The Role of Epigenetics in Type 1 Diabetes

Jerram, Samuel T.; Dang, Mary; Leslie, Richard

doi:10.1007/s11892-017-0916-x

Cited by 75 publications

(53 citation statements)

References 106 publications

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“…Although this is a relatively short amount of time in culture, data may suggest the potential for epigenetic regulation of gene expression in diabetes in bone. Epigenetic mechanisms occur in diabetes, where hyperglycemia can cause permanent and heritable changes in gene expression profiles …”

Section: Discussionmentioning

confidence: 99%

“…Epigenetic mechanisms occur in diabetes, where hyperglycemia can cause permanent and heritable changes in gene expression profiles. (61,62) To confirm that decreased GIP signaling is specifically due to dopamine and not some other signaling dysregulation in diabetes, we rescued GIP signaling and LOX production in diabetic osteoblasts by inhibiting dopamine receptor activity. Dopamine has five receptors, all of which are expressed by osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

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Impaired Gastric Hormone Regulation of Osteoblasts and Lysyl Oxidase Drives Bone Disease in Diabetes Mellitus

et al. 2019

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Diabetic bone disease is a complication of type I and type II diabetes, both of which are increasing in the United States and elsewhere. Increased hip and foot fracture rates do not correlate well with changes in bone mineral density (BMD), whereas studies support the importance of collagen structure to bone strength. Extracellular lysyl oxidase (LOX) catalyzes the oxidative deamination of hydroxylysine and lysine residues in collagens resulting in aldehydes that subsequently form critically important biosynthetic crosslinks that stabilize functional collagens. Although LOX‐dependent biosynthetic crosslinks in bone collagen are deficient in diabetic bone, the expression and regulation of bone LOXs in diabetes have not been comprehensively studied. Here, we found that LOX is profoundly downregulated in bone in diabetes. Moreover, we have identified a novel metabolic regulatory relationship that is dysregulated in diabetes using mouse models. Data indicate that the incretin (gastric hormone) known as glucose‐dependent insulinotropic polypeptide (GIP) that is anabolic to osteoblasts strongly upregulates LOX, and that this regulation is disrupted in the streptozotocin‐induced model of diabetes in mice. In vivo and in vitro studies support that diabetes results in elevated circulating peripheral dopamine, likely also derived from the gut, and is responsible for blocking GIP signaling and LOX levels in osteoblasts. Moreover, peripheral administration of the dopamine D2 receptor antagonist amisulpride to diabetic mice restored trabecular bone structure to near normal and partially reversed downregulation of LOX. Taken together our data identifies a novel metabolic relationship between the gut‐derived hormone GIP and bone‐derived LOX, and points to the importance of LOX dysregulation in the pathology of diabetic bone disease. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impaired Gastric Hormone Regulation of Osteoblasts and Lysyl Oxidase Drives Bone Disease in Diabetes Mellitus

et al. 2019

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“…Inconsistent findings of commonly studied factors such as viral infections, infant diet, and gut microbial composition suggest that the triggering environmental risk factors vary by age, autoimmune phasing, or genotype [5][6][7][8][9][10] . Though no particular environmental exposure has been firmly established in pathogenesis of T1D, epigenetics has been proposed as a link between genetic susceptibility and environmental exposures that may account for some of the disease heterogeneity 11,12 .…”

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confidence: 99%

Longitudinal DNA methylation differences precede type 1 diabetes

Johnson

Vanderlinden

Dong

et al. 2020

Sci Rep

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DNA methylation may be involved in development of type 1 diabetes (T1D), but previous epigenomewide association studies were conducted among cases with clinically diagnosed diabetes. Using multiple pre-disease peripheral blood samples on the Illumina 450 K and EPIC platforms, we investigated longitudinal methylation differences between 87 T1D cases and 87 controls from the prospective Diabetes Autoimmunity Study in the Young (DAISY) cohort. Change in methylation with age differed between cases and controls in 10 regions. Average longitudinal methylation differed between cases and controls at two genomic positions and 28 regions. Some methylation differences were detectable and consistent as early as birth, including before and after the onset of preclinical islet autoimmunity. Results map to transcription factors, other protein coding genes, and non-coding regions of the genome with regulatory potential. The identification of methylation differences that predate islet autoimmunity and clinical diagnosis may suggest a role for epigenetics in T1D pathogenesis; however, functional validation is warranted. open Scientific RepoRtS | (2020) 10:3721 | https://doi.

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“…It has been reported that epigenetics contributes significantly to T1DM [38]. Epigenetic modification including DNA methylation exists at cytosine residues primarily in the context of CpG dinucleotides.…”

Section: Epigenetic Factorsmentioning

confidence: 99%

Targeting Glycoproteins as a therapeutic strategy for diabetes mellitus and its complications

et al. 2020

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Objectives Glycoproteins are organic compounds formed from proteins and carbohydrates, which are found in many parts of the living systems including the cell membranes. Furthermore, impaired metabolism of glycoprotein components plays the main role in the pathogenesis of diabetes mellitus. The aim of this study is to investigate the influence of glycoprotein levels in the treatment of diabetes mellitus. Methods All relevant papers in the English language were compiled by searching electronic databases, including Scopus, PubMed and Cochrane library. The keywords of glycoprotein, diabetes mellitus, glycan, glycosylation, and inhibitor were searched until January 2019. Results Glycoproteins are pivotal elements in the regulation of cell proliferation, growth, maturation and signaling pathways. Moreover, they are involved in drug binding, drug transportation, efflux of chemicals and stability of therapeutic proteins. These functions, structure, composition, linkages, biosynthesis, significance and biological effects are discussed as related to their use as a therapeutic strategy for the treatment of diabetes mellitus and its complications. Conclusions The findings revealed several chemical and natural compounds have significant beneficial effects on glycoprotein metabolism. The comprehension of glycoprotein structure and functions are very essential and inevitable to enhance the knowledge of glycoengineering for glycoprotein-based therapeutics as may be required for the treatment of diabetes mellitus and its associated complications.

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The Role of Epigenetics in Type 1 Diabetes

Cited by 75 publications

References 106 publications

Impaired Gastric Hormone Regulation of Osteoblasts and Lysyl Oxidase Drives Bone Disease in Diabetes Mellitus

Impaired Gastric Hormone Regulation of Osteoblasts and Lysyl Oxidase Drives Bone Disease in Diabetes Mellitus

Longitudinal DNA methylation differences precede type 1 diabetes

Targeting Glycoproteins as a therapeutic strategy for diabetes mellitus and its complications

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