Islet biology, the CDKN2A/B locus and type 2 diabetes risk.

Type 2 diabetes, fuelled by the obesity epidemic, is an escalating worldwide cause of personal hardship and public cost. Diabetes incidence increases with age, and many studies link the classic senescence and ageing protein p16(INK4A) to diabetes pathophysiology via pancreatic islet biology. Genome-wide association studies (GWASs) have unequivocally linked the CDKN2A/B locus, which encodes p16 inhibitor of cyclin-dependent kinase (p16(INK4A)) and three other gene products, p14 alternate reading frame (p14(ARF)), p15(INK4B) and antisense non-coding RNA in the INK4 locus (ANRIL), with human diabetes risk. However, the mechanism by which the CDKN2A/B locus influences diabetes risk remains uncertain. Here, we weigh the evidence that CDKN2A/B polymorphisms impact metabolic health via islet biology vs effects in other tissues. Structured in a bedside-to-bench-to-bedside approach, we begin with a summary of the evidence that the CDKN2A/B locus impacts diabetes risk and a brief review of the basic biology of CDKN2A/B gene products. The main emphasis of this work is an in-depth look at the nuanced roles that CDKN2A/B gene products and related proteins play in the regulation of beta cell mass, proliferation and insulin secretory function, as well as roles in other metabolic tissues. We finish with a synthesis of basic biology and clinical observations, incorporating human physiology data. We conclude that it is likely that the CDKN2A/B locus influences diabetes risk through both islet and non-islet mechanisms.

Vitamin D status is associated with early markers of cardiovascular disease in prepubertal children.

BACKGROUND: The associations of 25-hydroxyvitamin D [25(OH)D], non-high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL), and related markers of early cardiovascular disease (CVD) are unclear in prepubertal children. OBJECTIVE: To investigate the association of 25(OH)D with markers of CVD. The hypothesis was that 25(OH)D would vary inversely with non-HDL-C. SUBJECTS AND METHODS: A prospective cross-sectional study of children (n=45; 26 males, 19 females) of mean age 8.3 ± 2.5 years to investigate the relationships between 25(OH)D and glucose, insulin, high-sensitivity C-reactive protein, and lipids. Vitamin D deficiency was defined as 25(OH)D <20 ng/mL; overweight as body mass index (BMI) ≥ 85 th but <95th percentile; and obesity as BMI >95th percentile. RESULTS: Twenty subjects (44.4%) had BMI <85%, and 25 had BMI of ≥ 85%. Eleven participants (24.4%) had 25(OH)D of <20 ng/mL, and 10 (22.2%) had 25(OH)D of >30 ng/mL. Patients with 25(OH)D of <20 ng/mL had significantly elevated non-HDL-C (136.08 ± 44.66 vs. 109.88 ± 28.25, p=0.025), total cholesterol (TC)/HDL ratio (3.89 ± 1.20 vs. 3.21 ± 0.83, p=0.042), and triglycerides (TG) (117.09 ± 71.27 vs. 73.39 ± 46.53, p=0.024), while those with 25(OH)D of >30 ng/mL had significantly lower non-HDL-C, TC/HDL, TG, and LDL (82.40 ± 18.03 vs. 105.15 ± 28.38, p=0.006). Multivariate analysis showed significant inverse correlations between 25(OH)D and non-HDL cholesterol (ß=-0.337, p=0.043), and TC/HDL ratio (ß=-0.339, p=0.028), and LDL (ß=-0.359, p=0.016), after adjusting for age, race, sex, BMI, and seasonality. CONCLUSIONS: Vitamin D varied inversely with non-HDL, TC/HDL, and LDL. A 25(OH)D level of 30 ng/mL is associated with optimal cardioprotection in children.

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

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.

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

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.

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

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 (T1DM) 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 TIDM patients, and demonstrated a significant inverse relationship between their HbA1c and 25OHD levels (beta=-0.42, p=0.02), compared to T1DM subjects (beta=-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.

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

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.

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

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.

Pseudohypoparathyroidism type 1a and insulin resistance in a child.

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.

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.

Newborn with klinefelter syndrome and posterior urethral valves.

We describe the case of a 10-day-old term infant with 47,XXY, in association with posterior urethral valves, a right ectopic ureter, a right dysplastic kidney, left hydronephrosis, cryptorchidism, and encephalomalacia. The renal anomaly was diagnosed prenatally by ultrasonography, and additional evaluation was performed after birth. Urinary tract anomalies are uncommon in Klinefelter syndrome. Unilateral and bilateral renal agenesis have been described. We describe, to our knowledge, the first case of posterior urethral valves, ectopic ureter, and encephalomalacia in association with 47,XXY.

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

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.

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

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.

Lack of telomere shortening with age in mouse resting zone chondrocytes.

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.

Short stature with normal growth hormone stimulation testing: lack of evidence for partial growth hormone deficiency or insensitivity.

OBJECTIVES: To test the hypothesis that children with short stature and peak stimulated GH (pGH) of 7-10 microg/l have partial GH deficiency and to test the hypothesis that short children with normal pGH but low IGF-I levels have partial GH deficiency or partial GH insensitivity. DESIGN AND PATIENTS: Retrospective analysis of the clinical and biochemical profiles of 76 children who underwent an evaluation for short stature (height < 5th percentile) that included two, sex steroid-primed GH stimulation tests. RESULTS: Patients with pGH < 7 microg/l (n = 14) differed significantly from those with pGH > 7 microg/l (n = 62), having greater midparental height (MPH) SDS, a greater disparity between height SDS and MPH SDS, and lower IGF-I SDS. Patients with pGH of 7-10 microg/l (n = 12) did not have characteristics intermediate between those with pGH < 7 microg/l and those with pGH > or = 10 microg/l, but instead resembled those with pGH > or = 10 microg/l. Patients with pGH > or = 7 microg/l, but low IGF-I (< -2 SDS) (n = 5), did not show characteristics intermediate between those with pGH < 7 microg/l and those with pGH > or = 7 microg/l and normal IGF-I. CONCLUSIONS: These data do not support either the hypothesis that children with pGH of 7-10 microg/l have partial GH deficiency or the hypothesis that children with normal pGH but subnormal IGF-I levels have partial GH deficiency or insensitivity.