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+{
+  "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",
+    "How many types of diabetes exist?",
+    "Is there a direct association between aging and susceptibility to having diabetes?",
+    "How does genetics influence the emergency of diabetes?",
+    "what genes are associated with diabetes?",
+    "What causes diabetes?",
+    "Does cycling reduce risk of diabetes?",
+    "How can GeneNetwork assist in identifying genetic factors involved in diabetes?",
+    "What specific tools within GeneNetwork are most useful for diabetes research, and how are they applied?",
+    "What role does insulin play in the regulation of blood glucose levels?",
+    "How does aging affect the risk of developing type 2 diabetes?",
+    "Can lifestyle changes reverse type 2 diabetes?"
+  ],
+  "answer": [
+    "The genetic bases for the varying efficacy of diabetes treatments among individuals are multifaceted and involve several genetic variants that influence drug response. Key points include:  1. **Genetic Variants in Drug Receptors and Metabolizers**: Variations in genes such as OCT, KCNJ11, ABCC8, and CYP2C9 have been associated with differing responses to antidiabetic drugs. These genes are involved in drug receptors or drug metabolism, which can affect how well a patient responds to a particular treatment [2].  2. **Gene-Gene and Gene-Environment Interactions**: The interplay between different genes and between genes and environmental factors can also contribute to the variability in treatment efficacy. This includes how genetic predispositions interact with lifestyle factors and other environmental influences [2].  3. **Specific Genetic Mutations**: For instance, mutations in the hepatocyte nuclear factor-1alpha gene have been linked to sensitivity to sulphonylureas, highlighting a specific pharmacogenetic interaction in diabetes treatment [3].  4. **Genetically Driven Dominant Processes**: Certain genetic variants may drive dominant processes such as beta-cell dysfunction, lipodystrophy, or obesity, which in turn can influence the effectiveness of drugs targeting these pathways, such as sulfonylureas, GLP-1 receptor agonists, DPP4 inhibitors, and thiazolidinediones [4].  5. **Pharmacogenetic Studies**: Although pharmacogenetic research in diabetes is still developing, studies have shown that genetic variations can significantly impact drug response. For example, variations in the glucose transporter gene SLC2A2 have been associated with differential responses to metformin [8].  6. **Complex Interplay of Factors**: The glycaemic response to treatments like metformin is likely determined by a complex interplay of genetic and environmental factors, with clinical variables such as BMI, drug adherence, and dosing also playing roles [5].  These genetic factors underscore the importance of personalized medicine in diabetes treatment, where understanding an individual's genetic makeup can help tailor more effective therapeutic strategies.",
+    "Protective genetic factors against diabetes in elderly populations can be understood through several key insights from the provided context:  1. **Genome-Wide Association Studies (GWAS)**: Research has identified common genetic variants associated with fasting proinsulin levels, which provide new insights into the pathophysiology of type 2 diabetes. These findings suggest that certain genetic variants may play a protective role by influencing insulin regulation and glucose metabolism in the elderly [3].  2. **Single Nucleotide Polymorphisms (SNPs)**: Studies have identified specific SNPs that are associated with diabetes risk. For example, some genetic mutations are linked to early-onset diabetes, but individuals with certain protective alleles may retain normal glucose tolerance into late adulthood. This indicates that specific genetic configurations can delay or prevent the onset of diabetes in elderly populations [6].  3. **Gene-Environment Interactions**: The interaction between genetic factors and environmental influences is crucial in understanding diabetes risk. Protective genetic factors may interact with lifestyle and environmental factors to reduce the likelihood of developing diabetes in older adults [7].  4. **Oxidative Stress Protection**: Certain genetic factors may protect against oxidative stress-induced insulin-deficient diabetes. This suggests that genetic mechanisms that enhance the body's ability to manage oxidative stress could be protective against diabetes in the elderly [9].  In summary, protective genetic factors against diabetes in elderly populations include specific genetic variants that influence insulin regulation, SNPs that delay diabetes onset, gene-environment interactions, and genetic mechanisms that protect against oxidative stress. These factors collectively contribute to a reduced risk of developing diabetes in older adults.",
+    "Lifestyle modifications, including increased physical activity (PA) and prudent food consumption, have been shown to be effective in preventing obesity and type 2 diabetes mellitus (T2DM) [1]. These modifications can have a sustained positive effect on diabetes risk, even independently of body weight and weight loss [1]. This suggests that the benefits of lifestyle changes extend beyond mere weight management.  Furthermore, lifestyle modifications can attenuate the negative effects on metabolic profiles, body weight, and diabetes risk, even in individuals with genetic susceptibility to T2DM [2]. This indicates that lifestyle changes can potentially eliminate the increased risk of developing T2DM in genetically predisposed individuals.  The effectiveness of lifestyle changes in reducing the rate of diabetes development has been demonstrated in prediabetic populations, where both reduced macronutrient intake and increased exercise have been shown to lower inflammation, a key factor in diabetes progression [6]. Additionally, randomized controlled trials have shown that lifestyle interventions can reduce the incidence of T2DM by approximately 60% [4].  In summary, lifestyle modifications play a crucial role in reducing the risk of aging-associated diabetes by improving metabolic health, reducing inflammation, and mitigating genetic risks, thereby offering a comprehensive approach to diabetes prevention [1], [2], [4], [6].",
+    "Longevity genes play a significant role in protecting against diabetes by influencing various biological pathways that contribute to better glucose tolerance and metabolic health. Here are some key points explaining their role:  1. **Favorable Glucose Tolerance and Lower Prevalence of Metabolic Syndrome**: Research has shown that individuals from long-lived families tend to have favorable glucose tolerance and a lower prevalence of metabolic syndrome, which are critical factors in reducing the risk of type 2 diabetes [3].  2. **Insulin/IGF-1 Pathway**: The insulin/IGF-1 signaling pathway is crucial in regulating lifespan and metabolic processes. Mutations in the insulin-like growth factor I receptor (IGF-1R) have been found in centenarians, suggesting that these mutations may contribute to longevity by enhancing insulin sensitivity and glucose metabolism, thereby protecting against diabetes [9].  3. **Genetic Risk and Longevity**: Studies have indicated that nonagenarians and centenarians carry the same number of disease risk alleles for type 2 diabetes as younger controls, yet they do not exhibit the disease. This suggests that longevity genes may counteract the effects of diabetes risk alleles, possibly through mechanisms that enhance metabolic health and insulin sensitivity [2], [5].  4. **Use of Centenarians as Super-Controls**: Centenarians are often used as super-controls in genetic studies to assess the biological relevance of genetic risk factors for common age-related diseases, including type 2 diabetes. This approach helps identify genetic factors that contribute to both longevity and protection against diabetes [6].  In summary, longevity genes contribute to protecting against diabetes by promoting favorable glucose tolerance, enhancing insulin sensitivity, and counteracting the effects of diabetes risk alleles through various genetic and metabolic pathways [2], [3], [5], [6], [9].",
+    "Diabetes is classified into several types based on different criteria. The main types of diabetes are:  1. **Type 1 Diabetes (T1D)**: Also known as insulin-dependent diabetes mellitus (IDDM) or juvenile onset diabetes, it is an autoimmune disease that usually occurs in childhood but can onset at any age [4], [6], [7].  2. **Type 2 Diabetes (T2D)**: Also known as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes, it is characterized by insulin resistance and relative insulin deficiency [4], [6].  3. **Gestational Diabetes Mellitus (GDM)**: This type occurs during pregnancy and is defined as any degree of glucose intolerance with onset or first recognition during pregnancy [4].  4. **Other Types**: These include monogenic diabetes (such as maturity onset diabetes of the young [MODY], neonatal diabetes, mitochondrial diabetes), and syndromes of insulin resistance [5].  Additionally, a 2018 study identified five novel subtypes of adult-onset diabetes, which include severe autoimmune diabetes (SAID, including type 1 diabetes and latent autoimmune diabetes in adults [LADA]), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes [10].",
+    "There are several types of diabetes. The classical classification includes type 1, type 2, other types, and gestational diabetes mellitus (GDM) [2]. Additionally, there are subtypes of adult-onset diabetes, including severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes [4]. Monogenic diabetes, such as Maturity Onset Diabetes of the Young (MODY), also exists [8]. Therefore, the main types of diabetes are:  1. Type 1 diabetes 2. Type 2 diabetes 3. Other types of diabetes 4. Gestational diabetes mellitus (GDM) 5. Monogenic diabetes (e.g., MODY)  In summary, there are at least five main types of diabetes, with additional subtypes identified in recent studies.",
+    "Yes, there is a direct association between aging and susceptibility to having diabetes. Aging is considered one of the main factors responsible for several complex diseases, including diabetes, particularly type 2 diabetes (T2D) [1]. Additionally, insulin resistance, which is a key factor in the development of diabetes, increases with age, and the incidence of diabetes rises sharply in the elderly [6].",
+    "Genetics plays a significant role in influencing the emergence of diabetes. Several key points highlight this influence:  1. **Genetic Predisposition**: Genetic factors are crucial in determining an individual's risk of developing diabetes [1]. There is a strong genetic component to type 2 diabetes, with many patients having a first-degree relative with the disease [6].  2. **Interaction with Environmental Factors**: The development of diabetes is generally presumed to result from interactions between genetic predisposition and environmental triggers such as dietary habits, physical inactivity, and obesity [2]. This interaction suggests that while genetics set the stage, environmental factors act as accelerants.  3. **Insulin Secretion and Resistance**: Specific genes are directly related to insulin secretion and indirectly to insulin resistance. This supports the idea that genetically programmed beta-cell dysfunction, when combined with environmentally triggered insulin resistance, precipitates diabetes [5].  4. **Familial Clustering**: There is evidence of familial clustering of diabetes, indicating a genetic predisposition to the disease and its complications [7].  5. **Genetic Models**: Genetic models of diabetes have been developed through selective breeding, which often results in monogenic forms of the disease due to single mutations [8].  6. **Concordance in Twins**: The concordance rate for diabetes in identical twins is less than 50%, indicating that while genetics play a significant role, environmental or developmental events also affect the progression of diabetes [4].  In summary, genetics significantly influences the emergence of diabetes by predisposing individuals to the disease, which is then often triggered or exacerbated by environmental factors.",
+    "Several genes have been associated with diabetes, both type 1 and type 2, according to the provided context:  1. **Type 1 Diabetes:**    - **Insulin gene minisatellite locus (IDDM2)**: Susceptibility to type 1 diabetes is determined by tandem repeat variation at this locus [2].    - **CTLA-4 gene region of chromosome 2q33**: This gene region is linked to and associated with type 1 diabetes [4].  2. **Type 2 Diabetes:**    - **ABCC8/SUR1**: A rare mutation in this gene affects ATP-sensitive K+ channel activity and beta-cell glucose sensing, leading to type 2 diabetes [1].    - **Common gene variants**: Several genome-wide association studies (GWAS) have linked common gene variants with increased risk of type 2 diabetes, including:      - **CDKAL1, CDKN2A, CDKN2B**: Associated with reduced insulin secretion via reduced beta-cell mass [3].      - **MTNR1B, TCF7L2, KCNJ11**: Associated with beta-cell dysfunction [3].      - **FTO**: Associated with increased insulin resistance related to obesity [3].      - **IRS1, PPARG**: Associated with increased insulin resistance unrelated to obesity [3].    - **Other genes**: Additional genes associated with type 2 diabetes include:      - **TCF7L2, KCNJ11, PPARG, CDKAL1, IGF2BP2, FTO, HHEX, SLC30A8, WFS1** [5].      - **JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, THADA, ADAMTS9, NOTCH2** [5].    - **Genes related to beta-cell dysfunction**: Many type 2 diabetes genes appear to be related to beta-cell dysfunction [6].    - **Monogenic diabetes genes**: Genes such as **HNF1A, HNF4A, HNF1B, INS, NEUROD1, PDX1, PAX4, ABCC8, KCNJ11, KLF11, CEL, BLK** are associated with monogenic forms of diabetes [7].    - **Genes associated with recessive diseases that include diabetes**: **WFS1, NEUROG3, EIF2AK3, GLIS3, RFX6, SLC19A2** [7].    - **Genes with heterozygous mutations causing diabetes mellitus**: **PAX6, GATA6, PPARG** [7].    - **Inflammatory genes**: Genes such as **IL-6, TNF-\u03b1, IL-10, IL12B, IL23R, IL23A** are associated with a greater risk of developing type 2 diabetes [9].  These references provide a comprehensive list of genes associated with both type 1 and type 2 diabetes.",
+    "Diabetes can be caused by different factors depending on the type.   1. **Type 1 Diabetes**: This type is primarily caused by an absolute deficiency of insulin secretion due to an autoimmune process that destroys insulin-producing beta cells in the pancreatic islets [1], [5]. Genetic markers and serological evidence can often identify individuals at increased risk [1].  2. **Type 2 Diabetes**: This type is caused by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response [1]. It develops over time as tissues become resistant to insulin, and the pancreas's ability to release insulin diminishes [3]. Obesity is a major risk factor for type 2 diabetes, with both genetic and environmental factors playing a role [8].  3. **General Factors**: Both types of diabetes ultimately lead to pancreatic beta-cell dysfunction [2]. Environmental factors, such as viral infections and chemicals, can contribute to the development of diabetes, particularly type 1, while obesity is a common predisposing factor for type 2 diabetes [10].  In summary, diabetes is caused by a combination of genetic, autoimmune, and environmental factors that affect insulin production and action [1], [3], [8], [10].",
+    "Yes, cycling, as a form of physical activity, can reduce the risk of diabetes. According to the context provided:  - The Atherosclerosis Risk in Communities (ARIC) study found that higher levels of leisure activity, which primarily included cycling and walking, were associated with a 34% lower odds of developing hypertension over six years compared to the least active group. This study also indicated that physical activity reduces the risk of developing diabetes and hypertension through mechanisms involving changes in body weight and glucose tolerance [3]. - Additionally, other studies have shown that exercise, including activities like cycling, can prevent the development of Type 2 diabetes in high-risk groups [5].  Thus, engaging in regular cycling can contribute to a reduced risk of developing diabetes.",
+    "GeneNetwork can assist in identifying genetic factors involved in diabetes by leveraging large-scale genetic studies and databases that focus on genetic susceptibility factors. For instance, the Diabetes (GoKinD) study provides a genetics collection specifically aimed at identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes [2], [4]. Additionally, advances in genotyping technology have facilitated rapid progress in large-scale genetic studies, enabling the identification of numerous novel genetic variants that increase susceptibility to diabetes and related traits [5]. These resources and technological advancements can be utilized within GeneNetwork to analyze genetic data and identify potential genetic factors involved in diabetes.",
+    "GeneNetwork offers several specific tools that are particularly useful for diabetes research:  1. **Multi-Omics Analysis**: GeneNetwork includes data from multiple species and supports multi-omics analysis, which integrates genomic, transcriptomic, and metabolomic datasets. This integration is crucial for understanding the complex regulatory networks and mechanisms underlying diabetes [1], [5].  2. **Correlation and Network Analysis**: These tools allow researchers to compare associations between tissues and between rodent or human datasets. This can help identify key molecular interactions and pathways involved in diabetes [6], [7].  3. **Systems Genetics Mapping**: Many datasets within GeneNetwork are amenable to systems genetics mapping, which can be used to link genetic variations to phenotypic traits related to diabetes. This helps in identifying genetic factors that contribute to the disease [6].  4. **Microarray Data Analysis**: GeneNetwork provides access to a large number of microarray datasets from multiple tissues. This data can be used to study gene expression patterns and identify genes that are differentially expressed in diabetic conditions [3], [9].  5. **Predictive Medicine and Systems Genetics**: GeneNetwork is designed as a resource for predictive medicine and systems genetics, which are essential for developing personalized treatment strategies for diabetes [1].  These tools are applied in diabetes research to gain insights into the genetic and molecular basis of the disease, identify potential biomarkers, and develop targeted therapeutic strategies. For example, integrated analysis of genomic, transcriptomic, and metabolomic datasets can reveal metabolic regulatory networks and mechanisms specific to diabetes [5]. Correlation and network analysis can help in understanding how different tissues interact and contribute to the disease pathology [6], [7].",
+    "Insulin plays a central role in the regulation of blood glucose levels by facilitating the uptake of glucose into peripheral tissues and suppressing glucose production by the liver. When blood glucose levels rise, such as after food intake, insulin is secreted by the pancreas into the bloodstream [1]. This secretion stimulates peripheral tissues, including muscle and adipose tissue, to absorb glucose, thereby lowering blood glucose levels [1], [3], [8].   Insulin also acts in the liver to suppress glucose production and gluconeogenesis, further contributing to the reduction of blood glucose levels [3], [6], [8]. Additionally, insulin triggers the translocation of GLUT4 receptors to the cell surface in skeletal muscle and adipose tissue, enhancing glucose uptake by these tissues [8]. This finely tuned balance between glucose absorption, production, and extraction ensures that blood glucose levels are maintained within a narrow range [4], [5].",
+    "Aging is considered one of the main factors responsible for the development of type 2 diabetes (T2D) [1]. As populations in Western countries are aging rapidly, the prevalence of T2D is increasing [5]. This is partly due to lifestyle changes that impede insulin action and increase hepatic glucose production, which are more pronounced in older adults [5]. Additionally, the severity of insulin resistance tends to be greater in older individuals, especially those with a history of prolonged and severe obesity [7]. Therefore, aging significantly increases the risk of developing type 2 diabetes.",
+    "Lifestyle changes, particularly those involving diet and physical activity, have been shown to be effective in managing and even reversing type 2 diabetes (T2DM). Several sources in the provided context support this:  1. **Prevention and Management**: Lifestyle interventions, including dietary modifications and increased physical activity, have been proven effective in preventing the progression from impaired glucose tolerance to type 2 diabetes [1], [2], [3], [5], [9]. These interventions are more efficacious than pharmacological treatments in some cases [5].  2. **Sustained Effects**: The positive effects of lifestyle changes on type 2 diabetes risk are sustained over longer periods, even if weight is partially or totally regained [4], [10]. This suggests that the benefits of lifestyle modifications are not solely dependent on weight loss.  3. **Cornerstone of Treatment**: Lifestyle modification, including exercise, nutrition, and behavioral changes, is considered the cornerstone for both preventing and treating type 2 diabetes [7].  In summary, lifestyle changes can indeed play a significant role in reversing type 2 diabetes, as evidenced by multiple clinical trials and studies [1], [2], [3], [4], [5], [7], [9], [10]."
+  ],
+  "contexts": [
+    [
+      "interindividual variation in responses to antidiabetic treatment and may provide the foundation for future genotype-based treatment standards. Pharmacogenetics and Genomics 25:475 484 Copyright  2015 Wolters Kluwer Health, Inc. All rights reserved. Pharmacogenetics and Genomics 2015, 25:475 484 Keywords: antidiabetic treatment, diabetes type 2, disease progression, genotype, pharmacogenetics aSection of Metabolic Genetics, Novo Nordisk Research Foundation Center for",
+      "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 beassociated with response to antidiabetic drugs. Some are present in drug receptors or drug metabolizers ( OCT genes, KCNJ11 ,ABCC8 , and CYP2C9 ). Numerous type 2 diabetes",
+      "mic control in the majority of insulin-treated  patients. Diabet Med . 2009;26(4):437441.  20. Pearson ER, et al. Sensitivity to sulphonylureas  in patients with hepatocyte nuclear factor-1alpha  gene mutations: evidence for pharmacogenetics  in diabetes. Diabet Med . 2000;17(7):543545.  21. Pearson ER, et al. Genetic cause of hypergly- caemia and response to treatment in diabetes.  Lancet . 2003;362(9392):12751281.  22. Fantasia KL, Steenkamp DW. Optimal glycemic",
+      "When considering etiological varia- tion, recent work partitioning diabe-tes-associated genetic variants by theirpresumed etiological process (parti-tioned polygenic scores) (6,42,101)may de ne genetically driven dominant processes. These processes, such asb-cell dysfunction, lipodystrophy, or obe- sity, could respond differently to drugsthat act on these pathways, such assulfonylureas, glucagon-like peptide 1 re- ceptor agonist (GLP-1RA), DPP4i, and thiazolidinediones.",
+      "source of such variation might help to identify patients most likely not to respond to metformin and could help to develop more e  ective agents by providing insight into  the biological mechanism of metformin. As with other complex traits, glycaemic response to  metformin is probably determined by the interplay between genetic and environmental factors. Clinical variables such as BMI, drug adherence, and dosing only account for part of the variation. 3 Pharmacogenetic",
+      "Pharmacogenetics and individual responses to treatment of hyperglycemia in type 2 diabetes Line Engelbrechtsena, Ehm Anderssona, Soeren Roepstorffb, Torben Hansenaand Henrik Vestergaarda 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",
+      "Genomics. 2010; 20:3844. [PubMed: 19898263] 168. Jablonski KA, McAteer JB, de Bakker PI, Franks PW, Pollin TI, et al. Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program. Diabetes. 2010; 59:26722681. [PubMed: 20682687] 169. Wolford JK, Yeatts KA, Dhanjal SK, Black MH, Xiang AH, et al. Sequence variation in PPARG may underlie differential response to troglitazone. Diabetes. 2005; 54:33193325. [PubMed: 16249460]",
+      "10.1007/s00125-017-4227-1.  42. Hattersley AT, et al. Precision diabetes: learning from monogenic diabetes. Diabetologia. 2017;60:769777. doi: 10.1007/s00125-017-4226-2.  43. Florez JC. The pharmacogenetics of metformin. Diabetologia.  2017;60:16481655. doi: 10.1007/s00125-017-4335-y.  44. Maruthur NM, et al. The pharmacogenetics of type 2 diabetes: a system-atic review. Diabetes Care. 2014;37:876886. doi: 10.2337/dc13-1276.  45. Zhou K, et al. Variation in the glucose transporter gene SLC2A2 is associ-",
+      "typically based on efficacy, yet favorable respon ses to such therapeutics are oftentimes  variable and difficult to pred ict. Characterization of drug  response is expected to  substantially enhance our ability to provide patients with the most effective treatment  strategy given their indivi dual backgrounds, yet pharmacogenetic study of diabetes  medications is still in its infancy. To date, major pharmacogenetic studies have focused on",
+      "treatment or adverse effects  and dosing of medications  are not likely to be adversely affected by environmental  exposures and tend to have large effect sizes [95]. There fore, some of the variability in response or dosing could  be due to genetic variation. Pharmacogenetics in the area  of diabetes is still in its infancy, although there have been  studies examining KCNJ11  and sulfonylurea therapy for  both rare [96,97] and common [98,99] variants and res"
+    ],
+    [
+      "Genetic factors appear to play a role in determining an individuals risk of developing diabetes. It is hoped",
+      "ger, will develop diabetes because the prevalence of diabetes increases with age. In order to circumvent this problem, age was adjusted for in2 K. Ramya et al. / Gene xxx (2013) xxx xxx Please cite this article as: Ramya, K., et al., Genetic association of ADIPOQ gene variants with type 2 diabetes, obesity and serum adiponectin levels in south Indian population, Gene (2013), http://dx.doi.org/10.1016/j.gene.2013.09.012",
+      "elderly population. PLoS One 9: e100548. doi: 10.1371/journal.pone.0100548 PMID: 24959828 23. Strawbridge RJ, Dupuis J, Prokopenko I, Barker A, Ahlqvist E, Rybin D, et al. (2011) Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. Diabetes 60: 2624 2634. doi: 10.2337/db11-0415 PMID: 21873549",
+      "information for diabetes risk prediction - differences according to sex, age, family history and obesity. PloS One 8(5):e64307. doi: 10.1371/journal.pone.0064307 Neel JV (1962) Diabetes mellitus: a thrifty genotype rendered detrimental by progress? Am J Hum Genet 14:353362 Neel JV (1999) The thrifty genotype in 1998. Nutr Rev 57(5 Pt 2):S2S9 Palmer ND, McDonough CW, Hicks PJ, Roh BH, Wing MR, An SS, Hester JM, Cooke JN,",
+      "insulin resistance, hypertension, and dyslipidemia (Obesity Education Initiative Expert Panel,  1998 ). Insulin resist-ance increases with age, and the incidence of diabetes rises sharply in the elderly (American Diabetes Association,  2010a ).   In a few patients, genetic mutations appear to be associ- ated with T2D (Roche  et al.  ,  2005 ; American Diabetes  Association,  2010a ). For example, recent work using the DPP data has led to the identi  cation of 27 single nucle-",
+      "early-onset diabetes in some pedigrees, but it also maybe observed in individuals who retain normal glucose tolerance into late adulthood and beyond ( ). Studying  individuals from  HNF A-MODY families, Lango Allen et al. () found that a -SNP T Dr s P S was signi cantly associated with earlier age of diabetes diagnosis, with each additional risk allele accelerating diagnosis by ~ months. Clinical application of predictive scores",
+      "12. de Miguel-Yanes JM, Shrader P, Pencina MJ, Fox CS, Manning AK, et al. 2011. Genetic risk reclassi- cation for type 2 diabetes by age below or above 50 years using 40 type 2 diabetes risk single nucleotide polymorphisms. Diabetes Care 34:12125 13. Dempe A, Scherag A, Hein R, Beckmann L, Chang-Claude J, Schafer H. 2008. Gene-environment interactions for complex traits: denitions, methodological requirements and challenges. Eur. J. Hum. Genet. 16:116472",
+      "diabetes risk genes predicts impaired glucose tolerance in female andobese individuals. PLoS One . 2012;7:e38224 . 74. Stevens JW, Khunti K, Harvey R, et al. Preventing the progression to type 2 diabetes mellitus in adults at high risk: a systematic review and network meta-analysis of lifestyle, pharmacological and surgicalinterventions. Diabetes Res Clin Pract . 2015;107:320 331(in eng).Cumulative Risk Alleles and Type 2 Diabetes Mellitus 18jJ Epidemiol 2018;28(1):3-18",
+      "and protects against oxidative stress-induced insulin-deficient  diabetes. PLoS One  2014; 9: e87941 [PMID: 24498408 DOI:  10.1371/journal.pone.0087941] 23 Maahs DM , West NA, Lawrence JM, Mayer-Davis EJ. Epidemiology  of type 1 diabetes. Endocrinol Metab Clin North Am  2010; 39:  481-497 [PMID: 20723815 DOI: 10.1016/j.ecl.2010.05.011] 24 Daneman D . Type 1 diabetes. Lancet  2006; 367: 847-858 [PMID:  16530579 DOI: 10.1016/S0140-6736(06)68341-4]",
+      "Sosenko JM, Skyler JS, Krischer JP , Greenbaum CJ, Mahon J, Rafkin LE, Cuthbertson D, Cowie C, Herold K, Eisen-barth G, et al. 2010. Glucose excursions between states of glycemia with progression to type 1 diabetes in the diabetes prevention trial-type 1 (DPT-1). Diabetes 59: 23862389. Steck AK, Armstrong TK, Babu SR, Eisenbarth GS. 2011. Type 1 Diabetes Genetics Consortium. Stepwise or linear decrease in penetrance of type 1 diabetes with lower-risk HLA genotypes over the past 40 years. Diabetes 60:"
+    ],
+    [
+      "demonstrate that lifestyle modi  cation comprising higher levels  of PA and prudent food consumption may be e  ective in obesity  and T2DM prevention. The positive e  ect of lifestyle on body  weight seems somewhat transient, whereas the e  ect on T2DM  is sustained for longer periods. Furthermore, lifestyle modi  ca- tion appears to have an e  ect on diabetes risk independently of  body weight and even of weight loss.      Lifestyle and Genetics in Obesity and Type 2 Diabetes",
+      "suggested to attenuate its negative e  ect on metabolic pro  le,  body weight, and diabetes risk (   Franks et al., 2007   ;    Kilpelainen et al., 2008   ;    Lindi et al., 2002   ;    Ruchat et al., 2010   ) (             Table 1   ).  The notion that lifestyle modi  cation can eliminate the increased  risk for development of T2DM in subjects with genetic suscepti-bility is also supported by  ndings of    Barwell et al. (2008)    who",
+      "M., Bray, G. A. et al (2006). Effect of weight loss withlifestyle intervention on risk of diabetes. Diabetes Care, 29 , 21022107. Herder, C., Peltonen, M., Koenig, W., Sutfels, K., Lindstrom, J. et al (2009). Anti-inammatory effect oflifestyle changes in the Finnish Diabetes PreventionStudy. Diabetologia, 52 , 433442. Hung, J., McQuillan, B. M., Thompson, P . L., and Beilby,",
+      "22        Medications for Diabetes  Prevention   Even in the most successful of the randomized  controlled trials, the risk reduction for incident diabetes following lifestyle intervention was ~60 % [  48  51 ]. That raises the argument as to",
+      "SRT2104 extend the life span of obese mice and protect against age- related changes in multiple tissues ( 215). The antidiabetic drug metformin also induces effects similar to CR (216). Diabetes is considered an age-associated disease, and disturbances in insulin signaling and carbohydrate homeostasis may essentially lead toother age-related complications, including cancer, if untreated. Along with its antidiabetic properties, metformin supplementation has been",
+      "74 The mechanism underlying this effect of exercise is not known;however, it is noteworthy that lifestyle change is a very effectiveway to reduce the rate of development of diabetes in a predia-betic population, as shown by the diabetes prevention study. 75,76 Both a reduction in macronutrient intake and exercise cause areduction in inflammation. References 1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes . 1988;37:15951607.",
+      "uals, but also for low-risk lean individuals (   Kriska et al., 2003   ;    Meisinger et al., 2005   ;    Schulze et al., 2006   ). Furthermore, health-ier lifestyle has been shown to be associated with decreased incidence of obesity- and T2DM-related complications such as hypertension and cardiovascular disease (   Manson et al., 2002   ;    Stampfer et al., 2000   ).     Evidence from randomized controlled trails   The e  cacy of lifestyle changes in obesity and T2DM prevention",
+      "extends lifespan. Cell Rep. 20, 451463 (2017). [PubMed: 28700945]  64. Barzilai N & Ferrucci L Insulin resistance and aging: A cause or a protective response? J.  Gerontol. Ser. A 67, 13291331 (2012). 65. Holmes MV , Ala-Korpela M & Smith GD Mendelian randomization in cardiometabolic disease:  challenges in evaluating causality. Nat. Rev. Cardiol. 14, 577590 (2017). [PubMed: 28569269]  66. Holmes MVet al.Mendelian randomization of blood lipids for coronary heart disease. Eur. Heart J.",
+      "70. Knowler WC, Barrett-Connor E, Fowler SE,et al.; Diabetes Prevention Program ResearchGroup. Reduction in the incidence of type 2diabetes with lifestyle intervention or metfor-min. N Engl J Med 2002;346:393 403 71. Crandall J, Schade D, Ma Y, et al.; DiabetesPrevention Program Research Group. The in-uence of age on the effects of lifestyle mod-",
+      "diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 134350. 114 Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in  the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393403. 115 Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD,"
+    ],
+    [
+      "Longitudinal Study of Aging. The natural history of progression from normalglucose tolerance to type 2 diabetes in the Baltimore Longitudinal Study of Aging. Diabetes 2003; 52:1475 1484. 22 Hornbak M, Allin KH, Jensen ML, Lau CJ, Witte D, Jrgensen ME ,e ta l .A combined analysis of 48 type 2 diabetes genetic risk variants shows nodiscriminative value to predict time to first prescription of a glucose lowering drug in Danish patients with screen detected type 2 diabetes. PLoS One 2014; 9:e104837.",
+      "A set of currently known alleles increasing the risk for coronary artery disease, cancer, and type 2 diabetes as identi ed by genome- wide association studies was tested for compatibility with human longevity. Here, we show that nonagenarian siblings from long- lived families and singletons older than 85 y of age from the general population carry the same number of disease risk alleles as young controls. Longevity in this study population is not compromised by",
+      "52561.x ) 17 Atzmon, G., Schechter, C., Greiner, W ., Davidson, D., Rennert, G. & Barzilai, N. 2004 Clinical phenotype of families with longevity. J. Am. Geriatr. Soc. 52, 274 277. ( doi:10.1111/j.1532-5415.2004.52068.x ) 18 Rozing, M. P . et al. 2009 Human insulin/IGF-1 and familial longevity at middle age. Aging (Albany NY )1, 714722. 19 Rozing, M. P . et al. 2010 Favorable glucose tolerance and lower prevalence of metabolic syndrome in",
+      "extends lifespan. Cell Rep. 20, 451463 (2017). [PubMed: 28700945]  64. Barzilai N & Ferrucci L Insulin resistance and aging: A cause or a protective response? J.  Gerontol. Ser. A 67, 13291331 (2012). 65. Holmes MV , Ala-Korpela M & Smith GD Mendelian randomization in cardiometabolic disease:  challenges in evaluating causality. Nat. Rev. Cardiol. 14, 577590 (2017). [PubMed: 28569269]  66. Holmes MVet al.Mendelian randomization of blood lipids for coronary heart disease. Eur. Heart J.",
+      "et al., 2012 ), possibly due to the indirect and/or a mixed relation- ship between individual genetic disease risk loci and exceptional longevity (as discussed by Fortney et al., 2015 ) versus the poten- tially more direct relationship between aging in the absence of disease and overall genetic disease risk. On the other hand, no difference in genetic risk is observed for type 2 diabetes genetic risk and cancer. Some of these ndings (type 2 diabetes, colon, and lung cancer) can be explained by the",
+      "5. Garagnani P, Giuliani C, Pirazzini C, etal. Centenarians as super-controls to assess the biological relevance of genetic risk factors for common age-related diseases: a proof of principle on type 2 diabetes. Aging (Albany NY). 2013;5:373385. doi:10.18632/aging.100562  6. Sebastiani P, Nussbaum L, Andersen SL, Black MJ, Perls TT. Increasing  sibling relative risk of survival to older and older ages and the importance",
+      "Genetic factors appear to play a role in determining an individuals risk of developing diabetes. It is hoped",
+      "The pursuit of longevity has been the goal of humanity since ancient times. Genetic alterations have been demonstrated to affect lifespan. As increasing numbers of pro-longevity genes and anti-longevity genes have been discovered in Drosophila, screening for functionally important genes among the large number of genes has become difficult. The aim of the present study was to explore critical genes and pathways affecting longevity in Drosophila melanogaster. In this study, 168 genes associated with",
+      "offspring without diabetes mellitus of nonagenariansiblings: the Leiden Longevity Study. J. Am. Geriatr. Soc. 58, 564569. ( doi:10.1111/j.1532-5415.2010. 02725.x ) 20 Suh, Y . et al. 2008 Functionally signicant insulin-like growth factor I receptor mutations in centenarians.Proc. Natl Acad. Sci. USA 105, 34383442. ( doi:10. 1073/pnas.0705467105 ) 21 Heijmans, B. T ., Beekman, M., Houwing-Duistermaat, J. J., Cobain, M. R., Powell, J., Blauw, G. J., van der",
+      "early-onset diabetes in some pedigrees, but it also maybe observed in individuals who retain normal glucose tolerance into late adulthood and beyond ( ). Studying  individuals from  HNF A-MODY families, Lango Allen et al. () found that a -SNP T Dr s P S was signi cantly associated with earlier age of diabetes diagnosis, with each additional risk allele accelerating diagnosis by ~ months. Clinical application of predictive scores"
+    ],
+    [
+      "disorder caused by different factors characterized by a chronic high level of blood sugar with distur-bances to carbohydrate, fat, and protein metabo-lism resulting from defects in insulin secretion, insulin action, or both [  83 ]. Scientists have  divided diabetes into three different types: Type 1 F. Assah and J.C. Mbanya",
+      "Type 1 and type 2 diabetes are the two main types, with type 2 diabetesaccounting for the majority ( >85%) of total diabetes prevalence. Both",
+      "classical classification of diabetes as proposed by the  American Diabetes Association (ADA) in 1997 as type  1, type 2, other types, and gestational diabetes mellitus  (GDM) is still the most accepted classification and  adopted by ADA[1]. Wilkin[8] proposed the accelerator  hypothesis that argues type 1 and type 2 diabetes  are the same disorder of insulin resistance set against  different genetic backgrounds[9]. The difference bet - ween the two types relies on the tempo, the faster",
+      "41 diabetes mellitus (formerly insulin- dependent  diabetes mellitus  IDDM) or type 1 diabetes is also known as juvenile onset diabetes. Type 2 diabetes mellitus (non-insulin-dependent diabe-tes mellitus (formerly non-insulin- dependent dia-betes, NIDDM) or type 2 diabetes  adult-onset diabetes) is found in individuals who are insulin-resistant and who usually have relative insulin de ciency. Gestational diabetes mellitus (GDM),  the third type, is de  ned as any degree of glucose",
+      "Diabetes is a metabolic disease characterized by uncontrolled hyper-glycemia resulting from the variable combination of dysfunctional in-sulin secretion by pancreatic beta cells and insulin resistance. It is generally classi ed into monogenic diabetes (maturity onset diabetes of the young [MODY], neonatal diabetes, mitochondrial diabetes[54,55] , syndromes of insulin resistance) [56], type 1 diabetes (T1D) and type 2 diabetes (T2D). The metabolic syndrome is a combination of",
+      "Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia (elevated levels of glucose in the blood) resulting from defects in insulin secretion, insulin action, or both. There are two major types of diabetes mellitus: type 1 (T1D) and T2D, although several other rarer forms also exist [13]. T1D is an autoimmune disease that usually occurs in childhood, but the onset may occur at any age. T1D results from a cellular-mediated autoimmune destruction of the beta-cells in the pancreatic",
+      "2. Classification of Diabetes On the basis of insulin deficiency, diabetes can be classifiedintothefollowingtypesasfollows.2.1. Insulin Dependent Diabetes Mellitus (IDDM). It is also known as juvenile onset diabetes or type 1 diabetes, which accounts for 510% of the patients, resulting from cellular-mediated autoimmune destruction of the pancreatic cells. Thediseasecanaffectpeopleofallagesbutusuallyoccursin childrenoryoungadults.Regularsupplyofinsulininjections",
+      "2 JournalofDiabetesResearch Type I diabetes  IDDM Type II diabetes  NIDDM  Gestational  diabetesPancreas Islet of Langerhans-glucagon beta cells: insulin Genomic mutationsadministration for  survival sugar levels Insulin  resistance Defective insulin  production Increased  mortalityY ounger  populationGlobal  pandemicHuman body  and diabetes  pregnancy, it needs complete care and  glucose monitorin g glycemic status individual level identification/development of  lead moleculesRegular insulin Exercise",
+      "However, there are two major clinical types, type 1  diabetes (T1D) and type 2  diabetes (T2D), according to the etiopathology of t he disorder.  T2D appears to be the",
+      "SIDD Severe insulin-deficient diabetes SIRD Severe insulin-resistant diabetes Introduction In 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 age-"
+    ],
+    [
+      "Type 1 and type 2 diabetes are the two main types, with type 2 diabetesaccounting for the majority ( >85%) of total diabetes prevalence. Both",
+      "classical classification of diabetes as proposed by the  American Diabetes Association (ADA) in 1997 as type  1, type 2, other types, and gestational diabetes mellitus  (GDM) is still the most accepted classification and  adopted by ADA[1]. Wilkin[8] proposed the accelerator  hypothesis that argues type 1 and type 2 diabetes  are the same disorder of insulin resistance set against  different genetic backgrounds[9]. The difference bet - ween the two types relies on the tempo, the faster",
+      "41 diabetes mellitus (formerly insulin- dependent  diabetes mellitus  IDDM) or type 1 diabetes is also known as juvenile onset diabetes. Type 2 diabetes mellitus (non-insulin-dependent diabe-tes mellitus (formerly non-insulin- dependent dia-betes, NIDDM) or type 2 diabetes  adult-onset diabetes) is found in individuals who are insulin-resistant and who usually have relative insulin de ciency. Gestational diabetes mellitus (GDM),  the third type, is de  ned as any degree of glucose",
+      "SIDD Severe insulin-deficient diabetes SIRD Severe insulin-resistant diabetes Introduction In 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 age-",
+      "7 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care  37(Suppl. 1), S81S90  (2014). 8 Daneman D. Type 1 diabetes. Lancet  367(9513), 847858  (2006). 9 Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of Type 2 diabetes: perspectives on the past, present, and future. Lancet  383(9922), 10681083 (2014). \t Describes\tthe\tpathophysiology\tof\tType\t2\tdiabetes\t(T2D)\tin \t detail\twith\tprospective\tof\t -cell\tdysfunction\tand\tpotential",
+      "However, there are two major clinical types, type 1  diabetes (T1D) and type 2  diabetes (T2D), according to the etiopathology of t he disorder.  T2D appears to be the",
+      "type 1 diabetes, 723 (53%) had LADA, 162 (12%) had secondary diabetes (coexisting pancreatic disease), and 519 (38%) were unclassifiable because of missing data. The remaining 12  112 (883%) patients were considered  to have type 2 diabetes (appendix). To classify patients into novel diabetes subgroups, first",
+      "4   monogenic diabetes not only provides opportunities for etiology- based treatment of the  minority of individuals with highly penetrant variants, but also informs broader  understanding of diabetes etiology. Types of monogenic diabetes   Maturity onset diabetes of the young (MODY)   MODY comprises most  monogenic diabetes cases, with classical characteristics",
+      "19 RACIALIZED ETIOLOGIES OF DIABETES Diabetes is not one disease but many. More than 90 percent of all diabetics",
+      "with young-onset diabetes. Diabetologia 55:1265 1272 13. Schwartz SS, Epstein S, Corkey BE, Grant SF, Gavin JR 3rd, Aguilar RB (2016) The time is right for a new classification system for diabetes: rationale and implications of the -cell-centric classi- fication schema. Diabetes Care 39:179 186 14. Gale EAM (2006) Declassifying diabetes. Diabetologia 49:1989  1995 15. V oight BF, Scott LJ, Steinthorsdottir V et al (2010) Twelve type 2"
+    ],
+    [
+      "The biological processes linking aging and disease risk are poorly understood. Still, aging is considered to date as  one of the main factors responsible for several complex diseases including cancer, cardiovascular diseases, and diabetes. Particularly, type 2 diabetes (T2D) has become very prevalent all over the world, with a projected increas- ing growth rate for the years ahead 1. The pathophysiological mechanism that underlines diabetic complications",
+      "fects correlate with the functional alterations associated withaging of the brain and with AD pathogenesis (411). The vastmajority of AD cases are late onset and sporadic in origin withaging being the most profound risk factor. Insulin signaling isknown to be involved in the process of brain aging (1220).Insulin dysfunction/resistance in diabetes mellitus (DM) is notonly a common syndrome in the elderly but also considered a riskfactor for AD, especially for vascular dementia (21, 22). The link",
+      "striking similarities to people with respect to age-associ- ated increases in risk for several diseases, the relative risk for individual diseases is not always shared. For example,although the prevalence of type II diabetes in older dogs increases with age, it is still much lower than the current prevalence of type II diabetes in people, and the mostcommon form of diabetes in dogs resembles type I diabetes in people (Nelson and Reusch 2014 ). Whether this reects",
+      "strong inverse association between BMI and age at diagnosis of type 2 diabetes. When type 2 diabetes presents in later life, the severity of insulin resistance is often greater among individuals with a history of protracted and severe obesity, particularly with excess visceral adiposity. 28",
+      "COMMENT In a cohort of more than 800 older persons, we found thatdiabetes mellitus sometime in the study was associated withan increased risk of developing AD during a mean of 5.5years of observation. The risk of incident AD was 65% higherin those with diabetes mellitus than in those without it.Overall, results were similar in analyses restricted to dia-",
+      "insulin resistance, hypertension, and dyslipidemia (Obesity Education Initiative Expert Panel,  1998 ). Insulin resist-ance increases with age, and the incidence of diabetes rises sharply in the elderly (American Diabetes Association,  2010a ).   In a few patients, genetic mutations appear to be associ- ated with T2D (Roche  et al.  ,  2005 ; American Diabetes  Association,  2010a ). For example, recent work using the DPP data has led to the identi  cation of 27 single nucle-",
+      "et al., 2012 ), possibly due to the indirect and/or a mixed relation- ship between individual genetic disease risk loci and exceptional longevity (as discussed by Fortney et al., 2015 ) versus the poten- tially more direct relationship between aging in the absence of disease and overall genetic disease risk. On the other hand, no difference in genetic risk is observed for type 2 diabetes genetic risk and cancer. Some of these ndings (type 2 diabetes, colon, and lung cancer) can be explained by the",
+      "equal number of adults over 18 are thought to develop the disease,although incidence in older people receives less media/research attention. In this review, we discuss our current understanding of the cellular/molecular mechanisms of disease aetiology and progres-sion, the usefulness and limitations of rodent models of spontaneousdiabetes, the factors that are influencing the current increased inci-dence and the clinical opportunities for those affected.",
+      "associated with maturity onset diabetes of the young and early onset-age of  type 2 diabetes. J. Diabetes Complications 26, 343347 (2012). 19. Langenberg, C. et al. Design and cohort description of the InterAct Project:    an examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes in the EPIC Study. Diabetologia 54, 22722282  (2011).",
+      "in the precipitation of diabetes. Saturated fatty acids drive the apoptosis  and senescence of beta cells27,41, with increased oxidative stress42 and  endoplasmic reticulum stress41. As increased body mass index is asso - ciated with earlier onset of T1D43, it is possible that dietary fat is acting  as a sensitizer similar to insHEL, in effect lowering the threshold for  autoimmune stress to precipitate clinical diabetes. The male-specific susceptibility to diabetes in this model is in sharp"
+    ],
+    [
+      "Genetic factors appear to play a role in determining an individuals risk of developing diabetes. It is hoped",
+      "the diabetes epidemic, and its predilection for certain ethnic groups, are unknown. However, interactions between genetic pre-disposition and environmental triggers (or accelerants) are generally presumed to un- derlie the etiology of diabetes (3 5) (Fig. 1). The best known environmental risk factors are dietary habits, physical inactivity, and obesity; interventions that ameliorate theserisk factors prevent the development oftype 2 diabetes (6,7). By contrast, knowledge of the genetic",
+      "increases the risk of type  2 diabetes. Such a strong environmental component to a dis - ease should perhaps have deterred geneticists  from studying the disorder. However, there  are many obese people who do not suffer  from diabetes and many non-obese people  who do, showing that obesity is not the only  factor involved in the aetiology of type   2  diabetes (FIG. 1). In the past 10 years, geneticists have  devoted a large amount of effort to finding type   2 diabetes genes. These efforts have",
+      "future diabetes, however, is not possible on a genetic basis alone. For  example, the concordance rate for identical twins is < 50%, indicating that  either environmental or developmental events (such as T cell development)  affect the progression of diabetes.  The ability of serologic studies to identify individuals at risk for  diabetes in the general population is under investigation. Among relatives of  patients with diabetes, serologic markers can identify patients at high risk.3",
+      "genes relate directly to insulin secretion and indirectly, through collaborating with other genes, to insulin resistance. Thisseems to support the epidemiological evidence that environmentally triggered insulin resistance interacts with geneticallyprogrammed bcell dysfunction to precipitate diabetes. Citation: Jain P, Vig S, Datta M, Jindel D, Mathur AK, et al. (2013) Systems Biology Approach Reveals Genome to Phenome Correlation in Type 2 Diabetes. PLoS ONE 8(1): e53522. doi:10.1371/journal.pone.0053522",
+      "Genetic factors Type 2 diabetes has a strong genetic component and most Asian patients have a   rst-degree relative with diabetes. 48,49 Much progress has been made in our  understanding of the genetics of this disease. Importantly, most of the loci originally associated with diabetes in European populations have been replicated in Asian populations. Whereas monogenic forms of diabetes result from rare genetic mutations with large e  ects,  such as those seen in maturity-onset diabetes of young people,",
+      "literature abounds with evidence for genetic mediation ofthe initiation and progression of diabetic nephropathy.First, there is familial clustering that is not completelyexplained by environmental factors [3947]. Our indexcase and her family are perfect examples of genetic pre-disposition to diabetes and its complications, or, at thevery least, familial clustering. Parving and colleagues es-timated that glycemic control, hypertension, and albu-minuria account for only one-third of the variability",
+      "GENETIC MODELS OF DIABETES  Classically, genetic models of diabetes and obesity have been produced in  two ways. One is serendipitous observation of a spontaneously arising  extreme phenotype, followed by selective breeding to fix the trait. The  resulting model will often be monogenic, i.e. due to a single mutation. The  other approach is by repeated selective breeding of initially normal appearing members of a genetically diverse ( outbred) population that are at",
+      "36 Herder C, Roden M. Genetics of type 2 diabetes: pathophysiologic  and clinical relevance. Eur J Clin Invest 2011; 41: 67992. 37 Dabelea D, Hanson RL, Lindsay RS, et al. Intrauterine exposure  to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 2000; 49: 220811. 38 Voight BF, Scott LJ, Steinthorsdottir V, et al. Twelve type 2 diabetes  susceptibility loci identi  ed through large-scale association analysis. Nat Genet 2010; 42: 57989.",
+      "Environmental influences interact with genetic factors to determine  susceptibility to type 2 diabetes by affecting either insulin action, insulin  secretion or both. The prevalence of type 2 diabetes has increased markedly  in populations that have rapidly adopted a Western lifestyle (for example the  Pima Indians) and in many populations that have migrated to regions with a  more affluent lifestyle compared to their native country (see Chapter IV.2)."
+    ],
+    [
+      "gene are associated with NIDDM in Caucasians. Diabetes 1996 , 45, 825-831.  46.  Tarasov, A.I.; Nicolson, T.J. ; Riveline, J.P.; Taneja, T.K. ; Baldwin, S.A.; Baldwin, J.M.;  Charpentier, G.; Gautier, J.F. ; Froguel, P.; Vaxillaire, M.; et al.  A rare mutation in ABCC8/SUR1  leading to altered ATP-sensitive K+ channel activ ity and beta-cell glucose sensing is associated  with type 2 diabetes in adults. Diabetes 2008 , 57, 1595-1604.",
+      "gene is associated with insulin-dependent diabetes mellitus. Diabetes 33:176 183, 1984 6. Bennett ST, Lucassen AM, Gough SCL, Powell EE, Undlien DE, Pritchard LE, Merriman ME, Kawaguchi Y, Drons eld MJ, Pociot F, Nerup J, Bouzekri N, Cambon-Thomasen A, R nningen KS, Barnett AH, Bain SC, Todd JA: Susceptibility to human type 1 diabetes at IDDM2 is determinedby tandem repeat variation at the insulin gene minisatellite locus. Nat Genet 9:284 292, 1995",
+      "of Diabetes   Results of several genome-wide association stud- ies (GWAS) have linked the following common gene variants with a 1520% increased risk of diabetes: reduced insulin secretion via reduce beta-cell mass (CDKAL1, CDKN2A, CDKN2B) and beta-cell dysfunction (MTNR1B, TCF7L2, KCNJ11) and increased insulin resistance related to obesity (FTO) and unrelated to obesity (IRS1, PPARG) [  11 ]. While most of the early studies",
+      "gene is associated with insulin-dependent diabetes mellitus. Diabetes 33:176 183, 1984 3. Nistico L, Buzzetti R, Pritchard L, Van der Auwera B, Giovannini C, Bosi E, Larrad M, Rios M, Chow C, Cockram C, Jacobs K, Mijovic C, Bain S,Barnett A, Vandewalle C, Schuit F, Gorus F, Tosi R, Pozzilli P, Todd J: TheCTLA-4 gene region of chromosome 2q33 is linked to, and associated with,type 1 diabetes: Belgian Diabetes Registry. Hum Mol Genet 5:1075 1080, 1996",
+      "ly associated with type 2 diabetes: TCF7L2, KCNJ11,   and PPARG . 5-7 However, in 2007, a number of novel  genetic variants ( CDKAL1, IGF2BP2,  the locus on  chromosome 9 close to CDKN2A/CDKN2B, FTO,  HHEX, SLC30A8,  and WFS1)8-14 were shown to in - crease susceptibility to type 2 diabetes in repro - ducible studies. Furthermore, a recent meta-analy - sis identified six novel variants ( JAZF1, CDC123/ CAMK1D, TSPAN8/LGR5, THADA, ADAMTS9, and NOTCH2 ) that are associated with type 2 dia - betes. 15",
+      "date gene approaches now have identified /H1101140 genes as- sociated with type 2 diabetes (17, 18) and a similar num-ber, albeit largely different, with obesity. Most type 2diabetes genes appear to be related to /H9252-cell dysfunction,",
+      "HNF1A ,HNF4A ,HNF1B ,INS,NEUROD1 ,PDX1 ,PAX4 , ABCC8 ,KCNJ11 ,KLF11 ,CEL, and BLK), 6 genes associ- ated with recessive diseases that include diabetes as a phenotype ( WFS1 ,NEUROG3 ,EIF2AK3 ,GLIS3 ,RFX6 , andSLC19A2 ), and 3 genes in which heterozygous mu- tations have been shown to cause diabetes mellitus (PAX6 ,GATA6 , and PPARG ). Our primary objectives were to (1) identify subjects with potentially undiag- nosed monogenic diabetes, (2) compare and contrast the",
+      "4. ORahilly S. Human genetics illumi - nates the paths to metabolic disease. Na - ture 2009;462:307-14. 5. McCarthy MI. Growing evidence for  diabetes susceptibility genes from genome scan data. Curr Diab Rep 2003;3:159-67. 6. Hattersley AT, McCarthy MI. What  makes a good genetic association study? Lancet 2005;366:1315-23. 7. Altshuler D, Hirschhorn JN, Klanne - mark M, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000;26:76-80.",
+      "genes including interlukin-6 ( IL-6), tumor necrosis  factor- and IL-10 genes were found to be associated  with greater risk of developing type 2 diabetes[171], in  addition to genetic variants in the genes for IL12B ,  IL23R  and IL23A  genes[172]. In a study involving the  hormone sensitive lipase re sponsible for lipolysis  in adipose tissues, a deletion null mutation, which  resulted in the absence of the protein from adipocytes,  was reported to be associated with diabetes[173]. Nine",
+      "2 diabetes[144,149,150], however, not all of these genes  showed consistent and reproducible association with  the disease[151]. Genome wide association studies  (GWAS) in various populations identified 70 loci  associated with type 2 diabetes and revealed positive  linkage of many mutations and SNPs that influence  the expression and physiological impact of the related  proteins and risk to develop type 2 diabetes. One study  involved several thousand type 2 diabetes patients and"
+    ],
+    [
+      "two broad etiopathogenetic groups. In one group (type I diabetes), the cause  is an absolute deficiency of insulin secretion. Individuals at increased risk of  developing this type of diabetes can often be identified by serological  evidence of an autoimmune process of the pancreatic islets and by genetic  markers. In the second and more prevalent group (type 2 diabetes), the cause  is a combination of resistance to insulin action with inadequate  compensatory insulin secretory response.",
+      "Diabetes mellitus.  Type1 diabetes mellitus (T1DM) and  T2DM have different causes, but both ultimately lead to  pancreatic -cell dysfunction. Damaging the pancreas  chemically or mechanically can induce experimental  diabetes mellitus. Pancreatic damage can be achieved by  surgically removing parts of or all of the pancreatic tissue  (pancreatectomy) to reduce or fully ablate endogenous  insulin production282. The benefit of this method is the  lack of toxic adverse effects (compared with diabetogenic",
+      "Diabetes is a disorder of carbohydrate metabolism charac-terized primarily by hyperglycemia resulting from ineffec-tive uptake of glucose by tissues. Type 1 diabetes is an autoimmune disease that typically occurs early in life and results in total loss of insulin production, whereas type 2 diabetes develops over time as tissues develop a resistance to insulin, and insulin release from the pancreas slowly diminishes. As carbohydrates have the greatest effect on blood glucose of all macronutrients, their",
+      "diabetes but a rare cause of diabetes diag - nosed in childhood or adulthood. Diabetes .  2008;57(4):10341042.  152. Molven A, et al. Mutations in the insulin gene can  cause MODY and autoantibody-negative type 1  diabetes. Diabetes . 2008;57(4):11311135.  153. Gloyn AL, et al. Mutations in the genes encoding  the pancreatic beta-cell KATP channel subunits  Kir6.2 (KCNJ11) and SUR1 (ABCC8) in diabe - tes mellitus and hyperinsulinism. Hum Mutat.  2006;27(3):220231.",
+      "Type 1 diabetes is an autoimmune disease caused by T-cell-mediated destruction of insulin-producing beta cellsin the pancreatic islets of Langerhans (Atkinson andMaclaren 1994). Various aberrations in immune regula-tion have been described in both human patients andanimal models of type 1 diabetes (Rosmalen et al. 2002).A recent study has demonstrated that the disturbance ofcentral and/or peripheral tolerance mechanisms existed indiabetes-prone humans and animals (Sakaguchi 2000).With respect to the",
+      "disorder caused by different factors characterized by a chronic high level of blood sugar with distur-bances to carbohydrate, fat, and protein metabo-lism resulting from defects in insulin secretion, insulin action, or both [  83 ]. Scientists have  divided diabetes into three different types: Type 1 F. Assah and J.C. Mbanya",
+      "(Fig. 1), indicating that insulin resistance and insulin secretory defect played a cooperative role in the development and exac- erbation of diabetes, even though neither was strong enough alone to cause overt diabetes. From another point of view, even if genetically determined insulin resistance itself might not be sufficient for the development of diabetes, insulin resis- tance results in diabetes if pancreatic /H9252 cell function is im- paired genetically (this study) or nongenetically. Development",
+      "tors, and other environmental factors that trigger isletautoimmunity and/or type 1 diabetes. Type 2 Diabetes Type 2 diabetes develops when b-cells fail to secrete suf- cient insulin to keep up with demand, usually in the context of increased insulin resistance. A minority of peo- ple diagnosed with type 2 diabetes also have evidence ofislet autoimmunity (57,58). Obesity is a major risk factor for type 2 diabetes (59,60) with complex genetic and en- vironmental etiology.",
+      "have environmental (islet-injuring drugs or a particular diet) and/or genetic  (monogenic or polygenic) causes. We have grouped the models by cause  and type of diabetes. While this grouping is reasonable and instructive, it  can over-emphasize distinctions. For example, it is believed that beta cell  failure (and/or poor islet regeneration) contributes to type 2 diabetes, but in  their pure, severe form these processes cause type I diabetes.  MODELS OF INSULIN-DEFICIENT DIABETES",
+      "Diabetes mellitus comprises a heterogenous group of disorders that have been classified as either insulin-dependent (IDDM) or non-insulin-depend- ent (NIDDM).1 Their causes are poorly understood but appear to involve some form of interaction between ge- netic and environmental factors.2-4 Some of the environmen- tal factors that can contribute to IDDM include viral infections and chemicals, while obesity is a common predisposing fac- tor for NIDDM. Genes that confer susceptibility or can cause"
+    ],
+    [
+      "2 diabetes suggest that regular exercise might play an important role in  decreasing the very high incidence of premature coronary artery disease.  Although there are no randomized controlled trials assessing reduction  in cardiovascular events induced by physical activity in type 2 diabetes,  available evidence is consistent with the concept that physical activity may play  an important role in reducing cardiovascular risk in type 2 diabetes. 44 Large",
+      "tern of weight change impact health. For example, in the DiabetesPrevention Program (DPP; described in more detail later), both short- and intermediate-term weight loss were associated with reduced diabetes risk and intermediate cardiometabolic risk factor levels, whereas weight cycling (defined as number of 5 lb [2.25 kg] weight cycles) raised diabetes risk, fasting glucose levels, insulinresistance, and systolic blood pressure. Initial (baseline to 1 month)",
+      "sclerosis Risk in Communities (ARIC) study, the highestquartile of leisure activity (primarily cycling and walking)had a 34% lower odds of developing hypertension over 6 years compared to the least active [ 107]. Thus, physical activity reduces the risk of developing diabetes and hyper- tension. The mechanism involves changes in body weight and glucose tolerance, as well as other factors [ 107]. The effect of obesity susceptibility genes on the onset of",
+      "exercise can reduce the incidence of type 2 diabetes. Tuomilehto and  coworkers demonstrated that the individuals on a consistent diet and exercise  program had 10% incidence of diabetes during 4 years of follow-up  compared to 22% for patients in the control group, who met only once a year  with the dietician and the physician.40 A six-year randomized trial conducted  by Pan and colleagues demonstrated that exercise resulted in 46% reduction",
+      "Exercise  Exercise has been shown to prevent development of Type 2  diabetes in high-risk groups. A number of studies have looked at the effect  of insulin on delaying the onset of diabetes. In a study of 5990 male  alumni from an American university followed over 10 years, 202 pts (3.3  percent) developed Type 2 diabetes mellitus. The relative risk was lower  in patients who exercised regularly even when adjusted for obesity,  hypertension, and a family history of diabetes. The benefit was greatest in",
+      "nonrandomized studies of both men and women with type 2 diabetes and  impaired glucose tolerance have found that physical activity is associated with  a decreased risk for cardiovascular disease. It also appears that the amount of  physical activity is inversely associated with coronary events.5354  RISK OF EXERCISE IN PATIENTS WITH DIABETES  The risks associated with exercise can be divided into metabolic,  vascular, neurologic and musculoskeletal (Table 4).",
+      "74 The mechanism underlying this effect of exercise is not known;however, it is noteworthy that lifestyle change is a very effectiveway to reduce the rate of development of diabetes in a predia-betic population, as shown by the diabetes prevention study. 75,76 Both a reduction in macronutrient intake and exercise cause areduction in inflammation. References 1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes . 1988;37:15951607.",
+      "physical training on carbohydrate metabolism and associated cardiovascular risk factors in patients with diabetes. Diabetes Rev. 1995;3:378407.      23.    Rogers MA, Yamamoto C, King DS, Harberg JM,  Ensani AA, Holloszy JO. Improvement in glucose tolerance after one week of exercise in patients with mild NIDDM. Diabetes Care. 1988;11:6138.      24.    Eriksson KF, Lindgarde F. Prevention of type 2 dia- betes mellitus by diet and physical exercise. Diabetologia. 1991;34:8918.",
+      "migrant and other observational studie!f86970 and prospective studies in subjects  at high risk for developing type 2 diabetes.717273 Recently, large interventional  trials have reinforced the benefits of exercise in reducing the risk for type 2  diabetes. These include the Malmo study from Sweden45, the Da Quing study  from China74 and the recently concluded Finnish Diabetes Prevention Study.75  These prospective but not randomized studies show a reduction in the risk of  560",
+      "reduce systolic blood pressure, reduce total cholesterol, raise HDL cholesterol, and improve endothelial function in overweight patients with young-onset type 2 diabetes. 47  However, any potential benefits to the cardiovascular disease risk profile are lost within 36 months after cessation of exercise training, and do not confer protection against later cardiovascular events. 47,121 Additionally,  reviews49,121,122 of the limited number of studies done to"
+    ],
+    [
+      "Genetic factors appear to play a role in determining an individuals risk of developing diabetes. It is hoped",
+      "Diabetes (GoKinD) study: a genetics collection  available for identifying genetic susceptibility  factors for diabetic nephropathy in type1  diabetes. J. Am. Soc. Nephrol.  17, 17821790  (2006). 137. Scott, R.A. etal. Large-scale association  analyses identify new loci influencing glycaemic  traits and provide insight into the underlying  biological pathways. Nat. Genet.  44, 9911005  (2012). Author contributions All authors researched the data for the article,",
+      "identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes. J Am Soc Nephrol 17: 17821790. 44. Manolio TA, Rodriguez LL, Brooks L, Abecasis G, Ballinger D, et al. (2007) New models of collaboration in genome-wide association studies: the Genetic Association Information Network. Nat Genet 39: 10451051. 45. Mailman MD, Feolo M, Jin Y, Kimura M, Tryka K, et al. (2007) The NCBI dbGaP database of genotypes and phenotypes. Nat Genet 39: 11811186.",
+      "in Diabetes (GoKinD) study: a genetics collection availablefor identifying genetic susceptibility factors for diabeticnephropathy in type 1 diabetes. J Am Soc Nephrol 2006; 177: 1782 1790. 10. Pezzolesi MG, Poznik GD, Mychaleckyj JC, et al. Genome- wide association scan for diabetic nephropathysusceptibility genes in type 1 diabetes. Diabetes 2009; 586: 14031410. 11. Paterson AD, Lopes-Virella MF, Waggott D, et al.",
+      "beta cell function, insulin mode of action, glucose  metabolism and/or other risk  factors.  It is a fact that advances in genotyping technology, over the past few years,  have facilitated rapid progress in large-scale gene tic studies.   Identification of a large  number of novel genetic variants increasing suscept ibility diabetes and related traits  opened up opportunities, not existing thus far, to associate this genetic information",
+      "DISCUSSION The findings of previous epidemiological and family studies suggest that diabetic nephropathy results from an interaction between metabolic abnormalities that are typical of poorlycontrolled IDDM and predisposing genetic factors (4,5). Thenature of the genetic factors, however, has remained un- known (22). Using a candidate gene approach, we have found in this",
+      "PLoS Genetics | www.plosgenetics.org June 2007 | Volume 3 | Issue 6 | e96 0963 Type 2 Diabetes Network-Based Analysis",
+      "PLoS Genetics | www.plosgenetics.org June 2007 | Volume 3 | Issue 6 | e96 0971 Type 2 Diabetes Network-Based Analysis",
+      "PLoS Genetics | www.plosgenetics.org June 2007 | Volume 3 | Issue 6 | e96 0967 Type 2 Diabetes Network-Based Analysis",
+      "High-Density Single Nucleotide Polymorphism Genome-Wide Linkage Scan for Susceptibility Genes forDiabetic Nephropathy in Type 1 Diabetes Discordant Sibpair Approach John J. Rogus,1,2G. David Poznik,1Marcus G. Pezzolesi,1,2Adam M. Smiles,1Jonathon Dunn,1 William Walker,1Krzysztof Wanic,1,2Dariusz Moczulski,1,2,3Luis Canani,1,2,4Shinichi Araki,1,2,5 Yuichiro Makita,1,2,6James H. Warram,1and Andrzej S. Krolewski1,2 OBJECTIVE Epidemiological and family studies have demon-"
+    ],
+    [
+      "GeneNetwork have reinvigorated it, including the addition  of data from  10 species, multi -omics  analysis, updated code, and new tools. The new GeneNetwork is now an exciting resource for  predictive medicine and systems genetics, which is constantly being maintained and improved.    Here, we give a brief overview of the process  for carrying out some of the most common  functions on GeneNetwork, as a gateway to deeper analyses , demonstrating how a small",
+      "GeneNetwork http://www.genenetwork.org is anexample of a bioinformatics tool that can be used to explore systems genetics data. The importance of defining biological networks and predicting molecular interactions has been emphasized by several reports [1,2]. Such studies emphasize that when knowledge about DNA variation within popula- tions is interfaced with data on gene expression, protein interactions and DNA-protein binding, biological networks can be constructed that are predictive of the",
+      "GeneNetwork provides users with an array of analyticaltools to compare a given trait with a number of data setsavailable from other experimenters. Microarray data ofgene expression in the brain and data of other phenotypes are two such examples of possible tools. For this study, we",
+      "subnetworks   GeneNetwork (www.genenetwork.org) is a depository of data- sets and tools for use in complex systems biology approaches in  order to generate or predict higher order gene function ( 23, 24 ).",
+      "of these tools to diabetes andmetabolic disease research at the cellular, animal model,and human disease levels are summarized, with a partic-ular focus on insights gained from the more quantitativetargeted methodologies. We also provide early examplesof integrated analysis of genomic, transcriptomic, andmetabolomic datasets for gaining knowledge about meta-bolic regulatory networks and diabetes mechanisms andconclude by discussing prospects for future insights.",
+      "including correlation and network analysis to compare associations  between tissues and between other rodent or human data sets[32] Many of the Data Sets are amenable to systems genetics mapping and other methods and are accessible at GeneNetwork. The Description and Usage column provides details about the data set and potential",
+      "including correlation and network analysis to compare associations  between tissues and between other rodent or human data sets[32] Many of the Data Sets are amenable to systems genetics mapping and other methods and are accessible at GeneNetwork. The Description and Usage column provides details about the data set and potential",
+      "data are entered into GeneNetwork after they have been shepherded through a system like PhenoGen that has extensive capabilities for normalization and quality control. A comparison of the brain gene expression datasets and some of the tools for data analysis available on PhenoGen and GeneNetwork is shown in Table 3, and more detailed information on features provided by each site is outlined in the Supplementary DiscussionHoffman et al. Page 5 Addict Biol . Author manuscript; available in PMC 2012 July 1.",
+      "of importance in the emergence of precision medicine ( Curtis, 2015 ; Desautels et al., 2014 ;  Glade Bender et al., 2015 ; Jorgensen, 2015 ; Kummar et al., 2015 ; Marquet et al., 2015 ;  Rubin, 2014 ) wherein therapeutic strategies need to be aligned with specific properties of  tumors. Methods GeneNetwork and WebGestalt GeneNetwork is an open access, online data analysis resource for systems biology and  systems genetics. It contains a large number of microarray datasets from multiple tissues of",
+      "results in applying the method  to type 2 diabetes mellitus suggest it may hold  promise as a useful research tool for complex diseases .  Further details on the  methodol ogy is available from the following paper: Liu M, Liberzon A, Kong  SW, Lai WR, Park PJ et al (2007) Network -based analysis of affected biological  processes in type 2 diabetes models.  PLoS Genet 3(6):e96.   doi:10.1371/journal.pgen.0030096."
+    ],
+    [
+      "Figure 3. Schematics view of insulin regulation. Elevated glucose level by either food intake or liver glycogenolysis is sensed by islet and leads to insulin secretion to the bloodstream. The increased insulin stimulates peripheral tissues to absorb glucose, and as a consequence, the glucose le vel",
+      "plays an important role in regulating insulin secretion in beta cells of the pancreas. It has been shown that glucosestimu-lated insulin secretion may be triggered by the autocrine ac-tivation of the insulin signaling pathway, including insulin receptor phosphorylation, tyrosine phosphorylation in IRS1, and the activation of PI3Kinase. Putting together these data leads to the hypothesis that a single molecular impairment in the pathway of insulin signaling, including an incomplete interaction between",
+      "(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",
+      "Insulin Action   In healthy, normal individuals, blood glucose concentra- tion is maintained within a narrow range. After an over-night fast or between meals, blood glucose normally falls within the range of 3.5  5.5   mM. Immediately after a meal containing carbohydrate, blood glucose concentration rises to a peak of 6  10   mM followed by a sharp decline back to baseline within 60 minutes. This exquisite control is achieved by a   ne balance between glucose absorption",
+      "from the gut, glucose production by the liver, and glucose extraction from the blood into the cells and tissues.   Insulin plays a central role in the regulation of blood",
+      "glucose transport into the cell. Concomitantly, insulin stimulates intracellular utili-zation of glucose by many other tissues as well. In the fasting state, the main physiological function of insulin is to suppress glucose production by the liver and prevent uncontrolled lipolysis and ketogenesis, without which dia-betic ketoacidosis would quickly develop. Hence, if either of these aspects of insulin action is impaired, then periph-eral or liver hepatic insulin resistance or both are said to be present.",
+      "and suppression ofglucose production are regulated by insulin.",
+      "the pancreas in response to an increase in blood glucose, such as that which follows a carbohydrate - containing meal. Insulin acts to decrease blood glucose levels by increasing glucose uptake by tissues and by decreasing gluconeogenesis by the liver. To increase tissue uptake, insulin triggers the translocation of GLUT4 receptors to the cell surface in skeletal muscle and adipose tissue. Insulin also stimulates each of the regulatory enzymes in the glycolytic pathway, while also inhibiting the key",
+      "insulin suppresses both hepatic and renal glucose release, 3031 and stimulates  glucose uptake exogenous insulin administration causes systemic glucose  utilization to exceed systemic glucose release so that plasma glucose  concentrations decrease.  As the plasma glucose levels decrease there is a characteristic  hierarchy of responses (Figure 1 ). Reduction of insulin secretion, the first in  the cascade of hypoglycemia counterregulation, 2 derepresses glucose",
+      "Counter-regulatory hormones antagonize the glucose lowering action  of insulin, and act to raise the blood glucose level. Glucagon, a potent  counter-regulatory hormone inhibited by insulin, is secreted from pancreatic  alpha cells when cells perceive low glucose. In diabetes, pancreatic insulin  levels are reduced and glucagon is chronically elevated. In DKA, in addition  to low insulin action, there is the cellular perception of low glucose , which"
+    ],
+    [
+      "The biological processes linking aging and disease risk are poorly understood. Still, aging is considered to date as  one of the main factors responsible for several complex diseases including cancer, cardiovascular diseases, and diabetes. Particularly, type 2 diabetes (T2D) has become very prevalent all over the world, with a projected increas- ing growth rate for the years ahead 1. The pathophysiological mechanism that underlines diabetic complications",
+      "unclear whether age at menopause is associated with risk of type2d i a b e t e s[ 3,4]. Data from cross-sectional studies examining the association between age at menopause and type 2 diabetes are contradictory, with a few studies reporting no association and some other reporting higher odds of having type 2 diabetes with early onset of menopause [ 57]. Recently, a nested case cohort study reported that an increased risk of type 2 diabetes is associ-",
+      "The mechanisms leading to development of type 2 diabetes in young people are similar to those in older patients; however, the speed of onset, severity, and interplay of reduced insulin sensitivity and defective insulin secretion might be different in patients who develop the disease at a younger age. 18 In adolescents with type 2 diabetes, as in  later onset type 2 diabetes, the initial deterioration in -cell function is characterised by loss of first-phase nutrient-stimulated insulin secretion.",
+      "anincreased risk of developing type 2 diabetes (T2D) later in their",
+      "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 [24], 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 endog-enous",
+      "tion. Many people with type 2 diabetes ultimately requirei n s u l i nt h e r a p y ,w h i c hr e ects long-standing type 2 diabetes and greatly diminished b-cell function but also likely includes individuals who have slowly progressingautoimmune diabetes with adult onset (LADA) or otherambiguous forms of diabetes. Age. Data from randomized controlled trials in people with type 2 diabetes under the age of 18 years or over the age of 65 years are scarce. Bene cial effects of tight",
+      "strong inverse association between BMI and age at diagnosis of type 2 diabetes. When type 2 diabetes presents in later life, the severity of insulin resistance is often greater among individuals with a history of protracted and severe obesity, particularly with excess visceral adiposity. 28",
+      "patients with young-onset type 2 diabetes than in patients without diabetes, whereas the risk of myocardial infarction was much less (typically 24 times higher) in patients with  type 2 diabetes presenting in middle and later life. 106 In  Hong Kong, where 20% of type 2 diabetes diagnosed since  1995 occurs in people aged 40 years or younger, a 7-year prospective study 107 showed that when adjusted for age,",
+      "type 2 diabetes, the major predisposing risk factors are obesity, family history, and sedentary lifestyle. Onset of diabetes at a younger age (defined here as up to age 40 years) is associated with longer disease exposure and increased risk for chronic complications. Young-onset type 2 diabetes also affects more individuals of working age, accentuating the adverse societal effects of the disease. Furthermore, evidence is accumulating that young-onset type 2 diabetes has a more aggressive disease phenotype,",
+      "pathophysiology of type 2 diabetes. Diabetes 60(10):26242634. doi:10.2337/db11-0415Aging Clin Exp Res 123"
+    ],
+    [
+      "of Type 2 Diabetes   The lifestyle intervention using physical exercise  and modi  cation of nutrition is ef  cient in pre- venting type 2 diabetes in patients with impaired glucose tolerance [  99 ]. Clinical trials con  rm  that lifestyle interventions (dietary modi  cation  and increased physical activity) reduce the risk of progressing from impaired glucose tolerance to type 2 diabetes [  105 ]. Assessing T2D risk accord- ing to FINDRISK scale [ 106 ] is quite common in",
+      "Major clinical trials have demonstrated that diet and lifestyle modifications are  effective in preventing T2DM in high-risk individuals.  T2DM management strategies including lifestyle modifications, social support and  ensuring medication adherence are key to reducing the incidence of diabetes  mellitus complications. REVIEWS NATURE REVIEWS | ENDOCRINOLOGY  VOLUME 14 | FEBRUARY 2018 | 89",
+      "focused on people with impaired glucose tolerance or impaired fasting glucose because of their high risk of development of type 2 diabetes. Several studies have examined the ability of lifestyle modi  cation and drugs to slow progression to diabetes (table 2). Findings from these trials have nearly all shown a bene  t, with lifestyle modi  cations being more e   cacious than any drug, with  the exception of the thiazolidinedione anti diabetics. 163175",
+      "no or just minor weight loss was achieved, diabetes incidence was also reduced (   Pan et al., 1997   ;    Ramachandran et al., 2006   ). In addition, on the long term weight was partially or totally regained in all of the studies (   Knowler et al., 2009   ;    Li et al., 2008   ;    Lindstrom et al., 2006   ;    Lindstrom et al., 2003   ). Despite this regain T2DM risk remained low or decreased further, thus the e  ect of lifestyle is unlikely to be solely due to",
+      "proven particularly effective for preven-tion and management of type 2 diabetes.For example, improvement in dietaryquality, in conjunction with other lifestylemodications like increased physical ac-tivity, was shown to be more effectivethan pharmacological treatment in pre-vention of diabetes in individuals at highrisk (1). Further, lifestyle modicationmay mitigate the risk associated with thestrongest known diabetes risk loci (2).While the existence of environmental in-uences on genetic risk (and vice",
+      "spite of our incomplete knowledge of the genetics of type 2diabetes today, the burden of type 2 diabetes can be amelio-rated at the population level. Recent studies have found thatlifestyle changes through diet and exercise can prevent or",
+      "Lifestyle modification including exercise, nutrition and behavioral changes is the cornerstone to prevent and treat type 2 diabetes. Oral antidiabetic medication either as single agent or combination therapy is frequently required to maintain metabolic control, as assessed by monitoring ofglycated hemoglobin A 1C(HbA 1C) levels. Eventually, asignificant proportion of patients with type 2 diabetes require the exogenous administration of insulin [40].",
+      "diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 134350. 114 Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in  the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393403. 115 Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD,",
+      "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 individ-uals with impaired glucose tolerance (IGT), including theFinnish Diabetes Prevention Study (DPS) (44) and the Diabe-tes Prevention Program (DPP) (22). In the DPS, increasedphysical activity was associated with a decreased risk of type",
+      "demonstrate that lifestyle modi  cation comprising higher levels  of PA and prudent food consumption may be e  ective in obesity  and T2DM prevention. The positive e  ect of lifestyle on body  weight seems somewhat transient, whereas the e  ect on T2DM  is sustained for longer periods. Furthermore, lifestyle modi  ca- tion appears to have an e  ect on diabetes risk independently of  body weight and even of weight loss.      Lifestyle and Genetics in Obesity and Type 2 Diabetes"
+    ]
+  ]
+}
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