Genetic and immunological risk factors of gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is a heterogeneous disorder that is defined as carbohydrate intolerance with onset or first recognition during pregnancy. Impaired beta-cell function and insulin resistance are the hallmarks of GDM. The overall aim of this thesis was to study the genetic and immunological risk factors that increase susceptibility to GDM. First, we investigated whether autoimmunity and genetic variants affecting insulin secretion or action, or both, contribute to the development of GDM. We found that GDM was associated with the presence of glutamic acid decarboxylase-65 antibodies (GAD65Ab) in Arabian and Scandinavian women. In addition, Scandinavian women with GDM were found to share some genetic features such as HLA DQB1 risk genotypes (odds ratio [OR] 1.36, [95% CI 1.03?1.79], p=0.03) with type 1 diabetes. Furthermore, Arabian women with GDM were more insulin resistant than Scandinavian women with GDM and with the same BMI. We also investigated whether GDM has a similar genetic predisposition as type 2 diabetes by studying common genetic polymorphisms that have previously been associated with type 2 diabetes. Among 5 studied polymorphisms, we found that the E23K polymorphism of the potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) gene was associated with a modestly increased risk (1.17, [1.02?1.35], p=0.027) of GDM. This is compatible with its effect on insulin secretion and the crucial role of impaired beta-cell function in the pathogenesis of GDM. Additionally, we studied whether common variants in MODY [Glucokinase (GCK), hepatocyte nuclear factor 1-alpha (HNF1A), and HNF4A] genes also increase the risk of GDM. We found that the A-allele of the ?30G>A polymorphism in the beta-cell-specific promoter of the GCK increases the risk of GDM with a modest OR of 1.28 ([1.06 ?1.53], p=0.008). Moreover, the HNF1A I27L polymorphism was also associated with an increased risk of GDM (1.16 [1.001?1.34], p=0.048). All these variants are supposed to influence beta-cell function. Finally, we tested whether common genetic variants that have been associated with the metabolic syndrome or its components would also confer risk for GDM. We found that the T-allele of the +276G>T polymorphism of the adiponectin (APM1) gene, which has previously been associated with insulin resistance, increases the risk of GDM with an OR of 1.17 ([1.01?1.36], p=0.039). We conclude that common variants in several type 1 and type 2 diabetes candidate genes in addition to immunological factors increase susceptibility to heterogeneous GDM

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. (C) 2012 Elsevier Ireland Ltd. All rights reserved

Novel subgroups of adult-onset diabetes and their association with outcomes : a data-driven cluster analysis of six variables

Background Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis. Methods We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA(1c), and homoeostatic model assessment 2 estimates of beta-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations. Findings We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes. Interpretation We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.Peer reviewe

Genetics of gestational diabetes mellitus.

About 2-5% of all pregnant women develop gestational diabetes mellitus (GDM) during their pregnancies and the prevalence has increased considerably during the last decade. GDM is a heterogeneous disorder that is defined as carbohydrate intolerance with onset or first recognition during pregnancy. It is manifested when pancreatic beta cells are no longer able to compensate for the increased insulin resistance during pregnancy, but the pathogenesis of the disease is still largely unknown. GDM is considered to result from interaction between genetic and environmental risk factors. Genetic predisposition to GDM has been suggested since GDM clusters in families. Also, women with mutations in MODY (Maturity onset diabetes of the young) genes often present with GDM. In addition, common variants in several candidate genes (e.g. potassium inwardly rectifying channel subfamily J, member 11 [KCNJ11], Glucokinase [GCK], Hepatocyte nuclear factor-1alpha [HNFIA] etc.) have been demonstrated to increase the risk of GDM. Old age, obesity and high fat diet represent some important non-genetic factors. There are several approaches to search for genes predisposing to a polygenic disease like GDM including linkage and association studies, expression profiling and animal models. A combination of several methods is usually necessary. Identification of the underlying genetic causes of GDM will eventually give a better view of the mechanisms that contribute to the pathophysiology of the disease, Furthermore, it may improve options to possibly prevent GDM and complications for the mother and her child. This review focuses on the genetics of GDM and possible implications in clinical practice

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 EtaNuF-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

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

HbA1c as a predictor of diabetes after gestational diabetes mellitus

Aim We wanted to investigate third-trimester HbA1c as a predictor of diabetes after gestational diabetes mellitus (GDM). Methods Women with GDM were followed up prospectively for five years from pregnancy to detect the development of diabetes. The ability of HbA1c to predict diabetes was evaluated with receiver-operating characteristic (ROC) curves and logistic regression analysis. Results By five years, 73 of 196 women had been diagnosed with diabetes. An optimal cut-off point for HbA1c of 36 mmol/mol (5.4%) could predict diabetes with 45% sensitivity and 92% specificity. For HbA1c ≥39 mmol/mol (≥5.7%), sensitivity, specificity, and positive predictive value were 30%, 97%, and 91%, respectively. In logistic regression analysis, adjusting for the diagnostic glucose concentration during pregnancy, HbA1c levels in the upper quartile (≥36 mmol/mol) were associated with a 5.5-fold increased risk of diabetes. Conclusion Third-trimester HbA1c levels in the pre-diabetes range revealed women with post-partum diabetes with high specificity and high positive predictive value. HbA1c testing could be used as a strategy to select high-risk women for lifestyle interventions aimed at prevention of diabetes starting during pregnancy. The results should encourage further validation in other populations using new diagnostic criteria for GDM

The impact of ethnicity on glucose homeostasis after gestational diabetes mellitus

Background and aims: Ethnicity influences the prevalence of gestationaldiabetes (GDM) and its progression to manifest diabetes postpartum, beinghigher in non-European populations. This may partly be explained by differences in insulin secretion and action. Aims of the present study were toevaluate glucose homeostasis after GDM, the impact of ethnicity and otherdeterminants of glucose tolerance postpartum.Material and methods: Women in southern Sweden undergoing a 75 g oralglucose tolerance test (OGTT) during pregnancy in 2003-2005 were invited to follow-up postpartum. Diagnostic criteria were those defined by theWHO in 1999. At 1-2 years after delivery 470 women with GDM and 166women with normal glucose tolerance (NGT) during pregnancy performedan OGTT with measurements of plasma glucose and insulin concentrationsat fasting, 30 min and 120 min. Homeostasis model assessment (HOMA-IR)was used to estimate insulin resistance. Beta cell function was quantified asthe ratio of the incremental insulin to glucose during the first 30 min of theOGTT (I/G30). The disposition index was used to adjust insulin secretion forthe degree of insulin resistance ([I/G30)]/HOMA-IR). Women were groupedaccording to ethnicity based on stated country of origin in at least three oftheir grandparents. Indices were log transformed and differences in meanswere tested by ANCOVA, adjusting for age, parity and interval to follow-up(results given as geometric mean [95% confidence interval (CI)]). Frequencydifferences were tested by the Chi-square test. Multivariate logistic regressionanalysis was used to assess the association of known predictor variables (age,BMI, parity, first degree relative(s) with diabetes, non-European origin) withdiabetes postpartum, adjusting for time to follow-up.Results: Comparing women with previous GDM (n=470) to controls (NGTduring pregnancy and follow-up, n=150), the former had higher HOMA-IR Diabetologia (2012) 55:[Suppl1]S1–S538 S 4411 C(1.5 [1.4-1.7] vs. 1.3 [1.2-1.5], p=0.020) and lower disposition index (8.4 [7.7-9.2] vs. 12.8 [10.8-15.2], p<0.001). These differences were more pronouncedin women with GDM who had diabetes postpartum (HOMA-IR 3.1 [2.2-4.4],disposition index 2.6 [1.9-3.7]) compared to controls (p<0.001), while thosewho stayed normoglycaemic had similar HOMA-IR as controls but lower disposition index (9.6 [8.7-10.6], p<0.001). Among women with GDM, estimatesof beta cell function did not differ between non-European (n=94) and European women (n=362), whereas non-European women were more insulin resistant (HOMA-IR 2.0 [1.7-2.3] vs. 1.5 [1.3-1.6], p=0.002, after adjustment forBMI p=0.015). Similarly, Arabic women (n=41) had higher HOMA-IR (2.1[1.6-2.7]) than European women (p=0.006), but insignificant after adjustment for BMI. Non-European origin was associated with higher frequency ofdiabetes at follow-up (16%) than was European origin (4%, p<0.001). Of thepredictor variables tested for an association with diabetes after GDM, BMIand non-European origin showed the highest associations; odds ratio (95%CI), 1.1 (1.1-1.2), p<0.001, and 5.3 (1.9-14.9), p=0.002, respectively.Conclusions: Women with a history of GDM display abnormalities in glucose homeostasis, also in the presence of NGT postpartum, including betacell dysfunction and insulin resistance. These derangements may be influenced by ethnicity and BMI

The impact of ethnicity on glucose homeostasis after gestational diabetes mellitus.

The objective of this study was to examine measures of insulin resistance and beta cell function in relation to ethnicity and the development of diabetes after gestational diabetes mellitus (GDM). Glucose homeostasis was assessed during a 75 g oral glucose tolerance test 1-2 years after delivery in 456 women with previous GDM (362 European, 94 non-European; including 41 Arab and 43 Asian women) and 133 control women. Insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR). The insulinogenic index (I/G30) and the disposition index [(I/G30)/HOMA-IR] were used to quantify insulin secretion. Women developing diabetes after GDM were characterized by increased HOMA-IR [p = 0.010, adjusted for body mass index (BMI)], whereas the disposition index was decreased in all women with previous GDM irrespective of glucose tolerance, most pronounced in the presence of diabetes (BMI-adjusted p = 1 × 10(-5)). Non-European origin was associated with increased HOMA-IR (p = 0.001 vs. European), strengthened by adjustment for BMI in Asian women (p = 0.046 vs. p = 0.016), but eradicated among Arab women (p = 0.004 vs. p = 0.65). Non-European women exhibited an increased frequency of diabetes after GDM (17 % vs. European 4 %, p = 2 × 10(-5)). In addition to BMI, non-European and Asian origin was associated with the development of diabetes after GDM in a multivariate logistic regression analysis, whereas Arab origin was not. Our results highlight the importance of preventive measures to ensure a healthy lifestyle in women with GDM, particularly in high-risk ethnic groups

Association of single nucleotide polymorphisms with insulin secretion, insulin sensitivity, and diabetes in women with a history of gestational diabetes mellitus

Background: This study investigated whether single nucleotide polymorphisms (SNPs) reported by previous genome-wide association studies (GWAS) to be associated with impaired insulin secretion, insulin resistance, and/or type 2 diabetes are associated with disposition index, the homeostasis model assessment of insulin resistance (HOMA-IR), and/or development of diabetes following a pregnancy complicated by gestational diabetes mellitus (GDM). Methods: Seventy-two SNPs were genotyped in 374 women with previous GDM from Southern Sweden. An oral glucose tolerance test was performed 1–2 years postpartum, although data on the diagnosis of diabetes were accessible up to 5 years postpartum. HOMA-IR and disposition index were used to measure insulin resistance and secretion, respectively. Results: The risk A-allele in the rs11708067 polymorphism of the adenylate cyclase 5 gene (ADCY5) was associated with decreased disposition index (beta = − 0.90, SE 0.38, p = 0.019). This polymorphism was an expression quantitative trait loci (eQTL) in islets for both ADCY5 and its antisense transcript. The risk C-allele in the rs2943641 polymorphism, near the insulin receptor substrate 1 gene (IRS1), showed a trend towards association with increased HOMA-IR (beta = 0.36, SE 0.18, p = 0.050), and the T-allele of the rs4607103 polymorphism, near the ADAM metallopeptidase with thrombospondin type 1 motif 9 gene (ADAMTS9), was associated with postpartum diabetes (OR = 2.12, SE 0.22, p = 0.00055). The genetic risk score (GRS) of the top four SNPs tested for association with the disposition index using equal weights was associated with the disposition index (beta = − 0.31, SE = 0.29, p = 0.00096). In addition, the GRS of the four SNPs studied for association with HOMA-IR using equal weights showed an association with HOMA-IR (beta = 1.13, SE = 0.48, p = 9.72874e−11). All analyses were adjusted for age, body mass index, and ethnicity. Conclusions: This study demonstrated the genetic susceptibility of women with a history of GDM to impaired insulin secretion and sensitivity and, ultimately, to diabetes development