Intergenerational Metabolomic Analysis of Mothers with a History of Gestational Diabetes Mellitus and Their Offspring.

Shared metabolomic patterns at delivery have been suggested to underlie the mother-to-child transmission of adverse metabolic health. This study aimed to investigate whether mothers with gestational diabetes mellitus (GDM) and their offspring show similar metabolomic patterns several years postpartum. Targeted metabolomics (including 137 metabolites) was performed in plasma samples obtained during an oral glucose tolerance test from 48 mothers with GDM and their offspring at a cross-sectional study visit 8 years after delivery. Partial Pearson's correlations between the area under the curve (AUC) of maternal and offspring metabolites were calculated, yielding so-called Gaussian graphical models. Spearman's correlations were applied to investigate correlations of body mass index (BMI), Matsuda insulin sensitivity index (ISI-M), dietary intake, and physical activity between generations, and correlations of metabolite AUCs with lifestyle variables. This study revealed that BMI, ISI-M, and the AUC of six metabolites (carnitine, taurine, proline, SM(-OH) C14:1, creatinine, and PC ae C34:3) were significantly correlated between mothers and offspring several years postpartum. Intergenerational metabolite correlations were independent of shared BMI, ISI-M, age, sex, and all other metabolites. Furthermore, creatinine was correlated with physical activity in mothers. This study suggests that there is long-term metabolic programming in the offspring of mothers with GDM and informs us about targets that could be addressed by future intervention studies.

Recruiting young pre-symptomatic children for a clinical trial in type 1 diabetes: Insights from the Fr1da insulin intervention study.

BACKGROUND: Although detection of children at high risk of developing type 1 diabetes and diagnosis of early stages is possible, up to now there exists no approved therapy to delay or prevent type 1 diabetes. Thus it is vital to develop evidence-based interventions. For this a sufficient number of trial participants is crucial but difficult to obtain especially in asymptomatic children. AIM: Identifying family characteristics that lead to or impede trial participation and analyze reasons stated by families for non-participation. METHODS: Participants for the Fr1da Insulin Intervention study are recruited from the Fr1da study, a population based screening for early stage type 1 diabetes in Bavaria. Families with eligible children were invited to enroll. We analyzed sex and age of the child, distance of the family to the study center in Munich and the existence of a first degree family member with type 1 as possible influential factors for study participation. We also analyzed reasons stated by families who declined study participation in a phone interview. RESULTS: Of 146 eligible children 77 (53%) were enrolled into the trial. None of the tested family characteristics differed significantly between the enrolling and the families not participating, but in general enrolling families lived closer to the study site than families not participating. This is also reflected in the reasons given by non-participating families. The most frequent reason stated were time restrictions. The second most frequent reason was the venous blood draw. CONCLUSION: The factors for non-participation identified in this project need be taken into account for the design of future trials in young children to ensure proper recruitment and thus to generate valid results for medical treatment of children. More research on the reason of participation and non-participation in clinical trials is needed.

Efficacy of vildagliptin for prevention of postpartum diabetes in women with a recent history of insulin-requiring gestational diabetes: A phase II, randomized, double-blind, placebo-controlled study.

OBJECTIVE: Women with insulin-requiring gestational diabetes mellitus (GDM) are at high risk of developing diabetes within a few years postpartum. We implemented this phase II study to test the hypothesis that vildagliptin, a dipeptidyl peptidase-4 inhibitor, is superior to placebo in terms of reducing the risk of postpartum diabetes. METHODS: Women with insulin-requiring GDM were randomized to either placebo or 50 mg vildagliptin twice daily for 24 months followed by a 12-month observation period (EudraCT: 2007-000634-39). Both groups received lifestyle counseling. The primary efficacy outcomes were the diagnosis of diabetes (American Diabetes Association (ADA) criteria) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT). RESULTS: Between 2008 and 2015, 113 patients (58 vildagliptin, 55 placebo) were randomized within 2.2-10.4 (median 8.6) months after delivery. At the interim analysis, nine diabetic events and 28 IFG/IGT events had occurred. Fifty-two women withdrew before completing the treatment phase. Because of the low diabetes rate, the study was terminated. Lifestyle adherence was similar in both groups. At 24 months, the cumulative probability of postpartum diabetes was 3% and 5% (hazard ratio: 1.03; 95% confidence interval: 0.15-7.36) and IFG/IGT was 43% and 22% (hazard ratio: 0.55; 95% confidence interval: 0.26-1.19) in the placebo and vildagliptin groups, respectively. Vildagliptin was well tolerated with no unexpected adverse events. CONCLUSIONS: The study did not show significant superiority of vildagliptin over placebo in terms of reducing the risk of postpartum diabetes. However, treatment was safe and suggested some improvements in glycemic control, insulin resistance, and ß-cell function. The study identified critical issues in performing clinical trials in the early postpartum period in women with GDM hampering efficacy assessments. With this knowledge, we have set a basis for which properly powered trials could be performed in women with recent GDM. TRIAL REGISTRATION NUMBER AT CLINICALTRIALS.GOV: NCT01018602.

Lactation is associated with altered metabolomic signatures in women with gestational diabetes.

AIMS/HYPOTHESIS: Lactation for >3 months in women with gestational diabetes is associated with a reduced risk of type 2 diabetes that persists for up to 15 years postpartum. However, the underlying mechanisms are unknown. We examined whether in women with gestational diabetes lactation for >3 months is associated with altered metabolomic signatures postpartum. METHODS: We enrolled 197 women with gestational diabetes at a median of 3.6 years (interquartile range 0.7-6.5 years) after delivery. Targeted metabolomics profiles (including 156 metabolites) were obtained during a glucose challenge test. Comparisons of metabolite concentrations and ratios between women who lactated for >3 months and women who lactated for ≤3 months or not at all were performed using linear regression with adjustment for age and BMI at the postpartum visit, time since delivery, and maternal education level, and correction for multiple testing. Gaussian graphical modelling was used to generate metabolite networks. RESULTS: Lactation for >3 months was associated with a higher total lysophosphatidylcholine/total phosphatidylcholine ratio; in women with short-term follow-up, it was also associated with lower leucine concentrations and a lower total branched-chain amino acid concentration. Gaussian graphical modelling identified subgroups of closely linked metabolites within phosphatidylcholines and branched-chain amino acids that were affected by lactation for >3 months and have been linked to the pathophysiology of type 2 diabetes in previous studies. CONCLUSIONS/INTERPRETATION: Lactation for >3 months in women with gestational diabetes is associated with changes in the metabolomics profile that have been linked to the early pathogenesis of type 2 diabetes.