Persistently high glucose levels in young children with type 1 diabetes.

OBJECTIVES: The aim of the study was to characterize glucose levels and variability in young children with type 1 diabetes (T1D). METHODS: A total of 144 children of 4-10 yr old diagnosed with T1D prior to age 8 were recruited at five DirecNet centers. Participants used a continuous glucose monitor (CGM) every 3 months during an 18-month study. Among the 144 participants, 135 (mean age 7.0 yr, 47% female) had a minimum of 48 h of CGM data at more than five of seven visits and were included in analyses. CGM metrics for different times of day were analyzed. RESULTS: Mean hemoglobin A1c (HbA1c) at the beginning and end of the study was 7.9% (63 mmol/mol). Fifty percent of participants had glucose levels >180 mg/dL (10.0 mmol/L) for >12 h/d and >250 mg/dL (13.9 mmol/L) for >6 h/d. Median time <70 mg/dL (3.9 mmol/L) was 66 min/d and <60 mg/dL (3.3 mmol/L) was 39 min/d. Mean amplitude of glycemic excursions (MAGE) was lowest overnight (00:00-06:00 hours). The percent of CGM values 71-180 mg/dL (3.9-10.0 mmol/L) and the overall mean glucose correlated with HbA1c at all visits. There were no differences in CGM mean glucose or coefficient of variation between the age groups of 4 and <6, 6 and <8, and 8 and <10. CONCLUSIONS: Suboptimal glycemic control is common in young children with T1D as reflected by glucose levels in the hyperglycemic range for much of the day. New approaches to reduce postprandial glycemic excursions and increase time in the normal range for glucose in young children with T1D are critically needed. Glycemic targets in this age range should be revisited.

Rediscovery of insulin pump treatment of childhood type 1 diabetes.

Currently, goals for the treatment of children and adolescents with type 1 diabetes mellitus are to achieve near normal glycemia; minimize the risks of severe hypoglycemia and excessive weight gain; optimize psychosocial functioning and quality of life (for children and their families); and prevent or delay long-term microvascular complications. Continuous subcutaneous insulin infusion (CSII), or insulin pump therapy, provides a treatment option that can assist in the attainment of all of these goals in all ages of children. Insulin pump therapy provides the opportunity for greater flexibility in meal timing and content due to the convenience of its bolus delivery of insulin. Insulin pump therapy can potentially reduce the risk of exercise-related and nocturnal hypoglycemia, through the use of programmable variable basal infusion rates. In pediatric patients, usage of CSII has been demonstrated to reduce both glycosylated hemoglobin levels and frequency of severe hypoglycemia, without sacrifices in safety, quality of life, or weight gain, particularly in conjunction with the use of new insulin analogs and improvements in pump technology. Clinical studies of safety and efficacy of CSII in children and the use of continuous glucose monitoring to optimize insulin pump therapy are reviewed.

Body composition and metabolic factors in obese children and adolescents.

OBJECTIVE: Body composition is associated with metablic factors in adults; however, data are limited regarding obese children. This study was undertaken to assess body composition, regional fat distribution, and metabolic factors in obese 6-18-y-old children and adolescents. DESIGN: Cross-sectional assessment. SUBJECTS: Thirty-six obese children and adolescents, (mean+/-s.e.m.) age 11.8+/-0.5 y, BMI 34.1+/-1.2 kg/m(2). MEASUREMENTS: Body composition was assessed by dual energy X-ray absorptiometry and computerized tomography. Fasting insulin, glucose and leptin levels, and the homeostasis model assessment of insulin sensitivity (HOMA-IR) were assessed. RESULTS: The girls had significantly lower glucose levels than the boys. The ethnic group differences (African American children vs white children) in fat mass, total CT fat, subcutaneous CT fat, insulin level, leptin level, and higher HOMA-IR were not significant after adjusting for age or pubertal stage. These differences in abdominal fat and subcutaneous abdominal fat were also not independent of total body fat or BMI. No ethnic group differences in visceral abdominal fat were noted. Insulin level and HOMA IR were associated with leptin level (independent of fat mass) and fat mass. Leptin level was associated with fat mass, total CT fat, and subcutaneous CT fat; however the associations between the CT fat measures and leptin were not independent of total body fat mass. CONCLUSIONS: Neither visceral abdominal fat, subcutaneous abdominal fat, insulin levels, or insulin resistance differed by ethnic group when adjusted for age or pubertal status. This contrasts with findings in adults and non-obese children which suggest lower levels of visceral fat and higher insulin levels and insulin resistance in African American children and adolescents.

Acarbose treatment of postprandial hypoglycemia in children after Nissen fundoplication.

Dumping syndrome and postprandial hypoglycemia have been reported after Nissen fundoplication. The physiopathologic mechanisms are poorly understood and a variety of therapies have failed to control the hypoglycemia in these patients. We report a series of 6 infants with postprandial hypoglycemia after Nissen fundoplication who were treated successfully with acarbose.

Graves' disease in patients with 22q11.2 deletion.

We report 4 female patients and 1 male patient with a 22q11.2 deletion and Graves' disease diagnosed at age 27 months, 7, 10, 17, and 16 years, respectively. The clinical presentations were typical for hyperthyroidism, but 1 female infant had seizures in addition to symptoms of hyperthyroidism. All patients had elevated serum levels of thyroid hormones in association with suppressed thyroid-stimulating hormone levels. From these observations, we suggest that Graves' disease may be a part of the clinical spectrum associated with the 22q11.2 deletion syndrome.

Endocrine aspects of the 22q11.2 deletion syndrome.

Hormonal disorders are common in patients with a 22q11.2 deletion. While hypoparathyroidism was the first endocrine disturbance documented in the DiGeorge syndrome, growth hormone deficiency, hypothyroidism, and hyperthyroidism are now known to occur in patients with a 22q11.2 deletion. This review briefly summarizes our current understanding of the spectrum of endocrinological manifestations of the 22q11.2 deletion and proposes guidelines for appropriate screening and management of endocrine disorders in patients with a 22q11.2 deletion.

Transferrin is an insulin-like growth factor-binding protein-3 binding protein.

Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) possesses both growth-inhibitory and -potentiating effects on cells that are independent of IGF action and are mediated through specific IGFBP-3 binding proteins/receptors located at the cell membrane, cytosol, or nuclear compartments and in the extracellular matrix. We have here characterized transferrin (Tf) as one of these IGFBP-3 binding proteins. Human serum was fractionated over an IGFBP-3 affinity column, and a 70-kDa protein was eluted, sequenced, and identified (through database searching and Western immunoblot) as human Tf. Tf bound IGFBP-3 but had negligible affinity to the other five IGFBPs, and iron-saturated holo-Tf bound IGFBP-3 more avidly than unsaturated Tf. Biosensor interaction analysis confirmed that this interaction is specific and sensitive, with a high association rate similar to IGF-I, and suggested that binding occurs in the vicinity of the IGFBP-3 nuclear localization site. As an independent confirmation of this interaction, using a yeast two-hybrid system, we cloned Tf from a human liver complementary DNA library as an IGFBP-3 protein partner. Tf treatment blocked IGFBP-3-induced cell proliferation in bladder smooth muscle cells, and IGFBP-3-induced apoptosis in prostate cancer cells. In summary, we have employed a combination of techniques to demonstrate that Tf specifically binds IGFBP-3, and we showed that this interaction has important physiological effects on cellular events.

Human papillomavirus type 16 E7 oncoprotein binds and inactivates growth-inhibitory insulin-like growth factor binding protein 3.

The E7 protein encoded by human papillomavirus type 16 is one of the few viral genes that can immortalize primary human cells and thereby override cellular senescence. While it is generally assumed that this property of E7 depends on its interaction with regulators of the cell cycle, we show here that E7 targets insulin-like growth factor binding protein 3 (IGFBP-3), the product of a p53-inducible gene that is overexpressed in senescent cells. IGFBP-3 can suppress cell proliferation and induce apoptosis; we show here that IGFBP-3-mediated apoptosis is inhibited by E7, which binds to IGFBP-3 and triggers its proteolytic cleavage. Two transformation-deficient mutants of E7 failed to inactivate IGFBP-3, suggesting that inactivation of IGFBP-3 may contribute to cell transformation.

Direct functional interactions between insulin-like growth factor-binding protein-3 and retinoid X receptor-alpha regulate transcriptional signaling and apoptosis.

Insulin-like growth factor-binding protein (IGFBP)-3 regulates apoptosis in an IGF-independent fashion and has been shown to localize to nuclei. We cloned the nuclear receptor retinoid X receptor-alpha(RXR-alpha) as an IGFBP-3 protein partner in a yeast two-hybrid screen. Multiple methodologies showed that IGFBP-3 and RXR-alpha bind each other within the nucleus. IGFBP-3-induced apoptosis was abolished in RXR-alpha-knockout cells. IGFBP-3 and RXR ligands were additive in inducing apoptosis in prostate cancer cells. IGFBP-3 enhanced RXR response element and inhibited RARE signaling. Thus, RXR-alpha-IGFBP-3 interaction leads to modulation of the transcriptional activity of RXR-alpha and is essential for mediating the effects of IGFBP-3 on apoptosis.

Serum IGF-I and IGFBP-3 concentrations do not accurately predict growth hormone deficiency in children with brain tumours.

OBJECTIVE: The growth hormone (GH)-dependent growth factors insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) may be superior to provocative GH testing in diagnosing GH deficiency (GHD) in children. In adults with brain tumours (BT) and GHD, however, provocative GH testing more accurately reflects GHD than either IGF-I or IGFBP-3. We assessed growth factor levels in children with GHD due to BT with respect to brain tumour type, pubertal stage, growth velocity, bone age delay, and body mass index (BMI). DESIGN: Retrospective case review of all patients followed at our centre with GHD following treatment of BT. PATIENTS: 72 children (51 M, 21 F) with BT diagnosed with GHD by clinical and auxological criteria, including provocative GH testing, in whom pre-GH treatment IGF-I and IGFBP-3 levels were obtained. MEASUREMENTS: Auxological data, including height, weight, growth velocity, and pubertal stage; and biochemical data, including GH response to provocative GH testing and pre-GH treatment serum IGF-I and IGFBP-3 concentrations. RESULTS: IGF-I levels were normal (above -2 SD) in 19 of 70 children (27%), and IGFBP-3 levels were normal in 21 of 42 (50%). In children with GHD, pubertal stage correlated significantly with both IGF-I (r = 0.328, p < 0.006) and IGFBP-3 (r = 0.364, P < 0.02). Normal IGF-1 levels were found in 1/15 children with craniopharyngioma (Cranio) (7%), 10/30 with primitive neuroectodermal tumours (PNET) (33%), and 5/12 children with hypothalamic/chiasmatic glioma (HCG) (42%) (P < 0. 05). IGFBP-3 levels were normal in 4/13 Cranio patients (31%), 8/15 PNET patients (53%), and 6/8 HCG patients (75%) (P = ns). Tanner staging varied significantly among tumour types: mode = 1 for Cranio and PNET vs. mode = 3 for HCG (P < 0.03). BMI did not differ between patients with low vs. normal growth factor levels. CONCLUSIONS: Low IGF-I levels were more predictive of growth hormone deficiency than low IGFBP-3 levels in our brain tumour patients, but both were poor predictors of growth hormone deficiency in children with hypothalamic-chiasmatic glioma and in pubertal children. Serum IGF-I and IGFBP-3 levels, therefore, do not always reflect growth hormone deficiency in children with brain tumours, particularly in those with hypothalamic-chiasmatic glioma or those already in puberty.

Cellular actions of insulin-like growth factor binding proteins.

The insulin-like growth factors (IGFs), insulin-like growth factor binding proteins (IGFBPs), and the IGFBP proteases are involved in the regulation of somatic growth and cellular proliferation both in vivo and in vitro. IGFs are potent mitogenic agents whose actions are determined by the availability of free IGFs to interact with the IGF receptors. IGFBPs comprise a family of proteins that bind IGFs with high affinity and specificity and thereby regulate IGF-dependent actions. IGFBPs have recently emerged as IGF-independent regulators of cell growth. Various IGFBP association proteins as well as cleavage of IGFBPs by specific proteases modulate levels of free IGFs and IGFBPs. The ubiquity and complexity of the IGF axis promise exciting discoveries and applications for the future.

Growth hormone deficiency in patients with 22q11.2 deletion: expanding the phenotype.

The list of findings associated with the 22q11.2 deletion is quite long and varies from patient to patient. The hallmark features include: conoruncal cardiac anomalies, palatal defects, thymic aplasia or hypoplasia, T cell abnormalities, mild facial dysmorphia, and learning disabilities. The 22q11.2 deletion has been seen in association with the DiGeorge sequence, velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome, isolated conotruncal cardiac anomalies, and some cases of autosomal dominant Optiz G/BBB syndrome. Short stature has been seen in one to two thirds of children reported in the literature with a diagnosis of VCFS, but growth hormone deficiency (GHD) has not been described in conjunction with this diagnosis. We present 4 patients with a 22q11.2 deletion and short stature who were found to have abnormalities in the growth hormone-insulin-like growth factor I axis. All had growth factors less than -2 SD for age and failed provocative growth hormone testing. Two patients were found to have abnormal pituitary anatomy. In our population, the incidence of GHD in 4 or 95 children with 22q11 deletion is significantly greater than the estimated incidence of GHD in the general population. Children with a 22q11.2 deletion appear to be at a greater risk for pituitary abnormalities. Therefore, those children with the 22q11.2 deletion and short stature or poor growth should be evaluated for GHD, as replacement growth hormone therapy may improve their growth velocity and final height prediction.

Diabetes and transport: a potentially bittersweet combination.

These cases represent a portion of the spectrum of medical issues that may be seen in patients with a diagnosis of IDDM. As the first case suggests, knowledge of the disease process and an expanded differential diagnosis is imperative when acting as medical command for these patients. Interfacility transport does not only involve rapid and safe transport between institutions, but must also offer the highest level of expertise available for the referring physician and the patient. For this reason, we recommend the immediate availability of a senior level experienced pediatric physician for involvement in all but the most routine pediatric interfacility transports. Rapid recognition at the time of initial presentation or transport of the correct diagnosis in patient one may have altered potential outcome. Case 2 represents a potential untoward outcome which might be potentiated or exacerbated by the care given during transport. Although this patient's transport time was short, a similar patient may present who needs prolonged transport. The patient might also present to the transport service prior to neurologic deterioration. One must be prepared to intervene for all potential complications as they arise. Case 3 represents a patient whose physical examination suggested more intense therapy was needed than is offered by many DKA protocols. It is important to listen to what the patients are trying to tell us, rather than relying strictly on protocols or guidelines. While protocols or guidelines offer a menu of potential therapies, one must be prepared to vary from these guidelines if suggested by the patient's condition. Recognition of delayed capillary refill in patient 3 allowed for an increase in fluid administration and rapid patient improvement. While not evident with the presented short transports, the use of point of care testing in a transport vehicle can be useful for these types of patients. The opportunity to closely monitor blood chemistry evaluations and gasses can give insight about an ongoing process, suggest therapies, and help direct interventions that, in the past, often waited until the patient arrived at the receiving hospital. That additional information can be invaluable for the ill patient whose outcome may hinge on early recognition of subtle changes with subsequent appropriate interventions.

A syndrome of congenital hyperinsulinism and hyperammonemia.

This report describes two patients from unrelated families with an unusual syndrome of hyperinsulinism plus hyperammonemia. The diagnosis of hyperinsulinism was based on the demonstration of fasting hypoglycemia with inappropriately elevated insulin levels, inappropriately low beta-hydroxybutyrate and free fatty acid levels, and inappropriately large glycemic response to the administration of glucagon. In both patients, plasma ammonium levels were persistently elevated and unaffected by protein feeding, protein restriction, or benzoate therapy. Plasma and urinary amino acids, urinary organic acids, and urinary orotic acid levels were not consistent with any of the urea cycle enzyme defects or other hyperammonemic disorders. These two patients appear to represent a unique form of congenital hyperinsulinism distinct from the previously described autosomal dominant and autosomal recessive variants. We speculate that the underlying defect involves a site that is common to the amino acid regulation of both insulin secretion in pancreatic beta-cells and urea synthesis in the liver.

The 22q11.2 deletion: screening, diagnostic workup, and outcome of results; report on 181 patients.

A submicroscopic deletion of chromosome 22q11.2 has been identified in the majority of patients with the DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, and in some patients with isolated conotruncal cardiac anomalies, Opitz G/BBB syndrome, and Cayler cardiofacial syndrome. We have evaluated 181 patients with this deletion. We describe our cohort of patients, how they presented, and what has been learned by having the same subspecialists evaluate all of the children. The results help define the extremely variable phenotype associated with this submicroscopic deletion and will assist clinicians in formulating a management plan based on these findings.