| 1. |
- Bonnefond, Amélie, et al.
(författare)
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From association to function : MTNR1B
- 2016
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Ingår i: The Genetics of Type 2 Diabetes and Related Traits: Biology, Physiology and Translation. - Cham : Springer International Publishing. - 9783319015743 - 9783319015736 ; , s. 403-421
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Bokkapitel (refereegranskat)abstract
- The discovery that variants in the melatonin receptor 2 (MTNR1B) gene were associated with glucose levels, insulin secretion, and risk for type 2 diabetes (T2D) in genome-wide association studies (GWAS) reinforced the previously suggested link between glucose homeostasis and circadian rhythmicity. Diurnal secretion of melatonin has reported to be altered in people with diabetes and rodent models of T2D. The proposed underlying mechanisms by which altered melatonin signaling could predispose to progression to T2D and gestational diabetes mellitus (GDM) involve altered expression of MTNR1B in pancreatic beta cells, leading to impaired insulin secretion, consequent increased fasting glucose concentrations, and eventually overt T2D. Thus blocking the inhibition of insulin secretion may have potential clinical implications, and these effects could be more pronounced in individuals carrying risk genotypes. Finally, given that melatonin could emerge as an attractive treatment for a variety of conditions including pregnancies associated with GDM, preeclampsia, and intrauterine growth retardation, pharmacogenetic studies are warranted to determine treatment response and side effects according to genotype.
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| 2. |
- Grant, Struan F A, et al.
(författare)
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Transcription factor 7-like 2 (TCF7L2)
- 2016
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Ingår i: The Genetics of Type 2 Diabetes and Related Traits: Biology, Physiology and Translation. - Cham : Springer International Publishing. - 9783319015743 - 9783319015736 ; , s. 297-316
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Bokkapitel (refereegranskat)abstract
- In 2006 a genetic signal within the gene encoding transcription factor 7-like 2 (TCF7L2) was first reported to be associated with type 2 diabetes. Since then multiple genome-wide association studies have revealed this signal to be among the most strongest associations reported with this disease to date. Furthermore, multiple studies around the world have revealed the global relevance of this locus in intron 3 of the gene and have helped pinpoint, with relative confidence, the causal lesion at this locus. However, despite this association being beyond doubt, there is still a lack of consensus with respect to mechanisms of action and which tissue(s) it actually exerts its influence on the pathogenesis of type 2 diabetes.
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| 3. |
- Ingelsson, Erik, et al.
(författare)
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Genome-wide association studies (GWAS) of adiposity
- 2016
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Ingår i: The Genetics of Type 2 Diabetes and Related Traits. - Cham : Springer Publishing Company. - 9783319015743 - 9783319015736 ; , s. 91-109
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Bokkapitel (refereegranskat)abstract
- Adiposity is strongly heritable and one of the leading risk factors for type 2 diabetes, cardiovascular disease, cancer, and premature death. In the past 8 years, genome-wide association studies (GWAS) have greatly increased our understanding of the genes and biological pathways that regulate adiposity by identifying more than 100 novel susceptibility loci for overall adiposity and more than 70 loci for body fat distribution. The results for overall adiposity highlight a significant neuronal component, whereas loci regulating body fat distribution demonstrate a central role for adipocyte biology and insulin resistance in the pathophysiology. The effect sizes of all identified loci are small, and even in aggregate, they explain <3 % of the variance in each adiposity trait. This and other evidence suggest that numerous new loci will be identified in extended meta-analyses in the future. The translation of the new discoveries into clinical care remains a major challenge. As the first step, further studies are required to establish the causal genes and variants and to disentangle the exact physiological mechanisms underlying each genotype-phenotype association.
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| 4. |
- Ling, Charlotte, et al.
(författare)
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Epigenetics in type 2 diabetes
- 2016
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Ingår i: The Genetics of Type 2 Diabetes and Related Traits: Biology, Physiology and Translation. - Cham : Springer International Publishing. - 9783319015743 - 9783319015736 ; , s. 241-258
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Bokkapitel (refereegranskat)abstract
- Combinations of genetic and environmental factors contribute to the pathogenesis of type 2 diabetes (T2D); however, our knowledge of the molecular mechanisms by which these factors trigger diabetes is still limited. While genome-wide association studies have identified and characterized more than 60 genomic loci associated with T2D, recent methylome charts and reference regulatory maps obtained from tissues central to T2D can help to pinpoint the causative genetic variants. Yet, the proportion of overall trait variance explained by these genetic variants is still modest. Aging, diet, obesity, and physical inactivity represent nongenetic risk factors that may be reflected in epigenetic processes promoting T2D. Recent studies have characterized epigenetic modifications in pancreatic islets, skeletal muscle, and adipose tissue from T2D patients suggesting a central role for epigenetic mechanisms in the pathogenesis of the disease. Altered epigenetic patterns have also been found in first-degree relatives of patients with T2D and in healthy subjects born with a low birth weight suggesting that epigenetic modifications may predispose to diabetes. Lifestyle interventions including exercise and diet have also been shown to alter the epigenome in target tissues for T2D. Overall, these data propose a model where combinations of genetic, epigenetic, and nongenetic factors contribute to the risk of T2D. In this book chapter, we will explore the potential role of epigenetic mechanisms in T2D and discuss how genetics, epigenetics, and environment may interact to define the risk of developing the disease.
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| 5. |
- Orho-Melander, Marju, et al.
(författare)
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GCKR : How genetic variation across the allelic spectrum influences protein function and metabolic traits in humans
- 2016
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Ingår i: The Genetics of Type 2 Diabetes and Related Traits: Biology, Physiology and Translation. - Cham : Springer International Publishing. - 9783319015743 - 9783319015736 ; , s. 317-336
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Bokkapitel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have generated considerable interest in glucokinase regulatory protein (GKRP; gene name GCKR) which is an inhibitor of hepatic glucokinase (GCK), an enzyme that plays a critical role in glucose update and disposal in liver. From the initial discovery of GCKR variants associated with triglyceride and glucose levels through the identification of pleiotropic associations with a wide variety of metabolic phenotypes, we have learned a great deal about the importance of GKRP as a critical node in hepatic metabolism. GKRP remains one of the few well-studied GWAS loci where attempts have been made to understand the functional as well as the phenotypic impact of genetic variants across the allelic spectrum. Given the interest in developing liver-specific glucokinase activators and small molecules which disrupt the GKRP:GCK interaction for the treatment of type 2 diabetes, these genetic insights provide a wealth of information regarding efficacy and potential adverse on-target effects in humans.
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| 6. |
- Qi, Lu, et al.
(författare)
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Nutrigenetics of type 2 diabetes
- 2016
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Ingår i: The genetics of type 2 diabetes and related traits. - Cham : Springer. - 9783319015743 - 9783319015736 - 9783319791289 ; , s. 539-560
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Bokkapitel (refereegranskat)abstract
- Type 2 diabetes has become a leading health problem throughout the world. The escalating epidemic of type 2 diabetes is believed to result from a collision between inherent biological susceptibilities (genotypes) and a shift toward dietary habits and lifestyle that promote obesity over the past several decades; the transition from "traditional" to modern "obesogenic" lifestyles is characterized by widespread access to highly palatable, nutrient-deficient, and calorie-dense foods and beverages, as well as circumstances that promote sedentary behaviors and inhibit physical activity. In the past decades, a large body of epidemiological studies has associated various dietary factors with type 2 diabetes risk. In the meantime, genetic studies have made great strides in unraveling the genetic basis of type 2 diabetes by identifying more about 100 common genetic loci related to the disease. Nutrigenetics, a relatively new branch of nutrition science, focuses on determining the interplay between dietary exposures and genetic factors in the etiology of many diseases including type 2 diabetes. Even with many hundreds of gene-diet/lifestyle interaction studies on diabetes-related traits published over the past two decades, few examples have been adequately replicated or validated. By contrast, a number of replicated examples of interactions between lifestyle factors (e.g., consumption of sugar sweetened beverages and fried foods and low physical activity and sedentary lifestyles) and genetic factors in obesity (a major risk factor for diabetes) have recently emerged. Further advances are likely to come from the optimization of methods and study designs for nutrigenetic analyses. The development of methods to integrate genetic, transcriptomic, epigenomic, proteomic, and metabolomic data to help define the functional mechanisms that might underlie observations of gene-lifestyle interactions is an especially exciting, yet challenging, area. Nutrigenetic studies hold great promise to inform personalized diet and lifestyle interventions to reduce type 2 diabetes risk and improve human health; however, deriving replicated examples of such interactions and determining how best to translate these findings into public health practice and medical intervention remain major challenges.
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