Bone Mass Accrual in First Six Months of Life: Impact of Maternal Diabetes, Infant Adiposity, and Cord Blood Adipokines.

The perinatal period is a time of substantial bone mass accrual with many factors affecting long-term bone mineralization. Currently it is unclear what effect maternal gestational/type 2 diabetes has on infant bone mass accrual. This is a prospective study of offspring of Native American and Hispanic mothers with normoglycemia (n = 94) and gestational diabetes or type 2 diabetes (n = 64). Infant anthropometrics were measured at birth, 1, and 6 months of age. Cord blood leptin, high-molecular weight adiponectin (HMWA), pigment epithelium-derived factor (PEDF), vascular epithelium growth factor (VEGF), endoglin, and C-peptide were measured by ELISA. Infants had bone mineral density measurement at 1 month or/and 6 months of age using dual-energy x-ray absorptiometry scan. Mothers with diabetes were older (31 ± 6 years vs 25 ± 4 years) and had higher pre-pregnancy BMI (32.6 ± 5.8 vs 27.2 ± 6.4 kg/m2) than control mothers. Mean HbA1C of mothers with diabetes was 5.9 ± 1.0% compared to 5.1 ± 0.3% in controls early in pregnancy. Infants born to mothers with diabetes (DM-O) were born at a slightly lower gestational age compared to infants born to control mothers (Con-O). There was no difference in total body less head bone mineral content (BMC) or bone mineral density (BMD) between DM-O and Con-O. For both groups together, bone area, BMD, and BMC tracked over the first 6 months of life (r: 0.56, 0.38, and 0.48, respectively). Percent fat was strongly and positively correlated with BMC at 1 month of age (r = 0.44; p < 0.001) and BMC at both 1 and 6 months of age correlated strongly with birth weight. There were no associations between infant bone mass and cord blood leptin, PEDF, or VEGF, while C-peptide had a significant correlation with BMC at 1 and 6 months only in DM-O (p = 0.01 and 0.03, respectively). Infants born to mothers with well-controlled gestational/type 2 diabetes have normal bone mass accrual. Bone mineral content during this time is highly correlated with indices of infant growth and the association of bone mineral indices with percent body fat suggests that bone-fat crosstalk is operative early in life.

Maternal diabetes alters microRNA expression in fetal exosomes, human umbilical vein endothelial cells and placenta.

BACKGROUND: Exposure to diabetes in utero influences future metabolic health of the offspring. MicroRNAs (miRNA) are small noncoding RNAs that may contribute mechanistically to the effects on offspring imparted by diabetes mellitus (DM) during pregnancy. We hypothesized that exposure to DM during pregnancy influences select miRNAs in fetal circulation, in human umbilical vein endothelial cells (HUVEC), and placenta. METHODS: miRNA abundance was quantified using real-time PCR from RNA isolated from umbilical cord serum exosomes, HUVEC, and placenta exposed to diabetes or normoglycemia during pregnancy. The abundance of each of these miRNAs was determined by comparison to a known standard and the relative expression assessed using the 2-ΔΔCt method. Multivariable regression models examined the associations between exposure to diabetes during pregnancy and miRNA expression. RESULTS: miR-126-3p was highly abundant in fetal circulation, HUVEC, and placenta. Diabetes exposure during pregnancy resulted in lower expression of miR-148a-3p and miR-29a-3p in the HUVEC. In the placenta, for miR-126-3p, there was a differential effect of DM by birth weight between DM versus control group, expression being lower at the lower birth weight, however not different at the higher birth weight. CONCLUSION: Exposure to DM during pregnancy alters miRNA expression in the offspring in a tissue-specific manner. IMPACT: miRNAs are differentially expressed in fetal tissues from offspring exposed to in utero diabetes mellitus compared to those who were not exposed. miRNA expression differs among tissue types (human umbilical vein endothelial cells, placenta and circulation exosomes) and response to diabetes exposure varies according to tissue of origin. miRNA expression is also affected by maternal and infant characteristics such as infant birth weight, infant sex, maternal age, and maternal BMI. miRNAs might be one of the potential mechanisms by which offspring's future metabolic status may be influenced by maternal diabetes mellitus.

Fetal circulating human resistin increases in diabetes during pregnancy and impairs placental mitochondrial biogenesis.

BACKGROUND: Diabetes during pregnancy affects placental mitochondrial content and function, which has the potential to impact fetal development and the long-term health of offspring. Resistin is a peptide hormone originally discovered in mice as an adipocyte-derived factor that induced insulin resistance. In humans, resistin is primarily secreted by monocytes or macrophages. The regulation and roles of human resistin in diabetes during pregnancy remain unclear. METHODS: Fetal resistin levels were measured in cord blood from pregnancies with (n = 42) and without maternal diabetes (n = 81). Secretion of resistin from cord blood mononuclear cells (CBMCs) was measured. The actions of human resistin in mitochondrial biogenesis were determined in placental trophoblastic cells (BeWo cells) or human placental explant. RESULTS: Concentrations of human resistin in cord sera were higher in diabetic pregnancies (67 ng/ml) compared to healthy controls (50 ng/ml, P < 0.05), and correlated (r = 0.4, P = 0.002) with a measure of maternal glycemia (glucose concentration 2 h post challenge). Resistin mRNA was most abundant in cord blood mononuclear cells (CBMCs) compared with placenta and mesenchymal stem cells (MSCs). Secretion of resistin from cultured CBMCs was increased in response to high glucose (25 mM). Exposing BeWo cells or human placental explant to resistin decreased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial abundance, and ATP production. CONCLUSIONS: Resistin is increased in fetal circulation of infants exposed to the diabetic milieu, potentially reflecting a response of monocytes/macrophages to hyperglycemia and metabolic stresses associated with diabetes during pregnancy. Increased exposure to resistin may contribute to mitochondrial dysfunction and aberrant energy metabolism characteristic of offspring exposed to diabetes in utero.

Beta cell function and insulin sensitivity in obese youth with maturity onset diabetes of youth mutations vs type 2 diabetes in TODAY: Longitudinal observations and glycemic failure.

OBJECTIVE: In treatment options for type 2 diabetes in adolescents and youth (TODAY), 4.5% of obese youth clinically diagnosed with type 2 diabetes (T2D) had genetic variants consistent with maturity onset diabetes of youth (MODY) diagnosis. The course of IS and ß-cell function in obese youth with MODY remains unknown. In this secondary analysis, we examined IS and ß-cell function in MODY vs. non-MODY obese youth at randomization and over time. METHODS: Genetic data in TODAY included 426 non-MODY (T2D) and 22 MODY youth (7 glucokinase MODY mutation positive [GCK-MODY], 12 hepatocyte nuclear factor MODY mutation positive [HNF-MODY], 2 Insulin gene mutation [insulin (INS)-MODY], and 1 Kruppel-like factor 11 [KLF11-MODY]). Oral glucose tolerance test (OGTT)-derived IS, C-peptide index, and ß-cell function relative to IS oral disposition index (oDI) was measured at randomization, and over 24 months in addition to total and high-molecular-weight adiponectin (HMWA). RESULTS: At randomization, IS, total adiponectin, and HMWA were significantly higher in the two MODY groups than in non-MODY. ß-cell function measured by C-peptide oDI was 3-fold higher in GCK-MODY than in HNF-MODY and 1.5-fold higher than non-MODY (P for both <.05). Glycemic failure rate was 75.0% in HNF-MODY, 46.9% in non-MODY, and zero in GCK-MODY youth. While the changes in IS and oDI were not different among the three groups in the first 6 months, IS improved from 6 to 24 months in HNF-MODY vs GCK-MODY youth. CONCLUSIONS: In TODAY, ß-cell function at randomization was worse in obese HNF-MODY youth compared with GCK-MODY youth, while insulin sensitivity was worse in non-MODY compared with the other two MODY groups. Over time, IS showed the greatest improvement in HNF-MODY youth. This raises the possibility that TODAY therapeutic modalities of insulin sensitization in these obese HNF-MODY youth may have played a beneficial role.

Role of microRNA-130b in placental PGC-1α/TFAM mitochondrial biogenesis pathway.

Diabetes during pregnancy is associated with abnormal placenta mitochondrial function and increased oxidative stress, which affect fetal development and offspring long-term health. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis and energy metabolism. The molecular mechanisms underlying the regulation of PGC-1α in placenta in the context of diabetes remain unclear. The present study examined the role of microRNA 130b (miR-130b-3p) in regulating PGC-1α expression and oxidative stress in a placental trophoblastic cell line (BeWo). Prolonged exposure of BeWo cells to high glucose mimicking hyperglycemia resulted in decreased protein abundance of PGC-1α and its downstream factor, mitochondrial transcription factor A (TFAM). High glucose treatment increased the expression of miR-130b-3p in BeWo cells, as well as exosomal secretion of miR-130b-3p. Transfection of BeWo cells with miR-130b-3p mimic reduced the abundance of PGC-1α, whereas inhibition of miR-130b-3p increased PGC-1α expression in response to high glucose, suggesting a role for miR-130b-3p in mediating high glucose-induced down regulation of PGC-1α expression. In addition, miR-130b-3p anti-sense inhibitor increased TFAM expression and reduced 4-hydroxynonenal (4-HNE)-induced production of reactive oxygen species (ROS). Taken together, these findings reveal that miR-130b-3p down-regulates PGC-1α expression in placental trophoblasts, and inhibition of miR-130b-3p appears to improve mitochondrial biogenesis signaling and protect placental trophoblast cells from oxidative stress.

Influence of gestational diabetes mellitus on human umbilical vein endothelial cell miRNA.

We aimed to identify miRNAs whose expression levels in fetal tissues are altered by exposure to a diabetic milieu and elucidate the impact on target protein expression. Gestational diabetes mellitus (GDM) affects both immediate and future disease risk in the offspring. We hypothesized that GDM alters miRNA expression in human umbilical vein endothelial cells (HUVECs) that may influence metabolic processes. A cross-sectional design compared differences in miRNA expression in HUVECs and target protein abundance in placentae between infants of women with GDM (IGDM) and infants born to normoglycaemic controls. miRNAs were identified using microarray profiling and literature review and validated by quantitative PCR (qPCR). In vitro transfection studies explored the impact of the miRNA on target protein expression. Expression of seven miRNA species, miR-30c-5p, miR-452-5p, miR-126-3p, miR-130b-3p, miR-148a-3p, miR-let-7a-5p and miR-let-7g-5p, was higher in the HUVECs of IGDM. Abundance of the catalytic subunit of AMP-activated protein kinase α1 (AMPKα1) was decreased in the HUVECs and BeWo cells (transformed trophoblast cell line) transfected with miR-130b and miR-148a mimics. AMPKα1 expression was also decreased in placental tissues of IGDM. The expression of several miRNAs were altered by in utero exposure to DM in infants of women whose dysglycaemia was very well controlled by current standards. Decreased expression of AMPKα1 as a result of increased levels of miR-130b and miR-148a may potentially explain the decrease in fat oxidation we reported in infants at 1 month of age and, if persistent, may predispose offspring to future metabolic disease.

Lower resting energy expenditure and fat oxidation in Native American and Hispanic infants born to mothers with diabetes.

OBJECTIVE: To determine whether exposure to diabetes in utero affects resting energy expenditure (REE) and fuel oxidation in infants. STUDY DESIGN: At 35 ± 5 days after birth, body composition and REE were measured in full-term offspring of Native American and Hispanic women with either well-controlled diabetes (13 girls, 11 boys) or normal healthy pregnancies (18 girls, 17 boys). RESULTS: Control of dysglycemia during gestation in the women with diabetes mellitus met current clinical standards, shown by average glycated hemoglobin (5.9 ± 0.2%; 40.6 ± 2.3 mmol/mol). Infant body mass (offspring of women with diabetes: 4.78 ± 0.13, control offspring: 4.56 ± 0.08 kg) and body fatness (offspring of women with diabetes: 25.2 ± 0.6, control offspring: 24.2 ± 0.5 %) did not differ between groups. REE, adjusted for lean body mass, was 14% lower in offspring of women with diabetes (41.7 ± 2.3 kJ/h) than control offspring (48.6 ± 2.0, P = .025). Fat oxidation was 26% lower in offspring of women with diabetes (0.54 ± 0.05 g/h) than control offspring (0.76 ± 0.04, P < .01) but carbohydrate oxidation did not differ. Thus, fat oxidation accounted for a lower fraction of REE in the offspring of women with diabetes (49 ± 4%) than control offspring (60 ± 3%, P = .022). Mothers with diabetes were older and had higher prepregnancy body mass index than control mothers. CONCLUSIONS: Well-controlled maternal diabetes did not significantly affect body mass or composition of offspring at 1-month old. However, infants with mothers with diabetes had reduced REE and fat oxidation, which could contribute to adiposity and future disease risk. Further studies are needed to assess the impact differences in age and higher prepregnancy body mass index.

Cord blood adipokines, neonatal anthropometrics and postnatal growth in offspring of Hispanic and Native American women with diabetes mellitus.

BACKGROUND: Offspring of women with diabetes mellitus (DM) during pregnancy have a risk of developing metabolic disease in adulthood greater than that conferred by genetics alone. The mechanisms responsible are unknown, but likely involve fetal exposure to the in utero milieu, including glucose and circulating adipokines. The purpose of this study was to assess the impact of maternal DM on fetal adipokines and anthropometry in infants of Hispanic and Native American women. METHODS: We conducted a prospective study of offspring of mothers with normoglycemia (Con-O; n = 79) or type 2 or gestational DM (DM-O; n = 45) pregnancies. Infant anthropometrics were measured at birth and 1-month of age. Cord leptin, high-molecular-weight adiponectin (HMWA), pigment epithelium-derived factor (PEDF) and C-peptide were measured by ELISA. Differences between groups were assessed using the Generalized Linear Model framework. Correlations were calculated as standardized regression coefficients and adjusted for significant covariates. RESULTS: DM-O were heavier at birth than Con-O (3.7 ± 0.6 vs. 3.4 ± 0.4 kg, p = 0.024), but sum of skinfolds (SSF) were not different. At 1-month, there was no difference in weight, SSF or % body fat or postnatal growth between groups. Leptin was higher in DM-O (20.1 ± 14.9 vs. 9.5 ± 9.9 ng/ml in Con-O, p < 0.0001). Leptin was positively associated with birth weight (p = 0.0007) and SSF (p = 0.002) in Con-O and with maternal hemoglobin A1c in both groups (Con-O, p = 0.023; DM-O, p = 0.006). PEDF was positively associated with birth weight in all infants (p = 0.004). Leptin was positively associated with PEDF in both groups, with a stronger correlation in DM-O (p = 0.009). At 1-month, HMWA was positively associated with body weight (p = 0.004), SSF (p = 0.025) and % body fat (p = 0.004) across the cohort. CONCLUSIONS: Maternal DM results in fetal hyperleptinemia independent of adiposity. HMWA appears to influence postnatal growth. Thus, in utero exposure to DM imparts hormonal differences on infants even without aberrant growth.

Proceedings from the Turner Resource Network symposium: the crossroads of health care research and health care delivery.

Turner syndrome, a congenital condition that affects ∼1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals. The inaugural "Turner Resource Network (TRN) Symposium" brought together individuals with Turner syndrome and their families, advocacy group leaders, clinicians, basic scientists, physician-scientists, trainees and other stakeholders with interest in the well-being of individuals and families living with the condition. The goal of this symposium was to establish a structure for a TRN that will be a patient-powered organization involving those living with Turner syndrome, their families, clinicians, and scientists. The TRN will identify basic and clinical questions that might be answered with registries, clinical trials, or through bench research to promote and advocate for best practices and improved care for individuals with Turner syndrome. The symposium concluded with the consensus that two rationales justify the creation of a TRN: inadequate attention has been paid to the health and psychosocial issues facing girls and women who live with Turner syndrome; investigations into the susceptibility to common disorders such as cardiovascular or autoimmune diseases caused by sex chromosome deficiencies will increase understanding of disease susceptibilities in the general population.

Adequacy of Infant Formula With Protein Content of 1.6 g/100 kcal for Infants Between 3 and 12 Months.

OBJECTIVES: Infant formulas provide more protein than breast milk. High protein intakes may place infants at risk of later obesity. The present study tested whether a formula with protein content below the regulatory level supports normal growth from age 3 months. METHODS: Randomized double-blind trial enrolled healthy infants less than age 3 months. At 3 months, formula-fed infants were assigned to experimental (EXPL, 1.61 g protein/100 kcal; modified bovine whey proteins with caseinoglycomacropeptide removed) or control (CTRL 2.15 g protein/100 kcal; unmodified bovine milk protein with a whey/casein ratio of 60/40) formula; breast-fed (BF) infants were enrolled in a reference group. Complementary foods were allowed in small amounts from 4 to 6 months and unrestricted after 6 months. RESULTS: Weight gain (g/day) from 3 to 6 months was similar in the EXPL and CTRL groups (EXPL-CTRL -0.84 g/day; 95% confidence interval -2.25 to 0.57) and faster in the EXPL and CTRL groups than in the BF group. Weight analyzed longitudinally from 4 to 12 months was lower in the EXPL group than in the CTRL group (P = 0.031) but higher than in the BF group (P < 0.0001). Longitudinal analysis of odds ratios from 4 to 12 months indicated fewer infants with weight >85th percentile in the EXPL group than in the CTRL group (P = 0.015). Length z scores were lower than, and body mass index z scores were similar to, World Health Organization Standards in all of the groups. Serum biochemical parameters in the EXPL group reflected lower protein intake and were closer to parameters in the BF infants than in the CTRL group. CONCLUSIONS: A formula with 1.61 g of protein/100 kcal supports normal growth of infants after age 3 months. This protein content is adequate if provided from a high-quality source.

Circulating MicroRNAs as Predictors of Beta Cell Function in Youth-Onset Type 2 Diabetes: The TODAY study.

AIMS: In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, an intervention trial followed by an observational phase, half the participants reached the primary outcome (HbA1c ≥ 8% for at least 6 months) within 4 years which was associated with a decrease in C-peptide oral disposition index (oDI). We aimed to identify circulating miRNA species associated with decline in beta cell function. METHODS: Following a preliminary survey of select participants using nCounter Human v3 miRNA Panel (NanoString Technologies), polymerase chain reaction analyses were carried out for 17 miRNAs from 365 participants from samples at baseline, 24, 60, 96, and 120 months. RESULTS: Using a backward selection approach, four baseline miRNA log2 fold changes independently predicted treatment failure; however, baseline HbA1c was higher in those with treatment failure. Three baseline miRNA log2 fold changes remained significant predictors of this C-peptide oDI decline ≥20% (p < 0.05). Increased levels of miRNA-155 (OR:1.2, 95%CI:1.1-1.4) and miRNA-130b (OR:1.3, 95%CI: 1.0-1.7) were associated with oDI decline, while decreased levels of miRNA-126 (OR:0.6, 95%CI: 0.4-0.8) were associated with oDI decline. miRNA-122 was negatively correlated with C-peptide oDI at baseline and 24-months (R = 0.22, p < 0.01 and R = 0.19, p < 0.01, respectively), and positively correlated with proinsulin, at baseline, 24-, and 60- months (R = 0.26, p < 0.01, R = 0.26, p < 0.01, R = 0.18, p < 0.01, respectively). CONCLUSIONS: The miRNA species associated with beta cell function are associated with alterations in cellular metabolism and apoptosis, suggesting that differences in baseline abundance may serve as circulating markers of beta cell dysfunction and provide potential mechanistic insights into the aggressive nature of youth-onset type 2 diabetes.

Assessing the prediction of type 2 diabetes risk using polygenic and clinical risk scores in South Asian study populations.

Background: Genome-wide polygenic risk scores (PRS) have shown high specificity and sensitivity in predicting type 2 diabetes (T2D) risk in Europeans. However, the PRS-driven information and its clinical significance in non-Europeans are underrepresented. We examined the predictive efficacy and transferability of PRS models using variant information derived from genome-wide studies of Asian Indians (AIs) (PRSAI) and Europeans (PRSEU) using 13,974 AI individuals. Methods: Weighted PRS models were constructed and analyzed on 4602 individuals from the Asian Indian Diabetes Heart Study/Sikh Diabetes Study (AIDHS/SDS) as discovery/training and test/validation datasets. The results were further replicated in 9372 South Asian individuals from UK Biobank (UKBB). We also assessed the performance of each PRS model by combining data of the clinical risk score (CRS). Results: Both genetic models (PRSAI and PRSEU) successfully predicted the T2D risk. However, the PRSAI revealed 13.2% odds ratio (OR) 1.80 [95% confidence interval (CI) 1.63-1.97; p = 1.6 × 10-152] and 12.2% OR 1.38 (95% CI 1.30-1.46; p = 7.1 × 10-237) superior performance in AIDHS/SDS and UKBB validation sets, respectively. Comparing individuals of extreme PRS (ninth decile) with the average PRS (fifth decile), PRSAI showed about two-fold OR 20.73 (95% CI 10.27-41.83; p = 2.7 × 10-17) and 1.4-fold OR 3.19 (95% CI 2.51-4.06; p = 4.8 × 10-21) higher predictability to identify subgroups with higher genetic risk than the PRSEU. Combining PRS and CRS improved the area under the curve from 0.74 to 0.79 in PRSAI and 0.72 to 0.75 in PRSEU. Conclusion: Our data suggest the need for extending genetic and clinical studies in varied ethnic groups to exploit the full clinical potential of PRS as a risk prediction tool in diverse study populations.

Maternal Diabetes in Youth-Onset Type 2 Diabetes Is Associated With Progressive Dysglycemia and Risk of Complications.

CONTEXT: Prenatal exposures, including undernutrition, overnutrition, and parental diabetes, are recognized risk factors for future cardiometabolic disease. There are currently no data on effects of parental diabetes on disease progression or complications in youth-onset type 2 diabetes (T2D). OBJECTIVE: We analyzed effects of parental diabetes history on glycemic outcomes, ß-cell function, and complications in a US cohort of youth-onset T2D. METHODS: Participants (N = 699) aged 10 to 17 years with T2D were enrolled at 15 US centers and followed for up to 12 years as part of the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) and TODAY2 follow-up studies. Information about diabetes diagnosis in biological mothers was available for 621 participants (never = 301; before or during pregnancy = 218; after pregnancy = 102) and in biological fathers for 519 (no diabetes = 352; paternal diabetes = 167). RESULTS: Maternal, but not paternal, diabetes was associated with loss of glycemic control over time, defined as glycated hemoglobin A1c greater than or equal to 8% for more than 6 months (P = .001). Similarly, maternal, but not paternal, diabetes was associated with increased risk of glomerular hyperfiltration (P = .01) and low heart rate variability (P = .006) after 12 years of follow-up. Effects were largely independent of age, sex, race/ethnicity, and household income. Maternal diabetes during vs after pregnancy had similar effects on outcomes. CONCLUSION: Maternal diabetes, regardless of whether diagnosed during vs after pregnancy, is associated with worse glycemic control, glomerular hyperfiltration, and reduced heart rate variability in youth with T2D in TODAY. The strong associations of diabetes outcomes with maternal diabetes suggest a possible role for in utero programming.

Impact of youth onset type 2 diabetes during pregnancy on microvascular and cardiac outcomes.

AIMS: To examine the impact of pregnancy on microvascular and cardiovascular measures in women with youth-onset T2D. METHODS: Microvascular and cardiovascular measures were compared in in a cohort of 116 women who experienced a pregnancy of ≥ 20 weeks gestation and 291 women who did not among women in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. RESULTS: Cox regression models adjusted for participant characteristics at baseline including age, race/ethnicity, household income, diabetes duration, HbA1c (>6%), and BMI, demonstrated those who experienced pregnancy had 2.76 (1.38-5.49; p = 0.004) fold increased risk of hyperfiltration (eGFR ≥ 135 ml/min/1.73 m2), compared to those without a pregnancy. No differences were observed in rates of retinopathy (48.9% vs. 41.1%) or neuropathy (23.3% vs. 16.3%) in women who experienced pregnancy vs. women who did not, respectively. In fully adjusted models, pregnancy did not impact changes in echocardiographic or arterial stiffness compared to changes in women who were never pregnant. CONCLUSIONS: These results indicate that pregnancy increases the risk of hyperfiltration in women with youth-onset T2D, but not other micro or macrovascular complications. The rates of vascular complications are very high in youth-onset T2D potentially obscuring micro- and macrovascular changes attributable to pregnancy. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov numbers,NCT01364350andNCT02310724.

International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood.

This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.

Degree of external genital malformation at birth in children with a disorder of sex development and subsequent caregiver distress.

PURPOSE: We determined whether the degree of genital malformation at birth in children with a disorder of sex development is related to subsequent caregiver distress, specifically symptoms of depression and anxiety. MATERIALS AND METHODS: A total of 66 caregivers of children with disorders of sex development were recruited from 3 centers that specialize in disorders of sex development medicine. The caregivers completed the Beck Depression Inventory, 2nd Edition and the Beck Anxiety Inventory. The child's Prader score at birth was determined by the child's treating pediatric endocrinologist and/or pediatric urologist at each institution. RESULTS: Results from the current study revealed that for caregivers of male children, under masculinization of the child's genitals at birth was significantly related to higher levels of subsequent caregiver depression. In contrast, over masculinization of the genitals of female children at birth was unrelated to caregiver depression or anxiety. CONCLUSIONS: These findings suggest that caregivers of male children with disorders of sex development may be at increased risk for psychological distress and could benefit from family based psychosocial interventions.

miR-130b/301b Is a Negative Regulator of Beige Adipogenesis and Energy Metabolism In Vitro and In Vivo.

Thermogenic brown or beige adipocytes dissipate energy in the form of heat and thereby counteract obesity and related metabolic complications. The miRNA cluster miR-130b/301b is highly expressed in adipose tissues and has been implicated in metabolic diseases as a posttranscriptional regulator of mitochondrial biogenesis and lipid metabolism. We investigated the roles of miR-130b/301b in regulating beige adipogenesis in vivo and in vitro. miR-130b/301b declined in adipose progenitor cells during beige adipogenesis, while forced overexpression of miR-130b-3p or miR-301b-3p suppressed uncoupling protein 1 (UCP1) and mitochondrial respiration, suggesting that a decline in miR-130b-3p or miR-301b-3p is required for adipocyte precursors to develop the beige phenotype. Mechanistically, miR-130b/301b directly targeted AMP-activated protein kinase (AMPKα1) and suppressed peroxisome proliferator-activated receptor γ coactivator-1α (Pgc-1α), key regulators of brown adipogenesis and mitochondrial biogenesis. Mice lacking the miR-130b/301b miRNA cluster showed reduced visceral adiposity and less weight gain. miR-130b/301b null mice exhibited improved glucose tolerance, increased UCP1 and AMPK activation in subcutaneous fat (inguinal white adipose tissue [iWAT]), and increased response to cold-induced energy expenditure. Together, these data identify the miR-130b/301b cluster as a new regulator that suppresses beige adipogenesis involving PGC-1α and AMPK signaling in iWAT and is therefore a potential therapeutic target against obesity and related metabolic disorders.

TVs in the bedrooms of children: does it impact health and behavior?

OBJECTIVES: To (1) determine socio-demographic characteristics associated with a TV in the bedroom (BTV) and (2) examine relationship of BTV, independent of total viewing time, with social and behavioral characteristics. METHODS: Children 6-17 years from the 2007 US National Survey of Children's Health were included (n=48,687). BTV, daily TV viewing time, demographic, behavioral and social outcomes (community involvement, social skills, health habits and status, and family) were examined using logistic regression, and adjusted for total viewing time. RESULTS: Overall prevalence of BTV was 49.3% in American children. Older age, non-Hispanic Black (71.3%), Hispanics (56.3%), higher level of poverty (>56.2%), non two-parent biological family structure (>62.6%), Midwest (47.1%), Northeast (46.7%), South Atlantic (56.4%) and South Central (59.8%) region of the country were associated with higher odds of BTV. Female gender (52.7%) and residence in Alaska (33.0%) were associated with lower prevalence of BTV. BTV was associated with higher prevalence of exhibiting problematic social behaviors (29%) and overweight status (44%). BTV was significantly associated with lower prevalence of regular family meals (13%), engagement in school (16%), participation in extracurricular activities (31%), regularly sleeping enough (20%), and participation in community service (25%) after adjustment for total viewing time. CONCLUSIONS: BTV appears associated with more social and behavioral indices than previously reported, in addition to total viewing time.

Parenting characteristics of female caregivers of children affected by chronic endocrine conditions: a comparison between disorders of sex development and type 1 diabetes mellitus.

Rearing a child with a chronic illness is stressful and can potentially affect parenting style, which may result in poorer outcomes for children. The purpose of this study was to compare parenting characteristics of female caregivers rearing children with a disorder of sex development (DSD) to female caregivers rearing children with type 1 diabetes mellitus (T1DM). Caregivers of both groups were matched according to age and compared on measures of stress and parenting practices. Both groups demonstrated significant levels of stress and negative parenting practices. Children with T1DM and male children with non-life-threatening DSD were perceived as more vulnerable by their caregivers. Better understanding of parenting experiences of female caregivers rearing children with DSD, particularly male children, will facilitate the development of individualized interventions to ameliorate negative parenting practices and stress, with the long-term goal of improved health outcomes for their children.