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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Globally, diabetes (and, in particular, type 2 diabetes) represents a major challenge to world health. Currently in the United States, the costs of treating diabetes and its associated complications exceed 100 billion US dollars annually, and this figure is expected to soar in the near future. Despite decades of intense research efforts, the genetic basis of the events involved in the pathogenesis of diabetes is still poorly understood. Diabetes is a complex multigenic syndrome primarily due to beta-cell dysfunction associated with a variable degree of insulin resistance. Recent advances have led to exciting new developments with regard to our understanding of the mechanisms that regulate insulin transcription. These include data that implicate chromatin as a critical regulator of this event. The 'Histone Code' is a widely accepted hypothesis, whereby sequential modifications to the histones in chromatin lead to regulated transcription of genes. One of the modifications used in the histone code is acetylation. This is probably the best characterized modification of histones, which is carried out under the control of histone acetyltransferases (HATs) and histone deacetylases (HDACs). These enzymes also regulate the activity of a number of transcription factors through acetylation. Increasing evidence links possible dysregulation of these mechanisms in the pathogenesis of diabetes, with important therapeutic implications.
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PMID:Role of histone and transcription factor acetylation in diabetes pathogenesis. 1590 5

Epigenetic changes associated with DNA methylation and histone modifications leading to chromatin remodeling and regulation of gene expression underlie the developmental programming of obesity, type 2 diabetes, cardiovascular diseases and metabolic syndrome. This review focuses on converging data supporting the hypothesis that, in addition to "thrifty genotype" inheritance, individuals with obesity, type 2 diabetes, and metabolic syndrome (MetS) with an increased risk of cardiovascular diseases have suffered improper "epigenetic programming" during their fetal/postnatal development due to maternal inadequate nutrition and metabolic disturbances and also during their lifetime, that could even be transmitted to the next generation(s). We highlight the susceptibility of epigenetic mechanisms controlling gene expression to environmental influences due to their inherent malleability, emphasizing the participation of transposable elements and the potential role of imprinted genes during critical time windows in epigenetic programming, from the very beginning of development, throughout life. Increasing our understanding on epigenetic patterns significance and their role in development, evolution and adaptation and on small molecules (nutrients, drugs) that reverse epigenetic (in)activation should provide us with the means to "unlock" silenced (enhanced) genes, and to "convert" the obsolete human thrifty genotype into a "squandering" phenotype.
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PMID:[Nutritionnal epigenomics: consequences of unbalanced diets on epigenetics processes of programming during lifespan and between generations]. 1595 93

Adiponectin is an adipokine with profound insulin-sensitizing, anti-inflammatory, and anti-atherogenic properties. Plasma levels of adiponectin are reduced in insulin resistant states such as obesity, type 2 diabetes and cardiovascular disease. However, the mechanism(s) by which adiponectin concentrations are decreased during disease development is unclear. Studies have shown that endothelin-1 (ET-1), a vasoconstrictor peptide, affects adipocyte glucose metabolism and secretion of adipokines such as leptin, resistin, and adiponectin. The goal of our study was to determine the mechanism by which ET-1 decreases adiponectin secretion. 3T3-L1 adipocytes were treated for 24h with ET-1 (10nM) and then stimulated with vehicle or insulin (100 nM) for a period of 1-2h. Chronic ET-1 (24h) treatment significantly decreased basal and insulin-stimulated adiponectin secretion by 66% and 47%, respectively. Inhibition of phosphatidylinositol 4,5-bisphosphate (PIP(2)) hydrolysis by the PLCbeta inhibitor, U73122, or exogenous addition of PIP(2):histone carrier complex (1.25:0.625 microM) ameliorated the decrease in basal and insulin-stimulated adiponectin secretion observed with ET-1. However, treatment with exogenous PIP(2):histone carrier complex and the actin depolymerizing agent latrunculin B (20 microM) did not reverse the ET-1-mediated decrease in adiponectin secretion. In conclusion, we demonstrate that ET-1 inhibits basal and insulin-stimulated adiponectin secretion through PIP(2) modulation of the actin cytoskeleton.
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PMID:Endothelin-1 inhibits adiponectin secretion through a phosphatidylinositol 4,5-bisphosphate/actin-dependent mechanism. 1668 5

There is accumulating evidence that many chronic diseases such as type 2 diabetes and coronary heart disease might originate during early life. This evidence gives rise to the developmental origins of disease hypothesis, and is supported by epidemiological data in humans and experimental animal models. A perturbed environment in early life is thought to elicit a range of physiological and cellular adaptive responses in key organ systems. These adaptive changes result in permanent alterations and might lead to pathology in later life. Aging organs and cells seem therefore to retain a 'memory' of their fetal history and adaptive responses. The mechanisms underlying the developmental origins of disease remain poorly defined. Epigenetic tagging of genes, such as DNA methylation and histone modification, controls the function of the genome at different levels and maintains cellular memory after many cellular divisions; importantly, tagging can be modulated by the environment and is involved in onset of diseases such as cancer. Here we review the evidence for the developmental origins of disease and discuss the role of the epigenotype as a contributing mechanism. Environmentally induced changes in the epigenotype might be key primary events in the developmental origins of disease, with important clinical implications.
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PMID:Mechanisms of disease: the developmental origins of disease and the role of the epigenotype. 1758 23

This review focuses on different animal models of nutrient perturbations, inclusive of restrictive and excessive states mimicking human situations during pregnancy and lactation that cause aberrations in the offspring. These aberrations consist of diminished insulin sensitivity in the presence of defective insulin production. These phenotypic changes are due to altered peripheral tissue post-insulin receptor signaling mechanisms and pancreatic beta-islet insulin synthesis and secretion defects. While these changes during in utero or postnatal life serve as essential adaptations to overcome adverse conditions, they become maladaptive subsequently and set the stage for type 2 diabetes mellitus. Pregnancy leads to gestational diabetes with trans-generational propagation of the insulin resistant phenotype. This is in response to the metabolically aberrant maternal in utero environment, and tissue specific epigenetic perturbations that permanently alter expression of critical genes transmitted to future generations. These heritable aberrations consisting of altered DNA methylation and histone modifications remodel chromatin and affect transcription of key genes. Along with an altered in utero environment, these chromatin modifications contribute to the world-wide epidemic of type 2 diabetes mellitus, with nutrient excess dominating in developed and nutrient restriction in developing countries.
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PMID:Metabolic programming in the pathogenesis of insulin resistance. 1765 4

Intrauterine growth retardation (IUGR) has been linked to the onset of diseases in adulthood, including type 2 diabetes, and has been proposed to result from altered gene regulation patterns due to epigenetic modifications of developmental genes. To determine whether epigenetic modifications may play a role in the development of adult diabetes following IUGR, we used a rodent model of IUGR that expresses lower levels of Pdx1, a pancreatic and duodenal homeobox 1 transcription factor critical for beta cell function and development, which develops diabetes in adulthood. We found that expression of Pdx1 was permanently reduced in IUGR beta cells and underwent epigenetic modifications throughout development. The fetal IUGR state was characterized by loss of USF-1 binding at the proximal promoter of Pdx1, recruitment of the histone deacetylase 1 (HDAC1) and the corepressor Sin3A, and deacetylation of histones H3 and H4. Following birth, histone 3 lysine 4 (H3K4) was demethylated and histone 3 lysine 9 (H3K9) was methylated. During the neonatal period, these epigenetic changes and the reduction in Pdx1 expression could be reversed by HDAC inhibition. After the onset of diabetes in adulthood, the CpG island in the proximal promoter was methylated, resulting in permanent silencing of the Pdx1 locus. These results provide insight into the development of type 2 diabetes following IUGR and we believe they are the first to describe the ontogeny of chromatin remodeling in vivo from the fetus to the onset of disease in adulthood.
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PMID:Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. 1846 33

Most human diseases are related in some way to the loss or gain in gene functions. Regulation of gene expression is a complex process. In addition to genetic mechanisms, epigenetic causes are gaining new perspectives in human diseases related to gene deregulation. Most eukaryotic genes are packed into chromatin structures, which lead to high condensations of the genes that require dynamic chromatin remodeling processes to facilitate their transcription. DNA methylation and histone modifications represent two of the major chromatin remodeling processes. They also serve to integrate environmental signals for the cells to modulate the functional output of their genome. Complex human diseases such as cancer and type 2 diabetes are believed to have a strong environmental component in addition to genetic causes. Aberrancies in chromatin remodeling are associated with both genetically and environmentally-related diseases. We will focus on recent findings of the epigenetic basis of human metabolic disorders to facilitate further exploration of epigenetic mechanisms and better understandings of the molecular cues underlying such complex diseases.
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PMID:Gene-environment interactions and epigenetic basis of human diseases. 1852 4

In 2007, five whole genome-wide association studies were published on the genetics of type 2 diabetes mellitus (T2DM), followed by the discovery of 11 genes consistently associated with T2DM. This breakthrough provided the first glimpses of a complete picture of the disease's genetic complexity. Currently, we are only beginning to understand how DNA methylation, histone acetylation, and deacetylation may introduce epigenetic changes throughout one's lifetime. Such changes may influence age-related modifications in gene-expression that contribute to age-related diseases. In the future, the possibility of whole-genome DNA methylation studies may elucidate the extent of these epigenetic effects. This article reviews genes that have recently been determined to be associated with T2DM.
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PMID:Genes and type 2 diabetes mellitus. 1862 15

Evidence is emerging that several diseases and behavioral pathologies result from defects in gene function. The best-studied example is cancer, but other diseases such as autoimmune disease, asthma, type 2 diabetes, metabolic disorders, and autism display aberrant gene expression. Gene function may be altered by either a change in the sequence of the DNA or a change in epigenetic programming of a gene in the absence of a sequence change. With epigenetic drugs, it is possible to reverse aberrant gene expression profiles associated with different disease states. Several epigenetic drugs targeting DNA methylation and histone deacetylation enzymes have been tested in clinical trials. Understanding the epigenetic machinery and the differential roles of its components in specific disease states is essential for developing targeted epigenetic therapy.
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PMID:Epigenetics, DNA methylation, and chromatin modifying drugs. 1885 83

Compared to the successful probing of genetic causes of monogenic disorders, dissecting the genetics of complex polygenic diseases has until recently been a fairly slow and cumbersome process. With the introduction of whole genome wide association studies (WGAS) the situation dramatically changed in 2007. The results from several recent WGAS on type 2 diabetes (T2D) and obesity have identified at least eighteen genes consistently associated with T2D. Many of the genes implicate pancreatic beta-cell function in the pathogenesis of T2D whereas only one clearly associate with insulin resistance. The identified genes most likely merely represent the tip of the iceberg in the explanation behind T2D. Refined tools will have to provide a more complete picture of the genetic complexity of T2D over the next few years. In addition to common variants increasing susceptibility for the disease, rare variants with stronger effects, copy number variations, and epigenetic effects like DNA methylation and histone acetylation will become important. Nevertheless, today we are able for the first time to anticipate that the genetics of a complex disease like T2D really can be dissected.
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PMID:Genetic dissection of type 2 diabetes. 1900 Jul 35


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