Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

The childhood obesity epidemic is expected to increase cardiovascular disease risk, but the impact of obesity on vascular function in children is not fully understood. The purpose of this study was to determine the effect of obesity and maturation on vascular function in normal weight (BMI: 25–75 percentile) and obese (BMI: ≥95 percentile) children ages 8–18 years old. Large and small artery elasticity (LAEI and SAEI, respectively), measured by diastolic radial pulsewave contour analysis, and reactive hyperemia index (RHI), measured by peripheral arterial tonometry, were obtained, along with anthropometric and biochemical outcomes, in 61 normal weight and 62 obese children. SAEI and LAEI increased with age and were 30% and 18% higher, respectively, in obese children (P < 0.01). In contrast, reactive hyperemia increased with age in the normal weight group but did not differ between groups. Multivariate modeling was used to select variables that explained differences in vascular outcomes. The best model for LAEI in normal weight children was height alone (r2 = 0.49), whereas for obese children the best model included height + fat mass (r2 = 0.40). For SAEI, there were no significant models for normal weight children, but for obese children the best model included lean mass + fat mass (r2 = 0.36). Obese children had greater lean and fat mass, and more advanced Tanner stages than their normal weight peers. The increased elasticity observed in obese children appears to reflect accelerated growth and maturation without affecting vascular reactivity measured by reactive hyperemia. Longitudinal follow up will be essential in determining effects on future vascular disease risk.

Summary With the rise in childhood obesity, type 2 diabetes mellitus (T2DM) has been recognized to occur in adolescents with increasing frequency. Although much is known about T2DM in adults, few studies have examined the treatment and complications of T2DM in youth. The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study was designed to evaluate the efficacy of various treatments and provided a unique opportunity to study the disease progression and appearance of complications in a pediatric cohort with recent onset of the disease. In the TODAY study, hypertension was present in 11.6% of the population at baseline and increased to 33.8% by the end of the study. Prevalence of high-risk LDL-cholesterol rose from 4.5% at baseline to 10.7% at the end of the study. Microalbuminuria was found in 6.3% of the cohort at baseline and increased to 16.6%. Retinopathy was not assessed upon entry into TODAY, but was present in 13.9% of the TODAY cohort at the end of the study. Experience to date indicates that these complications and comorbidities are similar to that seen in adults, but occur on an accelerated timeline. The early manifestation of diabetes complications in youth-onset T2DM suggests that this group will be burdened with the tangible consequences of cardiovascular disease, nephropathy, and retinopathy in the third and fourth decades of life. It is hoped that through an early, aggressive approach to treatment and prevention, we may be able to curb the onset and progression of these potentially devastating outcomes.

To determine whether prior type 2 diabetes (T2D) treatment or glycemic control over time are independently associated with heart rate variability (HRV) and whether the presence of cardiac autonomic dysfunction is associated with arterial stiffness in young adults with youth-onset T2D enrolled in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. RESEARCH DESIGN AND METHODS Heartbeats over 10 min were measured to derive the normal R-Rs (NN intervals). Outcomes included the standard deviation of the NN intervals (SDNN), the root mean square differences of successive NN intervals (RMSSD), percent of NN beats that differ by more than 50 ms (PNN50), and the low-frequency (LF) power domain, high-frequency (HF) power domain, and their ratio (LF:HF). Autonomic dysfunction was defined as ‡3 of 5 abnormal HRV indices compared with obese controls from a separate study. RESULTS A total of 397 TODAY participants were evaluated 7 years after randomization. TODAY participants had reduced HRV (SDNN 58.1 6 29.6 ms vs. controls 67.1 6 25.4 ms; P < 0.0001) with parasympathetic loss (RMSSD 53.2 6 36.7 ms vs. controls 67.9 6 35.2 ms; P < 0.0001) with sympathetic overdrive (LF:HF ratio 1.4 6 1.7 vs. controls 1.0 6 1.1; P < 0.0001). Cardiac autonomic dysfunction was present in 8% of TODAY participants, and these participants had greater pulse wave velocity compared with those without dysfunction (P 5 0.0001). HRV did not differ by randomized treatment, but higher hemoglobin A1c (HbA 1c) over time was independently associated with lower SDNN and RMSSD and higher LF:HF ratio after adjustment for age, race-ethnicity, sex, and BMI. CONCLUSIONS Young adults with youth-onset T2D show evidence of cardiac autonomic dysfunction with both parasympathetic and sympathetic impairments that are associated with higher HbA 1c .

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.

Obese youth without diabetes with monophasic oral glucose tolerance test (OGTT) glucose response curves have lower insulin sensitivity and impaired b-cell function compared with those with biphasic curves. The OGTT glucose response curve has not been studied in youth-onset type 2 diabetes. Here we test the hypothesis that the OGTT glucose response curve at randomization in youth in the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study forecasts heightened glycemic failure rates and accelerated decline in b-cell function. RESEARCH DESIGN AND METHODS OGTTs (n = 662) performed at randomization were categorized as monophasic, biphasic, or incessant increase. Demographics, insulin sensitivity (1/fasting insulin), C-peptide index (4C 30 /4G 30), and b-cell function relative to insulin sensitivity (oral disposition index [oDI]) were compared among the three groups. RESULTS At randomization, 21.7% had incessant increase, 68.6% monophasic, and 9.7% biphasic glucose response curves. The incessant increase group had similar insulin sensitivity but significantly lower C-peptide index and lower oDI, despite similar diabetes duration, compared with the other two groups. Glycemic failure rates were higher in the incessant increase group (58.3%) versus the monophasic group (42.3%) versus the biphasic group (39.1%) (P < 0.0001). The 6-month decline in C-peptide index (32.8% vs. 18.1% vs. 13.2%) and oDI (32.2% vs. 11.6% vs. 9.1%) was greatest in incessant increase versus monophasic and biphasic with no difference in insulin sensitivity. CONCLUSIONS In the TODAY study cohort, an incessant increase in the OGTT glucose response curve at randomization reflects reduced b-cell function and foretells increased glycemic failure rates with accelerated deterioration in b-cell function independent of diabetes duration and treatment assignment compared with monophasic and biphasic curves. The shape of the OGTT glucose response curve could be a metabolic biomarker prognosticating the response to therapy in youth with type 2 diabetes.

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Abnormal placental function in maternal diabetes affects fetal health and can predispose offspring to metabolic diseases in later life. There are fetal sex-specific differences in placenta structure and gene expression, which may affect placental responses to maternal diabetes. The present study examined the effects of maternal diabetes on indices of mitochondrial biogenesis in placentae from male and female offspring. Mitochondrial DNA (mtDNA) copy number and expression of key regulators of mitochondrial biogenesis were assessed in placentae from 19 diabetic and 23 non-diabetic women. The abundance of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and mitochondria transcription factor A (TFAM) were lower in female placentae compared to males, but not mtDNA content. In male offspring, maternal diabetes was associated with decreased placental PGC-1α and TFAM, and mitochondrial DNA (mtDNA) content. Male placental TFAM levels were highly correlated with PGC-1α and mtDNA content. However, despite decreased PGC-1α, concomitant changes in TFAM and mtDNA content by diabetes were not observed in females. In addition, TFAM abundance in female placentae was not correlated with PGC-1α or mtDNA content. In summary, placental PGC-1α/TFAM/mitochondrial biogenesis pathway is affected by maternal diabetes and offspring sex. Decreased PGC-1α in response to maternal diabetes plausibly contributes to impaired mitochondrial biogenesis in placentae of male offspring, which may affect long-term health and explain some of enhanced risk of future metabolic diseases in males.