妊娠期糖尿病患者基因DNA甲基化的研究进展

doi:10.3969/j.issn.1674-8115.2021.08.021

摘要/Abstract

摘要：

妊娠期糖尿病是指患者妊娠前糖代谢正常、妊娠期出现的糖耐量异常，表现为机体脂肪、肌肉等组织对胰岛素的敏感性降低，血糖水平异常，严重影响母体及子代健康。妊娠期糖尿病患者在产后及其子代罹患2型糖尿病及其他代谢性疾病的风险明显增加。研究发现，表观遗传修饰如DNA甲基化参与妊娠期糖尿病的发生及母胎并发症的发生过程。在妊娠期糖尿病患者多种临床标本如胎盘、脐血、外周血与脂肪等组织中，发现多个基因的甲基化水平改变，并可通过“胎儿编程”的方式影响子代终生。该文对妊娠期糖尿病相关基因的DNA甲基化研究进展进行综述。

关键词: 妊娠期糖尿病, 表观遗传修饰, DNA甲基化, 胎儿编程, 代谢模式

Abstract:

Gestational diabetes mellitus refers to patients with normal glucose metabolism before pregnancy and getting abnormal glucose tolerance during pregnancy. It is characterized by decreased insulin sensitivity of adipose and muscle tissues and abnormal blood glucose levels in the body. This disease can seriously affect the maternal and fetal health, and the risk of type 2 diabetes mellitus and other metabolic diseases in the postpartum period and the offsprings significantly increased. It has been found that epigenetic modifications such as DNA methylation can be involved in the pathogenesis of gestational diabetes mellitus and the occurrence of maternal and fetal complications. The differences in gene methylation levels appear in the various clinical specimens of patients with gestational diabetes mellitus, such as placentas, umbilical cord blood, peripheral blood and adipose tissues. It can also affect all the lives of the offsprings through “fetal programming”. In this paper, the research progress of DNA methylation in gestational diabetes mellitus is reviewed.

Key words: gestational diabetes mellitus (GDM), epigenetic modification, DNA methylation, fetal programming, metabolic pattern

中图分类号:

R714.256

吴丹, 葛莉萍. 妊娠期糖尿病患者基因DNA甲基化的研究进展[J]. 上海交通大学学报(医学版), 2021, 41(8): 1120-1124.

Dan WU, Li-ping GE. Research progress of DNA methylation in gestational diabetes mellitus[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(8): 1120-1124.

图/表 1

参考文献 47

1	Chiefari E, Arcidiacono B, Foti D, et al. Gestational diabetes mellitus: an updated overview[J]. J Endocrinol Invest, 2017, 40(9): 899-909.
2	Catalano PM, Kirwan JP, Haugel-de Mouzon S, et al. Gestational diabetes and insulin resistance: role in short- and long-term implications for mother and fetus[J]. J Nutr, 2003, 133(5 ): 1674S-1683S.
3	Wong CC, Caspi A, Williams B, et al. A longitudinal study of epigenetic variation in twins[J]. Epigenetics, 2010, 5(6): 516-526.
4	Gluckman PD, Hanson MA, Buklijas T, et al. Epigenetic mechanisms that underpin metabolic and cardiovascular diseases[J]. Nat Rev Endocrinol, 2009, 5(7): 401-408.
5	Tobi EW, Lumey LH, Talens RP, et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific[J]. Hum Mol Genet, 2009, 18(21): 4046-4053.
6	Zhao BH, Jiang Y, Zhu H, et al. Placental δ-like 1 gene DNA methylation levels are related to mothers' blood glucose concentration[J]. J Diabetes Res, 2019, 2019: 9521510.
7	Wang LZ, Fan HL, Zhou LD, et al. Altered expression of PGC-1α and PDX1 and their methylation status are associated with fetal glucose metabolism in gestational diabetes mellitus[J]. Biochem Biophys Res Commun, 2018, 501(1): 300-306.
8	Su RN, Wang C, Feng H, et al. Alteration in expression and methylation of IGF2/H19 in placenta and umbilical cord blood are associated with macrosomia exposed to intrauterine hyperglycemia[J]. PLoS One, 2016, 11(2): e0148399.
9	Xie XM, Gao HJ, Zeng WJ, et al. Placental DNA methylation of peroxisome-proliferator-activated receptor-γ co-activator-1α promoter is associated with maternal gestational glucose level[J]. Clin Sci (Lond), 2015, 129(4): 385-394.
10	Côté S, Gagné-Ouellet V, Guay SP, et al. PPARGC1α gene DNA methylation variations in human placenta mediate the link between maternal hyperglycemia and leptin levels in newborns[J]. Clin Epigenetics, 2016, 8: 72.
11	Houde AA, St-Pierre J, Hivert MF, et al. Placental lipoprotein lipase DNA methylation levels are associated with gestational diabetes mellitus and maternal and cord blood lipid profiles[J]. J Dev Orig Health Dis, 2014, 5(2): 132-141.
12	Gagné-Ouellet V, Houde AA, Guay SP, et al. Placental lipoprotein lipase DNA methylation alterations are associated with gestational diabetes and body composition at 5 years of age[J]. Epigenetics, 2017, 12(8): 616-625.
13	El Hajj N, Pliushch G, Schneider E, et al. Metabolic programming of MEST DNA methylation by intrauterine exposure to gestational diabetes mellitus[J]. Diabetes, 2013, 62(4): 1320-1328.
14	Steyn A, Crowther NJ, Norris SA, et al. Epigenetic modification of the pentose phosphate pathway and the IGF-axis in women with gestational diabetes mellitus[J]. Epigenomics, 2019, 11(12): 1371-1385.
15	Cvitic S, Novakovic B, Gordon L, et al. Human fetoplacental arterial and venous endothelial cells are differentially programmed by gestational diabetes mellitus, resulting in cell-specific barrier function changes[J]. Diabetologia, 2018, 61(11): 2398-2411.
16	Houde AA, Ruchat SM, Allard C, et al. LRP1B, BRD2 and CACNA1D: new candidate genes in fetal metabolic programming of newborns exposed to maternal hyperglycemia[J]. Epigenomics, 2015, 7(7): 1111-1122.
17	Wang YH, Xu XX, Sun H, et al. Cord blood leptin DNA methylation levels are associated with macrosomia during normal pregnancy[J]. Pediatr Res, 2019, 86(3): 305-310.
18	Yan J, Su RN, Zhang WY, et al. Epigenetic alteration of rho guanine nucleotide exchange Factor 11 (ARHGEF11) in cord blood samples in macrosomia exposed to intrauterine hyperglycemia[J]. J Matern Fetal Neonatal Med, 2021, 34(3): 422-431.
19	Weng XL, Liu FT, Zhang H, et al. Genome-wide DNA methylation profiling in infants born to gestational diabetes mellitus[J]. Diabetes Res Clin Pract, 2018, 142: 10-18.
20	Haertle L, El Hajj N, Dittrich M, et al. Epigenetic signatures of gestational diabetes mellitus on cord blood methylation[J]. Clin Epigenetics, 2017, 9: 28.
21	Howe CG, Cox B, Fore R, et al. Maternal gestational diabetes mellitus and newborn DNA methylation: findings from the pregnancy and childhood epigenetics consortium[J]. Diabetes Care, 2020, 43(1): 98-105.
22	Wu P, Farrell WE, Haworth KE, et al. Maternal genome-wide DNA methylation profiling in gestational diabetes shows distinctive disease-associated changes relative to matched healthy pregnancies[J]. Epigenetics, 2018, 13(2): 122-128.
23	Zhang Y, Ye JP, Fan JX. Regulation of malonyl-CoA-acyl carrier protein transacylase network in umbilical cord blood affected by intrauterine hyperglycemia[J]. Oncotarget, 2017, 8(43): 75254-75263.
24	Chen DQ, Zhang AP, Fang M, et al. Increased methylation at differentially methylated region of GNAS in infants born to gestational diabetes[J]. BMC Med Genet, 2014, 15: 108.
25	Dias S, Adam S, Van Wyk N, et al. Global DNA methylation profiling in peripheral blood cells of South African women with gestational diabetes mellitus[J]. Biomarkers, 2019, 24(3): 225-231.
26	Dias S, Adam S, Rheeder P, et al. Altered genome-wide DNA methylation in peripheral blood of South African women with gestational diabetes mellitus[J]. Int J Mol Sci, 2019, 20(23): 5828.
27	Enquobahrie DA, Moore A, Muhie S, et al. Early pregnancy maternal blood DNA methylation in repeat pregnancies and change in gestational diabetes mellitus status: a pilot study[J]. Reprod Sci, 2015, 22(7): 904-910.
28	Kang J, Lee CN, Li HY, et al. Association of interleukin-10 methylation levels with gestational diabetes in a Taiwanese population[J]. Front Genet, 2018, 9: 222.
29	Rancourt RC, Ott R, Ziska T, et al. Visceral adipose tissue inflammatory factors (TNF-α, SOCS3) in gestational diabetes (GDM): epigenetics as a clue in GDM pathophysiology[J]. Int J Mol Sci, 2020, 21(2): 479.
30	Zhang YH, Chen YY, Qu HM, et al. Methylation of HIF3A promoter CpG islands contributes to insulin resistance in gestational diabetes mellitus[J]. Mol Genet Genomic Med, 2019, 7(4): e00583.
31	Ott R, Melchior K, Stupin JH, et al. Reduced insulin receptor expression and altered DNA methylation in fat tissues and blood of women with GDM and offspring[J]. J Clin Endocrinol Metab, 2019, 104(1): 137-149.
32	Ott R, Stupin JH, Melchior K, et al. Alterations of adiponectin gene expression and DNA methylation in adipose tissues and blood cells are associated with gestational diabetes and neonatal outcome[J]. Clin Epigenetics, 2018, 10(1): 131.
33	Deng XL, Yang YL, Sun H, et al. Analysis of whole genome-wide methylation and gene expression profiles in visceral omental adipose tissue of pregnancies with gestational diabetes mellitus[J]. J Chin Med Assoc, 2018, 81(7): 623-630.
34	Houshmand-Oeregaard A, Hansen NS, Hjort L, et al. Differential adipokine DNA methylation and gene expression in subcutaneous adipose tissue from adult offspring of women with diabetes in pregnancy[J]. Clin Epigenetics, 2017, 9: 37.
35	Zhu ZL, Chen XF, Xiao YQ, et al. Gestational diabetes mellitus alters DNA methylation profiles in pancreas of the offspring mice[J]. J Diabetes Complications, 2019, 33(1): 15-22.
36	Zhu H, Chen B, Cheng Y, et al. Insulin therapy for gestational diabetes mellitus does not fully protect offspring from diet-induced metabolic disorders[J]. Diabetes, 2019, 68(4): 696-708.
37	Ren J, Cheng Y, Ming ZH, et al. Intrauterine hyperglycemia exposure results in intergenerational inheritance via DNA methylation reprogramming on F1 PGCs[J]. Epigenetics Chromatin, 2018, 11(1): 20.
38	Hjort L, Martino D, Grunnet LG, et al. Gestational diabetes and maternal obesity are associated with epigenome-wide methylation changes in children[J]. JCI Insight, 2018, 3(17): e122572.
39	Jiang Y, Yu YC, Ding GL, et al. Intrauterine hyperglycemia induces intergenerational Dlk1-Gtl2 methylation changes in mouse placenta[J]. Oncotarget, 2018, 9(32): 22398-22405.
40	Kelstrup L, Hjort L, Houshmand-Oeregaard A, et al. Gene expression and DNA methylation of PPARGC1A in muscle and adipose tissue from adult offspring of women with diabetes in pregnancy[J]. Diabetes, 2016, 65(10): 2900-2910.
41	Chen GQ, Chen J, Yan ZL, et al. Maternal diabetes modulates dental epithelial stem cells proliferation and self-renewal in offspring through apurinic/apyrimidinicendonuclease 1-mediated DNA methylation[J]. Sci Rep, 2017, 7: 40762.
42	Banik A, Kandilya D, Ramya S, et al. Maternal factors that induce epigenetic changes contribute to neurological disorders in offspring[J]. Genes (Basel), 2017, 8(6): 150.
43	Quilter CR, Cooper WN, Cliffe KM, et al. Impact on offspring methylation patterns of maternal gestational diabetes mellitus and intrauterine growth restraint suggest common genes and pathways linked to subsequent type 2 diabetes risk[J]. FASEB J, 2014, 28(11): 4868-4879.
44	Blue EK, Sheehan BM, Nuss ZV, et al. Epigenetic regulation of placenta-specific 8 contributes to altered function of endothelial colony-forming cells exposed to intrauterine gestational diabetes mellitus[J]. Diabetes, 2015, 64(7): 2664-2675.
45	Chen ZW, Gong L, Zhang P, et al. Epigenetic down-regulation of Sirtlvia DNA methylation and oxidative stress signaling contributes to the gestational diabetes mellitus-induced fetal programming of heart ischemia-sensitive phenotype in late life[J]. Int J Biol Sci, 2019, 15(6): 1240-1251.
46	Cao JL, Zhang L, Li J, et al. Up-regulation of miR-98 and unraveling regulatory mechanisms in gestational diabetes mellitus[J]. Sci Rep, 2016, 6: 32268.
47	Liu YF, Tan QY, Liu F. Differentially methylated circulating DNA: a novel biomarker to monitor β cell death[J]. J Diabetes Complications, 2018, 32(3): 349-353.

Specimen type	Gene involved in methylation	Impact of changes in methylation levels	Reference
Maternal side of placenta （from the mother， Homo sapiens）	DLK1	Glycemia	［6］
	PPARGC1， PDX1	Fetal glucose metabolism	［7］
	IGF2	Birth weight	［8］
	PPARGC1A	Newborn birth weight	［9-10］
	LPL	Energy homeostasis	［11］
	MEST， NR3C1	Obesity	［13］
	G6PD， IGF	Hyperglycemia， oxidative stress and fetal macrosomia	［14］
Peripheral blood （from the mother， Homo sapiens）	CAMTA1	Insulin synthesis and secretion	［26］
	IL10	Inflammation	［28］
	G6PD， IGF	Hyperglycemia， oxidative stress and fetal macrosomia	［14］
	NDUFC1， HAPLN3， RHOG， et al	Cell morphology， cellular organization and cell cycle	［27］
Cord blood （from the mother， Homo sapiens）	OR2L13， CYP2E1	Autism and diabetes	［21］
	IGF2	Fetal growth and newborn birth weight	［8］
	MEST， NR3C1	Obesity predisposition	［13］
	HIF3A， et al	Metabolic phenotype	［20］
	ARHGEF11	Macrosomia	［18］
Adipose and omental tissue （from the mother， Homo sapiens）	TNF， SOCS3	Inflamation	［29］
	HIF3A	Insulin resistance	［30］
	MSLN	Antigen process and presentation	［33］
Umbilical cord blood lymphocyte （from the mother， Homo sapiens）	MCAT	Mitochondrial fatty acid synthesis and insulin resistance	［23］
Fetal side of the placenta （from the offspring， Homo sapiens）	DLK1	Newborn birth weight	［6］
	LPL	Energy homeostasis	［12］
Adipose tissue （from the offspring， Homo sapiens）	PPARGC1A	Insulin secretion and metabolic disease	［40］
	ADIPOQ， RETN	Metabolic disease	［34］
Muscle （from the offspring， Homo sapiens）	PPARGC1A	Insulin secretion and metabolic disease	［40］
Dental epithelial stem cell （from the offspring， Homo sapiens）	APEX1	Proliferation and self-renew	［41］
Pancreas （from the offspring， Mus musculus）	Gnas， Fbp2， Wnt2， et al	Glycolipids metabolism	［35］
Pancreatic islet （from the offspring， Mus musculus）	Abcc8， et al	Insulin secretion	［36］
Heart （from the offspring， Mus musculus）	Sirt1	Heart ischemia sensitive phenotype	［45］
Placenta （from the offspring， Mus musculus）	Dlk1， et al	Insulin pathway	［39］
Primordial germ cell （from the offspring， Mus musculus）	Fyn	Obesity and insulin resistance	［37］

Specimen type	Gene involved in methylation	Impact of changes in methylation levels	Reference
Maternal side of placenta （from the mother， Homo sapiens）	DLK1	Glycemia	［6］
	PPARGC1， PDX1	Fetal glucose metabolism	［7］
	IGF2	Birth weight	［8］
	PPARGC1A	Newborn birth weight	［9-10］
	LPL	Energy homeostasis	［11］
	MEST， NR3C1	Obesity	［13］
	G6PD， IGF	Hyperglycemia， oxidative stress and fetal macrosomia	［14］
Peripheral blood （from the mother， Homo sapiens）	CAMTA1	Insulin synthesis and secretion	［26］
	IL10	Inflammation	［28］
	G6PD， IGF	Hyperglycemia， oxidative stress and fetal macrosomia	［14］
	NDUFC1， HAPLN3， RHOG， et al	Cell morphology， cellular organization and cell cycle	［27］
Cord blood （from the mother， Homo sapiens）	OR2L13， CYP2E1	Autism and diabetes	［21］
	IGF2	Fetal growth and newborn birth weight	［8］
	MEST， NR3C1	Obesity predisposition	［13］
	HIF3A， et al	Metabolic phenotype	［20］
	ARHGEF11	Macrosomia	［18］
Adipose and omental tissue （from the mother， Homo sapiens）	TNF， SOCS3	Inflamation	［29］
	HIF3A	Insulin resistance	［30］
	MSLN	Antigen process and presentation	［33］
Umbilical cord blood lymphocyte （from the mother， Homo sapiens）	MCAT	Mitochondrial fatty acid synthesis and insulin resistance	［23］
Fetal side of the placenta （from the offspring， Homo sapiens）	DLK1	Newborn birth weight	［6］
	LPL	Energy homeostasis	［12］
Adipose tissue （from the offspring， Homo sapiens）	PPARGC1A	Insulin secretion and metabolic disease	［40］
	ADIPOQ， RETN	Metabolic disease	［34］
Muscle （from the offspring， Homo sapiens）	PPARGC1A	Insulin secretion and metabolic disease	［40］
Dental epithelial stem cell （from the offspring， Homo sapiens）	APEX1	Proliferation and self-renew	［41］
Pancreas （from the offspring， Mus musculus）	Gnas， Fbp2， Wnt2， et al	Glycolipids metabolism	［35］
Pancreatic islet （from the offspring， Mus musculus）	Abcc8， et al	Insulin secretion	［36］
Heart （from the offspring， Mus musculus）	Sirt1	Heart ischemia sensitive phenotype	［45］
Placenta （from the offspring， Mus musculus）	Dlk1， et al	Insulin pathway	［39］
Primordial germ cell （from the offspring， Mus musculus）	Fyn	Obesity and insulin resistance	［37］

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