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Current Diabetes Reports
Published in: Current Diabetes Reports 2/2016

01-02-2016 | Pathogenesis of Type 2 Diabetes and Insulin Resistance (RM Watanabe, Section Editor)

Genetics of Gestational Diabetes Mellitus and Maternal Metabolism

Authors: William L. Lowe Jr., Denise M. Scholtens, Victoria Sandler, M. Geoffrey Hayes

Published in: Current Diabetes Reports | Issue 2/2016

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Abstract

Gestational diabetes mellitus (GDM) is defined as abnormal glucose tolerance with onset or first recognition during pregnancy. Women with a history of GDM are at long-term risk for developing type 2 diabetes (T2DM), raising the question to what extent GDM and T2DM share a common genetic architecture. Meta-analysis of candidate gene studies and genome-wide association analysis (GWAS) have identified a number of genes which are reproducibly associated with GDM, including TCF7L2, GCK, KCNJ11, KCNQ1, CDKAL1, IGF2BP2, MTNR1B, and IRS1. These genes are also associated with T2DM. Candidate gene and GWAS have also identified genes associated with maternal metabolic traits, most of which are also associated with metabolic traits in the general population. Two genes, BACE2 and HKDC1, are uniquely associated with maternal metabolic traits. These studies suggest that there are similarities and differences between the genetic architecture of GDM and T2DM and metabolic quantitative traits in pregnant and non-pregnant populations.
Literature
1.
Ashwal E, Hod M. Gestational diabetes mellitus: Where are we now? Clin Chim Acta 2015.
2.
Buchanan TA, Xiang A, Kjos SL, Watanabe R. What is gestational diabetes? Diabetes Care. 2007;30 Suppl 2:S105–11.CrossRefPubMed
3.
4.
5.
Dabelea D, Snell-Bergeon JK, Hartsfield CL, Bischoff KJ, Hamman RF, McDuffie RS. Kaiser Permanente of Colorado GDMSP, increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM screening program. Diabetes Care. 2005;28:579–84.CrossRefPubMed
6.
Ferrara A, Kahn HS, Quesenberry CP, Riley C, Hedderson MM. An increase in the incidence of gestational diabetes mellitus: Northern California, 1991-2000. Obstet Gynecol. 2004;103:526–33.CrossRefPubMed
7.
International association of diabetes and pregnancy groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010; 33:676-682
8.
Butte NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr. 2000;71:1256S–61.PubMed
9.
10.
Hadden DR, McLaughlin C. Normal and abnormal maternal metabolism during pregnancy. Semin Fetal Neonatal Med. 2009;14:66–71.CrossRefPubMed
11.
Di Cianni G, Miccoli R, Volpe L, Lencioni C, Del Prato S. Intermediate metabolism in normal pregnancy and in gestational diabetes. Diabetes Metab Res Rev. 2003;19:259–70.CrossRefPubMed
12.
Desoye G, Hauguel-de Mouzon S. The human placenta in gestational diabetes mellitus. The insulin and cytokine network. Diabetes Care. 2007;30(2):S120–6.CrossRefPubMed
13.
Newbern D, Freemark M. Placental hormones and the control of maternal metabolism and fetal growth. Curr Opin Endocrinol Diabet Obes. 2011;18:409–16.CrossRef
14.
Butler AE, Cao-Minh L, Galasso R, Rizza RA, Corradin A, Cobelli C, et al. Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia. 2010;53:2167–76.PubMedCentralCrossRefPubMed
15.
Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care. 2002;25:1862–8.CrossRefPubMed
16.
Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet. 2009;373:1773–9.CrossRefPubMed
17.
McLellan JA, Barrow BA, Levy JC, Hammersley MS, Hattersley AT, Gillmer MD, et al. Prevalence of diabetes mellitus and impaired glucose tolerance in parents of women with gestational diabetes. Diabetologia. 1995;38:693–8.CrossRefPubMed
18.
Robitaille J, Grant AM. The genetics of gestational diabetes mellitus: evidence for relationship with type 2 diabetes mellitus. Genet Med. 2008;10:240–50.CrossRefPubMed
19.
Watanabe RM, Black MH, Xiang AH, Allayee H, Lawrence JM, Buchanan TA. Genetics of gestational diabetes mellitus and type 2 diabetes. Diabetes Care. 2007;30 Suppl 2:S134–40.PubMedCentralCrossRefPubMed
20.
Morris AP, Voight BF, Teslovich TM, Ferreira T, Segre AV, Steinthorsdottir V, et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012;44:981–90.PubMedCentralCrossRefPubMed
21.
Basile KJ, Johnson ME, Xia Q, Grant SF. Genetic susceptibility to type 2 diabetes and obesity: follow-up of findings from genome-wide association studies. Int J Endocrinol. 2014;2014:769671.PubMedCentralCrossRefPubMed
22.
Mohlke KL, Boehnke M. Recent advances in understanding the genetic architecture of type 2 diabetes. Hum Mol Genet. 2015;24:R85–92.CrossRefPubMed
23.
24.
Lowe, Jr., William L., Reddy TE. Genomic approaches for understanding the genetics of complex disease. Genome Res. 2015;25:1432–41.
25.
Fu W, O’Connor TD, Akey JM. Genetic architecture of quantitative traits and complex diseases. Curr Opin Genet Dev. 2013;23:678–83.CrossRefPubMed
26.
Surakka I, Horikoshi M, Magi R, Sarin AP, Mahajan A, Lagou V, et al. The impact of low-frequency and rare variants on lipid levels. Nat Genet. 2015;47:589–97.CrossRefPubMed
27.
Mao H, Li Q, Gao S. Meta-analysis of the relationship between common type 2 diabetes risk gene variants with gestational diabetes mellitus. PLoS One. 2012;7, e45882.PubMedCentralCrossRefPubMed
28.••
Zhang C, Bao W, Rong Y, Yang H, Bowers K, Yeung E, et al. Genetic variants and the risk of gestational diabetes mellitus: a systematic review. Hum Reprod Update. 2013;19:376–90. Extensive meta-analysis of candidate gene studies which identifies a number of genetic variants associated with GDM.PubMedCentralCrossRefPubMed
29.
Mulder H, Nagorny CL, Lyssenko V, Groop L. Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene. Diabetologia. 2009;52:1240–9.CrossRefPubMed
30.
Peschke E, Muhlbauer E. New evidence for a role of melatonin in glucose regulation. Best Pract Res Clin Endocrinol Metab. 2010;24:829–41.CrossRefPubMed
31.
Stancakova A, Kuulasmaa T, Paananen J, Jackson AU, Bonnycastle LL, Collins FS, et al. Association of 18 confirmed susceptibility loci for type 2 diabetes with indices of insulin release, proinsulin conversion, and insulin sensitivity in 5,327 nondiabetic Finnish men. Diabetes. 2009;58:2129–36.PubMedCentralCrossRefPubMed
32.
Groenewoud MJ, Dekker JM, Fritsche A, Reiling E, Nijpels G, Heine RJ, et al. Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps. Diabetologia. 2008;51:1659–63.CrossRefPubMed
33.
34.
Ullrich S, Su J, Ranta F, Wittekindt OH, Ris F, Rosler M, et al. Effects of I(Ks) channel inhibitors in insulin-secreting INS-1 cells. Pflugers Arch. 2005;451:428–36.CrossRefPubMed
35.
Dimas AS, Lagou V, Barker A, Knowles JW, Magi R, Hivert MF, Benazzo A, Rybin D, Jackson AU, Stringham HM, Song C, Fischer-Rosinsky A, Boesgaard TW, Grarup N, Abbasi FA, Assimes TL, Hao K, Yang X, Lecoeur C, Barroso I, Bonnycastle LL, Bottcher Y, Bumpstead S, Chines PS, Erdos MR, Graessler J, Kovacs P, Morken MA, Narisu N, Payne F, Stancakova A, Swift AJ, Tonjes A, Bornstein SR, Cauchi S, Froguel P, Meyre D, Schwarz PE, Haring HU, Smith U, Boehnke M, Bergman RN, Collins FS, Mohlke KL, Tuomilehto J, Quertemous T, Lind L, Hansen T, Pedersen O, Walker M, Pfeiffer AF, Spranger J, Stumvoll M, Meigs JB, Wareham NJ, Kuusisto J, Laakso M, Langenberg C, Dupuis J, Watanabe RM, Florez JC, Ingelsson E, McCarthy MI, Prokopenko I, on behalf of the Mi. Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. Diabetes 2014;63:2158–71.
36.
Kurokawa N, Young EH, Oka Y, Satoh H, Wareham NJ, Sandhu MS, et al. The ADRB3 Trp64Arg variant and BMI: a meta-analysis of 44 833 individuals. Int J Obes (Lond). 2008;32:1240–9.CrossRef
37.
38.
Huopio H, Cederberg H, Vangipurapu J, Hakkarainen H, Paakkonen M, Kuulasmaa T, et al. Association of risk variants for type 2 diabetes and hyperglycemia with gestational diabetes. Eur J Endocrinol. 2013;169:291–7.CrossRefPubMed
39.
Stuebe AM, Wise A, Nguyen T, Herring A, North KE, Siega-Riz AM. Maternal genotype and gestational diabetes. Am J Perinatol. 2014;31:69–76.PubMed
40.
Huerta-Chagoya A, Vazquez-Cardenas P, Moreno-Macias H, Tapia-Maruri L, Rodriguez-Guillen R, Lopez-Vite E, et al. Genetic determinants for gestational diabetes mellitus and related metabolic traits in Mexican women. PLoS One. 2015;10, e0126408.PubMedCentralCrossRefPubMed
41.
Li Q, Chen M, Zhang R, Jiang F, Wang J, Zhou J, et al. KCNJ11 E23K variant is associated with the therapeutic effect of sulphonylureas in Chinese type 2 diabetic patients. Clin Exp Pharmacol Physiol. 2014;41:748–54.CrossRefPubMed
42.
Maruthur NM, Gribble MO, Bennett WL, Bolen S, Wilson LM, Balakrishnan P, et al. The pharmacogenetics of type 2 diabetes: a systematic review. Diabetes Care. 2014;37:876–86.PubMedCentralCrossRefPubMed
43.
Balsells M, Garcia-Patterson A, Sola I, Roque M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ. 2015;350:h102.PubMedCentralCrossRefPubMed
44.
Manolio TA. Genomewide association studies and assessment of the risk of disease. N Engl J Med. 2010;363:166–76.CrossRefPubMed
45.
46.••
Kwak SH, Kim SH, Cho YM, Go MJ, Cho YS, Choi SH, et al. A genome-wide association study of gestational diabetes mellitus in Korean women. Diabetes. 2012;61:531–41. The first and only GWAS performed to identify genetic variants associated with GDM.PubMedCentralCrossRefPubMed
47.
Scott RA, Lagou V, Welch RP, Wheeler E, Montasser ME, Luan J, et al. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat Genet. 2012;44:991–1005.PubMedCentralCrossRefPubMed
48.
Marullo L, El-Sayed Moustafa JS, Prokopenko I. Insights into the genetic susceptibility to type 2 diabetes from genome-wide association studies of glycaemic traits. Curr Diab Rep. 2014;14:551.CrossRefPubMed
49.
Mei J, Liao S, Liu Y, Tan Y, Wang H, Liang Y, et al. Association of variants in CDKN2A/2B and CDKAL1 genes with gestational insulin sensitivity and disposition in pregnant Han Chinese women. J Diabetes Investig. 2015;6:295–301.PubMedCentralCrossRefPubMed
50.
Liao S, Liu Y, Chen X, Tan Y, Mei J, Song W, Gan L, Wang H, Yin S, Dong X, Chi S, Deng S. The Impact of Genetic Variants for Different Physiological Characterization of Type 2 Diabetes Loci on Gestational Insulin Signaling in Nondiabetic Pregnant Chinese Women. Reprod Sci 2015.
51.
Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet. 2010;42:105–16.PubMedCentralCrossRefPubMed
52.
Freathy RM, Hayes MG, Urbanek M, Lowe LP, Lee H, Ackerman C, et al. Hyperglycemia and adverse pregnancy outcome (HAPO) study: common genetic variants in GCK and TCF7L2 are associated with fasting and postchallenge glucose levels in pregnancy and with the new consensus definition of gestational diabetes mellitus from the international association of diabetes and pregnancy study groups. Diabetes. 2010;59:2682–9.PubMedCentralCrossRefPubMed
53.
Weedon MN, Clark VJ, Qian Y, Ben-Shlomo Y, Timpson N, Ebrahim S, et al. A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses. Am J Hum Genet. 2006;79:991–1001.PubMedCentralCrossRefPubMed
54.
Lowe LP, Metzger BE, Lowe Jr WL, Dyer AR, McDade TW, McIntyre HD. Inflammatory mediators and glucose in pregnancy: results from a subset of the hyperglycemia and adverse pregnancy outcome (HAPO) study. J Clin Endocrinol Metab. 2010;95:5427–34.PubMedCentralCrossRefPubMed
55.
Urbanek M, Hayes MG, Lee H, Freathy RM, Lowe LP, Ackerman C, et al. The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy. PLoS One. 2012;7, e32958.PubMedCentralCrossRefPubMed
56.
Guzman-Flores JM, Escalante M, Sanchez-Corona J, Garcia-Zapien AG, Cruz-Quevedo EG, Munoz-Valle JF, et al. Association analysis between -308G/A and -238G/A TNF-alpha gene promoter polymorphisms and insulin resistance in Mexican women with gestational diabetes mellitus. J Investig Med. 2013;61:265–9.PubMed
57.••
Hayes MG, Urbanek M, Hivert MF, Armstrong LL, Morrison J, Guo C, Lowe LP, Scheftner DA, Pluzhnikov A, Levine DM, McHugh CP, Ackerman CM, Bouchard L, Brisson D, Layden BT, Mirel D, Doheny KF, Leya MV, Lown-Hecht RN, Dyer AR, Metzger BE, Reddy TE, Cox NJ, Lowe WL, Jr. for the HSCRG. Identification of HKDC1 and BACE2 as Genes Influencing Glycemic Traits During Pregnancy Through Genome-Wide Association Studies. Diabetes 2013;62:3282–91. A recent GWAS which identified genetic variants associated with maternal metabolic traits during pregnancy.
58.
Esterhazy D, Stutzer I, Wang H, Rechsteiner MP, Beauchamp J, Dobeli H, et al. Bace2 is a beta cell-enriched protease that regulates pancreatic beta cell function and mass. Cell Metab. 2011;14:365–77.CrossRefPubMed
59.
Casas S, Casini P, Piquer S, Altirriba J, Soty M, Cadavez L, et al. BACE2 plays a role in the insulin receptor trafficking in pancreatic ss-cells. Am J Physiol Endocrinol Metab. 2010;299:E1087–95.CrossRefPubMed
60.•
Guo C, Ludvik AE, Arlotto ME, Hayes MG, Armstrong LL, Scholtens DM, et al. Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1. Nat Commun. 2015;6:6069. A follow-up study to a recent GWAS which further characterizes the association of genetic variants in HKDC1 with maternal glucose levels.
61.
62.
Petry CJ, Ong KK, Dunger DB. Does the fetal genotype affect maternal physiology during pregnancy? Trends Mol Med. 2007;13:414–21.CrossRefPubMed
63.
Petry CJ, Seear RV, Wingate DL, Manico L, Acerini CL, Ong KK, et al. Associations between paternally transmitted fetal IGF2 variants and maternal circulating glucose concentrations in pregnancy. Diabetes. 2011;60:3090–6.PubMedCentralCrossRefPubMed
Metadata
Title
Genetics of Gestational Diabetes Mellitus and Maternal Metabolism
Authors
William L. Lowe Jr.
Denise M. Scholtens
Victoria Sandler
M. Geoffrey Hayes
Publication date
01-02-2016
Publisher
Springer US
Published in
Current Diabetes Reports / Issue 2/2016
Print ISSN: 1534-4827
Electronic ISSN: 1539-0829
DOI
https://doi.org/10.1007/s11892-015-0709-z

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