Genetic Studies of Gestational Diabetes and Glucose Metabolism in Pregnancy.
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ABSTRACT: Purpose of review
In this review, we summarize studies investigating genetics of gestational diabetes mellitus (GDM) and glucose metabolism in pregnancy. We describe these studies in the context of the larger body of literature on type 2 diabetes (T2D) and glycemic trait genomics.Recent findings
We reviewed 23 genetic association studies for GDM and performed a meta-analysis, which revealed variants at eight T2D loci significantly associated with GDM after the Bonferroni correction. These studies suggest that GDM and T2D share a number of genetic risk loci. Only two unbiased genome-wide association studies (GWASs) have successfully revealed genetic associations for GDM and related glycemic traits in pregnancy. A GWAS for GDM in Korean women identified two loci (near CDKAL1 and MTNR1B) known to be associated with T2D, though the association of the MTNR1B locus with GDM appears to be stronger than that for T2D. A multi-ethnic GWAS for glycemic traits in pregnancy identified two novel loci (near HKDC1 and BACE2) which appear to be associated with post-load glucose and fasting c-peptide specifically in pregnant women. There are ongoing efforts to use this genetic information, in the form of polygenic scores, to predict risk of GDM and postpartum T2D. The body of literature examining genetic associations with GDM is limited, especially when compared to the available literature on T2D and glycemic trait genomics. Additional genetic discovery for glucose metabolism in pregnant women will require larger pregnancy cohorts and international collaborative efforts. Studies on the clinical implications of these findings are also warranted.
SUBMITTER: Powe CE
PROVIDER: S-EPMC8132191 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aims/hypothesisThis study aimed to determine, in women with gestational diabetes (GDM), the changes in insulin sensitivity (Matsuda Insulin Sensitivity Index; ISOGTT), insulin response and disposition index (DI) from late pregnancy (34-37 weeks gestation, T1), to early postpartum (1-5 days, T2) and late postpartum (6-12 weeks, T3). A secondary aim was to correlate the longitudinal changes in maternal lipids, adipokines, cytokines and weight in relation to the changes in ISOGTT, insulin response and DI.MethodsISOGTT, insulin response and DI were calculated at the three time points (T1, T2 and T3) using the results of a 75 g OGTT. Adipokines, cytokines and lipids were measured prior to each OGTT. Linear mixed-effects models were used to compare changes across each time point. Changes in ISOGTT, insulin response and DI were correlated with changes in maternal adipokines, cytokines and lipids at each time point.ResultsA total of 27 women completed all assessments. Compared with T1, ISOGTT was 11.20 (95% CI 8.09, 14.31) units higher at 1-5 days postpartum (p < 0.001) and was 5.49 (95% CI 2.38, 8.60) units higher at 6-12 weeks postpartum (p < 0.001). Compared with T1, insulin response values were 699.6 (95% CI 957.5, 441.6) units lower at T2 (p < 0.001) and were 356.3 (95% CI 614.3, 98.3) units lower at T3 (p = 0.004). Compared with T1, the DI was 6434.1 (95% CI 2486.2, 10,381.0) units higher at T2 (p = 0.001) and was 4262.0 (95% CI 314.6, 8209.3) units higher at T3 (p = 0.03). There was a decrease in mean cholesterol, triacylglycerol, LDL-cholesterol and VLDL-cholesterol from T1 to T2 (all p < 0.001), and an increase in mean C-reactive protein, IL-6 and IL-8 from T1 to T2 (all p < 0.001). Mean leptin decreased from T1 to T2 (p = 0.001). There was no significant change in mean adiponectin (p = 0.99) or TNF-α (p = 0.81) from T1 to T2. The mean maternal BMI decreased from T1 to T2 (p = 0.001) and T3 (p < 0.001). There were no significant correlations between any measure of change in ISOGTT, insulin response and DI and change in maternal cytokines, adipokines, lipids or weight from T1 to T2.Conclusions/interpretationIn women with GDM, delivery was associated with improvement in both insulin sensitivity and insulin production within the first few days. Improvement in insulin production persisted for 6-12 weeks, but insulin sensitivity deteriorated slightly. These changes in glucose metabolism were not associated to changes in lipids, leptin, inflammation markers or body weight.Trial registrationClinicalTrials.gov NCT02082301.
| S-EPMC7277959 | biostudies-literature
Project description:Glypican-4 (GPC-4) is an adipokine that enhances insulin receptor signaling. Plasma concentrations were found to be elevated in patients with prediabetes but reduced in type 2 diabetes mellitus. No study on Glypican-4 in pregnancy and pregnancy-related insulin resistance has been published yet. GPC-4 levels were investigated in 59 overweight women throughout their pregnancy at the Medical University of Vienna. GPC-4 levels, fasting insulin, fasting glucose, estradiol, liver and renal parameters, and markers of bone development were assessed before the < 21st week of gestation (GW), and at GW 35-37. GPC-4 levels increased from < 21 GW (mean = 2.38 pg/ml, SD = 0.68 pg/ml) to GW 35-37 (mean = 2.96 pg/ml, SD = 0.77 pg/ml, p < 0.001). At the same time, GPC-4 levels correlated negatively with estimated glomerular filtration rate (eGFR), serum protein and serum albumin levels and were positively related to creatinine and uric acid levels at GW 35-37. Concerning glucose metabolism, GPC-4 levels were inversely related to ISSI-2, fasting insulin and HOMA-IR, however, not significantly different between women with normal glucose tolerance (NGT) and GDM (p = 0.239). In conclusion, GPC-4 levels rose significantly during pregnancy, correlated negatively with fasting insulin and HOMA-IR but might not be related to gestational diabetes mellitus status.
| S-EPMC8668887 | biostudies-literature
Project description:ObjectiveWhether hyperglycemia in utero less than overt diabetes is associated with altered childhood glucose metabolism is unknown. We examined associations of gestational diabetes mellitus (GDM) not confounded by treatment with childhood glycemia in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort.Research design and methodsHAPO Follow-up Study (FUS) included 4,160 children ages 10-14 years who completed all or part of an oral glucose tolerance test (OGTT) and whose mothers had a 75-g OGTT at ?28 weeks of gestation with blinded glucose values. The primary predictor was GDM by World Health Organization criteria. Child outcomes were impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes. Additional measures included insulin sensitivity and secretion and oral disposition index.ResultsFor mothers with GDM, 10.6% of children had IGT compared with 5.0% of children of mothers without GDM; IFG frequencies were 9.2% and 7.4%, respectively. Type 2 diabetes cases were too few for analysis. Odds ratios (95% CI) adjusted for family history of diabetes, maternal BMI, and child BMI z score were 1.09 (0.78-1.52) for IFG and 1.96 (1.41-2.73) for IGT. GDM was positively associated with child's 30-min, 1-h, and 2-h but not fasting glucose and inversely associated with insulin sensitivity and oral disposition index (adjusted mean difference -76.3 [95% CI -130.3 to -22.4] and -0.12 [-0.17 to -0.064]), respectively, but not insulinogenic index.ConclusionsOffspring exposed to untreated GDM in utero are insulin resistant with limited ?-cell compensation compared with offspring of mothers without GDM. GDM is significantly and independently associated with childhood IGT.
| S-EPMC6385693 | biostudies-literature
Project description:AimsTo determine the relationship between thyroid markers during pregnancy and gestational diabetes mellitus (GDM) or post-partum glucose metabolism.Materials and methodsBased on pregnancy 75-g oral glucose tolerance test (OGTT) results, 1467 subjects were grouped into normal glucose tolerance (NGTp; n = 768) and GDM (n = 699) groups. Furthermore, based on post-partum 75-g OGTT results, 286 GDM subjects, screened for glucose metabolism after delivery, were grouped into NGTd (n = 241) and abnormal glucose tolerance (AGT; n = 45) groups.ResultsMaternal age, family history of diabetes, acanthosis nigricans, previous adverse pregnancy outcomes and caesarean section incidence, and thyroid positive antibody rates were higher in the GDM group than in the NGTp group. In the first trimester, free triiodothyronine (FT3), thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) levels were higher in the GDM group than in the NGTp group. In the second trimester, free thyroxine (FT4) levels were lower and TPOAb and TgAb levels were higher in the GDM group than in the NGTp group. After adjusting for confounding factors, FT3, TPOAb and TgAb (first trimester), and FT4, TPOAb and TgAb (second trimester) were risk factors for GDM. TPOAb and TgAb levels were higher in the AGT group than in the NGTd group and were potential predictors of abnormal post-partum glucose tolerance.ConclusionsGDM risk significantly increased with increased FT3 (first trimester), TPOAb and TgAb (first and second trimesters) or with decreased FT4 (second trimester). Presence of thyroid antibodies predicted post-partum glucose abnormalities in subjects with GDM.
| S-EPMC8243952 | biostudies-literature
Project description:IntroductionPre-pregnancy obesity, gestational diabetes mellitus (GDM), and gestational weight gain (GWG) are associated with each other. This is the first study to investigate whether genetic variants were associated with having GDM, and whether genetic variants-related GDM were associated with adiposity including pre-pregnancy obesity and excessive GWG in Turkish women.Patients and methodsWomen with GDM (n = 160) and without GDM (n = 145) were included in case-controlled study. Genotyping of the HNF1A gene (p.I27L rs1169288, p.98V rs1800574, p.S487N rs2464196), the VDR gene (p.BsmI rs1544410, p.ApaI rs7975232, p.TaqI rs731236, p.FokI rs2228570), and FTO gene (rs9939609) SNPs were performed by using RT-PCR.ResultsThe FTO AA genotype was associated with an increased risk of having GDM (AA vs. AT + TT, 24.4% vs. 12.4%, OR = 2.27, 95% CI [1.23-4.19], p = 0.007). The HNF1A p.I27L GT/TT genotype was associated with increased GDM risk (GT + TT vs. GG-wild, 79.4% vs. 65.5%, OR = 2.02, 95% CI 1.21-3.38], p = 0.007). However, all VDR gene SNPs and the HNF1A p.A98V, p.S487N were not associated with having GDM (p > 0.05). The FTO AA genotype was associated with an increased risk for pre-pregnancy overweight/obesity (OR = 1.43, 95% CI [1.25-3.4], p = 0.035), but not associated with excessive GWG after adjusting for pre-pregnancy weight (p > 0.05). Pre-pregnancy weight, weight at delivery, and GWG did not differ in both VDR and HNF1A gene carriers (p > 0.05). HOMA-IR and HbA1c were increased in both p.I27L TT and FTO AA genotype carriers (p < 0.05).ConclusionThe adiposity-related gene FTO is associated with GDM by the effect of FTO on pre-pregnancy obesity. The diabetes-related p.I27L gene is associated with GDM by increasing insulin resistance.
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Project description:Aims/hypothesisDespite recommendations to screen women with diabetes risk factors for hyperglycaemia in the first trimester, criteria for normal glucose values in early pregnancy have not been firmly established. We aimed to compare glucose levels in early pregnancy with those later in gestation and outside of pregnancy in women with diabetes risk factors.MethodsIn pregnant women (N = 123) followed longitudinally through the postpartum period, and a separate cohort of non-pregnant women (N = 65), we performed 75 g oral glucose tolerance tests. All participants had one or more risk factors for diabetes. Using linear regression, we tested for differences in glucose levels between non-pregnant and pregnant women at early (7-15 weeks) and mid-late (24-32 weeks) gestation as well as postpartum, with adjustment for maternal age, parity, marital status and BMI. In a longitudinal analysis using mixed-effects models, we tested for differences in glucose levels across early and mid-late pregnancy compared with postpartum. Differences are expressed as β (95% CI).ResultsFasting glucose was lower in pregnant compared with non-pregnant women by 0.34 (0.18, 0.51) mmol/l (p < 0.0001) in early pregnancy and by 0.45 (0.29, 0.61) mmol/l (p < 0.0001) in mid-late pregnancy. In longitudinal models, fasting glucose was lower by 0.13 (0.04, 0.21) mmol/l (p = 0.003) in early pregnancy and by 0.16 (0.08, 0.25) mmol/l (p = 0.0003) in mid-late pregnancy compared with the same women postpartum. Early pregnancy post-load glucose levels did not differ from those in non-pregnant women or the same women postpartum. In mid-late pregnancy, compared with non-pregnant women, elevations in 1 h post-load glucose level (0.60 [-0.12, 1.33] mmol/l, p = 0.10) and 2 h post-load glucose (0.49 [-0.21, 1.19] mmol/l, p = 0.17) were not statistically significant. However, in longitudinal analyses, 1 h and 2 h post-load glucose levels were higher in mid-late pregnancy (by 0.78 [0.35, 1.21] mmol/l, p = 0.0004, and 0.67 [0.30, 1.04] mmol/l, p = 0.0005, respectively) when compared with postpartum.Conclusions/interpretationIn women with diabetes risk factors, fasting glucose declines in the first trimester. Post-load glucose increases later in pregnancy. These findings may inform criteria for diagnosing hyperglycaemia early in pregnancy.
| S-EPMC8904203 | biostudies-literature
Project description:Gestational diabetes mellitus (GDM) is today universally diagnosed during late pregnancy. Treating hyperglycaemia during pregnancy reduces the risk of complications, the effect of interventions is however limited due to the late diagnosis. It is thus important to identify biomarkers reaching a high precision for GDM development in early pregnancy. Here we aim to investigate soluble CD163 (sCD163) and soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK) in early pregnancy GDM and their association to the development of later glucose intolerance. In this case-control study, women diagnosed with GDM in early pregnancy (n = 70) at Lund University Hospital, Lund, Sweden in 2011-2015 were age- and BMI matched to pregnant volunteers without diabetes (n = 70) recruited in early pregnancy from maternal health care centres in 2014-2015. Plasma levels of sCD163 and sTWEAK were analysed using commercial ELISA. Plasma levels of sCD163 did not differ between patients with and without GDM in early pregnancy (p = 0.86), plasma levels of sTWEAK however was decreased in women with GDM (0.71 [0.4-1.75] ng/ml) compared to controls (1.38 [0.63-4.86] ng/ml; p = 0.003). Women with sTWEAK levels in the lowest tertile had an increased risk of GDM in early pregnancy (p = 0.014). Neither sCD163 nor sTWEAK were associated with later glucose intolerance in women with GDM. This study reports decreased levels of sTWEAK in women with early pregnancy GDM, independent of age and BMI. Neither sCD163 nor sTWEAK were found to be associated to later glucose intolerance.
| S-EPMC6508637 | biostudies-literature
Project description:Fasting plasma glucose (FPG) is nowadays routinely measured during early pregnancy to detect preexisting diabetes (FPG ≥ 7 mmol/L). This screening has concomitantly led to identify early intermediate hyperglycemia, defined as FPG in the 5.1 to 6.9 mmol/L range, also early gestational diabetes mellitus (eGDM). Early FPG has been associated with poor pregnancy outcomes, but the recommendation by the IADPSG to refer women with eGDM for immediate management is more pragmatic than evidence based. Although eGDM is characterized by insulin resistance and associated with classical risk factors for type 2 diabetes and incident diabetes after delivery, it is not necessarily associated with preexisting prediabetes. FPG ≥ 5.1 mmol/L in early pregnancy is actually poorly predictive of gestational diabetes mellitus diagnosed after 24 weeks of gestation. An alternative threshold should be determined but may vary according to ethnicity, gestational age, and body mass index. Finally, observational data suggest that early management of intermediate hyperglycemia may improve prognosis, through reduced gestational weight gain and potential early introduction of hypoglycemic agents. Considering all these issues, we suggest an algorithm for the management of eGDM based on early FPG levels that would be measured in case of risk factors. Nevertheless, interventional randomized trials are still missing.
| S-EPMC5664285 | biostudies-literature
Project description:Importance:The sequelae of gestational diabetes (GD) by contemporary criteria that diagnose approximately twice as many women as previously used criteria are unclear. Objective:To examine associations of GD with maternal glucose metabolism and childhood adiposity 10 to 14 years' postpartum. Design, Setting, and Participants:The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study established associations of glucose levels during pregnancy with perinatal outcomes and the follow-up study evaluated the long-term outcomes (4697 mothers and 4832 children; study visits occurred between February 13, 2013, and December 13, 2016). Exposures:Gestational diabetes was defined post hoc using criteria from the International Association of Diabetes and Pregnancy Study Groups consisting of 1 or more of the following 75-g oral glucose tolerance test results (fasting plasma glucose ?92 mg/dL; 1-hour plasma glucose level ?180 mg/dL; 2-hour plasma glucose level ?153 mg/dL). Main Outcomes and Measures:Primary maternal outcome: a disorder of glucose metabolism (composite of type 2 diabetes or prediabetes). Primary outcome for children: being overweight or obese; secondary outcomes: obesity, body fat percentage, waist circumference, and sum of skinfolds (>85th percentile for latter 3 outcomes). Results:The analytic cohort included 4697 mothers (mean [SD] age, 41.7 [5.7] years) and 4832 children (mean [SD] age, 11.4 [1.2] years; 51.0% male). The median duration of follow-up was 11.4 years. The criteria for GD were met by 14.3% (672/4697) of mothers overall and by 14.1% (683/4832) of mothers of participating children. Among mothers with GD, 52.2% (346/663) developed a disorder of glucose metabolism vs 20.1% (791/3946) of mothers without GD (odds ratio [OR], 3.44 [95% CI, 2.85 to 4.14]; risk difference [RD], 25.7% [95% CI, 21.7% to 29.7%]). Among children of mothers with GD, 39.5% (269/681) were overweight or obese and 19.1% (130/681) were obese vs 28.6% (1172/4094) and 9.9% (405/4094), respectively, for children of mothers without GD. Adjusted for maternal body mass index during pregnancy, the OR was 1.21 (95% CI, 1.00 to 1.46) for children who were overweight or obese and the RD was 3.7% (95% CI, -0.16% to 7.5%); the OR was 1.58 (95% CI, 1.24 to 2.01) for children who were obese and the RD was 5.0% (95% CI, 2.0% to 8.0%); the OR was 1.35 (95% CI, 1.08 to 1.68) for body fat percentage and the RD was 4.2% (95% CI, 0.9% to 7.4%); the OR was 1.34 (95% CI, 1.08 to 1.67) for waist circumference and the RD was 4.1% (95% CI, 0.8% to 7.3%); and the OR was 1.57 (95% CI, 1.27 to 1.95) for sum of skinfolds and the RD was 6.5% (95% CI, 3.1% to 9.9%). Conclusions and Relevance:Among women with GD identified by contemporary criteria compared with those without it, GD was significantly associated with a higher maternal risk for a disorder of glucose metabolism during long-term follow-up after pregnancy. Among children of mothers with GD vs those without it, the difference in childhood overweight or obesity defined by body mass index cutoffs was not statistically significant; however, additional measures of childhood adiposity may be relevant in interpreting the study findings.
| S-EPMC6143108 | biostudies-literature
Project description:Though gut microbiome disturbance may be involved in the etiology of gestational diabetes mellitus (GDM), data on the gut microbiome's dynamic change during pregnancy and associations with gestational glucose metabolism are still inadequate. In this prospective study comprising 120 pairs of GDM patients and matched pregnant controls, a decrease in the diversity of gut microbial species and changes in the microbial community composition with advancing gestation are found in controls, while no such trends are observed in GDM patients. Multivariable analysis identifies 10 GDM-related species (e.g., Alistipes putredinis), and the integrated associations of these species with glycemic traits are modified by habitual intake of fiber-rich plant foods. In addition, the microbial metabolic potentials related to fiber fermentation (e.g., mannan degradation pathways) and their key enzymes consistently emerge as associated with both GDM status and glycemic traits. Microbial features especially those involved in fiber fermentation, provide an incremental predictive value in a prediction model with established risk factors of GDM. These data suggest that the gut microbiome remodeling with advancing gestation is different in GDM patients compared with controls, and dietary fiber fermentation contributes to the influence of gut microbiome on gestational glycemic regulation.
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