Explore the vast range of titles available.

Richard Lifton and colleagues identify somatic and germline mutations in the CACNA1D calcium channel gene in aldosterone-producing adenomas and primary aldosteronism. Their functional studies show that these mutations result in channel activation at more hyperpolarized membrane potentials, implicating increased Ca 2+ influx in disease pathogenesis. Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca 2+ influx cause ∼40% of these tumors 1 . We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D , encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5 . The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca 2+ influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa 2 . We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca 2+ channel mutations in APAs and primary aldosteronism.

Type 1 diabetes (T1D) is associated with lower scores on tests of cognitive and neuropsychological function and alterations in brain structure and function in children. This proof-of-concept pilot study (ClinicalTrials.gov Identifier NCT03428932) examined whether MRI-derived indices of brain development and function and standardized IQ scores in adolescents with T1D could be improved with better diabetes control using a hybrid closed-loop insulin delivery system. Eligibility criteria for participation in the study included age between 14 and 17 years and a diagnosis of T1D before 8 years of age. Randomization to either a hybrid closed-loop or standard diabetes care group was performed after pre-qualification, consent, enrollment, and collection of medical background information. Of 46 participants assessed for eligibility, 44 met criteria and were randomized. Two randomized participants failed to complete baseline assessments and were excluded from final analyses. Participant data were collected across five academic medical centers in the United States. Research staff scoring the cognitive assessments as well as those processing imaging data were blinded to group status though participants and their families were not. Forty-two adolescents, 21 per group, underwent cognitive assessment and multi-modal brain imaging before and after the six month study duration. HbA1c and sensor glucose downloads were obtained quarterly. Primary outcomes included metrics of gray matter (total and regional volumes, cortical surface area and thickness), white matter volume, and fractional anisotropy. Estimated power to detect the predicted treatment effect was 0.83 with two-tailed, α = 0.05. Adolescents in the hybrid closed-loop group showed significantly greater improvement in several primary outcomes indicative of neurotypical development during adolescence compared to the standard care group including cortical surface area, regional gray volumes, and fractional anisotropy. The two groups were not significantly different on total gray and white matter volumes or cortical thickness. The hybrid closed loop group also showed higher Perceptual Reasoning Index IQ scores and functional brain activity more indicative of neurotypical development relative to the standard care group (both secondary outcomes). No adverse effects associated with study participation were observed. These results suggest that alterations to the developing brain in T1D might be preventable or reversible with rigorous glucose control. Long term research in this area is needed. Children with type 1 diabetes (T1D) are at risk for reduced cognitive ability and atypical brain development. This study shows that brain and cognitive measures can be improved in adolescents with T1D using a semi-automated insulin delivery system.

OBJECTIVE: Continuous glucose monitoring (CGM) has been demonstrated to improve glycemic control in adults with type 1 diabetes but less so in children. We designed a study to assess CGM benefit in young children aged 4 to 9 years with type 1 diabetes. RESEARCH DESIGN AND METHODS: After a run-in phase, 146 children with type 1 diabetes (mean age 7.5 ± 1.7 years, 64% on pumps, median diabetes duration 3.5 years) were randomly assigned to CGM or to usual care. The primary outcome was reduction in HbA1c at 26 weeks by ≥0.5% without the occurrence of severe hypoglycemia. RESULTS: The primary outcome was achieved by 19% in the CGM group and 28% in the control group (P = 0.17). Mean change in HbA1c was –0.1% in each group (P = 0.79). Severe hypoglycemia rates were similarly low in both groups. CGM wear decreased over time, with only 41% averaging at least 6 days/week at 26 weeks. There was no correlation between CGM use and change in HbA1c (rs = –0.09, P = 0.44). CGM wear was well tolerated, and parental satisfaction with CGM was high. However, parental fear of hypoglycemia was not reduced. CONCLUSIONS: CGM in 4- to 9-year-olds did not improve glycemic control despite a high degree of parental satisfaction with CGM. We postulate that this finding may be related in part to limited use of the CGM glucose data in day-to-day management and to an unremitting fear of hypoglycemia. Overcoming the barriers that prevent integration of these critical glucose data into day-to-day management remains a challenge.

Objective Both diabetes and obesity can affect the brain, yet their impact is not well characterized in children with type 2 (T2) diabetes and obesity. This pilot study aims to explore differences in brain function and cognition in adolescents with T2 diabetes and obesity and nondiabetic controls with obesity and lean controls. Research design and methods Participants were 12‐17 years old (5 T2 diabetes with obesity [mean HgbA1C 10.9%], 6 nondiabetic controls with obesity and 10 lean controls). Functional MRI (FMRI) during hyperglycemic/euglycemic clamps was performed in the T2 diabetes group. Results When children with obesity, with and without diabetes, were grouped (mean BMI 98.8%), cognitive scores were lower than lean controls (BMI 58.4%) on verbal, full scale, and performance IQ, visual‐spatial and executive function tests. Lower scores correlated with adiposity and insulin resistance but not HgbA1C. No significant brain activation differences during task based and resting state FMRI were noted between children with obesity (with or without diabetes) and lean controls, but a notable effect size for the visual‐spatial working memory task and resting state was observed. Conclusions In conclusion, our pilot study suggests that obesity, insulin resistance, and dysglycemia may contribute to relatively poorer cognitive function in adolescents with T2 diabetes and obesity. Further studies with larger sample size are needed to assess if cognitive decline in children with obesity, with and without T2 diabetes, can be prevented or reversed.

Chronic administration of glucocorticosteroids (GCs) can have significant catabolic effects in vivo in a host of metabolic systems, including amino acid metabolism, skeletal muscle, bone and linear growth. GCs inhibit protein synthesis and increase protein breakdown at the skeletal muscle and whole-body level and impair growth hormone (GH) secretion and action. Conversely, GH and insulin-like growth factor I (IGF-I) are potent protein-anabolic and growth-promoting agents in vitro and in vivo. This review summarizes both the catabolic effects of GCs and the anabolic and metabolic effects of GH and IGF-I. Both GH and IGF-I may decrease the catabolic effects of chronic steroid use in humans, particularly by enhancing lean body mass accrual and, in children, by increasing linear growth.

Optimal glycemic control is particularly difficult to achieve in children and adolescents with type 1 diabetes (T1D), yet the influence of dysglycemia on the developing brain remains poorly understood. Using a large multi-site study framework, we investigated activation patterns using functional magnetic resonance imaging (fMRI) in 93 children with T1D (mean age 11.5 ± 1.8 years; 45.2% female) and 57 non-diabetic (control) children (mean age 11.8 ± 1.5 years; 50.9% female) as they performed an executive function paradigm, the go/no-go task. Children underwent scanning and cognitive and clinical assessment at 1 of 5 different sites. Group differences in activation occurring during the contrast of \"no-go > go\" were examined while controlling for age, sex, and scan site. Results indicated that, despite equivalent task performance between the 2 groups, children with T1D exhibited increased activation in executive control regions (e.g., dorsolateral prefrontal and supramarginal gyri; p = 0.010) and reduced suppression of activation in the posterior node of the default mode network (DMN; p = 0.006). Secondary analyses indicated associations between activation patterns and behavior and clinical disease course. Greater hyperactivation in executive control regions in the T1D group was correlated with improved task performance (as indexed by shorter response times to correct \"go\" trials; r = -0.36, 95% CI -0.53 to -0.16, p < 0.001) and with better parent-reported measures of executive functioning (r values < -0.29, 95% CIs -0.47 to -0.08, p-values < 0.007). Increased deficits in deactivation of the posterior DMN in the T1D group were correlated with an earlier age of T1D onset (r = -0.22, 95% CI -0.41 to -0.02, p = 0.033). Finally, exploratory analyses indicated that among children with T1D (but not control children), more severe impairments in deactivation of the DMN were associated with greater increases in hyperactivation of executive control regions (T1D: r = 0.284, 95% CI 0.08 to 0.46, p = 0.006; control: r = 0.108, 95% CI -0.16 to 0.36, p = 0.423). A limitation to this study involves glycemic effects on brain function; because blood glucose was not clamped prior to or during scanning, future studies are needed to assess the influence of acute versus chronic dysglycemia on our reported findings. In addition, the mechanisms underlying T1D-associated alterations in activation are unknown. These data indicate that increased recruitment of executive control areas in pediatric T1D may act to offset diabetes-related impairments in the DMN, ultimately facilitating cognitive and behavioral performance levels that are equivalent to that of non-diabetic controls. Future studies that examine whether these patterns change as a function of improved glycemic control are warranted.

Abstract Context The assessment and treatment of children with growth retardation is increasingly complex, and due to availability of targeted genetic sequencing, an ever-expanding number of conditions impeding growth are being identified. Among endocrine-related etiologies of short stature amenable to hormonal treatment, defects in the growth hormone (GH)–insulin-like growth factor I axis remain pre-eminent, with a multiplicity of disorders causing decreased secretion or insensitivity to GH action. Sex steroids in puberty increase epiphyseal senescence and eventual growth plate closure. This is mediated mostly via estrogen receptor (ER)α in males and females, effects that can greatly limit time available for growth. Evidence Acquisition Extensive literature review through PubMed and other search engines. Evidence Synthesis Therapeutic strategies to be considered in peripubertal and pubertal children with disordered growth are here discussed, including daily and weekly GH, low-dose sex steroids, gonadotropin hormone releasing hormone (GnRH) analogues in combination with GH, aromatase inhibitors (AIs) alone and in combination with GH in boys. When used for at least 2 to 3 years, GnRH analogues combined with GH can result in meaningful increases in height. AIs used with GH permit puberty to progress in boys without hindrance, selectively decreasing estrogen, and resulting in taller height. With more than 20 years of cumulative experience in clinical use of these medications, we discuss the safety profile of these treatments. Conclusion The approach of growth retardation in the peripubertal and pubertal years must consider the sex steroid milieu and the tempo of bone acceleration. Treatment of affected children in this period must be individualized.

OBJECTIVE:--This study assesses the effects of insulin pump therapy on diabetes control and family life in children 1-6 years old with type 1 diabetes. RESEARCH DESIGN AND METHODS--Twenty-six children with type 1 diabetes for [>/=]6 months were randomly assigned to current therapy (two or three shots per day using NPH insulin and rapid-acting analog) or continuous subcutaneous insulin infusion (CSII) for 6 months. After 6 months, current therapy subjects were offered CSII. Changes in HbA[subscript 1c], mean blood glucose (MBG), hypoglycemia frequency, diabetes-related quality of life (QOL), and parental adjustment were recorded. RESULTS:--Eleven subjects from each group completed the trial (age 46.3 ± 3.2 months [means ± SE]). At baseline, there were no differences between groups in HbA[subscript 1c], MBG, age, sex, diabetes duration, or parental QOL. Mean HbA[subscript 1c], MBG, and parental QOL were similar between groups at 6 months. Mean HbA[subscript 1c] and MBG did not change from baseline to 6 months in either group. The frequency of severe hypoglycemia, ketoacidosis, or hospitalization was similar between groups at any time period. Subjects on CSII had more fasting and predinner mild/moderate hypoglycemia at 1 and 6 months. Diabetes-related QOL improved in CSII fathers from baseline to 6 months. Psychological distress increased in current therapy mothers from baseline to 6 months. All subjects continued CSII after study completion. CONCLUSIONS:--CSII is safe and well tolerated in young children with diabetes and may have positive effects on QOL. CSII did not improve diabetes control when compared with injections, despite more mild/moderate hypoglycemia. The benefits and realistic expectations of CSII should be thoroughly examined before starting this therapy in very young children.

The decline in insulin sensitivity (SI) associated with puberty increases the difficulty of achieving glycemic control in adolescents with type 1 diabetes (T1D). The aim of this study was to determine whether glutamine supplementation affects blood glucose by enhancing SI in adolescents with T1D. Thirteen adolescents with T1D (HbA1C 8.2 ± 0.1%) were admitted to perform afternoon exercise (four 15-min treadmill/5-min rest cycles of exercise) on two occasions within a 4-wk period. They were randomized to receive a drink containing either glutamine (0.25 g/kg) or placebo before exercise, at bedtime, and early morning in a double-blind, crossover design. Blood glucose was monitored overnight, and a hyperinsulinemic-euglycemic clamp was performed the following morning. Blood glucose concentration dropped comparably during exercise on both days. However, the total number of nocturnal hypoglycemic events (17 versus 7, P = 0.045) and the cumulative probability of overnight hypoglycemia (50% versus 33%, P = 0.02) were higher on the glutamine day than on the placebo day. During clamp, glucose infusion rate was not affected by glutamine supplementation (7.7 ± 1 mg • kg−1 • min−1 versus 7.0 ± 1; glutamine versus placebo; P = 0.4). Oral glutamine supplementation decreases blood glucose in adolescents with T1D after exercise. Insulin sensitivity, however, was unaltered during the euglycemic clamp. Although the mechanisms involved remain to be elucidated, studies to explore the potential use of glutamine to improve blood glucose control are needed. •In adolescents with type 1 diabetes with no residual insulin secretion, oral glutamine supplementation increased the incidence of postexercise, nocturnal hypoglycemia compared with a calorie- and nitrogen-free placebo.•Insulin sensitivity, as measured using a two-dose hyperinsulinemic-euglycemic clamp clamp the following morning, did not differ between oral glutamine and placebo.•Whether long-term oral glutamine would have a role as an oral supplement to affect glucose control remains to be explored.

Growth hormone is produced by the somatotroph cells of the anterior pituitary. Its secretion is stimulated by growth hormone–releasing hormone and inhibited by somatostatin, which are both produced by the hypothalamus. Growth hormone secretion is pulsatile, and the amplitude of the pulses is greatest at night. Twenty-four-hour growth hormone secretion is maximal during puberty and declines gradually thereafter in both women and men. Growth hormone acts by binding to receptors on liver cells and other cells. One growth hormone molecule binds to two receptor molecules on the target cell, initiating a cascade of events that results in the secretion of . . .