Benjamin U. Nwosu

Double Diabetes: The Search for a Treatment Paradigm in Children and Adolescents

Benjamin U. Nwosu — Tue, 14 May 2013 08:53:32 PDT

Discusses double diabetes -- the coexistence of features of both type 1 and type 2 diabetes in the same individual -- with a comprehensive discussion of the various aspects of this disorder and a focus on the search for a treatment paradigm in children and adolescents.

Double Diabetes: The Evolving Treatment Paradigm in Children and Adolescents

Benjamin U. Nwosu — Thu, 04 Apr 2013 08:30:50 PDT

The global pandemic of obesity in children and adolescents has resulted in a new expression of diabetes mellitus designated as double diabetes. The entity encompasses the autoimmune load of Type 1 Diabetes and the metabolic load of Type 2 Diabetes. There is no consensus on the best therapeutic modality for this new expression of diabetes mellitus. Optimal therapeutic options must address the coexistence of both metabolic and autoimmune components of diabetes mellitus in the patient. There have also been calls to revise the current classification of diabetes mellitus to take into account the surging prevalence of double diabetes in children and adolescents.

Serum 25-hydroxyvitamin D levels do not correlate with asthma severity in a case-controlled study of children and adolescents

Jennifer Menon et al. — Thu, 23 Aug 2012 07:05:21 PDT

Background: There is no consensus on the association between vitamin D and asthma.

Objective: To determine the relationship between 25-hydroxyvitamin D [25(OH)D] levels and asthma symptom severity in children and adolescents.

Methods: A retrospective, case-control study of 263 subjects of ages 2–19 years with asthma who were compared to 284 non-asthmatic controls of similar ages. Subjects were excluded if they had diseases of calcium or vitamin D metabolism or were receiving calcium or vitamin D supplementation. Serum 25(OH)D was measured in all subjects. Asthma symptom severity, usually stratified into 6 steps, was stratified into five steps [1–5] based on the number and dose of controller medications used as outlined by the National Heart, Lung, and Blood Institute’s guidelines. Mean 25(OH)D values were compared between the asthmatic patients and controls, as well as among the five steps of asthma symptom severity. Results were adjusted for age, sex, BMI, race and severity of asthma symptoms.

Results: There was no difference in 25(OH)D between asthmatic patients and controls (28.64±10.09 vs. 28.42±11.47, p=1.0). However, there was a significant difference in 25(OH)D between obese and non-obese asthmatic patients (23.33±7.67 vs. 30.16±10.20, p<0.0001), as well as obese and non-obese controls (24.56±9.90 vs. 29.50±11.66, p=0.003). Mean 25(OH)D levels did not vary significantly among the five steps of asthma symptom severity.

Conclusions: There were no differences in mean 25(OH)D levels between asthmatic patients and controls. Mean 25(OH)D level was significantly lower in both the obese asthmatic patients and obese controls. Asthma severity had no relationship to mean 25(OH)D levels.

Is vitamin D deficiency a feature of pediatric celiac disease?

Jeffrey Villanueva et al. — Wed, 20 Jun 2012 13:13:31 PDT

Background: Celiac disease (CD) is an autoimmune enteropathy characterized by villus atrophy and malabsorption of essential nutrients. Vitamin D deficiency has been described in autoimmune diseases, but its status in prepubertal children with CD has not been adequately studied.

Objective: To determine the vitamin D status of prepubertal children with CD.

Study design: A retrospective study of prepubertal children aged 3–12 years with CD (n=24) who were compared to prepubertal, non-CD children of the same age (n=50). Children were included in the study if they had a diagnosis of CD by intestinal biopsy, and were not on a gluten-free diet (GFD). Patients were excluded if they had diseases of calcium or vitamin D metabolism, or were receiving calcium or vitamin D supplementation or had other autoimmune diseases. All subjects had their serum 25-hydroxyvitamin D [25(OH)D] level measured.

Results: There was no difference in 25(OH)D level between the CD and non-CD children (27.58±9.91 vs. 26.20±10.45, p=0.59). However, when the patients were subdivided into obese and non-obese groups, the non-obese CD patients had a significantly higher 25(OH)D level than the obese normal children (28.39±10.26 vs. 21.58±5.67, p=0.009). In contrast, there was no difference in 25(OH)D level between non-obese CD patients and non-obese normal children (28.39±10.26 vs. 30.64±12.08, p=0.52). The season of 25(OH)D measurement was not a significant confounder (p=0.7).

Conclusions: Our data showed no difference in 25(OH)D levels between normal children and those with CD when adjusted for body mass index.

Stroke in a child with Adams-Oliver syndrome and mixed diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome

Benjamin U. Nwosu et al. — Wed, 18 Apr 2012 12:50:29 PDT

Diabetes mellitus complicated by mixed diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome presents a special challenge to physicians. There is no standard protocol for the management of mixed hyperglycemic hyperosmolar syndrome and diabetic ketoacidosis in children. The commonest cause of neurological deterioration during an episode of diabetic ketoacidosis is cerebral edema, whereas hyperosmolality often leads to thrombosis. The risks for these complications are further increased in diseases associated with vasculopathies. We present the first case of complex cerebral arteriovenous thrombosis leading to stroke in a child with Adams-Oliver syndrome, a genetic condition that is associated with abnormal vasculogenesis. He presented with new-onset double diabetes complicated by a combination of diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Magnetic resonance imaging, magnetic resonance angiography, and magnetic resonance venography provided evidence for an ischemic stroke. Children and adolescents who present with a combination of hyperglycemic hyperosmolar syndrome and diabetic ketoacidosis should be monitored for neurologic deficits and must be investigated for both stroke and cerebral edema in the event of neurological deterioration.

Does Hepatic Dysfunction Worsen Glucose Homeostasis by Impairing Vitamin D Metabolism?

Benjamin U. Nwosu — Thu, 12 Apr 2012 11:30:03 PDT

The Management of diabetes mellitus (DM) remains an enigma even though the symptoms of the disease had been described more than 3000 years ago. This is because the central therapeutic goal of DM therapy, euglycemia, is influenced by complex physiologic and pathologic processes, some of which are clearly understood, while others are less clear. Suboptimal glycemic control is a recognized risk factor for acute and chronic complications of diabetes including microvascular and macrovascular diseases. The central question for this editorial is whether mild hepatic dysfunction could impair vitamin D metabolism and secondarily lead to sub-optimal glycemic control.

Hepatic dysfunction is associated with vitamin D deficiency and poor glycemic control in diabetes mellitus

Benjamin U. Nwosu et al. — Mon, 12 Mar 2012 08:34:24 PDT

Background/Aims: The effect of the rising prevalence of nonalcoholic fatty liver disease on the 25-hydroxylation of pre-vitamin D in the liver, and consequent glycemic control in children with diabetes mellitus is not known. Our aim was to determine whether mild hepatic dysfunction was associated with impaired 25-hydroxylation of pre-vitamin D, and if this vitamin D deficiency was associated with impaired glycemic control in children and adolescents with type 1 diabetes (TIDM) and type 2 diabetes (T2DM).

Methods: We analyzed simultaneously measured HbA1c, ALT, AST, and 25OHD levels and clinical parameters in 121 children and adolescents with T1DM (n=81) and T2DM (n=40). The subjects, ages 11–21 years, all had diabetes of >6 months duration. Multivariate linear regression was used to analyze the associations, while comparisons between subgroups were made using two-tailed Student’s t-test.

Results: Vitamin D deficiency (25OHD <15 ng>/mL (37.5 nmol/L) was more prevalent in T2DM patients (47.5%) compared to T1DM patients (18.5%). Subjects with T2DM had significantly elevated transaminases (AST 39.3±2.0 vs. 22.4±1.4, p<0.001; ALT 30.6±1.8 vs. 18.7±1.3, p<0.001) compared to T1DM patients, and demonstrated a significant inverse relationship between their HbA1c and 25OHD levels (β=–0.42, p=0.02), compared to T1DM subjects (β=–0.06, p=0.62).

Conclusions: The association of elevated ALT with vitamin D deficiency suggests that hepatic dysfunction could impair vitamin D metabolism and negatively impact glycemic control in youth with T2DM.

Hypothyroidism in children and adolescents

Benjamin U. Nwosu — Fri, 02 Mar 2012 13:48:36 PST

Hypothyroidism is a term that describes insufficient levels or absolute lack of thyroid hormone in an individual. Congenital hypothyroidism describes a condition of insufficient or absent thyroid hormone in a neonate or an infant and is usually caused by abnormal development of the thyroid gland. This could be due to absence of the gland, or the migration of the gland to a different site during the period of early development. It could also result from poor development or formation of the gland. In some cases the gland is present but is unable to make thyroid hormone. In most cases, congenital hypothyroidism is detected by newborn screening tests. Although there are other numerous causes of hypothyroidism in children and adolescents, such as surgical removal of the gland, this article focuses on acquired hypothyroidism (diminished or absent thyroid hormone production after infancy).

Do Atypical Antipsychotic Agents Trigger Autoimmune Diabetes?

Benjamin U. Nwosu et al. — Fri, 02 Mar 2012 13:48:34 PST

Atypical or second-generation antipsychotic agents, such as aripiprazole and olanzapine, are increasingly used in the management of schizophrenia and bipolar disorders in children. The atypical antipsychotic agents have been associated with the development of hyperglycemia, ketoacidosis, and diabetes. The mechanism of atypical antipsychotic-mediated hyperglycemia is unclear. Most of the published reports have been on individuals at risk for type 2 diabetes. We present the first known cases of the development of diabetes and positive glutamic acid decarboxylase antibodies (suggestive of autoimmune diabetes) in adolescents while on treatment with atypical antipsychotics. The nature of their clinical presentations and the time course of antipsychotic therapy to clinical diagnosis of diabetes make us speculate that atypical antipsychotics may shorten the time course of the development of autoimmune diabetes in predisposed children.

Rieger's anomaly and other ocular abnormalities in association with osteogenesis imperfecta and a COL1A1 mutation

Benjamin U. Nwosu et al. — Fri, 02 Mar 2012 13:48:33 PST

A patient with osteogenesis imperfecta (OI) and some features of Ehlers-Danlos syndrome had Rieger's anomaly and other associated ocular abnormalities. He carried a COL1A1 mutation (c.3313delA) that has only rarely been seen in OI. The association of ocular anterior chamber abnormalities with OI has not been reported previously, while OI with Ehlers-Danlos syndrome features has only been described in some kindreds. The patient had serious complications as a result of his ocular anomalies. We speculate that the course of his disease and, perhaps, its co-existence with OI could be exacerbated by his collagen type-I defect, although no causality can be established by this report of a single case.

Design of a family-based lifestyle intervention for youth with type 2 diabetes: the TODAY study

The TODAY Study Group et al. — Fri, 02 Mar 2012 13:48:32 PST

Type 2 diabetes is associated with obesity and is increasing at an alarming rate in youth. Although weight loss through lifestyle change is one of the primary treatment recommendations for adults with type 2 diabetes, the efficacy of this approach has not been tested with youth. This paper provides a summary of the reviews and meta-analyses of pediatric weight-loss interventions that informed the design and implementation of an intensive, family-based lifestyle weight management program for adolescents with type 2 diabetes and their families developed for the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. A total of 1092 youth have been screened, and 704 families have been randomized for inclusion in this 15-center clinical trial sponsored by the National Institutes of Health. The TODAY study is designed to test three approaches (metformin, metformin plus rosiglitazone and metformin plus an intensive lifestyle intervention) to the treatment of a diverse cohort of youth, 10-17 years of age, within 2 years of their diagnosis. The principal goal of the TODAY Lifestyle Program (TLP) is to decrease baseline weight of youth by 7-10% (or the equivalent for children who are growing in height) through changes in eating and physical activity habits, and to sustain these changes through ongoing treatment contact. The TLP is implemented by interventionists called Personal Activity and Nutrition Leaders (PALs) and delivered to youth with type 2 diabetes, and at least one family support person. The TLP provides a model for taking a comprehensive, continuous care approach to the treatment of severe overweight in youth with comorbid medical conditions such as type 2 diabetes.

Multifetal Pregnancy May Increase the Risk for Severe Maternal and Neonatal Vitamin D Deficiency

Benjamin U. Nwosu et al. — Fri, 02 Mar 2012 13:48:31 PST

Vitamin D deficiency is prevalent in pregnant women. This deficiency could be exaggerated in multifetal pregnancies by the increased demand on maternal stores of vitamin D. We present 2 cases in which hypocalcemia and secondary hyperparathyroidism occurred in 2 sets of twins from mothers with vitamin D deficiency. The first mother had gastric bypass surgery and Crohn disease. The second mother had no apparent cause of vitamin D deficiency. Both women had iron deficiency anemia and lived in Northeastern United States. We speculate that in twins, the demand for 25-hydroxyvitamin D by 2 fetuses could deplete the 25-hydroxyvitamin D stores in a mother.

A potential role for adjunctive vitamin D therapy in the management of weight gain and metabolic side effects of second-generation antipsychotics

Benjamin U. Nwosu et al. — Fri, 02 Mar 2012 13:48:29 PST

Second-generation antipsychotic (SGA) medications introduced about 20 years ago are increasingly used to treat psychiatric illnesses in children and adolescents. There has been a five-fold increase in the use of these medications in U.S. children and adolescents in the past decade. However, there has also been a parallel rise in the incidence of side effects associated with these medications, such as obesity, dyslipidemia, insulin resistance, and diabetes mellitus. Despite the severity of these complications and their financial impact on the national healthcare budget, there is neither a clear understanding of the mechanisms contributing to these side effects nor the best ways to address them. Studies that examined lifestyle modification and pharmaceutical agents have yielded mixed results. Therefore, clinical studies using agents, such as vitamin D, which are inexpensive, readily available, with low side effects profile, and have mechanisms to counteract the metabolic side effects of SGA agents, are warranted. Vitamin D is a prohormone with skeletal and extraskeletal properties that could potentially reduce the severity of these metabolic side effects. Its role as an adjunctive therapy for the management of metabolic side effects of SGA agents has not been adequately studied. Effective strategies to curb these side effects will improve the overall health of youths with psychiatric illnesses who receive SGAs. Herein we present a pilot study on the use of vitamin D in patients on treatment with SGAs.

Pseudohypoparathyroidism type 1a and insulin resistance in a child

Benjamin U. Nwosu et al. — Fri, 02 Mar 2012 13:48:28 PST

Background. A 5-year-old white girl with a history of hypothyroidism in infancy presented to the endocrinology clinic of a tertiary hospital. Her physical examination noted a stocky physique, broad chest, short neck and short digits. Two years later, skin examination revealed subcutaneous nodules and acanthosis nigricans.

Investigations. Measurement of levels of serum phosphate, parathyroid hormone, ionized calcium and insulin; measurement of peak growth hormone by the arginine-levodopa stimulation test; calculation of homeostasis model assessment of insulin resistance; assessment of bone age; DNA analysis of the GNAS gene.

Diagnosis. Pseudohypoparathyroidism type 1a in a patient with Albright hereditary osteodystrophy, characterized by hypocalcemia, hypothyroidism, growth-hormone deficiency and insulin resistance.

Management. The child continued to take levothyroxine 25 microg once daily, and at 5 years of age she was started on 40 mg/kg elemental calcium as calcium carbonate daily, and calcitriol (active vitamin D) 0.25 microg twice daily. Lifestyle modifications were also recommended for weight control. At 6 years and 4 months of age, treatment with growth hormone was initiated at a dose of 0.3 mg/kg weekly.

Evaluation of short and tall stature in children

Benjamin U. Nwosu et al. — Fri, 02 Mar 2012 13:48:26 PST

Children and adolescents whose heights and growth velocities deviate from the normal percentiles on standard growth charts present a special challenge to physicians. Height that is less than the 3rd percentile or greater than the 97th percentile is deemed short or tall stature, respectively. A growth velocity outside the 25th to 75th percentile range may be considered abnormal. Serial height measurements over time documented on a growth chart are key in identifying abnormal growth. Short or tall stature is usually caused by variants of a normal growth pattern, although some patients may have serious underlying pathologies. A comprehensive history and physical examination can help differentiate abnormal growth patterns from normal variants and identify specific dysmorphic features of genetic syndromes. History and physical examination findings should guide laboratory testing.

Pediatrics for Parents Podcast Show 107: Short Stature (Audio File)

Benjamin U. Nwosu — Fri, 02 Mar 2012 13:48:25 PST

Interview (mp3 audio file, 13 MB, 29 minutes) by Benjamin Nwosu, MD with Rich Sagall, MD, editor and host of the "Pediatrics for Parents Podcast", October 24, 2010. Dr. Nwosu was interviewed about an article that he and Mary Lee, MD, wrote on the diagnosis and treatment of short and tall stature in children.

Citation: Nwosu, BU. Interview with Rich Sagall, MD, editor and host, “Pediatrics for Parents Show 107- Short Stature”, Pediatrics for Parents Podcast. October 24, 2010. Available from iTunes and http://pedsforparents.libsyn.com/2010/10.

Pseudohypoparathyroidism in Children

Benjamin U. Nwosu — Fri, 02 Mar 2012 13:48:24 PST

Summary: Albright hereditary osteodystrophy (AHO) is a genetic syndrome characterized by a distinctive set of developmental and skeletal defects that may easily be misdiagnosed as exogenous obesity in children. There are very few publications detailing the comprehensive management of children and adolescents with this disorder. This chapter provides a comprehensive discussion of the various aspects of this disorder. At the end, the reader should be able to: (1) List the clinical features of Albright hereditary osteodystrophy, (2) Identify the genetic and molecular abnormalities of AHO, (3) List the clinical features of pseudohypoparathyroidism type 1a (PHP 1a), (4) Describe the management of children and adolescents with PHP 1a.

Citation: Benjamin U. Nwosu (2011). Pseudohypoparathyroidism in Children, Contemporary Aspects of Endocrinology, Evanthia Diamanti-Kandarakis (Ed.), ISBN: 978-953-307-357-6, InTech, Available from: http://www.intechopen.com/articles/show/title/pseudohypoparathyroidism-in-children

A novel activating mutation in transmembrane helix 6 of the thyrotropin receptor as cause of hereditary nonautoimmune hyperthyroidism

Benjamin U. Nwosu et al. — Fri, 02 Mar 2012 13:48:23 PST

Constitutively-activating germline mutations of the thyrotropin receptor (TSHR) gene are very rare and are considered the cause of hereditary nonautoimmune hyperthyroidism. We describe four affected individuals from a Caucasian family: a mother and her three children, and an unaffected father. The mother and her first two children presented in a similar manner: lifelong histories of heat intolerance, hyperactivity, fast heart rate, reduced energy, increased appetite, and scrawny build. They all developed goiter in childhood and showed a suppressed TSH and elevated thyroxine (T(4)). The last child, a 12-year-old female, presented with no clinical symptoms or palpable neck mass, but with a suppressed TSH, elevated T(4) and thyromegaly detected by ultrasound. Mutation analysis of the TSHR gene in all family members revealed a novel heterozygous germline mutation resulting in the substitution of phenylalanine (TTC) by serine (TCC) at codon 631 in transmembrane helix 6 in the mother and all three children. Functional characterization of this germline mutation showed constitutive activation of the G(s)-mediated cyclic adenosine monophosphate (cAMP) pathway, which controls thyroid hormone production and thyroid growth. Molecular characterization of F631S demonstrates that this activating mutation plays a key role in the development of hereditary hyperthyroidism in this family although the timing of onset of clinical manifestations in the subjects may depend on other, as yet unidentified, factors.

Evidence of insulin-like growth factor binding protein-3 proteolysis during growth hormone stimulation testing

Benjamin U. Nwosu et al. — Fri, 02 Mar 2012 13:48:21 PST

OBJECTIVES: The ternary complex is composed of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3 and acid labile subunit (ALS). Growth hormone (GH) promotes IGFBP-3 proteolysis to release free IGF-I, ALS, and IGFBP-3 fragments. Our aim was to determine whether elevated GH levels during GH stimulation testing would trigger IGFBP-3 proteolysis.

DESIGN: This prospective study of 10 short prepubertal children (height standard deviation score -2.37 +/- 0.31) used arginine and GH releasing hormone stimulation to study dynamic changes in the ternary complex moieties. IGFBP-3 was measured in two assays: a radioimmunoassay (RIA) that detects both cleaved and intact IGFBP-3; and an immunochemiluminescence assay (ICMA) that detects only intact IGFBP-3.

RESULTS: IGFBP-3 measured by RIA increased by 19% (p < 0.05), while IGFBP-3 measured by ICMA did not significantly increase (6.1%).

CONCLUSION: The significant increase in IGFBP-3 measured by RIA, but not ICMA, provides evidence of IGFBP-3 proteolysis during acute GH stimulation.

Lack of telomere shortening with age in mouse resting zone chondrocytes

Benjamin U. Nwosu et al. — Fri, 02 Mar 2012 13:48:20 PST

BACKGROUND AND AIM: Telomeres are hexameric repeat sequences that flank eukaryotic chromosomes. The telomere hypothesis of cellular aging proposes that replication of normal somatic cells leads to progressive telomere shortening which induces replicative senescence. Previous studies suggest that growth plate chondrocytes have a finite proliferative capacity in vivo. We therefore hypothesized that telomere shortening in resting zone chondrocytes leads to replicative senescence.

METHOD: To test this hypothesis we compared the telomere restriction fragment (TRF) length of Mus casteneus at 1, 4, 8, and 56 weeks of age.

RESULTS AND CONCLUSIONS: We found that TRF length did not diminish measurably with age, suggesting that telomere shortening in resting zone chondrocytes is not the mechanism that limits proliferation of growth plate chondrocytes in vivo.