Genetic prediction of postpartum diabetes in women with gestational diabetes mellitus.

AIMS: To examine whether genetic variants that predispose individuals to type 2 diabetes (T2D) could predict the development of diabetes after gestational diabetes mellitus (GDM). METHODS: 13 SNPs (FTO rs8050136, CDKAL1 rs7754840 and rs7756992, CDKN2A/2B rs10811661, HHEX rs1111875, IGF2BP2 rs1470579 and rs4402960, SLC30A8 rs13266634, TCF7L2 rs7903146, PPARG rs1801282, GCK rs1799884, HNF1A rs1169288, and KCNJ11 rs5219) were genotyped in 793 women with GDM after a median follow-up of 57 months. RESULTS: After adjustment for age and ethnicity, the TCF7L2 rs7903146 and the FTO rs8050136 variants significantly predicted postpartum diabetes; hazard ratio (95% confidence interval 1.29 (1.01-1.66) and 1.36 (1.06-1.74), respectively (additive model) versus 1.45 (1.01-2.08) and 1.56 (1.06-2.29) (dominant model)). Adjusting for BMI attenuated the effect of the FTO variant, suggesting that the effect was mediated through its effect on BMI. Combining all risk alleles to a weighted risk score was significantly associated with the risk of postpartum diabetes (hazard ratio 1.11, 95% confidence interval 1.05-1.18, p=0.00016 after adjustment for age and ethnicity). CONCLUSIONS: The TCF7L2 rs7903146 and FTO rs8050136 polymorphisms, and particularly a weighted risk score of T2D risk alleles, predict diabetes after GDM. Further studies in other populations are needed to confirm our results.

Characterization of beta cell and incretin function in patients with MODY1 (HNF4A MODY) and MODY3 (HNF1A MODY) in a Swedish patient collection.

The aim of this study was to evaluate the beta cell and incretin function in patients with HNF4A and HNF1A MODY during a test meal. Clinical characteristics and biochemical data (glucose, proinsulin, insulin, C-peptide, GLP-1 and GIP) during a test meal were compared between MODY patients from eight different families. BMI-matched T2D and healthy subjects were used as two separate control groups. The early phase of insulin secretion was attenuated in HNF4A, HNF1A MODY and T2D (AUC0-30 controls: 558.2 ± 101.2, HNF4A MODY: 93.8 ± 57.0, HNF1A MODY: 170.2 ± 64.5, T2D: 211.2 ± 65.3, P < 0.01). Markedly reduced levels of proinsulin were found in HNF4A MODY compared to T2D and that tended to be so also in HNF1A MODY (HNF4A MODY: 3.7 ± 1.2, HNF1A MODY: 8.3 ± 3.8 vs. T2D: 26.6 ± 14.3). Patients with HNF4A MODY had similar total GLP-1 and GIP responses as controls (GLP-1 AUC: (control: 823.9 ± 703.8, T2D: 556.4 ± 698.2, HNF4A MODY: 1,257.0 ± 999.3, HNF1A MODY: 697.1 ± 818.4) but with a different secretion pattern. The AUC insulin during the test meal was strongly correlated with the GIP secretion (Correlation coefficient 1.0, P < 0.001). No such correlation was seen for insulin and GLP-1. Patients with HNF4A and HNF1A MODY showed an attenuated early phase of insulin secretion similar to T2Ds. AUC insulin during the test meal was strongly correlated with GIP secretion, whereas no such correlation was seen for insulin and GLP-1. Thus, GIP may be a more important factor for insulin secretion than GLP-1 in MODY patients.

Gestational diabetes mellitus is associated with TCF7L2 gene polymorphisms independent of HLA-DQB1*0602 genotypes and islet cell autoantibodies.

AIMS: To test whether the TCF7L2 gene was associated with gestational diabetes, whether the association between TCF7L2 and gestational diabetes was independent of HLA-DQB1*0602 and islet cell autoantibodies, as well as maternal age, number of pregnancies, family history of diabetes and the HLA-DQB1 genotypes, and to test whether the distribution of HLA-DQB1 alleles was affected by country of birth. METHODS: We genotyped the rs7903146, rs12255372 and rs7901695 single nucleotide polymorphisms of the TCF7L2 gene in 826 mothers with gestational diabetes and in 1185 healthy control subjects in the Diabetes Prediction in Skåne Study. The mothers were also typed for HLA-DQB1 genotypes and tested for islet cell autoantibodies against GAD65, insulinoma-associated antigen-2 and insulin. RESULTS: The heterozygous genotypes CT, GT and TC of the rs7903146 (T is risk for Type 2 diabetes), rs12255372 (T is risk for Type 2 diabetes) and rs7901695 (C is risk for Type 2 diabetes), respectively, as well as the homozygous genotypes TT, TT and CC of the rs7903146, rs12255372 and rs7901695, respectively, were strongly associated with gestational diabetes (P < 0.0001). These associations remained statistically significant after adjusting for maternal age, number of pregnancies, family history of diabetes and HLA-DQ genotypes and were independent of the presence of islet cell autoantibodies. No interaction was observed between TCF7L2 and HLA-DQB1*0602, which was shown to be negatively associated with gestational diabetes in mothers born in Sweden (P = 0.010). CONCLUSIONS: The TCF7L2 was associated with susceptibility for gestational diabetes independently of the presence of HLA-DQB1*0602 and islet cell autoantibodies and other factors such as maternal age, number of pregnancies, family history of diabetes and other HLA-DQ genotypes. The HLA-DQB1*0602 was negatively associated with gestational diabetes in mothers born in Sweden.

Prediction of postpartum diabetes in women with gestational diabetes mellitus.

AIMS/HYPOTHESIS: We studied the incidence of postpartum diabetes after gestational diabetes mellitus and investigated biochemical and clinical predictors of postpartum diabetes. METHODS: We monitored 174 women with gestational diabetes by performing oral glucose tolerance tests during pregnancy as well as 1, 2 and 5 years postpartum. Women who developed impaired fasting glucose, impaired glucose tolerance or diabetes were compared with women who remained normoglycaemic at 5 years. Insulinogenic index, disposition index and HOMA-beta cell index were used to assess beta cell function; insulin resistance was estimated by HOMA index of insulin resistance. RESULTS: At 5 years postpartum, 30% of the women had developed diabetes and 51% some form of abnormal glucose tolerance. Women who developed diabetes had higher fasting glucose and HbA(1c) during pregnancy than those who remained normoglycaemic. They also had lower HOMA-beta cell index, insulinogenic index and disposition index than the normoglycaemic women. HbA(1c) and fasting glucose during pregnancy as well as the number of previous pregnancies and family history of diabetes were independent predictors of postpartum diabetes. HbA(1c) > or =4.7% (Swedish Mono S) or > or =5.7% (National Glycohemoglobin Standardization Program) and fasting blood glucose > or =5.2 mmol/l were associated with a four- to sixfold increased risk. CONCLUSIONS/INTERPRETATION: Among women with gestational diabetes mellitus, those at risk of future diabetes can be identified by HbA(1c) and fasting glucose values in the upper normal range during pregnancy. A family history of diabetes and previous pregnancies further increase this risk.

The type 1 diabetes protective HLA DQB1*0602 allele is less frequent in gestational diabetes mellitus.

AIMS/HYPOTHESIS: We tested whether gestational diabetes mellitus (GDM) is associated with HLA-DQ genotypes. METHODS: A total of 764 mothers with non-autoimmune (GAD65, insulinoma-associated protein 2 [IA-2] and insulin autoantibody-negative) GDM were ascertained between September 2000 and August 2004 in the population-based Diabetes Prediction in Skåne (DiPiS) study. HLA-DQB1 genotypes were determined in these mothers and in 1191 randomly selected non-diabetic control mothers also negative for islet autoantibodies. The data were analysed in relation to maternal age, country of birth, number of pregnancies/siblings and pregnancy weight gain. RESULTS: The frequency of type 1 diabetes high-risk HLA-DQ alleles (DQB1*0201, DQB1*0302) did not differ between GDM mothers and controls. In contrast, the low-risk DQB1*0602 allele was less prevalent (OR 0.64, 95% CI = 0.51-0.80, p = 0.0006) in GDM than in control mothers. The difference in DQB1*0602 frequency between GDM mothers and controls remained after multiple logistic regression analysis correcting for maternal age, country of birth, number of pregnancies/siblings and weight gain during pregnancy (OR 0.67, 95% CI 0.51-0.88, p = 0.009). CONCLUSIONS/INTERPRETATION: The negative association between mothers who have non-autoimmune GDM and HLA-DQ*0602 suggest that this allele may protect not only from type 1 diabetes but also from GDM.

Can complement factors 5 and 8 and transthyretin be used as biomarkers for MODY 1 (HNF4A-MODY) and MODY 3 (HNF1A-MODY)?

AIMS: Genetic testing is needed for the formal diagnosis of maturity-onset diabetes of the young (MODY), but this is not widely available. If any MODY biomarkers were known, these could possibly be used as an alternative. Hepatocyte nuclear factor (HNF)-1alpha and HNF-4alpha regulate transcription of genes encoding complement 5 (C5), complement 8 (C8) and transthyretin (TTR), suggesting that these could be potential biomarkers for the disease. We therefore set out to determine whether serum concentrations of C5, C8 and TTR can be used as biomarkers for patients with HNF4A-MODY and HNF1A-MODY. METHODS: The serum concentrations of C5, C8 and TTR were analysed in patients with mutations in the HNF-1alpha (n=29) and HNF-4alpha (N=13) genes. Type 2 diabetic (n = 14) and healthy subjects (n = 20), matched for body mass index (BMI), served as diabetic and non-diabetic control groups, respectively. RESULTS: Type 2 diabetic patients had markedly increased levels of C5 and C8 compared with healthy control subjects. Levels of C5 and C8 correlated with glycated haemoglobin (C5: r = 0.48, P = 0.019). After adjustment for BMI, glycated haemoglobin, age and gender, HNF4A-MODY and HNF1A patients had reduced levels of C5 and C8 compared with Type 2 diabetic patients (C5: P = 0.001; C8: P = 0.004). In addition, patients with HNF4A-MODY, but not those with HNF1A-MODY, had decreased TTR compared with diabetic patients (P = 0.038). CONCLUSIONS: Serum concentrations of C5 and C8 seem to distinguish HNF4A and HNF1A-MODY from other forms of diabetes. However, hyperglycaemia per se increases the serum concentrations, thereby attenuating their potential role as biomarkers for MODY.

Immigrants from the Middle-East have a different form of Type 2 diabetes compared with Swedish patients.

AIMS: To compare the clinical characteristics of Type 2 diabetes (T2DM) between immigrants from the Middle-East and Swedish patients. METHODS: The study group included 450 consecutive patients with T2DM, 379 Swedish-born aged 61 +/- 12 years and 71 patients originally from the Middle-East aged 50 +/- 11 years from the diabetes clinic of Malmo University Hospital. RESULTS: Onset of diabetes had occurred 12 years earlier in the Middle-East immigrants compared with the Swedish-born patients (43 +/- 10 vs. 55 +/- 12 years, P < 0.001). Immigrants had lower fasting serum C-peptide [0.7 (0.1-2.6) vs. 0.9 (0.1-4.0) nmol/l, P = 0.013], lower homeostasis model assessment (HOMA)-beta[1.7 (0.1-9.1) vs. 2.7 (0.1-59.0), P = 0.010], lower HOMA-IR [0.4 (0.02-1.19) vs. 0.4 (0.01-2.8), P = 0.005] than the Swedish group. A first-degree family history of diabetes was reported in 61% of immigrants, compared with 47% of Swedish-born (P = 0.022). CONCLUSIONS: Immigrants from the Middle-East have an earlier onset, stronger family history and more rapid decline of pancreatic B-cell function than Swedish patients, suggesting that they have a different form of T2DM compared with Swedish patients.

A variant in the transcription factor 7-like 2 (TCF7L2) gene is associated with an increased risk of gestational diabetes mellitus.

AIMS/HYPOTHESIS: Genetic and epidemiological studies suggest an association between gestational diabetes mellitus and type 2 diabetes. Both are polygenic multifactorial disorders characterised by beta cell dysfunction and insulin resistance. Our aim was to investigate whether common genetic variants that have previously been associated with type 2 diabetes or related phenotypes would also confer risk for gestational diabetes mellitus. MATERIALS AND METHODS: In 1,881 unrelated pregnant Scandinavian women (649 women with gestational diabetes mellitus, 1,232 non-diabetic control subjects) we genotyped the transcription factor 7-like 2 (TCF7L2 rs7903146), adiponectin (ADIPOQ +276G > T), peroxisome-proliferator activated receptor, gamma 2 (PPARG Pro12Ala), PPARG-coactivator, 1 alpha (PPARGC1A Gly482Ser), forkhead box C2 (FOXC2 -512C > T) and beta3-adrenergic receptor (ADRB3 Trp64Arg) polymorphisms using TaqMan allelic discrimination assay or RFLP. RESULTS: The CC, CT and TT genotype frequencies of the TCF7L2 rs7903146 variant differed significantly between women with gestational diabetes mellitus and control women (46.3, 43.6 and 10.1% vs 58.5, 35.3 and 6.2%, p = 3.7 x 10(-6), corrected p value [Pc] for multiple testing Pc = 2.2 x 10(-5)). The T-allele was associated with an increased risk of gestational diabetes mellitus (odds ratio 1.49 [95% CI 1.28-1.75], p = 4.9 x 10(-7) [Pc = 2.8 x 10(-6)]). Compared with wild-type CC-genotype carriers, heterozygous (CT-genotype) and homozygous (TT-genotype) carriers had a 1.6-fold (95% CI 1.26-1.93, p = 3.7 x 10(-5) [Pc = 0.0002]) and a 2.1-fold (95% CI 1.41-2.99, p = 0.0001 [Pc = 0.0008]) increased risk of gestational diabetes mellitus, respectively. The other polymorphisms studied were not significantly associated with gestational diabetes mellitus (ADIPOQ +276G > T: 1.17 [1.01-1.36], p = 0.039 [Pc = 0.23]; PPARG Pro12Ala: 1.06 [0.87-1.29], p = 0.53; PPARGC1A Gly482Ser: 0.96 [0.83-1.10], p = 0.54; FOXC2 -512C > T: 1.01 [0.87-1.16], p = 0.94; and ADRB3 Trp64Arg: 1.22 [0.95-1.56], p = 0.12). CONCLUSIONS/INTERPRETATION: The TCF7L2 rs7903146 variant is associated with an increased risk of gestational diabetes mellitus in Scandinavian women.

Common variants in MODY genes increase the risk of gestational diabetes mellitus.

AIMS/HYPOTHESIS: Impaired beta cell function is the hallmark of gestational diabetes mellitus (GDM) and MODY. In addition, women with MODY gene mutations often present with GDM, but it is not known whether common variants in MODY genes contribute to GDM. SUBJECTS AND METHODS: We genotyped five common variants in the glucokinase (GCK, commonly known as MODY2), hepatocyte nuclear factor 1-alpha (HNF1A, commonly known as MODY3) and 4-alpha (HNF4A commonly known as MODY1) genes in 1,880 Scandinavian women (648 women with GDM and 1,232 pregnant non-diabetic control women). RESULTS: The A allele of the GCK -30G-->A polymorphism was more common in GDM women than in control subjects (odds ratio [OR] 1.28 [95% CI 1.06-1.53], p=0.008, corrected p value, p=0.035). Under a recessive model [AA vs GA+GG], the OR increased further to 2.12 (95% CI 1.21-3.72, p=0.009). The frequency of the L allele of the HNF1A I27L polymorphism was slightly higher in GDM than in controls (1.16 [95% CI 1.001-1.34], p=0.048, corrected p value, p=0.17). However, the OR increased under a dominant model (LL+IL vs II; 1.31 [95% CI 1.08-1.60], p=0.007). The rs2144908, rs2425637 and rs1885088 variants, which are located downstream of the primary beta cell promoter (P2) of HNF4A, were not associated with GDM. CONCLUSIONS/INTERPRETATION: The -30G-->A polymorphism of the beta-cell-specific promoter of GCK and the I27L polymorphism of HNF1A seem to increase the risk of GDM in Scandinavian women.

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

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.

Genotypic and phenotypic differences between Arabian and Scandinavian women with gestational diabetes mellitus.

AIMS/HYPOTHESIS: Gestational diabetes mellitus is a heterogeneous disorder characterised by impaired insulin secretion and action. Our aim was to study whether autoimmunity, variations in genes affecting insulin secretion and action, or both, contribute to the development of gestational diabetes and whether the pathogenesis of the disease differs between women with a Scandinavian or Arabian background. METHODS: We studied a total of 500 unrelated women with gestational diabetes (400 Scandinavian and 100 Arabian) and 550 unrelated pregnant non-diabetic control women (428 Scandinavian and 122 Arabian) matched for ethnicity. RESULTS: Arabian women with gestational diabetes were 50% more insulin resistant for the same BMI compared with Scandinavian women with the disease (homeostasis model assessment [HOMA-IR]; 3.2+/-0.3 vs 2.2+/-0.2, p=0.02). Both Scandinavian (4.2% vs 0.9%, p=0.008) and Arabian (4.6% vs 0.0%, p=0.03) women with gestational diabetes had a higher frequency of GAD antibodies (GAD65Ab) than the matched controls. The frequency of HLA-DQB1 risk genotypes was slightly higher in Scandinavian women with gestational diabetes than in the Scandinavian controls (46.3% vs 38.8%, p=0.03) but no significant difference was found between the Arabian women with gestational diabetes and the Arabian controls (47% vs 51.6%, p=0.47). There were no significant differences in the frequency of the insulin gene variable number of tandem repeat ( INS VNTR) alleles and genotypes or the peroxisome proliferator-activated receptor-gamma 2 ( PPAR gamma 2-Pro12Ala) polymorphism between the women with gestational diabetes and the control women either in Arabian or in Scandinavian women. CONCLUSIONS/INTERPRETATION: Gestational diabetes mellitus was associated with the presence of GAD65Ab in both study groups. Scandinavian women with gestational diabetes may share some genetic features with Type 1 diabetes. In addition, Arabian women with gestational diabetes are more insulin resistant than Scandinavian women with gestational diabetes and with the same BMI.