Gremlin-1 in pregnancy and postpartum: relation to the fatty liver index, markers of bone health, glucose metabolism and gestational diabetes mellitus status.

INTRODUCTION: Gremlin-1 is a peptide that functions as an antagonist to bone morphogenic proteins and is overexpressed in obesity and type 2 diabetes mellitus. Gremlin-1 has not yet been investigated in pregnancy, pregnancy-related insulin resistance or gestational diabetes mellitus (GDM). PATIENTS AND METHODS: Gremlin-1 levels were measured throughout the pregnancy of 58 women at high risk for GDM at the Medical University of Vienna. Furthermore, an oral glucose tolerance test, fasting insulin, fasting glucose, sex hormones, blood lipids, liver and renal parameters, and markers of bone development were evaluated at two points during pregnancy (< 20 weeks of gestation (GW), GW 24-28) and 12-14 weeks postpartum. RESULTS: Gremlin-1 levels decreased from < 20 GW (mean = 9.2 pg/ml, SD = 8.4 pg/ml) to GW 24-28 (mean = 6.7 pg/ml, SD = 5.7 pg/ml, p = 0.033) and increased again postpartum, albeit not significantly (mean = 10.7 pg/ml, SD = 13.1 pg/ml, p = 0.339). During pregnancy, Gremlin-1 levels correlated negatively with osteocalcin and procollagen type I aminoterminal propeptide (P1NP), markers of bone health. Concerning glucose metabolism, Gremlin-1 levels were inversely related to the Insulinogenic Index at GW < 20. However, Gremlin-1 levels were not significantly different between women with normal glucose tolerance and GDM during pregnancy. Postpartum, Gremlin-1 was associated with the fatty liver index, osteocalcin levels, diastolic blood pressure and weight. CONCLUSION: Gremlin-1 levels decreased significantly during pregnancy. The biomarker is not related to GDM status, but correlates negatively with the Insulinogenic Index, an index related to beta cell function. Trial Registry Number ACTRN12616000924459.

Glypican-4 in pregnancy and its relation to glucose metabolism, insulin resistance and gestational diabetes mellitus status.

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.

HbA1c during early pregnancy reflects beta-cell dysfunction in women developing GDM.

INTRODUCTION: It is of current interest to assess eligibility of hemoglobin A1c (HbA1c) as a screening tool for earlier identification of women with risk for more severe hyperglycemia in pregnancy but data regarding accuracy are controversial. We aimed to evaluate if HbA1c mirrors pathophysiological precursors of glucose intolerance in early pregnancy that characterize women who develop gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: 220 pregnant women underwent an HbA1c measurement as well as an oral glucose tolerance test (OGTT) with multiple measurements of glucose, insulin and C-peptide for evaluation of insulin sensitivity and beta-cell function at 16th gestational week (IQR: 14-18). Clinical follow-ups were performed until end of pregnancy. RESULTS: Increased maternal HbA1c ≥5.7% (39 mmol/mol) corresponding to pre-diabetes outside of pregnancy was associated with altered glucose dynamics during the OGTT. Pregnancies with early HbA1c ≥5.7% showed higher fasting (90.4±13.2 vs 79.7±7.2 mg/dL, p<0.001), mean (145.6±31.4 vs 116.2±21.4 mg/dL, p<0.001) as well as maximum glucose concentrations and tended to a delay in reaching the maximum glucose level compared with those with normal-range HbA1c (186.5±42.6 vs 147.8±30.1 mg/dL, p<0.001). Women with increased HbA1c showed impaired beta-cell function and differences in disposition index independent of body mass index status. We observed a high specificity for the HbA1c cut-off of 5.7% for GDM manifestation (0.96, 95% CI 0.91 to 0.98) or need of glucose-lowering medication (0.95, 95% CI 0.90 to 0.98) although overall predictive accuracy was moderate to fair. Further, elevated HbA1c was associated with higher risk for delivering large-for-gestational-age infants, also after adjustment for GDM status (OR 4.4, 95% CI 1.2 to 15.0, p=0.018). CONCLUSIONS: HbA1c measured before recommended routine screening period reflects early pathophysiological derangements in beta-cell function and glucose disposal that are characteristic of GDM development and may be useful in early risk stratification.

CTRP-1 levels are related to insulin resistance in pregnancy and gestational diabetes mellitus.

Recent studies have shown higher levels of CTRP-1 (C1QTNF-related protein) in patients with type 2 diabetes compared to controls. We aimed at investigating CTRP-1 in gestational diabetes mellitus (GDM). CTRP-1 levels were investigated in 167 women (93 with normal glucose tolerance (NGT), 74 GDM) of a high-risk population for GDM. GDM was further divided into GDM subtypes depending on a predominant insulin sensitivity issue (GDM-IR) or secretion deficit (GDM-IS). Glucose tolerance was assessed with indices [Matsuda index, Stumvoll first phase index, insulin-secretion-sensitivity-index 2 (ISSI-2), area-under-the-curve (AUC) insulin, AUC glucose] derived from an oral glucose tolerance test (oGTT) performed at < 21 and 24-28 weeks of gestation. In pregnancy, CTRP-1 levels of GDM (76.86 ± 37.81 ng/ml) and NGT (82.2 ± 35.34 ng/ml; p = 0.104) were similar. However, GDM-IR women (65.18 ± 42.18 ng/ml) had significantly lower CTRP-1 levels compared to GDM-IS (85.10 ± 28.14 ng/ml; p = 0.009) and NGT (p = 0.006). CTRP-1 levels correlated negatively with weight, AUC insulin, Stumvoll first phase index, bioavailable estradiol and positively with HbA1c, Matsuda Index and ISSI-2. A multiple regression analysis revealed bioavailable estradiol (ß = - 0.280, p = 0.008) and HbA1c (ß = 0.238; p = 0.018) as the main variables associated with CTRP-1 in GDM. Postpartum, waist and hip measurements were predictive of CRTP-1 levels instead. CTRP-1 levels were higher postpartum than during pregnancy (91.92 ± 47.27 vs.82.44 ± 38.99 ng/ml; p = 0.013). CTRP-1 is related to insulin resistance in pregnancy and might be a metabolic biomarker for insulin resistance in GDM. CTRP-1 levels were significantly lower during pregnancy than postpartum, probably due to rising insulin resistance during pregnancy.

Secretagogin is Related to Insulin Secretion but Unrelated to Gestational Diabetes Mellitus Status in Pregnancy.

Secretagogin (SCGN) is a calcium binding protein related to insulin release in the pancreas. Although SCGN is not co-released with insulin, plasma concentrations have been found to be increased in type 2 diabetes mellitus patients. Until now, no study on SCGN levels in pregnancy or patients with gestational diabetes mellitus (GDM) has been published. In 93 women of a high-risk population for GDM at the Medical University of Vienna, secretagogin levels of 45 GDM patients were compared to 48 women with a normal glucose tolerance (NGT). Glucose tolerance, insulin resistance and secretion were assessed with oral glucose tolerance tests (OGTT) between the 10th and 28th week of gestation (GW) and postpartum. In all women, however, predominantly in women with NGT, there was a significant positive correlation between SCGN levels and Stumvoll first (rp = 0.220, p = 0.032) and second phase index (rp = 0.224, p = 0.028). SCGN levels were not significantly different in women with NGT and GDM. However, SCGN was higher postpartum than during pregnancy (postpartum: 88.07 ± 35.63 pg/mL; pregnancy: 75.24 ± 37.90 pg/mL, p = 0.004). SCGN was directly correlated with week of gestation (rp = 0.308; p = 0.021) and triglycerides (rp = 0.276; p = 0.038) in women with GDM. Therefore, SCGN is related to insulin secretion and hyperinsulinemia during pregnancy; however, it does not display differences between women with NGT and GDM.

Decreased beta-cell function in breastfeeding obese and non-obese women: A prospective observational study.

BACKGROUND & AIMS: Obesity is associated with lower breastfeeding rates. The underlying pathophysiological mechanisms are not well-understood, but there is increasing evidence on an association between parameters of maternal glucose metabolism and prolactin concentrations. In this cross-sectional observational study we investigate the relationship between breastfeeding, maternal obesity, and maternal glucose metabolism postpartum with beta cell function as a primary outcome measure. METHODS: We investigated 106 women (44% obese) prospectively recruited during the pregnancy, who underwent a 75 g - 2 h oral glucose tolerance test (OGTT) between the 3rd and 5th months postpartum. At this time point, we tested the relationship between breastfeeding status, maternal prolactin concentrations, maternal obesity, and fasting and dynamic indices of glucose metabolism using multivariate logistic regression in a post hoc analysis of prospective observational data. RESULTS: During the study visit at a mean of 122 (SE 9.3) days after delivery, 47% of obese women and 68% of non-obese women were breastfeeding (p < 0.05). Lactation and higher prolactin concentrations were associated with lower prepregnancy weight and lower postpartum insulin concentrations. Prehepatic beta-cell function was decreased in both obese (mean (SD); 0.16 (0.04) vs. 0.19 (0.05), p < 0.05) and non-obese (0.12 (0.05) vs. 0.16 (0.06), p < 0.01), lactating women. Obese lactating women have significantly lower first (1135.1 (306.7) pmol/L vs. 1517.3 (475.8) pmol/L, p < 0.01) and second phase insulin secretion (mean (SD), 300.2 (70.7) pmol/L vs. 393.1 (115.5) pmol/L, p < 0.01) as shown by Stumvoll indices when comparing to obese non-lactating women. Prehepatic beta-cell function and Stumvoll 1st phase insulin secretion index, but not BMI, were independently and negatively associated with breastfeeding and circulating prolactin concentrations. CONCLUSIONS: Beta-cell function during lactation relates to breastfeeding and circulating prolactin concentrations independently of obesity. The well-known positive effects of lactation on maternal and offspring outcomes might reflect a causative relationship of higher breastfeeding rates in metabolically healthier women.

Similarities in trabecular hypertrophy with site-specific differences in cortical morphology between men and women with type 2 diabetes mellitus.

The goal of our study was to investigate interactions between sex and type 2 diabetes mellitus (T2DM) with regard to morphology of the peripheral skeleton. We recruited 85 subjects (mean age, 57±11.4 years): women with and without T2DM (n = 17; n = 16); and men with and without T2DM (n = 26; n = 26). All patients underwent high-resolution, peripheral, quantitative, computed tomography (HR-pQCT) imaging of the ultradistal radius (UR) and tibia (UT). Local bone geometry, bone mineral density (BMD), and bone microarchitecture were obtained by quantitative analysis of HR-pQCT images. To reduce the amount of data and avoid multi-collinearity, we performed a factor-analysis of HR-pQCT parameters. Based on factor weight, trabecular BMD, trabecular number, cortical thickness, cortical BMD, and total area were chosen for post-hoc analyses. At the radius and tibia, diabetic men and women exhibited trabecular hypertrophy, with a significant positive main effect of T2DM on trabecular number. At the radius, cortical thickness was higher in diabetic subjects (+20.1%, p = 0.003). Interestingly, there was a statistical trend that suggested attenuation of tibial cortical hypertrophy in diabetic men (cortical thickness, pinteraction = 0.052). Moreover, we found an expected sexual dichotomy, with higher trabecular BMD, Tb.N, cortical BMD, Ct.Th, and total area in men than in women (p≤ 0.003) at both measurement sites. Our results suggest that skeletal hypertrophy associated with T2DM is present in men and women, but appears attenuated at the tibial cortex in men.

Microvascular function in women with former gestational diabetes: A cohort study.

OBJECTIVE: In the long term, diabetes mellitus is potentially associated with the occurrence of microvascular damage. This study sought to assess whether a history of prior gestational diabetes mellitus is associated with long-term effects on the women's microcirculation. METHODS: Within the scope of a long-term follow-up of the 'Viennese Post-Gestational Diabetes Project', women with prior gestational diabetes mellitus as well as women with previous pregnancy but with no history of gestational diabetes mellitus (controls) were enrolled in this cross-sectional study. Microvascular function was assessed by post-occlusive reactive hyperaemia using laser Doppler fluxmetry. Baseline perfusion, biological zero, peak perfusion, time to peak and recovery time were recorded and compared between both groups. RESULTS: Microvascular function was assessed in 55 women with prior gestational diabetes mellitus (46.1 ± 4.6 years) and 32 women with previous pregnancy but without prior gestational diabetes mellitus (42.9 ± 5.3 years). The mean period of time between delivery and the assessment of microvascular function was 16.2 ± 5.2 years in women with prior gestational diabetes mellitus group and 14.2 ± 4.8 years in controls. Regarding microvascular function, baseline perfusion, biological zero, peak perfusion, time to peak and recovery time did not differ between women with prior gestational diabetes mellitus and controls (all p > 0.05). CONCLUSION: In the long term, microvascular function appears not to be impaired in women with prior gestational diabetes mellitus.

Combined Metabolomic Analysis of Plasma and Urine Reveals AHBA, Tryptophan and Serotonin Metabolism as Potential Risk Factors in Gestational Diabetes Mellitus (GDM).

Gestational diabetes mellitus during pregnancy has severe implications for the health of the mother and the fetus. Therefore, early prediction and an understanding of the physiology are an important part of prenatal care. Metabolite profiling is a long established method for the analysis and prediction of metabolic diseases. Here, we applied untargeted and targeted metabolomic protocols to analyze plasma and urine samples of pregnant women with and without GDM. Univariate and multivariate statistical analyses of metabolomic profiles revealed markers such as 2-hydroxybutanoic acid (AHBA), 3-hydroxybutanoic acid (BHBA), amino acids valine and alanine, the glucose-alanine-cycle, but also plant-derived compounds like sitosterin as different between control and GDM patients. PLS-DA and VIP analysis revealed tryptophan as a strong variable separating control and GDM. As tryptophan is biotransformed to serotonin we hypothesized whether serotonin metabolism might also be altered in GDM. To test this hypothesis we applied a method for the analysis of serotonin, metabolic intermediates and dopamine in urine by stable isotope dilution direct infusion electrospray ionization mass spectrometry (SID-MS). Indeed, serotonin and related metabolites differ significantly between control and GDM patients confirming the involvement of serotonin metabolism in GDM. Clustered correlation coefficient visualization of metabolite correlation networks revealed the different metabolic signatures between control and GDM patients. Eventually, the combination of selected blood plasma and urine sample metabolites improved the AUC prediction accuracy to 0.99. The detected GDM candidate biomarkers and the related systemic metabolic signatures are discussed in their pathophysiological context. Further studies with larger cohorts are necessary to underpin these observations.

Circulating Betatrophin Is Strongly Increased in Pregnancy and Gestational Diabetes Mellitus.

AIMS/HYPOTHESIS: Betatrophin has recently been introduced as a novel hormone and promotor of beta cell proliferation and improved glucose tolerance in mouse models of insulin resistance. In obese and diabetic humans altered levels were reported and a role in pathophysiology of metabolic diseases was therefore hypothesized. However its release and regulation in women with gestational diabetes mellitus (GDM), as well as its associations with markers of obesity, glucose and lipid metabolism during pregnancy still remain unclear. METHODS: Circulating betatrophin was quantified in 21 women with GDM and 19 pregnant body mass index-matched women with normal glucose tolerance (NGT) as well as 10 healthy age-matched non-pregnant women by enzyme-linked immunosorbent assay. Additionally we performed radioimmunassay (RIA) to confirm the results. RESULTS: Betatrophin concentrations measured by ELISA were significantly higher in GDM than in NGT (29.3±4.4 ng/ml vs. 18.1±8.7 ng/ml, p<0.001) which was confirmed by RIA. Betatrophin did not correlate with BMI or insulin resistance but showed a weak association with leptin levels in pregnancy and negative relationship with fasting C-peptide levels in all women. Moreover it correlated significantly with lipid parameters including triglycerides and total cholesterol in pregnancy, as well as estrogen, progesteron and birth weight. CONCLUSIONS/INTERPRETATION: Circulating betatrophin concentrations are dramatically increased in pregnancy and are significantly higher in GDM versus pregnant NGT. In the light of the previously reported role in lipid metabolism, betatrophin may represent a novel endocrine regulator of lipid alterations in pregnancy. However additional studies are needed to elucidate whether hormonal factors, such as estrogen, control the production of betatrophin and if targeting betatrophin could hold promise in the fight against metabolic disease.

Pathophysiological characteristics and effects of obesity in women with early and late manifestation of gestational diabetes diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria.

CONTEXT: Appropriate risk stratification is essential in gestational diabetes (GDM) diagnosis to optimize therapeutic strategies during pregnancy. However, there are sparse data related to the newly recommended International Association of Diabetes and Pregnancy Study Groups criteria and their use in early pregnancy. OBJECTIVE: This study sought to evaluate clinical and pathophysiological characteristics less up to gestational week (GW) 21 in women with early and late GDM onset. DESIGN AND SETTING: This was a prospective study conducted at the Medical University of Vienna. PATIENTS AND INTERVENTIONS: Pregnant women (n = 211) underwent an oral glucose tolerance test at 16 GW (interquartile range, 14-18 wk) with multiple measurements of glucose, insulin, and C-peptide for evaluation of insulin sensitivity and ß-cell function in addition to detailed obstetrical risk assessment. Clinical followups were performed until end of pregnancy. MAIN OUTCOME MEASURE: We performed a metabolic characterization of early-onset GDM. RESULTS: Of 81 women, 49 (23%) showed early (GDMEarly ≤ 21 GW) and 32 (15%) later manifestation (GDMLate ≥ 24 GW) whereas 130 (62%) remained normal-glucose-tolerant (NGT). In contrast with GDMLate, GDMEarly were affected by decreased insulin sensitivity (GDMEarly vs NGT, P < .001; GDMEarlyvs GDMLate, P < .001; GDMLate vs NGT, P = .410). However, both early and late manifested subjects showed impairments in ß-cell function. GDMEarly showed highest levels of preconceptional and actual body mass index (BMI), which was related to fasting glucose (r = 0.42, P < .001) and particularly insulin sensitivity (r = -0.51, P < .001). Differences in glucose disposal between the subgroups remained constant in multivariable analysis including the strongest risk factors for GDM, ie, age, history of GDM, and BMI in our population. CONCLUSIONS: Early manifestation of GDM is affected by insulin resistance that is partly explained by higher degree in obesity. However, ß-cell dysfunction was also detectable in GDMLate, indicating defective compensatory mechanisms emerging already in early pregnancy.

Lipoprotein(a) is not related to markers of insulin resistance in pregnancy.

BACKGROUND: Dyslipidemia, a major risk factor for cardiovascular disease is a common finding in patients with type 2 diabetes and among women with gestational diabetes. Elevated levels of lipoprotein(a) [Lp(a)] are linked to increased risk of cardiovascular disease. However, its relationship with insulin resistance, type 2 diabetes and gestational diabetes is controversial and unproven. Here we aimed to clarify whether Lp(a) levels are associated with insulin sensitivity in pregnancy. METHODS: Sixty-four women with gestational diabetes and 165 with normal glucose tolerance were enrolled in the study. Fasting Lp(a) serum levels were measured in all women at 24-28 weeks of gestation. RESULTS: In pregnancy, there was no significant difference in serum Lp(a) concentrations between the two groups. Its level did not correlate with markers of insulin resistance (HOMA-IR), insulin sensitivity (HOMA-S%), pancreatic beta-cell function (HOMA-B%) and insulin sensitivity in dynamic conditions (OGIS). In addition, fasting glucose and insulin levels and those throughout an oral glucose tolerance test were independent of Lp(a) concentrations in our study group. CONCLUSIONS: Lp(a) levels in pregnant women do not differ with respect to the presence or absence of gestational diabetes. Although influenced by some components of the lipid profile, such as triglycerides and HDL-C, insulin resistance in pregnancy is not affected by Lp(a).