Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 4/2017

01-04-2017 | Article

Differential methylation of genes in individuals exposed to maternal diabetes in utero

Authors: Peng Chen, Paolo Piaggi, Michael Traurig, Clifton Bogardus, William C. Knowler, Leslie J. Baier, Robert L. Hanson

Published in: Diabetologia | Issue 4/2017

Login to get access

Abstract

Aims/hypothesis

Individuals exposed to maternal diabetes in utero are more likely to develop metabolic and cardiovascular diseases later in life. This may be partially attributable to epigenetic regulation of gene expression. We performed an epigenome-wide association study to examine whether differential DNA methylation, a major source of epigenetic regulation, can be observed in offspring of mothers with type 2 diabetes during the pregnancy (OMD) compared with offspring of mothers with no diabetes during the pregnancy (OMND).

Methods

DNA methylation was measured in peripheral blood using the Illumina HumanMethylation450K BeadChip. A total of 423,311 CpG sites were analysed in 388 Pima Indian individuals, mean age at examination was 13.0 years, 187 of whom were OMD and 201 were OMND. Differences in methylation between OMD and OMND were assessed.

Results

Forty-eight differentially methylated CpG sites (with an empirical false discovery rate ≤0.05), mapping to 29 genes and ten intergenic regions, were identified. The gene with the strongest evidence was LHX3, in which six CpG sites were hypermethylated in OMD compared with OMND (p ≤ 1.1 × 10−5). Similarly, a CpG near PRDM16 was hypermethylated in OMD (1.1% higher, p = 5.6 × 10−7), where hypermethylation also predicted future diabetes risk (HR 2.12 per SD methylation increase, p = 9.7 × 10−5). Hypermethylation near AK3 and hypomethylation at PCDHGA4 and STC1 were associated with exposure to diabetes in utero (AK3: 2.5% higher, p = 7.8 × 10−6; PCDHGA4: 2.8% lower, p = 3.0 × 10−5; STC1: 2.9% lower, p = 1.6 × 10−5) and decreased insulin secretory function among offspring with normal glucose tolerance (AK3: 0.088 SD lower per SD of methylation increase, p = 0.02; PCDHGA4: 0.08 lower SD per SD of methylation decrease, p = 0.03; STC1: 0.072 SD lower per SD of methylation decrease, p = 0.05). Seventeen CpG sites were also associated with BMI (p ≤ 0.05). Pathway analysis of the genes with at least one differentially methylated CpG (p < 0.005) showed enrichment for three relevant biological pathways.

Conclusions/interpretation

Intrauterine exposure to diabetes can affect methylation at multiple genomic sites. Methylation status at some of these sites can impair insulin secretion, increase body weight and increase risk of type 2 diabetes.
Appendix
Available only for authorised users
Literature
1.
Lehnen H, Zechner U, Haaf T (2013) Epigenetics of gestational diabetes mellitus and offspring health: the time for action is in early stages of life. Mol Hum Reprod 19:415–422CrossRefPubMedPubMedCentral
2.
Pettitt DJ, Aleck KA, Baird HR, Carraher MJ, Bennett PH, Knowler WC (1988) Congenital susceptibility to NIDDM. Role of intrauterine environment. Diabetes 37:622–628CrossRefPubMed
3.
Dabelea D, Hanson RL, Lindsay RS et al (2000) Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 49:2208–2211CrossRefPubMed
4.
Gautier JF, Wilson C, Weyer C et al (2001) Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes 50:1828–1833CrossRefPubMed
5.
Ruchat SM, Hivert MF, Bouchard L (2013) Epigenetic programming of obesity and diabetes by in utero exposure to gestational diabetes mellitus. Nutr Rev 71(Suppl 1):S88–S94CrossRefPubMed
6.
Yan J, Yang H (2014) Gestational diabetes mellitus, programing and epigenetics. J Mater Fetal Neonatal Med 27:1266–1269CrossRef
7.
del Rosario MC, Ossowski V, Knowler WC, Bogardus C, Baier LJ, Hanson RL (2014) Potential epigenetic dysregulation of genes associated with MODY and type 2 diabetes in humans exposed to a diabetic intrauterine environment: an analysis of genome-wide DNA methylation. Metab Clin Exp 63:654–660CrossRefPubMedPubMedCentral
8.
9.
Chen D, Zhang A, Fang M et al (2014) Increased methylation at differentially methylated region of GNAS in infants born to gestational diabetes. BMC Med Genet 15:108CrossRefPubMedPubMedCentral
10.
Dabelea D, Palmer JP, Bennett PH, Pettitt DJ, Knowler WC (1999) Absence of glutamic acid decarboxylase antibodies in Pima Indian children with diabetes mellitus. Diabetologia 42:1265–1266CrossRefPubMed
11.
Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553CrossRefPubMed
12.
Du P, Zhang X, Huang CC et al (2010) Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis. BMC Bioinforma 11:587CrossRef
13.
14.
Hanis CL, Chakraborty R, Ferrell RE, Schull WJ (1986) Individual admixture estimates: disease associations and individual risk of diabetes and gallbladder disease among Mexican-Americans in Starr County, Texas. Am J Phys Anthropol 70:433–441CrossRefPubMed
15.
Tian C, Hinds DA, Shigeta R et al (2007) A genomewide single-nucleotide-polymorphism panel for Mexican American admixture mapping. Am J Hum Genet 80:1014–1023CrossRefPubMedPubMedCentral
16.
Millstein J, Volfson D (2013) Computationally efficient permutation-based confidence interval estimation for tail-area FDR. Front Genet 4:179PubMedPubMedCentral
17.
Hanson RL, Pratley RE, Bogardus C et al (2000) Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J Epidemiol 151:190–198CrossRefPubMed
18.
Baron RM, Kenny DA (1986) The moderator–mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol 51:1173–1182CrossRefPubMed
19.
Preacher KJ, Kelley K (2011) Effect size measures for mediation models: quantitative strategies for communicating indirect effects. Psychol Methods 16:93–115CrossRefPubMed
20.
21.
Zhang B, Kirov S, Snoddy J (2005) WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res 33:W741–W748CrossRefPubMedPubMedCentral
22.
Barker DJ, Godfrey KM, Fall C, Osmond C, Winter PD, Shaheen SO (1991) Relation of birth weight and childhood respiratory infection to adult lung function and death from chronic obstructive airways disease. BMJ 303:671–675CrossRefPubMedPubMedCentral
23.
Tyrrell J, Richmond RC, Palmer TM et al (2016) Genetic evidence for causal relationships between maternal obesity-related traits and birth weight. JAMA 315:1129–1140CrossRefPubMedPubMedCentral
24.
Netchine I, Sobrier ML, Krude H et al (2000) Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet 25:182–186CrossRefPubMed
25.
Malik RE, Rhodes SJ (2014) The role of DNA methylation in regulation of the murine Lhx3 gene. Gene 534:272–281CrossRefPubMed
26.
Gadd MS, Jacques DA, Nisevic I et al (2013) A structural basis for the regulation of the LIM-homeodomain protein islet 1 (Isl1) by intra- and intermolecular interactions. J Biol Chem 288:21924–21935CrossRefPubMedPubMedCentral
27.
28.
Nitert MD, Nagorny CL, Wendt A, Eliasson L, Mulder H (2008) CaV1.2 rather than CaV1.3 is coupled to glucose-stimulated insulin secretion in INS-1 832/13 cells. J Mol Endocrinol 41:1–11CrossRefPubMed
29.
Cote S, Gagne-Ouellet V, Guay SP et al (2016) PPARGC1α gene DNA methylation variations in human placenta mediate the link between maternal hyperglycemia and leptin levels in newborns. Clin Epigenetics 8:72CrossRefPubMedPubMedCentral
30.
Dayeh T, Volkov P, Salo S et al (2014) Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet 10:e1004160CrossRefPubMedPubMedCentral
31.
Kajimura S, Seale P, Kubota K et al (2009) Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature 460:1154–1158CrossRefPubMedPubMedCentral
32.
Urano T, Shiraki M, Sasaki N, Ouchi Y, Inoue S (2014) Large-scale analysis reveals a functional single-nucleotide polymorphism in the 5′-flanking region of PRDM16 gene associated with lean body mass. Aging Cell 13:739–743CrossRefPubMedPubMedCentral
33.
Sugiyama T, Benitez CM, Ghodasara A et al (2013) Reconstituting pancreas development from purified progenitor cells reveals genes essential for islet differentiation. Proc Natl Acad Sci U S A 110:12691–12696CrossRefPubMedPubMedCentral
34.
Ohno H, Shinoda K, Ohyama K, Sharp LZ, Kajimura S (2013) EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 504:163–167CrossRefPubMedPubMedCentral
35.
Doherty MJ, Moorhead G, Morrice N, Cohen P, Cohen PT (1995) Amino acid sequence and expression of the hepatic glycogen-binding (GL)-subunit of protein phosphatase-1. FEBS Lett 375:294–298CrossRefPubMed
36.
Munro S, Cuthbertson DJ, Cunningham J, Sales M, Cohen PT (2002) Human skeletal muscle expresses a glycogen-targeting subunit of PP1 that is identical to the insulin-sensitive glycogen-targeting subunit GL of liver. Diabetes 51:591–598CrossRefPubMed
37.
Bogardus C, Lillioja S, Stone K, Mott D (1984) Correlation between muscle glycogen synthase activity and in vivo insulin action in man. J Clin Invest 73:1185–1190CrossRefPubMedPubMedCentral
38.
Hansen L, Hansen T, Vestergaard H et al (1995) A widespread amino acid polymorphism at codon 905 of the glycogen-associated regulatory subunit of protein phosphatase-1 is associated with insulin resistance and hypersecretion of insulin. Hum Mol Genet 4:1313–1320CrossRefPubMed
39.
Xia J, Scherer SW, Cohen PT et al (1998) A common variant in PPP1R3 associated with insulin resistance and type 2 diabetes. Diabetes 47:1519–1524CrossRefPubMed
40.
Maegawa H, Shi K, Hidaka H et al (1999) The 3′-untranslated region polymorphism of the gene for skeletal muscle-specific glycogen-targeting subunit of protein phosphatase 1 in the type 2 diabetic Japanese population. Diabetes 48:1469–1472CrossRefPubMed
41.
Wang G, Qian R, Li Q, Niu T, Chen C, Xu X (2001) The association between PPP1R3 gene polymorphisms and type 2 diabetes mellitus. Chin Med J 114:1258–1262PubMed
42.
Doney AS, Fischer B, Cecil JE et al (2003) Male preponderance in early diagnosed type 2 diabetes is associated with the ARE insertion/deletion polymorphism in the PPP1R3A locus. BMC Genet 4:11CrossRefPubMedPubMedCentral
43.
Haworth KE, Farrell WE, Emes RD et al (2014) Methylation of the FGFR2 gene is associated with high birth weight centile in humans. Epigenomics 6:477–491CrossRefPubMed
44.
Gunawardhana LP, Baines KJ, Mattes J, Murphy VE, Simpson JL, Gibson PG (2014) Differential DNA methylation profiles of infants exposed to maternal asthma during pregnancy. Pediatr Pulmonol 49:852–862CrossRefPubMed
45.
Suderman M, Borghol N, Pappas JJ et al (2014) Childhood abuse is associated with methylation of multiple loci in adult DNA. BMC Med Genet 7:13
46.
Feinberg AP, Irizarry RA, Fradin D et al (2010) Personalized epigenomic signatures that are stable over time and covary with body mass index. Sci Transl Med 2:49ra67CrossRefPubMedPubMedCentral
47.
48.
Simpkin AJ, Suderman M, Gaunt TR et al (2015) Longitudinal analysis of DNA methylation associated with birth weight and gestational age. Hum Mol Genet 24:3752–3763PubMedPubMedCentral
49.
Terry MB, Ferris JS, Pilsner R et al (2008) Genomic DNA methylation among women in a multiethnic New York City birth cohort. Cancer Epidemiol Biomarkers Prev 17:2306–2310CrossRefPubMed
50.
Richmond RC, Simpkin AJ, Woodward G et al (2015) Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC). Hum Mol Genet 24:2201–2217CrossRefPubMed
Metadata
Title
Differential methylation of genes in individuals exposed to maternal diabetes in utero
Authors
Peng Chen
Paolo Piaggi
Michael Traurig
Clifton Bogardus
William C. Knowler
Leslie J. Baier
Robert L. Hanson
Publication date
01-04-2017
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 4/2017
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-016-4203-1

Other articles of this Issue 4/2017

Diabetologia 4/2017 Go to the issue

Article

Enhanced VEGF signalling mediates cerebral neovascularisation via downregulation of guidance protein ROBO4 in a rat model of diabetes

List of Refereees

Referees 2016

Letter

PCSK9 inhibition and the global diabetes epidemic

Article

Inflammation and N-formyl peptide receptors mediate the angiogenic activity of human vitreous humour in proliferative diabetic retinopathy

Article

Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry

Erratum

Erratum to: Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits