Does maternal low-dose cadmium exposure increase the risk of offspring to develop metabolic syndrome and/or type 2 diabetes?

Cadmium is a hazardous metal with multiple organ toxicity that causes great harm to human health. Cadmium enters the human body through occupational exposure, diet, drinking water, breathing, and smoking. Cadmium accumulation in the human body is associated with increased risk of developing obesity, cardiovascular disease, diabetes, and metabolic syndrome (MetS). Cadmium uptake is enhanced during pregnancy and can cross the placenta affecting placental development and function. Subsequently, cadmium can pass to fetus, gathering in multiple organs such as the liver and pancreas. Early-life cadmium exposure can induce hepatic oxidative stress and pancreatic ß-cell dysfunction, resulting in insulin resistance and glucose metabolic dyshomeostasis in the offspring. Prenatal exposure to cadmium is also associated with increasing epigenetic effects on the offspring's multi-organ functions. However, whether and how maternal exposure to low-dose cadmium impacts the risks of developing type 2 diabetes (T2D) in the young and/or adult offspring remains unclear. This review collected available data to address the current evidence for the potential role of cadmium exposure, leading to insulin resistance and the development of T2D in offspring. However, this review reveals that underlying mechanisms linking prenatal cadmium exposure during pregnancy with T2D in offspring remain to be adequately investigated.

Cardiovascular Effects of Environmental Metal Antimony: Redox Dyshomeostasis as the Key Pathogenic Driver.

Significance: Cardiovascular diseases (CVDs) are the leading cause of death worldwide, which may be due to sedentary lifestyles with less physical activity and over nutrition as well as an increase in the aging population; however, the contribution of pollutants, environmental chemicals, and nonessential metals to the increased and persistent CVDs needs more attention and investigation. Among environmental contaminant nonessential metals, antimony has been less addressed. Recent Advances: Among environmental contaminant nonessential metals, several metals such as lead, arsenic, and cadmium have been associated with the increased risk of CVDs. Antimony has been less addressed, but its potential link to CVDs is being gradually recognized. Critical Issues: Several epidemiological studies have revealed the significant deleterious effects of antimony on the cardiovascular system in the absence or presence of other nonessential metals. There has been less focus on whether antimony alone can contribute to the pathogenesis of CVDs and the proposed mechanisms of such possible effects. This review addresses this gap in knowledge by presenting the current available evidence that highlights the potential role of antimony in the pathogenesis of CVDs, most likely via antimony-mediated redox dyshomeostasis. Future Directions: More direct evidence from preclinical and mechanistic studies is urgently needed to evaluate the possible roles of antimony in mitochondrial dysfunction and epigenetic regulation in CVDs. Antioxid. Redox Signal. 38, 803-823.

Facilitators and barriers to pediatric clinical trial recruitment and retention in rural and community settings: A scoping review of the literature.

Children in rural settings are under-represented in clinical trials, potentially contributing to rural health disparities. We performed a scoping review describing available literature on barriers and facilitators impacting participation in pediatric clinical trials in rural and community-based (nonclinical) settings. Articles identified via PubMed, CINAHL, Embase, and Web of Science were independently double-screened at title/abstract and full-text levels to identify articles meeting eligibility criteria. Included articles reported on recruitment or retention activities for US-based pediatric clinical studies conducted in rural or community-based settings and were published in English through January 2021. Twenty-seven articles describing 31 studies met inclusion criteria. Most articles reported on at least one study conducted in an urban or suburban or unspecified community setting (n = 23 articles; 85%); fewer (n = 10; 37%) reported on studies that spanned urban and rural settings or were set in rural areas. More studies discussed recruitment facilitators (n = 25 studies; 81%) and barriers (n = 19; 61%) versus retention facilitators (n = 15; 48%) and barriers (n = 8; 26%). Descriptions of recruitment and retention barriers and facilitators were primarily experiential or subjective. Recruitment and retention facilitators were similar across settings and included contacts/reminders, community engagement, and relationship-building, consideration of participant logistics, and incentives. Inadequate staff and resources were commonly cited recruitment and retention barriers. Few studies have rigorously examined optimal ways to recruit and retain rural participants in pediatric clinical trials. To expand the evidence base, future studies examining recruitment and retention strategies should systematically assess and report rurality and objectively compare relative impact of different strategies.

Regional and sociodemographic differences in average BMI among US children in the ECHO program.

OBJECTIVE: The aim of this study was to describe the association of individual-level characteristics (sex, race/ethnicity, birth weight, maternal education) with child BMI within each US Census region and variation in child BMI by region. METHODS: This study used pooled data from 25 prospective cohort studies. Region of residence (Northeast, Midwest, South, West) was based on residential zip codes. Age- and sex-specific BMI z scores were the outcome. RESULTS: The final sample included 14,313 children with 85,428 BMI measurements, 49% female and 51% non-Hispanic White. Males had a lower average BMI z score compared with females in the Midwest (ß = -0.12, 95% CI: -0.19 to -0.05) and West (ß = -0.12, 95% CI: -0.20 to -0.04). Compared with non-Hispanic White children, BMI z score was generally higher among children who were Hispanic and Black but not across all regions. Compared with the Northeast, average BMI z score was significantly higher in the Midwest (ß = 0.09, 95% CI: 0.05 to 0.14) and lower in the South (ß = -0.12, 95% CI: -0.16 to -0.08) and West (ß = -0.14, 95% CI: -0.19 to -0.09) after adjustment for age, sex, race/ethnicity, and birth weight. CONCLUSIONS: Region of residence was associated with child BMI z scores, even after adjustment for sociodemographic characteristics. Understanding regional influences can inform targeted efforts to mitigate BMI-related disparities among children.

Best Practices for Conducting Clinical Trials With Indigenous Children in the United States.

We provide guidance for conducting clinical trials with Indigenous children in the United States. We drew on extant literature and our experience to describe 3 best practices for the ethical and effective conduct of clinical trials with Indigenous children. Case examples of pediatric research conducted with American Indian, Alaska Native, and Native Hawaiian communities are provided to illustrate these practices. Ethical and effective clinical trials with Indigenous children require early and sustained community engagement, building capacity for Indigenous research, and supporting community oversight and ownership of research. Effective engagement requires equity, trust, shared interests, and mutual benefit among partners over time. Capacity building should prioritize developing Indigenous researchers. Supporting community oversight and ownership of research means that investigators should plan for data-sharing agreements, return or destruction of data, and multiple regulatory approvals. Indigenous children must be included in clinical trials to reduce health disparities and improve health outcomes in these pediatric populations. Establishment of the Environmental Influences on Child Health Outcomes Institutional Development Award States Pediatric Clinical Trials Network (ECHO ISPCTN) in 2016 creates a unique and timely opportunity to increase Indigenous children's participation in state-of-the-art clinical trials.

Depression and Anxiety Screening in Adolescents With Diabetes.

Adolescents with diabetes are at increased risk for depression and anxiety, which when untreated negatively affects diabetes control. During a 6-month period, the Patient Health Questionnaire for Depression and Anxiety (PHQ-4) screening tool was utilized. Those with a positive screen then completed the Patient Health Questionnaire for Adolescents (PHQ-A) and the Generalized Anxiety Disorder 7-item (GAD-7) scale. In this article, we report on the correlations in outcomes between the PHQ-4 and the PHQ-A and GAD-7 and its clinical utility for determining the need for standard versus acute behavioral health care. Over 6 months, 77 patients aged 10 to 18 years screened positive on the PHQ-4. Thirty-two patients had positive screening with the PHQ-A and/or the GAD-7. Thoughts of self-harm were reported by 13 (40%), with 1 experiencing current/active symptoms. The PHQ-4 as a screening tool was able to identify adolescents with symptoms of depression and/or anxiety who would benefit from further evaluation by a behavioral health provider.

Predicting Nocturnal Hypoglycemia with Measures of Physical Activity Intensity in Adolescent Athletes with Type 1 Diabetes.

For someone managing type 1 diabetes, understanding their body's glucose response to physical activity could aid in effectively addressing nocturnal hypoglycemia. The purpose of this investigation was to examine the acute temporal associations between blood glucose and measures of moderate-vigorous physical activity (MVPA) through an accelerometer. Ten adolescent athletes with type 1 diabetes wore an accelerometer and continuous glucose monitor (CGM) consecutively for a minimum of 2 weeks. Physical activity was analyzed according to intensity indicating time spent in light, moderate, and vigorous intensities. Hypoglycemic episodes were defined as two successive CGM readings <70 mg/dL, at 5-min intervals, with an episode ending with at least two CGM readings >70 mg/dL. Incidence of nocturnal hypoglycemia occurred during 29% of the nights measured with an average duration of 52.33 ± 41.04 min. When combining total minutes of moderate and vigorous intensities a significant difference was observed between combined MVPA and number of nocturnal hypoglycemic episodes (62.92 min vs. 49 episodes, P = 0.02). Moderate intensity activity alone was not significant in predicting hypoglycemic events or duration. Vigorous intensity physical activity was a significant predictor of nocturnal hypoglycemia after controlling for sedentary and light intensity minutes, age, and gender (ß = 0.21, P = 0.01) with an average time of 26 min of vigorous intensity. Engaging in vigorous intensity physical activity increased the risk of prolonged nocturnal hypoglycemia in adolescent athletes with type 1 diabetes. Incorporating accelerometers into patient care could prove beneficial when making further recommendations for athletes.

Continuous Glucose Monitoring Profiles in Healthy Nondiabetic Participants: A Multicenter Prospective Study.

CONTEXT: Use of continuous glucose monitoring (CGM) is increasing for insulin-requiring patients with diabetes. Although data on glycemic profiles of healthy, nondiabetic individuals exist for older sensors, assessment of glycemic metrics with new-generation CGM devices is lacking. OBJECTIVE: To establish reference sensor glucose ranges in healthy, nondiabetic individuals across different age groups using a current generation CGM sensor. DESIGN: Multicenter, prospective study. SETTING: Twelve centers within the T1D Exchange Clinic Network. PATIENTS OR PARTICIPANTS: Nonpregnant, healthy, nondiabetic children and adults (age ≥6 years) with nonobese body mass index. INTERVENTION: Each participant wore a blinded Dexcom G6 CGM, with once-daily calibration, for up to 10 days. MAIN OUTCOME MEASURES: CGM metrics of mean glucose, hyperglycemia, hypoglycemia, and glycemic variability. RESULTS: A total of 153 participants (age 7 to 80 years) were included in the analyses. Mean average glucose was 98 to 99 mg/dL (5.4 to 5.5 mmol/L) for all age groups except those over 60 years, in whom mean average glucose was 104 mg/dL (5.8 mmol/L). The median time between 70 to 140 mg/dL (3.9 to 7.8 mmol/L) was 96% (interquartile range, 93 to 98). Mean within-individual coefficient of variation was 17 ± 3%. Median time spent with glucose levels >140 mg/dL was 2.1% (30 min/d), and median time spent with glucose levels <70 mg/dL (3.9 mmol/L) was 1.1% (15 min/d). CONCLUSION: By assessing across age groups in a healthy, nondiabetic population, normative sensor glucose data have been derived and will be useful as a benchmark for future research studies.

Characteristics of Obstructive Sleep Apnea Across the Spectrum of Glucose Tolerance in Obese Adolescents.

BACKGROUND: It is not known if dysglycemia and sleep-disordered breathing are linked in adolescents, as in adults. OBJECTIVE: To perform a pilot study evaluating measures of sleep-disordered breathing across the spectrum of glucose tolerance in obese adolescents. We hypothesized that dysglycemia would be associated with sleep-disordered breathing. PARTICIPANTS/METHODS: This was a prospective, cross-sectional clinical pilot study that included 57 adolescents [body mass index (BMI) 38.9 ± 8.4 kg/m2] aged 12-18 years (14.5 ± 1.6) with normal glucose tolerance (NGT), or dysglycemia [impaired glucose tolerance (IGT) or type 2 diabetes (T2D)]. MEASURES: Anthropometrics, overnight polysomnogram, and oral glucose tolerance tests were performed. Participant characteristics and outcome measures were compared by glucose tolerance status. Correlational analyses were conducted to assess the associations between variables of interest. RESULTS: Participants with dysglycemia (n = 21) were not different from those with NGT (n = 36) for BMI, waist circumference, body fat, or sleep characteristics. Nocturnal oxygen desaturation was associated with higher BMI (r = -0.334, p = 0.012). The apnea-hypopnea index (AHI) was not associated with physical and metabolic parameters. Although participants with dysglycemia tended to have higher AHIs (median 3.2, 2.2, and 1.6 events/h for T2D, IGT, and NGT, respectively), there was not a linear relationship between measures of glycemia and AHI. CONCLUSION: Further study with a larger proportion of youth with prediabetes and T2D is necessary to determine whether evaluation for sleep-disordered breathing is uniformly warranted.

The impact of insurance coverage and the family on pediatric diabetes management.

BACKGROUND/OBJECTIVE: The impact of family composition on glycemic control in children with type 1 diabetes remains unclear. We sought to evaluate the relationship between health insurance coverage, family composition, and insulin management, and assess their impact on glycemic control in a pediatric type 1 diabetes population. METHODS: A retrospective chart review was completed for patients seen in the Pediatric Endocrinology Clinic at the University of Louisville in 2012. RESULTS: The analysis included 729 patients with type 1 diabetes; 268 (37%) had public insurance while 461(63%) had private insurance. Compared with publicly insured patients, privately insured patients had higher rates of intensive insulin management with multiple daily injections (MDI) plans or pump devices (88 vs. 83.2%, p = 0.066) and lower HbA1c levels [8.57 vs. 9.39% (70 vs. 79 mmol/mol), p < 0.001]. Of the 729 patients, 243 were in single-adult homes (33%). Single-adult homes had higher HbA1c levels than two-adult homes, [9.3 vs. 8.6% (78 vs. 70 mmol/mol), p < 0.001]. Among publicly insured, there was no difference in HbA1c levels for single-adult vs. two-adult homes [9.4 (79 mmol/mol), p = 0.868]. For privately insured, patients in single-adult homes had higher HbA1c levels than peers in two-adult homes [9.2 vs. 8.4% (77 vs. 68), p < 0.001]. CONCLUSION: Insurance type and family composition have significant associative effects on glycemic control and insulin management that may be mitigated by insulin pump therapy. Identifying and addressing factors such as availability of resources, family education, and adult support and supervision, may help improve glycemic control in high-risk pediatric diabetes patients.

BIRD'S-EYE VIEW OF GnRH ANALOG USE IN A PEDIATRIC ENDOCRINOLOGY REFERRAL CENTER.

OBJECTIVE: Gonadotropin-releasing hormone analogs (GnRHa) are standard of care for the treatment of central precocious puberty (CPP). GnRHa have also been prescribed in other clinical settings with the hope of increasing adult stature, although evidence to support this practice is lacking. The degree to which GnRHa are being prescribed for indications other than CPP in routine clinical care has not been described. We sought to systematically examine GnRHa prescribing practices among the pediatric endocrinologists at our academic medical center. METHODS: We reviewed medical records of children treated with GnRHa during a 6-year interval. Variables analyzed included gender, age at start of treatment, indication for therapy, and use of growth hormone as adjunctive treatment. Nonparametric analyses were utilized to compare treatment characteristics of those with CPP versus those without. RESULTS: A total of 260 patients (82% female) aged 8.06 ± 2.68 years were identified. Of these, 191 (73.5%) were treated for CPP, whereas 69 (26.5%) were treated for normally timed puberty in the context of idiopathic short stature/poor predicted height (n = 37), growth hormone deficiency (n = 17), congenital adrenal hyperplasia (n = 10), primary hypothyroidism (n = 4), and developmental delay (n = 1). Of the 161 girls with CPP, GnRHa therapy was initiated at ≥8 years of age in 62 (39%). CONCLUSION: Whereas most patients were treated for CPP, ~27% were treated for other indications. Of girls with CPP, 39% were treated at an age when benefit in terms of height is unlikely. This highlights the need for rigorous studies of GnRHa use for indications beyond CPP.

Morning blood pressure is associated with sleep quality in obese adolescents.

OBJECTIVE: To examine relationships among blood pressure (BP), adiposity, and sleep quality with the use of overnight polysomnography in obese adolescents. STUDY DESIGN: Overnight polysomnogram and morning BP measurements were performed in obese (body mass index [BMI] >95th percentile) nondiabetic adolescents (eligible age range 12-18 years, n = 49). Subjects were stratified into 2 groups, one with normal BP, and one with elevated BP, and demographic and clinical characteristics were compared between the groups. Multiple linear regression analysis was used to assess the effects of sleep quality on BP. RESULTS: Participants (n = 27) had a normal morning BP, and 22 (44.9%) had elevated morning BP. There were no differences in age (P = .53), sex (P = .44), race (P = .58), or BMI (P = .56) between the 2 BP groups. The group with elevated BP spent shorter percentages of time in rapid eye movement (REM; P = .006) and slow-wave sleep (SWS; P = .024). Multiple linear regression analysis showed that a lower percentage of both REM and SWS was associated with increased morning BP after we adjusted for pubertal stage, sex, race, and BMI. CONCLUSION: Lack of deeper stages of sleep, REM sleep, and SWS is associated with greater morning BP in obese adolescents, independent of BMI. Poor sleep quality should be considered in the work-up of obese youth with hypertension. Intervention studies are needed to evaluate whether improving the quality of sleep will decrease BP elevation.

Diet complexity and estrogen receptor ß status affect the composition of the murine intestinal microbiota.

Intestinal microbial dysbiosis contributes to the dysmetabolism of luminal factors, including steroid hormones (sterones) that affect the development of chronic gastrointestinal inflammation and the incidence of sterone-responsive cancers of the breast, prostate, and colon. Little is known, however, about the role of specific host sterone nucleoreceptors, including estrogen receptor ß (ERß), in microbiota maintenance. Herein, we test the hypothesis that ERß status affects microbiota composition and determine if such compositionally distinct microbiota respond differently to changes in diet complexity that favor Proteobacteria enrichment. To this end, conventionally raised female ERß(+/+) and ERß(-/-) C57BL/6J mice (mean age of 27 weeks) were initially reared on 8604, a complex diet containing estrogenic isoflavones, and then fed AIN-76, an isoflavone-free semisynthetic diet, for 2 weeks. 16S rRNA gene surveys revealed that the fecal microbiota of 8604-fed mice and AIN-76-fed mice differed, as expected. The relative diversity of Proteobacteria, especially the Alphaproteobacteria and Gammaproteobacteria, increased significantly following the transition to AIN-76. Distinct patterns for beneficial Lactobacillales were exclusive to and highly abundant among 8604-fed mice, whereas several Proteobacteria were exclusive to AIN-76-fed mice. Interestingly, representative orders of the phyla Proteobacteria, Bacteroidetes, and Firmicutes, including the Lactobacillales, also differed as a function of murine ERß status. Overall, these interactions suggest that sterone nucleoreceptor status and diet complexity may play important roles in microbiota maintenance. Furthermore, we envision that this model for gastrointestinal dysbiosis may be used to identify novel probiotics, prebiotics, nutritional strategies, and pharmaceuticals for the prevention and resolution of Proteobacteria-rich dysbiosis.

Recent updates on recombinant human growth hormone outcomes and adverse events.

PURPOSE OF REVIEW: To provide up-to-date information on outcomes and adverse events associated with the use of recombinant human growth hormone (rhGH). We will focus on patients with Prader Willi Syndrome and Idiopathic Short Stature. We will also discuss recent reports on long-term adverse events from the European database. RECENT FINDINGS: Prader Willi Syndrome is associated with hypogonadism, which does not appear to be affected by treatment with rhGH. However, there is new evidence that treatment may improve cognition. For patients with Idiopathic Short Stature, the gain in near adult height with treatment with rhGH appears to be 3-4 cm. Although a recent analysis of this group shows that certain patient characteristics may help identify those most likely to have a good response to treatment. Additionally, the safety and appropriateness of growth hormone treatments in Europe study released preliminary data from patients treated in two separate locations that showed conflicting information on risk of mortality from treatment with rhGH. SUMMARY: Although we will continue to receive new information regarding the safety and effects of treatment with rhGH, it is important to discuss the risks and benefits with our patients. Additionally, it is incumbent on us to help guide the treatment to those most likely to benefit.