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
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 12/2005

01-12-2005 | Article

Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus

Authors: N. Shaat, M. Ekelund, Å. Lernmark, S. Ivarsson, P. Almgren, K. Berntorp, L. Groop

Published in: Diabetologia | Issue 12/2005

Login to get access

Abstract

Aims/hypothesis

Gestational diabetes mellitus (GDM) and type 2 diabetes share a common pathophysiological background, including beta cell dysfunction and insulin resistance. In addition, women with GDM are at increased risk of developing type 2 diabetes later in life. Our aim was to investigate whether, like type 2 diabetes, GDM has a genetic predisposition by studying five common polymorphisms in four candidate genes that have previously been associated with type 2 diabetes.

Materials and methods

We studied 1,777 unrelated Scandinavian women (588 with GDM and 1,189 pregnant non-diabetic controls) for polymorphisms in the genes encoding potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11 E23K), insulin receptor substrate 1 (IRS1 G972R), uncoupling protein 2 (UCP2 −866G→A) and calpain 10 (CAPN10 SNP43 and SNP44).

Results

The EE, EK and KK genotype frequencies of the KCNJ11 E23K polymorphism differed significantly between GDM and control women (31.5, 52.7 and 15.8% vs 37.3, 48.8 and 13.9%, respectively; p=0.050). In addition, the frequency of the K allele was increased in women with GDM (odds ratio [OR]=1.17, 95% CI 1.02−1.35; p=0.027), and this effect was greater under a dominant model (KK/EK vs EE) (OR=1.3, 95% CI 1.05−1.60; p=0.016). Analysis of the IRS1 G972R polymorphism showed that RR homozygosity was found exclusively in women with GDM (91.0, 8.3 and 0.7% vs 90.7, 9.3 and 0.0% for GG, GR and RR genotypes, respectively; p=0.014). The genotype and allele frequencies of the other polymorphisms studied were not statistically different between the GDM and control women.

Conclusions/interpretation

The E23K polymorphism of KCNJ11 seems to predispose to GDM in Scandinavian women.
Appendix
Available only for authorised users
Literature
1.
Metzger BE, Coustan DR, the Organizing Committee (1998) Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 21 (Suppl 2):B161–B167PubMed
2.
Aberg A, Rydhstroem H, Frid A (2001) Impaired glucose tolerance associated with adverse pregnancy outcome: a population-based study in southern Sweden. Am J Obstet Gynecol 184:77–83CrossRefPubMed
3.
King H (1998) Epidemiology of glucose intolerance and gestational diabetes in women of childbearing age. Diabetes Care 21 (Suppl 2):B9–B13PubMed
4.
Catalano PM, Huston L, Amini SB, Kalhan SC (1999) Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol 180:903–916CrossRefPubMed
5.
Xiang AH, Peters RK, Trigo E, Kjos SL, Lee WP, Buchanan TA (1999) Multiple metabolic defects during late pregnancy in women at high risk for type 2 diabetes. Diabetes 48:848–854PubMedCrossRef
6.
Buchanan TA, Metzger BE, Freinkel N, Bergman RN (1990) Insulin sensitivity and B-cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes. Am J Obstet Gynecol 162:1008–1014PubMed
7.
Ryan EA, Imes S, Liu D et al (1995) Defects in insulin secretion and action in women with a history of gestational diabetes. Diabetes 44:506–512PubMedCrossRef
8.
Osei K, Gaillard TR, Schuster DP (1998) History of gestational diabetes leads to distinct metabolic alterations in nondiabetic African-American women with a parental history of type 2 diabetes. Diabetes Care 21:1250–1257PubMedCrossRef
9.
Buchanan TA, Xiang AH, Kjos SL, Trigo E, Lee WP, Peters RK (1999) Antepartum predictors of the development of type 2 diabetes in Latino women 11–26 months after pregnancies complicated by gestational diabetes. Diabetes 48:2430–2436PubMedCrossRef
10.
Kim C, Newton KM, Knopp RH (2002) Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 25:1862–1868PubMedCrossRef
11.
Groop L (2000) Pathogenesis of type 2 diabetes: the relative contribution of insulin resistance and impaired insulin secretion. Int J Clin Pract 113 (Suppl 1):3–13
12.
Lyssenko V, Almgren P, Anevski D et al (2005) Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes. Diabetes 54:166–174PubMedCrossRef
13.
Ben-Haroush A, Yogev Y, Hod M (2004) Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes. Diabet Med 21:103–113CrossRefPubMed
14.
Williams MA, Qiu C, Dempsey JC, Luthy DA (2003) Familial aggregation of type 2 diabetes and chronic hypertension in women with gestational diabetes mellitus. J Reprod Med 48:955–962PubMed
15.
16.
Altshuler D, Hirschhorn JN, Klannemark M et al (2000) The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26:76–80CrossRefPubMed
17.
Florez JC, Burtt N, de Bakker PI et al (2004) Haplotype structure and genotype–phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes 53:1360–1368PubMedCrossRef
18.
Florez JC, Sjogren M, Burtt N et al (2004) Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes. Diabetes 53:3313–3318PubMedCrossRef
19.
Esterbauer H, Schneitler C, Oberkofler H et al (2001) A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. Nat Genet 28:178–183CrossRefPubMed
20.
Wang H, Chu WS, Lu T, Hasstedt SJ, Kern PA, Elbein SC (2004) Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am J Physiol Endocrinol Metab 286:E1–E7CrossRefPubMed
21.
Bulotta A, Ludovico O, Coco A et al (2005) The common −866G→A polymorphism in the promoter region of the UCP-2 gene is associated with reduced risk of type 2 diabetes in Caucasians from Italy. J Clin Endocrinol Metab 90:1176–1180CrossRefPubMed
22.
D'Adamo M, Perego L, Cardellini M et al (2004) The −866A/A genotype in the promoter of the human uncoupling protein 2 gene is associated with insulin resistance and increased risk of type 2 diabetes. Diabetes 53:1905–1910PubMedCrossRef
23.
Ober C, Xiang KS, Thisted RA, Indovina KA, Wason CJ, Dooley S (1989) Increased risk for gestational diabetes mellitus associated with insulin receptor and insulin-like growth factor II restriction fragment length polymorphisms. Genet Epidemiol 6:559–569CrossRefPubMed
24.
Festa A, Krugluger W, Shnawa N, Hopmeier P, Haffner SM, Schernthaner G (1999) Trp64Arg polymorphism of the beta3-adrenergic receptor gene in pregnancy: association with mild gestational diabetes mellitus. J Clin Endocrinol Metab 84:1695–1699CrossRefPubMed
25.
Rissanen J, Markkanen A, Karkkainen P et al (2000) Sulfonylurea receptor 1 gene variants are associated with gestational diabetes and type 2 diabetes but not with altered secretion of insulin. Diabetes Care 23:70–73PubMedCrossRef
26.
Leipold H, Knofler M, Gruber C, Haslinger P, Bancher-Todesca D, Worda C (2004) Calpain-10 haplotype combination and association with gestational diabetes mellitus. Obstet Gynecol 103:1235–1240PubMed
27.
Megia A, Gallart L, Fernandez-Real JM et al (2004) Mannose-binding lectin gene polymorphisms are associated with gestational diabetes mellitus. J Clin Endocrinol Metab 89:5081–5087CrossRefPubMed
28.
Shaat N, Ekelund M, Lernmark A et al (2004) Genotypic and phenotypic differences between Arabian and Scandinavian women with gestational diabetes mellitus. Diabetologia 47:878–884CrossRefPubMed
29.
Alevizaki M, Thalassinou L, Grigorakis SI et al (2000) Study of the Trp64Arg polymorphism of the beta3-adrenergic receptor in Greek women with gestational diabetes. Diabetes Care 23:1079–1083PubMedCrossRef
30.
Tsai PJ, Ho SC, Tsai LP et al (2004) Lack of relationship between beta3-adrenergic receptor gene polymorphism and gestational diabetes mellitus in a Taiwanese population. Metabolism 53:1136–1139CrossRefPubMed
31.
Lind T, Phillips PR (1991) Influence of pregnancy on the 75-g OGTT. A prospective multicenter study. The Diabetic Pregnancy Study Group of the European Association for the Study of Diabetes. Diabetes 40 (Suppl 2):8–13PubMed
32.
Lernmark B, Elding-Larsson H, Hansson G, Lindberg B, Lynch K, Sjoblad S (2004) Parent responses to participation in genetic screening for diabetes risk. Pediatr Diabetes 5:174–181CrossRefPubMed
33.
34.
Schwanstecher C, Meyer U, Schwanstecher M (2002) K(IR)6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K(+) channels. Diabetes 51:875–879PubMedCrossRef
35.
Hirayama I, Tamemoto H, Yokota H et al (1999) Insulin receptor-related receptor is expressed in pancreatic beta-cells and stimulates tyrosine phosphorylation of insulin receptor substrate-1 and -2. Diabetes 48:1237–1244PubMedCrossRef
36.
Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K (2002) A comprehensive review of genetic association studies. Genet Med 4:45–61PubMedCrossRef
37.
Stumvoll M, Fritsche A, Volk A et al (2001) The Gly972Arg polymorphism in the insulin receptor substrate-1 gene contributes to the variation in insulin secretion in normal glucose-tolerant humans. Diabetes 50:882–885PubMedCrossRef
38.
Marchetti P, Lupi R, Federici M et al (2002) Insulin secretory function is impaired in isolated human islets carrying the Gly(972)→Arg IRS-1 polymorphism. Diabetes 51:1419–1424PubMedCrossRef
39.
Clausen JO, Hansen T, Bjorbaek C et al (1995) Insulin resistance: interactions between obesity and a common variant of insulin receptor substrate-1. Lancet 346:397–402CrossRefPubMed
40.
Catalano PM, Nizielski SE, Shao J, Preston L, Qiao L, Friedman JE (2002) Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. Am J Physiol Endocrinol Metab 282:E522–E533PubMed
41.
Zhang CY, Baffy G, Perret P et al (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 105:745–755CrossRefPubMed
42.
Chan CB, De Leo D, Joseph JW et al (2001) Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action. Diabetes 50:1302–1310PubMedCrossRef
43.
Sesti G, Cardellini M, Marini MA et al (2003) A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 52:1280–1283PubMedCrossRef
44.
Orho-Melander M, Klannemark M, Svensson MK, Ridderstrale M, Lindgren CM, Groop L (2002) Variants in the calpain-10 gene predispose to insulin resistance and elevated free fatty acid levels. Diabetes 51:2658–2664PubMedCrossRef
45.
Horikawa Y, Oda N, Cox NJ et al (2000) Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26:163–175CrossRefPubMed
46.
Marshall C, Hitman GA, Partridge CJ et al (2005) Evidence that an isoform of calpain-10 is a regulator of exocytosis in pancreatic beta-cells. Mol Endocrinol 19:213–224CrossRefPubMed
47.
Sreenan SK, Zhou YP, Otani K et al (2001) Calpains play a role in insulin secretion and action. Diabetes 50:2013–2020PubMedCrossRef
48.
Baier LJ, Permana PA, Yang X et al (2000) A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest 106:R69–R73PubMedCrossRef
49.
Carlsson E, Fredriksson J, Groop L, Ridderstrale M (2004) Variation in the calpain-10 gene is associated with elevated triglyceride levels and reduced adipose tissue messenger ribonucleic acid expression in obese Swedish subjects. J Clin Endocrinol Metab 89:3601–3605CrossRefPubMed
50.
Stumvoll M, Fritsche A, Madaus A et al (2001) Functional significance of the UCSNP-43 polymorphism in the CAPN10 gene for proinsulin processing and insulin secretion in nondiabetic Germans. Diabetes 50:2161–2163PubMedCrossRef
Metadata
Title
Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus
Authors
N. Shaat
M. Ekelund
Å. Lernmark
S. Ivarsson
P. Almgren
K. Berntorp
L. Groop
Publication date
01-12-2005
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 12/2005
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-005-0035-0

Other articles of this Issue 12/2005

Diabetologia 12/2005 Go to the issue

For debate

Contraindications can damage your health—is metformin a case in point?

Article

Weight gain in relation to plasma levels of complement factor 3: results from a population-based cohort study

Review

Cognitive decline and dementia in diabetes—systematic overview of prospective observational studies

Article

Reduced intrahepatic fat content is associated with increased whole-body lipid oxidation in patients with type 1 diabetes

Letter

Comment on: McClung JA, Naseer N, Saleem M et al (2005) Circulating endothelial cells are elevated in patients with type 2 diabetes mellitus independently of HbA1c. Diabetologia 48:345–350

Article

Longitudinal changes in insulin sensitivity and secretion from birth to age three years in small- and appropriate-for-gestational-age children
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

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

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

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

Watch now

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