyed a relatively long history of geneticized explanations.Medical geneticist James Neel's (1962) famous thrifty genotype hypothesis, for example, postulated that in the early stages of evolution those people who had a \"quick insulin trigger\" could rapidly convert sugar to fat in times of famine.Accordingly, peoples who have recently undergone a shift from hunter-gathering to a modern sedentary lifestyle (with concomitant energy dense food intake) are at increased risk of diabetes because they still carry genes that conferred this selective advantage. \"The Coca Colonization\" hypothesis (Zimmet 1997), as the thrifty genotype hypothesis is sometimes called, posits that recently \"primitive\" groups have undergone a \"domestication of lifestyle\" as they have moved to urban areas or lost their old way of life (Neel 1962(Neel , 1982;;Zimmet 1982).According to this hypothesis, these populations have, over time, evolved genetic traits that could metabolically compensate for periods of food scarcity.Because such scarcity is no longer the norm, the theory contends, the phenotypic consequence of thrifty genes in combination with the abundance of food and sedentary lifestyle typical of contemporary urban living make for impaired metabolic regulation of glucose.In other words, diabetes is thought to result from a genetic anachronism.",
      "In support of our focus on developmental genes, pathway analysis of recent genome-wide association studies, which so far have yielded few T2D candidate genes, provided an integrated interpretation of the highest ranked risk genes for T2D [97].This analysis found that lipid metabolism and developmental genes were significantly over-represented in the upper ranked genes of the T2D genome-wide association studies, an observation based on thousands of samples, and one strongly consistent with the present independent analysis.Combined, we believe this presents strong evidence that developmental genes may play a role in setting or regulating the long-term responses of skeletal muscle to diabetes.",
      "It has long been understood that genetics play a role in predisposition to type 2 diabetes (1).Mutations giving rise to several rare monogenic forms of this disorder have been cloned, including mutations in the insulin gene and in a number of genes conferring lean early-onset type 2 diabetes (maturity-onset diabetes of the young [MODY]); however, no gene predisposing to the common obese adultonset phenotype has been identified.One important reason for this is the substantial locus heterogeneity associated with diabetes risk.Despite identification of at least five MODY loci to date, there remain pedigrees that segregate autosomal dominant type 2 diabetes not attributable to detectable mutations in any of these genes (2).Similarly, it has been recognized that as many as 10% of patients diagnosed with type 2 diabetes may instead suffer from a disease etiologically (and presumably genetically) more akin to type 1 diabetes (3).",
      "The future will see intensified research and improvement in such methodologies to identify and characterise the multiple genes underlying complex diseases.One of the most important goals of genetic studies of diabetes is to determine which multilocus genotypes (across all susceptibility loci) create the highest risk for development of diabetes.Individuals with those genotypes would be targeted for treatment to prevent diabetes when safe and effective prophylactic therapies become available.It is possible that several prophylactic options could be available, with effectiveness depending on the exact set of predisposing genes carried by the at-risk person.Thus, the next generation of genetic studies of Type I diabetes (and other complex disorders) will involve dissection of gene-gene interactions in order to clarify which persons, by virtue of their multilocus genotype, are most susceptible to diabetes.This research will be accompanied by studies of gene-environment interaction, when the relevant non-genetic factors are more clearly understood (eg.do differences in diabetes susceptibility via antiviral defence genes relate primarily to certain types of virus? ).",
      "The molecular mechanisms involved in the development of type 2 diabetes are poorly understood.Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia.We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8.Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect.The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.",
      "The molecular mechanisms involved in the development of type 2 diabetes are poorly understood.Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia.We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8.Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect.The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.",
      "Genetic factors appear to play a role in determining an individual's risk of developing diabetes.It is hoped that genetic studies will ultimately identify key genetic elements that help determine susceptibility to diabetes, disease progression, and responsiveness to specific therapies, as well as help identify novel targets for future intervention.A substantial number of genetic loci, gene polymorphisms, and mutations have already been reported as having variable degrees of association with one or other type of diabetes (type 1, type 2, maturity onset diabetes of the young [MODY]), while others appear to be involved in response to antihyperglycemic agents.We have compiled the following glossary of genetic and genomic terms relating to diabetes, which we hope will prove a useful reference to researchers and clinicians with an interest in this disease.This is by no means an exhaustive list, but includes many of the genetic loci and variants that have been studied in association with diabetes.Gene encoding insulin-like growth factor 2 mRNA binding protein 2 (also known as IMP-2).SNPs in the gene have been associated with type 2 diabetes IFIH1",
      "More than 65 loci, encoding up to 500 different genes, have been implicated by genome-wide association studies (GWAS) as conferring an increased risk of developing type 2 diabetes (T2D).Whilst mouse models have in the past been central to understanding the mechanisms through which more penetrant risk genes for T2D, for example, those responsible for neonatal or maturity-onset diabetes of the young, only a few of those identified by GWAS, notably TCF7L2 and ZnT8/SLC30A8, have to date been examined in mouse models.We discuss here the animal models available for the latter genes and provide perspectives for future, higher throughput approaches towards efficiently mining the information provided by human genetics.More than 65 loci, encoding up to 500 different genes, have been implicated by genome-wide association studies (GWAS) as conferring an increased risk of developing type 2 diabetes (T2D).Whilst mouse models have in the past been central to understanding the mechanisms through which more penetrant risk genes for T2D, for example, those responsible for neonatal or maturity-onset diabetes of the young, only a few of those identified by GWAS, notably TCF7L2 and ZnT8/SLC30A8, have to date been examined in mouse models.We discuss here the animal models available for the latter genes and provide perspectives for future, higher throughput approaches towards efficiently mining the information provided by human genetics.",
      "BackgroundMultiple genetic loci have been convincingly associated with the risk of type 2 diabetes mellitus.We tested the hypothesis that knowledge of these loci allows better prediction of risk than knowledge of common phenotypic risk factors alone."
    ],
    [
      "IntroductionDiabetes is one of the most common metabolic disorders.It is estimated that the number of diabetes patients worldwide has already exceeded 200 million [92].This creates a need to understand the etiology of the disease, genetic and enviromental factors influencing development of diabetes.Diabetes is a group of metabolic diseases that are characterized by elevated glucose level.Poorly controlled or undiagnosed disease may be associated with so called late complications of diabetes such as accelerated atherosclerosis, blindness, renal insufficiency, stroke, and amputation of extremities.Diabetes is also associated with a decrease in life expectancy.These facts make diabetes a major health problem.There are two main forms of diabetes: type 1 and type 2. It is type 2 diabetes (T2DM), previously known as non-insulin dependent, that is the much more prevalent form, responsible for 90% of the disease prevalence [92,125].In the majority of the industrialised world societies this disease affects a few percent of the entire population [125].Recent publications indicate an increase in the prevalence of diabetes world-wide, especially in younger people [80] affecting a substantial percentage of the pediatric age group in some populations [30].T2DM is characterised by the presence of two basic abnormalities: impairment of insulin secretion and decrease in insulin sensitivity [52].The disease creates a large pathophysiological spectrum from a predominantly secretory defect with moderate, if any, degree of insulin resistance to a predominantly insulin resistant disease with relative insulin deficiency.Whereas insulin resistance can be demonstrated early in life, many years before the diagnosis of diabetes, impairment of insulin secretion develops later in life, usually along with the onset of impaired glucose tolerance [52].",
      "The ADA lists four subtypes of diabetes based on the clinical symptoms at time of presentation, [4] namely, Type 1 diabetes, Type 2 diabetes (T2D), gestational diabetes, and diabetes due to specific causes (genetic defects causing deficient insulin secretion or action, diseases of pancreas, use of certain drugs such as steroids, thiazides among others).Of these, T2D is the most prevalent (close to 90% of all cases) and is the major cause of morbidity and mortality in both developed and developing nations [1].At times it is difficult to assign a patient to a particular subtype due to the difference in conditions associated with hyperglycemia at the time of diagnosis [4,7].For example, a lady diagnosed with gestational diabetes mellitus during pregnancy is highly susceptible to develop T2D later.Therefore, other than proper treatment during and post pregnancy, a regular follow-up is required for stratifying disease risk, and for timely management before progression to another subtype.It is clear that the classification of diabetes may not be as simple as just categorizing it into any one of the four given subtypes due to its miscellaneous nature.Every case needs to be considered at the time of presentation, on the basis of the risk factors or underlying cause of hyperglycemia, the clinical symptoms, and disease prognosis.Table 1 lists the various subtypes of diabetes based on the classification suggested by the ADA [4].",
      "Type 2 diabetes is the most common type of diabetes with prevalence in the United Kingdom of around 4%.It is most commonly diagnosed in middle-aged adults, although more recently the age of onset is decreasing with increasing levels of obesity (Pinhas-Hamiel and Zeitler, 2005).Indeed, although development of the disease shows high hereditability, the risk increases proportionally with body mass index (Lehtovirta et al., 2010).Type 2 diabetes is associated with insulin resistance, and a lack of appropriate compensation by the beta cells leads to a relative insulin deficiency.Insulin resistance can be improved by weight reduction and exercise (Solomon et al., 2008).If lifestyle intervention fails, there are a variety of drugs available to treat type 2 diabetes (Krentz et al., 2008), which can be divided into five main classes: drugs that stimulate insulin production from the beta cells (e.g.sulphonylureas), drugs that reduce hepatic glucose production (e.g.biguanides), drugs that delay carbohydrate uptake in the gut (e.g.a-glucosidase inhibitors), drugs that improve insulin action (e.g.thiazolidinediones) or drugs targeting the GLP-1 axis (e.g.GLP-1 receptor agonists or DPP-4 inhibitors).",
      "RACIALIZED ETIOLOGIES OF DIABETESDiabetes is not one disease but many.More than 90 percent of all diabetics have type 2 diabetes, which is characterized by elevated blood glucose triggered by a combination of poor insulin production, insulin resistance in skeletal muscle and lipid tissue, or both.Type 2 diabetes is also known as Non-Insulin-Dependent Diabetes because, unlike the rarer form of the disease, people with type 2 diabetes produce insulin and therefore seldom need therapeutic insulin at the initial onset of disease.Type 2 diabetes (hereafter, \"diabetes\"), like heart disease, hypertension and asthma, is referred to as a complex disease because its putative determinants lay in both environmental and biological domains.That is, diabetes is caused by a still-unknown combination of factors that include lifestyle, diet, physical activity, and an array of physiological triggers.",
      "IntroductionDiabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia, which results from defects in insulin secretion, insulin activity or both.DM is associated with the dysfunction and failure of different organs, such as the blood vessels, heart and kidneys [1], and this disease is considered a global burden [2].The International Diabetes Federation's most recent estimates indicate that 8.3% of adults (382 million individuals) have diabetes, and the number of individuals with this disease is expected to rise beyond 592 million in less than 25 years [2].The vast majority of cases of DM fall into two broad etiopathogenetic categories: type 1 and type 2 DM (T1DM and T2DM, respectively).T1DM, previously named insulin-dependent diabetes or juvenile-onset diabetes, results from cellular-mediated autoimmune destruction of pancreatic  cells; therefore, patients are dependent on exogenous insulin.Individuals with T1DM are considered to have a genetic predisposition, although environmental factors, such as dietary components, also contribute to T1DM development [3].Thus, T1DM is the result of a complex interrelation among  cells, the immune system and environmental factors in genetically susceptible individuals [3].T1DM appears predominately in children and young adults and affects 5%-10% of diabetic patients [2].T2DM is chronic disorder caused by insulin secretion deficiency and insulin resistance.T2DM is a complex trait that results from the contribution of many genes [4], many environmental factors, including diet [5], and the interactions among these genes and environmental factors.T2DM is more common among individuals aged 40 to 60 years and accounts for most cases of DM (more than 90%) [2].",
      "ACCEPTED MANUSCRIPTmost common form of diabetes (90% of all diabetic patients), mainly characterized by insulin resistance.The main causes of T2D include lifestyle, physical activity, dietary habits and heredity, whereas T1D is thought to be due to autoimmunological destruction of the Langerhans islets hosting pancreatic- cells.T1D affects almost 10% of all diabetic patients worldwide, with 10% of them ultimately developing idiopathic diabetes.Other forms of DM, classified on the basis of insulin secretion profile and/or onset, include Gestational Diabetes, endocrinopathies, MODY (Maturity Onset Diabetes of the Young), neonatal, mitochondrial, and pregnancy diabetes.The symptoms of DM include polyurea, polydipsia, and significant weight loss among others.Diagnosis depends on blood glucose levels (Fasting plasma glucose = 7.0 mmol/L) [15].From the perspective of DM, although there are several types of diabetes, the overall results suggest that the articles reviewed refer to T1D and T2D, with T2D representing the majority of the articles.A few articles refer to prediabetes and only one pertains to the metabolic syndrome, which is a term for metabolism-related pathophysiology.The types of data used in each case of the present collection were either clinical, genetic, electrochemical, chemical or medical.Only a few articles used clinical data in combination with genetic data.In addition, it is worth mentioning that the vast majority of the articles reviewed handled only clinical datasets.When it comes to prediction, the main biomarkers used involve anthropometric parameters, demographic characteristics, known risk factors, medical and drug history data, laboratory measurements, and epidemiological data.The most",
      "Classification of DiabetesOn the basis of insulin deficiency, diabetes can be classified into the following types as follows.",
      "| INTRODUCTIONToday, more than 265 million people are affected across the world.It is estimated that by the year 2030 this number will reach 366 million people (about 4/4 percent of the world's population), and now the cause of death is more than 1.1 million per year (including 50% of the population under-70 years of age and 55% of women).On the other hand, given its negative effect on the economic growth of developing countries, it calls for universal mobilization to combat this disease (Bhattacharya, Dey, & Roy, 2007).Diabetes or diabetes mellitus is referred to as a heterogeneous group of metabolic disorders characterized by chronic hyperglycemia and carbohydrate, fat and protein metabolism disorders that result from a defect in the secretion of insulin, or impairment in its function, or both.Types of diabetes mellitus include type 1, type 2 diabetes and other kind of diabetes, but the two most common types of diabetes mellitus are type 1 and type 2, which are different in several aspects (Meshkani, Taghikhani, Mosapour et al., 2007).Type 1 diabetes has been identified with autoimmune destruction of pancreatic beta cells (insulin secreting cells) and accounts for about 5% of all diabetic people, while type 2 diabetes is a predominant disorder characterized by insulin resistance or a relative decline in insulin production, and accounts for about 90% of all types of diabetes mellitus (Meshkani, Taghikhani, Al-Kateb et al., 2007).Important factors that predispose a person to type 2 diabetes are multifactorial, including genetic factors and environments.However, its inheritance has certainly not been proven, but it is believed that first-degree relatives of diabetic patients have a higher chance to develop the disease.In this regard, recognizing gene polymorphisms of this disease seems to be necessary (Hring et al., 2014).Multiple genes have been studied in the pathogenesis of type 2 diabetes.",
      "CONCLUSIONSDiabetes is currently broadly classified as type 1, type 2, gestational, and a group of \"other specific syndromes. \"However, increasing evidence suggests that there are populations of individuals within these broad categories that have subtypes of disease with a well-defined etiology that may be clinically characterized (e.g., LADA, MODY).These developments suggest that perhaps, with more focused research in critical areas, we are approaching a point where it would be possible to categorize diabetes in a more precise manner that can inform individual treatment decisions.Type 2 DiabetesIn the U.S., an estimated 95% of the nearly 30 million people living with diabetes have type 2 diabetes.An additional 86 million have prediabetes, putting them at high risk for developing type 2 diabetes (9).Among the demographic associations for type 2 diabetes are older age, race/ ethnicity, male sex, and socioeconomic status (9).",
      "Type 2 diabetes mellitus (T2DM) is characterized by dysregulation of carbohydrate, lipid and protein metabolism, and results from impaired insulin secretion, insulin resistance or a combination of both.Of the three major types of diabetes, T2DM is far more common (accounting for more than 90% of all cases) than either type 1 diabetes mellitus (T1DM) or gestational diabetes.Over the past few decades, our understanding of the development and progression of T2DM has evolved rapidly.Its main cause is progressively impaired insulin secretion by pancreatic -cells, usually upon a background of pre-existing insulin resistance in skeletal muscle, liver and adipose tissue 1",
      "Background Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous.A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis.",
      "IntroductionIn 2018, a ground-breaking study identified five novel subtypes of adult-onset diabetes: severe autoimmune diabetes (SAID, including type 1 diabetes and latent autoimmune diabetes in adults [LADA]) and four subtypes of type 2 diabetes (severe insulin-deficient diabetes [SIDD], severe insulin-resistant diabetes [SIRD], mild obesity-related diabetes [MOD] and mild agerelated diabetes [MARD]) [1].These subtypes differ in their clinical characteristics, complications and genetic backgrounds [1,2].It is unclear if they also differ in modifiable risk factors.",
      "Animal models of Type 2 diabetesType 2 diabetes represents a heterogeneous group of disorders characterized by insulin resistance and impaired insulin secretion and defined by a raised fasting or post-challenge blood glucose.Some subtypes of diabetes are now recognized as being because of specific single gene defects [e.g. the maturityonset diabetes of the young (MODY) syndromes [94], syndromes of severe insulin resistance [95] and mitochondrial diabetes [96]].However, for most patients with diabetes, several (if not many) genetic and environmental factors contribute to the causation and progression of the disease and also the late complications.",
      "The disease burden related to diabetes is high and rising in every country, fuelled by the global rise in the prevalence of obesity and unhealthy lifestyles.The latest estimates show a global prevalence of 382 million people with diabetes in 2013, expected to rise to 592 million by 2035.The aetiological classification of diabetes has now been widely accepted.Type 1 and type 2 diabetes are the two main types, with type 2 diabetes accounting for the majority (>85%) of total diabetes prevalence.Both forms of diabetes can lead to multisystem complications of microvascular endpoints, including retinopathy, nephropathy and neuropathy, and macrovascular endpoints including ischaemic heart disease, stroke and peripheral vascular disease.The premature morbidity, mortality, reduced life expectancy and financial and other costs of diabetes make it an important public health condition.The disease burden related to diabetes is high and rising in every country, fuelled by the global rise in the prevalence of obesity and unhealthy lifestyles.The latest estimates show a global prevalence of 382 million people with diabetes in 2013, expected to rise to 592 million by 2035.The aetiological classification of diabetes has now been widely accepted.Type 1 and type 2 diabetes are the two main types, with type 2 diabetes accounting for the majority (>85%) of total diabetes prevalence.Both forms of diabetes can lead to multisystem complications of microvascular endpoints, including retinopathy, nephropathy and neuropathy, and macrovascular endpoints including ischaemic heart disease, stroke and peripheral vascular disease.The premature morbidity, mortality, reduced life expectancy and financial and other costs of diabetes make it an important public health condition.",
      "IntroductionDiabetes mellitus, also known as simply diabetes, is the most prevalent disease in Westernized, developed countries, and the prevalence of this disease increases with age, accounting for 8.4% of all deaths worldwide [1].Diabetes is a well-recognized multifactorial endocrine metabolic disorder characterized by hyperglycemia (high blood sugar levels over a prolonged period) triggered by insulin secretion deficiencies, insulin action or both [2].The chronic hyperglycemia of diabetes is associated with dysfunction, long-term damage and failure of different organs, particularly the kidneys, heart, blood vessels, nerves and eyes.The development of diabetes involves various pathogenic processes including autoimmune destruction of the pancreatic -cells with subsequent insulin insufficiency which causes insulin resistance [3].The reason for the carbohydrate, fat and protein metabolism disorders in diabetes is insulin deficient activity on target tissues.Insulin deficient action results from insufficient insulin secretion and/or diminished tissue response [4].The great majority of diabetes cases fall into two broad categories of etiopathogenetics.Type 1 diabetes (T1D), falls in one category, is caused due to an absolute deficiency in insulin secretion from pancreatic beta cells.Genetic marker tests and serological evidences of an autoimmune pathological process in pancreatic islets can often be utilized for identification of individuals with increased risk of developing T1D [5].The more prevalent form of diabetes is type 2 diabetes mellitus (T2DM), which falls in the second category and is caused by a combination of insulin resistance and an inadequate compensatory insulin secretory response [6].Consequently, a degree of hyperglycemia occurs that might cause pathological and functional changes in different target tissues but without clinical symptoms and the condition may persist for a long time before T2DM is detected.There are other specific types of diabetes, such as exocrine pancreatic diseases, endocrinopathies, diabetes induced by drugs or chemicals, infection, uncommon forms of immune-mediated diabetes, other genetic syndromes, such as Down syndrome chromosomal abnormalities, Klinefelter syndrome, and sometimes diabetes-related Turner syndrome.Depending on the severity of the underlying disease, the degree of hyperglycemia can change over time [7].",
      "TYPE 1 DIABETESDiabetes (or Diabetes mellitus) is a set of disorders characterized by either an absolute or a relative deficiency of insulin and/or insulin resistance.T1D accounts for about 10% of all diabetes cases (Maahs et al., 2010).It has been reported to be the second most prevalent chronic disease of childhood, with a peak onset at about twelve years (Imkampe and Gulliford, 2011)."
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