Christian S. Göbl

Early possible risk factors for overt diabetes after gestational diabetes mellitus.

OBJECTIVE: To assess a cluster of risk factors, including parameters of the metabolic syndrome, in women with gestational diabetes mellitus (GDM) early after delivery, that features the best prediction for developing diabetes. METHODS: Women with GDM 3–6 months after delivery received a complete metabolic characterization at baseline as well as annually for up to 10 years of follow-up (N=110). We used parameters characterizing the metabolic syndrome as well as demographic variables at baseline to predict diabetes manifestation. RESULTS: Metabolic disturbances and insulin treatment during pregnancy were significantly associated with overt diabetes. Waist circumference of 80 cm or higher failed to show a significant effect on later development of the disease; however, it was significant when 88 cm or more was used as a cutoff value. We identified impaired glucose tolerance (13 [56.5%]; hazard ratio 6.77, confidence interval [CI] 2.96–15.45, P<.001) as well as high-density lipoprotein (HDL) cholesterol less than 50 mg/dL (14 [60.9%]; hazard ratio 2.88, CI 1.24–6.67, P=.010) and age older than 35 years (12 [52.2%]; hazard ratio 3.06, CI 1.32–7.12, P=.006) as the best predictors with additive effects. Women with at least two risk factors had a higher risk to develop the disease as compared with those women who showed only one risk factor (hazard ratio 3.2, CI 1.4–7.7, P=.008). CONCLUSION: Impaired glucose tolerance, HDL cholesterol less than 50 mg/dL, and age older than 35 years were identified as the best predictors of developing diabetes after GDM. LEVEL OF EVIDENCE: II

Thyrotropin Serum Concentrations in Patients with Papillary Thyroid Microcancers

BACKGROUND Recent studies have shown that elevated serum thyrotropin (thyroid-stimulating hormone [TSH]) concentrations are associated with an increased risk of differentiated thyroid cancers in patients with nodular goiter. Therefore, the measurement of TSH concentrations might support the clinical estimation of cancer risk, especially in patients with thyroid nodules that are too small for fine-needle aspiration biopsies. Thus, the objective of this study was to compare preoperative serum TSH concentrations in patients with papillary thyroid microcarcinoma (PTMC) and individuals in whom the presence of even small differentiated thyroid cancers was excluded by thorough histological examination of the thyroid after total thyroidectomy because of medullary thyroid carcinoma or c-cell hyperplasia. METHODS The study was a retrospective cross-sectional analysis. Thirty-three patients with PTMC who had undergone a hemi- or total thyroidectomy and 54 subjects with medullary thyroid carcinoma or c-cell hyperplasia in whom a total thyroidectomy had been performed between 1994 and 2008 were included. Exclusion criteria were the intake of medication that might affect thyroid function and previous thyroid cancer or thyroid surgery. RESULTS The mean TSH value was comparable between patients with PTMCs (1.40 +/- 0.92 mLU/L, 95% CI = 1.07-1.72) and the control group (1.43 +/- 1.44 mLU/L; 95% CI = 1.04-1.82, p = 0.912). There was a positive trend in correlation between nodule size and TSH levels in patients with PTMC (p = 0.066). CONCLUSIONS TSH is not elevated in subjects with PTMCs, indicating that it is not likely involved in the de novo oncogenesis of these small cancers. However, TSH might rather play a role in the progression of preexisting PTMCs.

Fatty Liver Index Predicts Further Metabolic Deteriorations in Women with Previous Gestational Diabetes

Background and Aims Determinants of fatty liver (FL) might be predictive for further deterioration in insulin resistance (IR) in women with previous gestational diabetes (pGDM). The aim was to evaluate the association between pGDM, FL and future manifestation of type 2 diabetes (T2DM) by a detailed pathophysiological characterization early after pregnancy. Methods 68 pGDM and 29 healthy controls were included 3–6 months after delivery and underwent specific metabolic assessments: status of IR was determined via oral- and intravenous-glucose-tolerance-tests with analysis of proinflammatory factors and kinetics of free-fatty-acids (FFA). According to the fatty-liver-index (FLI), pGDMs were categorized into three groups with low (FLI≤20), intermediate (20<FLI<60) and high (FLI≥60) risk for FL to assess differences in metabolic parameters at baseline as well as in the 10-year incidence for T2DM. Accuracy of FLI was proven with 1H-magnetic-resonance-spectroscopy. Results FL was strongly associated with IR in pGDM. pGDM with FLI≥60 showed significantly increased interleukin-6, plasminogen-activator-inhibitor-1, tissue-plasminogen-activator, fibrinogen and increased ultrasensitive-C-reactive-protein compared to the low risk group (FLI≤20). Analysis of FFA indicated a less pronounced decrease of plasma FFA levels during the oral-glucose-tolerance-test in subjects with FLI≥60. History of GDM plus FLI≥60 conferred a high risk for the manifestation of diabetes over 10 years of observation as compared to pGDMs with FLI≤20 (HR:7.85, Cl:2.02–30.5, p = 0.003). Conclusion FL is closely linked to GDM, especially to IR and inflammation. Most interestingly, subjects with the highest FLI values showed significant alterations in FFA kinetics and a higher risk to develop T2DM in future.

Sex-Specific Differences in Glycemic Control and Cardiovascular Risk Factors in Older Patients With Insulin-Treated Type 2 Diabetes Mellitus

BACKGROUND Because women have been excluded from many study populations in investigations of diabetes care, there is insufficient information on sex-specific differences in glycemic control. OBJECTIVE The aim of the present study was to assess whether treatment goals for glycemic and cardiovascular risk factor control are achieved equally in older, Central European, female and male patients with type 2 diabetes mellitus (T2DM). METHODS In a retrospective cross-sectional study, data were analyzed from consecutive older (aged ≥60 years) female and male patients with insulin-treated T2DM who attended a diabetes outpatient clinic between January 2007 and April 2008 at the Medical University of Vienna, Austria. Sex-specific differences in glycosylated hemoglobin (HbA₁(c)) levels were assessed as the primary outcome. LDL-C and HDL-C, as well as systolic and diastolic blood pressure (SBP and DBP, respectively), were assessed as secondary outcomes and were adjusted for age, duration of diabetes, duration of insulin treatment, body mass index, insulin units per kilogram per day, and secondary causes of diabetes. P values were adjusted using the Bonferroni correction. RESULTS Data were analyzed from 183 female and 209 male patients with insulin-treated T2DM. In multivariate linear regression models, women had significantly higher levels of LDL-C (P = 0.008), HDL-C (P < 0.001), SBP (P < 0.001), and DBP (P = 0.034), but not HbA₁(c) (P = NS). Multivariate logistic regression models revealed that women were significantly less likely to meet treatment goals for blood pressure (SBP, P = 0.044; DBP, P = 0.024), but not for cholesterol or HbA₁(c) levels (P = NS for LDL-C, HDL-C, and HbA₁(c)). CONCLUSION In this study of older patients with insulin-treated T2DM, whereas glycemic control was comparable between women and men, a more adverse cardiovascular risk factor profile was observed in female patients.

Biomarkers of endothelial dysfunction in relation to impaired carbohydrate metabolism following pregnancy with gestational diabetes mellitus

BackgroundHistory of gestational diabetes mellitus (GDM) identifies a very young population of females predisposed for type 2 diabetes and cardiovascular disease. Endothelial dysfunction might represent a shared precursor of both disorders. Hence, this study aimed to characterize endothelial biomarkers in relation to impaired insulin sensitivity and progression to overt diabetes early after index pregnancy.Methods108 women with previous GDM and 40 controls were included three to six months after delivery and underwent specific metabolic assessments including a frequently sampled intravenous glucose tolerance test and an oral glucose tolerance test. Diabetes progression was assessed in females with pGDM over 10 years of follow-up. Circulating sICAM-1 (intracellular-adhesion-molecule-1), sVCAM-1 (vascular-cell-adhesion-molecule-1) and sE-selectin, representing biomarkers of endothelial dysfunction were assessed at baseline and annually over five years.ResultsEndothelial biomarkers were significantly associated with insulin sensitivity (sICAM-1: r = -0.23, p = 0.009; sVCAM-1: r = -0.22, p = 0.011; sE-selectin: r = -0.21, p = 0.018) as well as with GDM status and parameters of subtle inflammation. Analysis of long-term trajectories revealed constantly elevated sICAM-1 (p = 0.033) and sE-selectin (p = 0.007) in 25 subjects with diabetes progression. Accordingly, sE-selectin levels at the early post partum visit predicted a later development of the disease (HR =1.02 95%CI 1.01 to 1.04, p = 0.013), however, this was attenuated after adjustment for BMI.ConclusionsElevated circulating markers of endothelial dysfunction in young females with GDM history might reflect an early stage on the pathway to the manifestation of future cardiometabolic disorders. Timely identification of women at high risk and optimization of follow-up management might provide an opportunity to prevent disease progression.

Changes in Serum Lipid Levels During Pregnancy in Type 1 and Type 2 Diabetic Subjects

OBJECTIVE Alterations in maternal lipid metabolism could affect fetal programming and the susceptibility for atherosclerosis in the offspring; therefore, we studied differences in lipid profiles of pregnant women with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 173 diabetic pregnancies were studied prior to conception (V0), at each trimester (V1–V3), and after delivery and were compared with 137 healthy women at V3. RESULTS During gestation, the increase in serum lipid concentrations was less pronounced in type 2 diabetic subjects. At V3, the lipid levels of type 1 diabetic women with normal glucose tolerance were similar but significantly higher then those of type 2 diabetic women. Elevated triglycerides and low HDL cholesterol at V3 were significant predictors for large-for-gestational-age (LGA) newborns. CONCLUSIONS Our data suggest smaller changes in serum lipid concentrations during pregnancy in type 2 diabetic mothers. Additionally, we found a positive association between maternal triglycerides and LGA infants independently of chronic glycemic control.

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.

A two-step screening algorithm including fasting plasma glucose measurement and a risk estimation model is an accurate strategy for detecting gestational diabetes mellitus

Aims/hypothesisIt is currently not clear how to construct a time- and cost-effective screening strategy for gestational diabetes mellitus (GDM). Thus, we elaborated a simple screening algorithm combining (1) fasting plasma glucose (FPG) measurement; and (2) a multivariable risk estimation model focused on individuals with normal FPG levels to decide if a further OGTT is indicated.MethodsA total of 1,336 women were prospectively screened for several risk factors for GDM within a multicentre study conducted in Austria. Of 714 women (53.4%) who developed GDM using recent diagnostic guidelines, 461 were sufficiently screened with FPG. A risk prediction score was finally developed using data from the remaining 253 women with GDM and 622 healthy women. The screening algorithm was validated with a further 258 pregnant women.ResultsA risk estimation model including history of GDM, glycosuria, family history of diabetes, age, preconception dyslipidaemia and ethnic origin, in addition to FPG, was accurate for detecting GDM in participants with normal FPG. Including an FPG pretest, the receiver operating characteristic AUC of the screening algorithm was 0.90 (95% CI 0.88, 0.91). A cut-off value of 0.20 was able to differentiate between low and intermediate risk for GDM with a high sensitivity. Comparable results were seen with the validation cohort. Moreover, we demonstrated an independent association between values derived from the risk estimation and macrosomia in offspring (OR 3.03, 95% CI 1.79, 5.19, p < 0.001).Conclusions/interpretationThis study demonstrates a new concept for accurate but cheap GDM screening. This approach should be further evaluated in different populations to ensure an optimised diagnostic algorithm.

Increasing live birth rate by preimplantation genetic screening of pooled polar bodies using array comparative genomic hybridization.

Meiotic errors during oocyte maturation are considered the major contributors to embryonic aneuploidy and failures in human IVF treatment. Various technologies have been developed to screen polar bodies, blastomeres and trophectoderm cells for chromosomal aberrations. Array-CGH analysis using bacterial artificial chromosome (BAC) arrays is widely applied for preimplantation genetic diagnosis (PGD) using single cells. Recently, an increase in the pregnancy rate has been demonstrated using array-CGH to evaluate trophectoderm cells. However, in some countries, the analysis of embryonic cells is restricted by law. Therefore, we used BAC array-CGH to assess the impact of polar body analysis on the live birth rate. A disadvantage of polar body aneuploidy screening is the necessity of the analysis of both the first and second polar bodies, resulting in increases in costs for the patient and complex data interpretation. Aneuploidy screening results may sometimes be ambiguous if the first and second polar bodies show reciprocal chromosomal aberrations. To overcome this disadvantage, we tested a strategy involving the pooling of DNA from both polar bodies before DNA amplification. We retrospectively studied 351 patients, of whom 111 underwent polar body array-CGH before embryo transfer. In the group receiving pooled polar body array-CGH (aCGH) analysis, 110 embryos were transferred, and 29 babies were born, corresponding to live birth rates of 26.4% per embryo and 35.7% per patient. In contrast, in the control group, the IVF treatment was performed without preimplantation genetic screening (PGS). For this group, 403 embryos were transferred, and 60 babies were born, resulting in live birth rates of 14.9% per embryo and 22.7% per patient. In conclusion, our data show that in the aCGH group, the use of aneuploidy screening resulted in a significantly higher live birth rate compared with the control group, supporting the benefit of PGS for IVF couples in addition to the suitability and effectiveness of our polar body pooling strategy.

To Assess the Association between Glucose Metabolism and Ectopic Lipid Content in Different Clinical Classifications of PCOS.

Aims There are emerging data indicating an association between PCOS (polycystic ovary syndrome) and metabolic derangements with potential impact on its clinical presentation. This study aims to evaluate the pathophysiological processes beyond PCOS with particular focus on carbohydrate metabolism, ectopic lipids and their possible interaction. Differences between the two established classifications of the disease should be additionally evaluated. Methods A metabolic characterization was performed in 53 untreated PCOS patients as well as 20 controls including an extended oral glucose tolerance test (OGTT, to assess insulin sensitivity, secretion and ß-cell function) in addition to a detailed examination of ectopic lipid content in muscle and liver by nuclear magnetic resonance spectroscopy. Results Women with PCOS classified by the original NIH 1990 definition showed a more adverse metabolic risk profile compared to women characterized by the additional Rotterdam 2003 phenotypes. Subtle metabolic derangements were observed in both subgroups, including altered shapes of OGTT curves, impaired insulin action and hyperinsulinemia due to increased secretion and attenuated hepatic extraction. No differences were observed for ectopic lipids between the groups. However, particularly hepatocellular lipid content was significantly related to clinical parameters of PCOS like whole body insulin sensitivity, dyslipidemia and free androgen index. Conclusions Subtle alterations in carbohydrate metabolism are present in both PCOS classifications, but more profound in subjects meeting the NIH 1990 criteria. Females with PCOS and controls did not differ in ectopic lipids, however, liver fat was tightly related to hyperandrogenism and an adverse metabolic risk profile.