Impact of Pregnancy on the Pharmacokinetics and Metabolism of Nicotinamide in Humans.

In pre-eclampsia models, nicotinamide (NAM) has protective effects in pre-eclampsia and is being evaluated as a therapeutic nutraceutical in clinical studies. NAM undergoes extensive hepatic metabolism by NAM N-methyltransferase to methylnicotinamide (MNA), which is subsequently metabolized to methyl-2-pyridone-5-carboxamide (M2PY) by aldehyde oxidase. However, the pharmacokinetics of NAM and its major metabolites has never been studied in pregnant individuals. Blood samples were collected before and 1, 2, 4, 8, and 24 hours after single 1 g oral NAM dose in healthy pregnant (gestational age 24-33 weeks) and nonpregnant female volunteers (n = 6/group). Pooled urine was collected from 0 to 8 hours. NAM, MNA, and M2PY area under the concentration-time curve (AUC) data were analyzed by noncompartmental analysis. No difference in the plasma AUC0→24 of NAM (median (25%-75%): 463 (436-576) vs. 510 (423, 725) µM*hour, P = 0.430) and its intermediate metabolite MNA (89.1 (60.4, 124.4) vs. 83.8 (62.7, 93.7) µM*hour, P = 0.515) was observed in pregnant and nonpregnant volunteers, respectively; however, the terminal metabolite M2PY AUC0 → 24 was significantly lower in pregnant individuals (218 (188, 254) vs. 597 (460, 653) µM*hour, P < 0.001). NAM renal clearance (CLR ; P = 0.184), MNA CLR (P = 0.180), and total metabolite formation clearance (P = 0.405) did not differ across groups; however, M2PY CLR was significantly higher in pregnant individuals (10.5 (9.3-11.3) vs. 7.5 (6.4-8.5) L/h, P = 0.002). These findings demonstrate that the PK of NAM and systemic exposure to its intermediate metabolite MNA are not significantly altered during pregnancy, and systemic exposure to NAM's major metabolite M2PY was reduced during pregnancy due to increased renal elimination.

Rationale, design, and methods for the Medical Optimization and Management of Pregnancies with Overt Type 2 Diabetes (MOMPOD) study.

BACKGROUND: Annually in the US, over 100,000 pregnant women with overt type 2 diabetes give birth. Strict maternal glycemic control is the key to optimizing infant outcomes. Medical treatment of type 2 diabetes in pregnancy is generally restricted to insulin, as data on the safety and efficacy of oral hypoglycemic agents in pregnancy are limited. However, over one-third of infants born to women with type 2 diabetes experience an adverse outcome, such as premature delivery, large-for-gestational age, hypoglycemia, hyperbilirubinemia, or birth trauma, suggesting that current treatment regimens fall short of optimizing outcomes. Metformin is the pharmacologic treatment of choice for type 2 diabetes outside of pregnancy. Metformin is favored over insulin because it results in less weight gain, fewer hypoglycemic episodes, and is administered orally rather than injected. However, metformin is not typically used for treatment of type 2 diabetes complicating pregnancy, mainly because no large clinical studies have been conducted to examine its use in this context. METHODS/DESIGN: This is a randomized double-blind multi-center clinical trial of insulin plus metformin versus insulin plus placebo for the treatment of type 2 diabetes complicating pregnancy. A total of 1200 women with type 2 diabetes will be randomized between 10 weeks 0 days' and 20 weeks 6 days' gestation and followed until 30 days after delivery. Neonate outcomes will be followed until 30 days of age. The primary aim is to compare the effect of insulin and metformin versus insulin and placebo on composite adverse neonatal outcomes, comprising perinatal mortality, preterm delivery, neonatal hypoglycemia, hyperbilirubinemia, large-for-gestational age small for gestational age, low birth weight, and/or birth trauma. Key secondary aims are to compare treatment groups for neonatal fat mass and rate of maternal hypoglycemia. Additional aims are to assess the side effects and safety of insulin and metformin among pregnant women with overt type 2 diabetes and to compare gestational weight gain among women treated with metformin plus insulin versus insulin alone. DISCUSSION: Successful completion of this study will result in high-quality, contemporary evidence for management of overt type 2 diabetes complicating pregnancy to improve neonatal outcomes. TRIAL REGISTRATION: NCT02932475 (05/17/2016).

Identification of Epigenetic Factor Proteins Expressed in Human Embryonic Stem Cell-Derived Trophoblasts and in Human Placental Trophoblasts.

Human embryonic stem cells (hESCs) have been used to derive trophoblasts through differentiation in vitro. Intriguingly, mouse ESCs are prevented from differentiation to trophoblasts by certain epigenetic factor proteins such as Dnmt1, thus necessitating the study of epigenetic factor proteins during hESC differentiation to trophoblasts. We used stable isotope labeling by amino acids in cell culture and quantitative proteomics to study changes in the nuclear proteome during hESC differentiation to trophoblasts and identified changes in the expression of 30 epigenetic factor proteins. Importantly, the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B were downregulated. Additionally, we hypothesized that nuclear proteomics of hESC-derived trophoblasts may be used for screening epigenetic factor proteins expressed by primary trophoblasts in human placental tissue. Accordingly, we conducted immunohistochemistry analysis of six epigenetic factor proteins identified from hESC-derived trophoblasts-DNMT1, DNMT3B, BAF155, BAF60A, BAF57, and ING5-in 6-9 week human placentas. Indeed, expression of these proteins was largely, though not fully, consistent with that observed in 6-9 week placental trophoblasts. Our results support the use of hESC-derived trophoblasts as a model for placental trophoblasts, which will enable further investigation of epigenetic factors involved in human trophoblast development.

Rationale, design, and methodology for the optimizing outcomes in women with gestational diabetes mellitus and their infants study.

BACKGROUND: Women who are diagnosed with gestational diabetes mellitus (GDM) are at increased risk for developing prediabetes and type 2 diabetes mellitus (T2DM). To date, there have been few interdisciplinary interventions that target predominantly ethnic minority low-income women diagnosed with GDM. This paper describes the rationale, design and methodology of a 2-year, randomized, controlled study being conducted in North Carolina. METHODS/DESIGN: Using a two-group, repeated measures, experimental design, we will test a 14- week intensive intervention on the benefits of breastfeeding, understanding gestational diabetes and risk of progression to prediabetes and T2DM, nutrition and exercise education, coping skills training, physical activity (Phase I), educational and motivational text messaging and 3 months of continued monthly contact (Phase II). A total of 100 African American, non-Hispanic white, and bilingual Hispanic women between 22-36 weeks of pregnancy who are diagnosed with GDM and their infants will be randomized to either the experimental group or the wait-listed control group. The first aim of the study is to determine the feasibility of the intervention. The second aim of study is to test the effects of the intervention on maternal outcomes from baseline (22-36 weeks pregnant) to 10 months postpartum. Primary maternal outcomes will include fasting blood glucose and weight (BMI) from baseline to 10 months postpartum. Secondary maternal outcomes will include clinical, adiposity, health behaviors and self-efficacy outcomes from baseline to 10 months postpartum. The third aim of the study is to quantify the effects of the intervention on infant feeding and growth. Infant outcomes will include weight status and breastfeeding from birth through 10 months of age. Data analysis will include general linear mixed-effects models. Safety endpoints include adverse event reporting. DISCUSSION: Findings from this trial may lead to an effective intervention to assist women diagnosed with GDM to improve maternal glucose homeostasis and weight as well as stabilize infant growth trajectory, reducing the burden of metabolic disease across two generations. TRIAL REGISTRATION: NCT01809431.