Genetic and epigenetic control of metabolic health

Schwenk, Robert W.; Vogel, Heike; Schürmann, Annette

doi:10.1016/j.molmet.2013.09.002

Cited by 124 publications

(83 citation statements)

References 130 publications

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“…Accordingly, genomewide association studies (GWAS) of common single nucleotide polymorphisms in large cohorts have established associations between ;100 genes and T2D (1)(2)(3)(4). However, these associations explain only a small portion of the total heritability.…”

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confidence: 99%

Differential Transcriptome Analysis of Diabetes-Resistant and -Sensitive Mouse Islets Reveals Significant Overlap With Human Diabetes Susceptibility Genes

et al. 2014

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Type 2 diabetes in humans and in obese mice is polygenic. In recent genome-wide association studies, genetic markers explaining a small portion of the genetic contribution to the disease were discovered. However, functional evidence linking these genes with the pathogenesis of diabetes is scarce. We performed RNA sequencing-based transcriptomics of islets from two obese mouse strains, a diabetes-susceptible (NZO) and a diabetes-resistant (B6-ob/ob) mouse, after a short glucose challenge and compared these results with human data. Alignment of 2,328 differentially expressed genes to 106 human diabetes candidate genes revealed an overlap of 20 genes, including TCF7L2, IGFBP2, CDKN2A, CDKN2B, GRB10, and PRC1. The data provide a functional validation of human diabetes candidate genes, including those involved in regulating islet cell recovery and proliferation, and identify additional candidates that could be involved in human b-cell failure.The susceptibility for type 2 diabetes (T2D) in humans is, to a substantial degree, inherited. Accordingly, genomewide association studies (GWAS) of common single nucleotide polymorphisms in large cohorts have established associations between ;100 genes and T2D (1-4). However, these associations explain only a small portion of the total heritability. Furthermore, little direct functional evidence links the genetic variants with the pathogenesis of the disease. In several mouse models, diabetes exhibits all features of the human pathogenesis with obesity-associated insulin resistance, failure of insulin secretion, and subsequent b-cell loss. Thus, it appears reasonable to assume that the cellular mechanism of the pathogenesis of diabetes in mice and humans is similar and that at least some of the genes involved are identical. Furthermore, identification of such an overlap would validate the GWAS results by providing biological plausibility. Thus, we tested this hypothesis by aligning human GWAS results with data from a genomewide screen of islets from a mouse model of T2D. This screen was based on a comparison of a diabetes-sensitive with a diabetes-resistant obese mouse strain subjected to sequential dietary fat and carbohydrate challenges. The alignment indicated that 20 of the 106 genes identified in the GWAS were also detected in the screen of mouse islets. RESEARCH DESIGN AND METHODS Experimental AnimalsMale NZO/HIBomDife mice from our own colony and male B6.V-Lep ob/ob /JBomTac (B6-ob/ob) mice (Charles

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confidence: 99%

Differential Transcriptome Analysis of Diabetes-Resistant and -Sensitive Mouse Islets Reveals Significant Overlap With Human Diabetes Susceptibility Genes

et al. 2014

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“…Hence, both, glucose and palmitate are able to affect the binding of transcription factors that control the activity of the insulin promoter, pointing to an involvement of these regulators of gene expression in the mechanisms of glucolipotoxicity (68) . Emerging evidence suggests an impact of dietdependent epigenetic modifications in the aetiology of metabolic disorders (69) . Hu et al (70) observed an aberrant DNA methylation profile in β-cells cultured for 1 month in a medium containing high glucose and lipid concentrations.…”

Section: Impact Of Nutrients On β-Cell Gene Expressionmentioning

confidence: 99%

Insulin secretion in health and disease: nutrients dictate the pace

2015

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Insulin is a key hormone controlling metabolic homeostasis. Loss or dysfunction of pancreatic β-cells lead to the release of insufficient insulin to cover the organism needs, promoting diabetes development. Since dietary nutrients influence the activity of β-cells, their inadequate intake, absorption and/or utilisation can be detrimental. This review will highlight the physiological and pathological effects of nutrients on insulin secretion and discuss the underlying mechanisms. Glucose uptake and metabolism in β-cells trigger insulin secretion. This effect of glucose is potentiated by amino acids and fatty acids, as well as by enteroendocrine hormones and neuropeptides released by the digestive tract in response to nutrients. Glucose controls also basal and compensatory β-cell proliferation and, along with fatty acids, regulates insulin biosynthesis. If in the short-term nutrients promote β-cell activities, chronic exposure to nutrients can be detrimental to β-cells and causes reduced insulin transcription, increased basal secretion and impaired insulin release in response to stimulatory glucose concentrations, with a consequent increase in diabetes risk. Likewise, suboptimal early-life nutrition (e.g. parental high-fat or low-protein diet) causes altered β-cell mass and function in adulthood. The mechanisms mediating nutrient-induced β-cell dysfunction include transcriptional, post-transcriptional and translational modifications of genes involved in insulin biosynthesis and secretion, carbohydrate and lipid metabolism, cell differentiation, proliferation and survival. Altered expression of these genes is partly caused by changes in non-coding RNA transcripts induced by unbalanced nutrient uptake. A better understanding of the mechanisms leading to β-cell dysfunction will be critical to improve treatment and find a cure for diabetes.

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“…People with a family history of T2DM have more six and three times higher risk of developing this disease than unrelated individuals, respectively 18,19 . More than 70% of T2D risk has been attributed to genetics, with multiple genes involved and different combinations of genes playing roles in different subsets of individuals are involved in T2DM 20 . Those that have garnered the most attention are the ATP-binding cassette transporter subfamily C member 8 (ABCC8) gene; the KCNJ11 gene and the peroxisome proliferator-activated receptor-gamma (PPARG) gene.…”

Section: Role Of Genetics In the Development Of Type 2 Diabetes Mellitusmentioning

confidence: 99%