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ABSTRACT: To examine whether higher physical fitness is associated with lower levels of blood pressure independent of adiposity in an established cohort of children. We explored how the method used to adjust fitness for body size would influence the findings.
Blood pressure, adiposity (DXA scan) and fitness (predicted work capacity at a heart rate of 170 bpm [PWC170]) were assessed in children aged 9 years (n = 3594). Separate regression analyses for boys and girls yielded strong linear relationships between blood pressure (dependent variable) and ratio of fat to lean + bone (independent variable; all P < 0.001). An independent effect of fitness was assessed by adding PWC170 to the above models. Blood pressure was strongly inversely related to PWC170 when the latter was first adjusted for size in the conventional way (division by weight; all P < 0.001), probably because of mathematical ?coupling? (via weight). PWC170 expressed as a residual from our own regression of PWC170 on weight showed no association with systolic blood pressure and a small negative association with diastolic blood pressure (girls P = 0.042; boys P < 0.001). Across the observed ranges of fitness, mean blood pressure differed by 1 [95% CI 0?3] mm Hg for boys and 3 [95% CI 2?4] mm Hg for girls.
Fitness is not associated with systolic blood pressure independent of levels of adiposity but there is a small but independent association with diastolic blood pressure.
International journal of pediatric obesity: IJPO: an official journal of the International Association for the Study of Obesity 06/2011; 6(3-4):275-84. · 2.00 Impact Factor
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ABSTRACT: To examine transaminitis in obese children, its association with glucose metabolism and the metabolic syndrome and the response to weight loss through lifestyle modification.
216 children (90 male), aged 2.9-17.6 (median 12.4 years) with median body mass index (BMI) SD score (SDS) of 3.36 (range 1.92-6.22) attending a hospital obesity clinic in Bristol (UK) underwent an oral glucose tolerance test (OGTT) with fasting lipid and liver profile. Auxological measures included weight, height, waist circumference, percentage body fat. Parental history of type 2 diabetes (T2DM) was recorded. The 2007 International Diabetes Federation definition of metabolic syndrome was used. 90 children undergoing a trial of lifestyle modification to improve weight were re-assessed at 12 months.
34/216 (16%) children had raised alanine aminotransferase (ALT) (>40 IU/l) with greater prevalence in boys (23% vs 10%, p=0.01) and in those with a parental history of T2DM (30% vs 13.2% p=0.019). Patients with transaminitis were more likely to fulfil the criteria for metabolic syndrome (p<0.001) and have subtle abnormalities in glucose metabolism during an OGTT with elevated glucose levels at 90 (p=0.041) and 120 (p=0.014) min and a greater glucose area-under-the-curve (p=0.014). Improvement in BMI SDS over 1 year correlated with improvement in ALT levels (τ = -0.29, p<0.001).
Prevalence of transaminitis is significant in obese children and is associated with components of the metabolic syndrome. Lifestyle-based improvement in BMI SDS offers an effective tool for correcting transaminitis and should remain the central component of therapy.
Archives of Disease in Childhood 11/2010; 96(11):1003-7. · 2.88 Impact Factor
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ABSTRACT: Transient Neonatal Diabetes (type 1) is the commonest cause of diabetes presenting in the first week of life. The majority of infants recover by 3 months of age but are predisposed to developing type 2 diabetes in later life. It is associated with low birth weight but rapid catch up by 1 year of life. The condition is usually due to genetic or epigenetic aberrations at an imprinted locus on chromosome 6q24 and can be sporadic or inherited. Early diagnosis alters medical treatment strategies and differentiates it from other types of early onset diabetes. In some individuals, diabetes may be the initial presentation of a more complex imprinting disorder due to recessive mutations in the gene ZFP57 and may be associated with other developmental problems.
Reviews in Endocrine and Metabolic Disorders 10/2010; 11(3):199-204. · 3.17 Impact Factor
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ABSTRACT: To determine whether modifying eating behaviour with use of a feedback device facilitates weight loss in obese adolescents.
Randomised controlled trial with 12 month intervention.
Hospital based obesity clinic.
106 newly referred obese young people aged 9-17.
A computerised device, Mandometer, providing real time feedback to participants during meals to slow down speed of eating and reduce total intake; standard lifestyle modification therapy.
Change in body mass index (BMI) standard deviation score (SDS) over 12 months with assessment 18 months after the start of the intervention. Secondary outcomes were body fat SDS, metabolic status, quality of life evaluation, change in portion size, and eating speed.
Using the last available data on all participants (n=106), those in the Mandometer group had significantly lower mean BMI SDS at 12 months compared with standard care (baseline adjusted mean difference 0.24, 95% confidence interval 0.11 to 0.36). Similar results were obtained when analyses included only the 91 who attended per protocol (baseline adjusted mean difference 0.27, 0.14 to 0.41; P<0.001), with the difference maintained at 18 months (0.27, 0.11 to 0.43; P=0.001) (n=87). The mean meal size in the Mandometer group fell by 45 g (7 to 84 g). Mean body fat SDS adjusted for baseline levels was significantly lower at 12 months (0.24, 0.10 to 0.39; P=0.001). Those in the Mandometer group also had greater improvement in concentration of high density lipoprotein cholesterol (P=0.043).
Retraining eating behaviour with a feedback device is a useful adjunct to standard lifestyle modification in treating obesity among adolescents.
ClinicalTrials.gov NCT00407420.
BMJ (Clinical research ed.). 01/2010; 340:b5388.
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ABSTRACT: To study the impact of body mass index (BMI) SD score (SDS) improvement through lifestyle modification on metabolic risk and body composition over 12 months.
Prospective cohort study.
Hospital outpatient weight management clinic in the UK.
88 adolescents (40 males, 86% Caucasian) of median age 12.4 years (range 9.1-17.4) and mean (SD) BMI SDS 3.23 (0.49).
BMI at baseline and 12 months was adjusted for age and gender providing BMI SDS using British 1990 growth reference data. Body composition was measured by bioimpedance. A standard oral glucose tolerance test (OGTT) examined glucose metabolism. Fasting lipid profiles, high sensitivity C-reactive protein (HsCRP) and blood pressure (BP) were measured.
Reducing BMI SDS by >or=0.5 achieved significant improvements in important measures of body composition with mean waist circumference SDS reducing by 0.74 units and body fat SDS by 0.60 units, while also leading to significant reductions in key metabolic risk factors (triglycerides (-30%), low-density lipoprotein-cholesterol (-15%), HsCRP (-45%)). A lesser reduction of >or=0.25 improved insulin sensitivity, total cholesterol/high-density lipoprotein ratio and BP. The greater the BMI SDS reduction, the better the improvement seen in insulin sensitivity. The most insulinsensitive individuals at baseline were most likely to achieve BMI SDS changes of >or=0.5 regardless of baseline BMI SDS.
Improvement in body composition and cardiometabolic risk can be seen with BMI SDS reductions of >or=0.25 in obese adolescents, while greater benefits accrue from losing at least 0.5 BMI SDS. The most insulin-sensitive individuals seem best able to effect these changes.
Archives of Disease in Childhood 12/2009; 95(4):256-61. · 2.88 Impact Factor
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ABSTRACT: To screen for microvascular complications in adolescents with type 2 diabetes mellitus (T2DM). Subjects and methods: Seven adolescents with T2DM were assessed for early secondary complications. Median duration of diabetes was 1.8 (0.8-3.0) yr. All were assessed as follows: blood pressure, ophthalmologic examination for diabetic retinopathy, renal function, full blood count and vitamin B12 levels (to exclude B12 malabsorption - a side effect of metformin), random urine for microalbuminuria, an electrocardiogram (ECG) rhythm strip and podiatry performed by an experienced podiatrist. Testing for peripheral neuropathy included foot pulse palpation, tendo-Achilles reflexes, plantar callus test, large nerve fibre function (vibration and threshold for light touch/pressure) assessed by a 128-Hz tuning fork, and by the standard 10-g Semmes-Weinstein monofilament test, and small nerve fibre function (pain) assessed by pinprick neurotip.
Four adolescents had evidence of peripheral neuropathy on clinical examination, with abnormal large and small nerve fibre function. Six had plantar callus present, and four had weak but palpable posterior tibial pulses. All had normal tendo-Achilles reflex and normal response to vibration. None had diabetic retinopathy or hypertension. Renal function, full blood count (FBC), B12 levels and ECGs were normal. None of 120 adolescents with type 1 diabetes mellitus (T1DM) assessed by the same podiatrist had any signs of peripheral neuropathy.
Unlike T1DM, peripheral neuropathy can be present soon after diagnosis in those with T2DM. Children with T2DM need surveillance for complications from the time of diagnosis.
Pediatric Diabetes 05/2008; 9(2):110-4. · 2.16 Impact Factor
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ABSTRACT: Activating mutations in the KCNJ11 and ABCC8 genes encoding the Kir6.2 and SUR1 subunits of the pancreatic ATP-sensitive K(+) channel are the most common cause of permanent neonatal diabetes. In contrast to KCNJ11, where only dominant heterozygous mutations have been identified, recessively acting ABCC8 mutations have recently been found in some patients with neonatal diabetes. These genes are co-located on chromosome 11p15.1, centromeric to the imprinted Beckwith-Wiedemann syndrome (BWS) locus at 11p15.5. We investigated a male with hemihypertrophy, a condition classically associated with neonatal hyperinsulinemia and hypoglycemia, who developed neonatal diabetes at age 5 weeks.
The KCNJ11 and ABCC8 genes and microsatellite markers on chromosome 11 were analyzed in DNA samples from the patient and his parents.
A paternally inherited activating mutation (N72S) in the ABCC8 gene was identified in the proband. The mutation was present at 70% in the patient's leukocytes and 50% in buccal cells. Microsatellite analysis demonstrated mosaic segmental paternal uniparental isodisomy (UPD) of 11pter-11p14 in the proband that encompassed the ABCC8 gene and the BWS locus.
We report a patient with neonatal diabetes, hemihypertrophy, and relatively high birth weight resulting from telomeric segmental paternal UPD of chromosome 11, which unmasks a recessively acting gain-of-function mutation in the ABCC8 gene and causes deregulation of imprinted genes at the BWS locus on 11p15.5.
Diabetes 02/2008; 57(1):255-8. · 8.29 Impact Factor
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ABSTRACT: The objective of this study was to examine the major constituent of nonesterified fatty acids in children with respect to auxologic parameters, insulin sensitivity, and lipid levels, because nonesterified fatty acid levels are elevated in obesity and are important in the development of comorbidities.
Fasting blood samples were obtained from 73 children (43 girls; 49 obese; median [range] age: 11.4 [0.9-17.6] years). Concentrations of the major circulating nonesterified fatty acids (myristate, palmitate, oleate, stearate, and arachidate) were determined by gas chromatography mass spectrometry, alongside measurement of insulin, adiponectin, and lipid profiles.
The sum of all nonesterified fatty acids was significantly higher in obese versus normal-weight children, although gender (but not age or puberty) was an important determinant, with the difference remaining significant only in boys. Overall, obese children had higher concentrations of myristate, palmitate, and oleate but not stearate or arachidate. Age was an important determinant of myristate and arachidate, whereas gender proved more important for palmitate and stearate. Fasting insulin concentrations were not associated with either total nonesterified fatty acid concentrations or any of the individual nonesterified fatty acids, although a positive correlation was found between adiponectin and total nonesterified fatty acid concentrations that was independent of obesity status and that seemed mediated by changes in palmitate and stearate. Serum total cholesterol and low-density lipoprotein (but not high-density lipoprotein) levels seemed to correlate positively with circulating concentrations of palmitate, oleate, and stearate, whereas serum triacylglycerols correlated with myristate, palmitate, and oleate concentrations.
Nonesterified fatty acid concentrations are elevated in obese children, primarily as a result of increases in myristate, palmitate, and oleate. Independent effects of nonesterified fatty acids on circulating adiponectin levels and lipid parameters were observed, although we found no relationship between nonesterified fatty acid concentrations and the insulin resistance identified with obesity.
PEDIATRICS 01/2008; 120(6):e1426-33. · 4.47 Impact Factor
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Sian Ellard,
Sarah E Flanagan,
Christophe A Girard,
Ann-Marie Patch,
Lorna W Harries,
Andrew Parrish,
Emma L Edghill,
Deborah J G Mackay,
Peter Proks,
Kenju Shimomura,
Holger Haberland,
Dennis J Carson, Julian P H Shield,
Andrew T Hattersley,
Frances M Ashcroft
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ABSTRACT: Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell K(ATP) channel are the most common cause of permanent neonatal diabetes (PNDM). Patients with PNDM due to a heterozygous activating mutation in the ABCC8 gene encoding the SUR1 regulatory subunit of the K(ATP) channel have recently been reported. We studied a cohort of 59 patients with permanent diabetes who received a diagnosis before 6 mo of age and who did not have a KCNJ11 mutation. ABCC8 gene mutations were identified in 16 of 59 patients and included 8 patients with heterozygous de novo mutations. A recessive mode of inheritance was observed in eight patients with homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present.
The American Journal of Human Genetics 09/2007; 81(2):375-82. · 10.60 Impact Factor
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ABSTRACT: Transient neonatal diabetes mellitus (TNDM) is diagnosed in the first 6 months of life, with remission in infancy or early childhood. For approximately 50% of patients, their diabetes will relapse in later life. The majority of cases result from anomalies of the imprinted region on chromosome 6q24, and 14 patients with ATP-sensitive K+ channel (K(ATP) channel) gene mutations have been reported. We determined the 6q24 status in 97 patients with TNDM. In patients in whom no abnormality was identified, the KCNJ11 gene and/or ABCC8 gene, which encode the Kir6.2 and SUR1 subunits of the pancreatic beta-cell K(ATP) channel, were sequenced. K(ATP) channel mutations were found in 25 of 97 (26%) TNDM probands (12 KCNJ11 and 13 ABCC8), while 69 of 97 (71%) had chromosome 6q24 abnormalities. The phenotype associated with KCNJ11 and ABCC8 mutations was similar but markedly different from 6q24 patients who had a lower birth weight and who were diagnosed and remitted earlier (all P < 0.001). K(ATP) channel mutations were identified in 26 additional family members, 17 of whom had diabetes. Of 42 diabetic patients, 91% diagnosed before 6 months remitted, but those diagnosed after 6 months had permanent diabetes (P < 0.0001). K(ATP) channel mutations account for 89% of patients with non-6q24 TNDM and result in a discrete clinical subtype that includes biphasic diabetes that can be treated with sulfonylureas. Remitting neonatal diabetes was observed in two of three mutation carriers, and permanent diabetes occurred after 6 months of age in subjects without an initial diagnosis of neonatal diabetes.
Diabetes 07/2007; 56(7):1930-7. · 8.29 Impact Factor
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ABSTRACT: To identify factors important in determining whether an obese child achieves significant reductions in Body Mass Index Standard Deviation Score (BMI SDS) within a UK, hospital-based paediatric obesity service aimed at lifestyle modification.
Observational Study.
137 obese children (63 boys) who have attended our childhood obesity service within the last three and a half years at The Royal Hospital for Children, Bristol, UK.
BMI SDS with a target reduction of - 0.5 or greater.
70% of children achieved reductions in BMI SDS with 18% achieving the target reduction. In those attending the clinic for a year or more the levels improved to 83% and 28% respectively. Age was found to be the most important predictor with younger children achieving larger reductions in BMI SDS. More boys than girls were likely to achieve target reductions in BMI SDS and those without a parental history of obesity were more likely to achieve greater reductions in BMI SDS. Socio-economic status did not appear to impact upon the child's level of success.
In families of obese children, motivated to seek help by attending a hospital-based weight control clinic, improvements in BMI are possible by a simple approach of education and continued support. Improvement is greatest in younger children with maximal benefit being seen in boys without a parental history of obesity. We believe this emphasizes the importance of identifying significant obesity in primary school aged children, who seem most likely to benefit from simple lifestyle modification, while many older children may require additional intervention programmes to improve BMI.
Journal of Evaluation in Clinical Practice 07/2007; 13(3):364-8. · 1.23 Impact Factor
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ABSTRACT: To determine which clinical measure of childhood obesity should be monitored to best reflect change in adiposity in a weight management programme and estimate the degree of change needed to be relatively certain of fat reduction.
92 obese children with a mean (range) age of 12.8 (6.9-18.9) years and a mean body mass index standard deviation score (BMI SDS) of +3.38 (+2.27 to +4.47) attending a hospital-based clinic on a regular, 3 monthly basis. Measurements: Pairs of weight and height measured up to 2.41 years apart used to derive BMI as kg/m2, and adjusted for age and gender to give weight and BMI SDS (BMI-z score) using British 1990 Growth Reference Data. Contemporaneous adiposity estimated by fatness measured by a bioimpedance segmental body composition analyser.
Changes in BMI-z scores, compared to BMI, weight and weight SDS, most accurately reflected loss of fat. Reductions of 0.25, 0.5, 0.75, and 1 BMI SDS equate to expected mean falls in total body fat percentage of 2.9%, 5.8%, 8.7% and 11.6%. Approximate 95% prediction intervals indicated that a fall in BMI SDS of at least 0.6 over 6-12 months (or 0.5 over 0-6 months) is consistent with actual fat loss.
Change in BMI-z score best reflects percentage fat loss compared to BMI, weight and weight SDS. The wide variation in likely percentage fat loss for a given BMI SDS reduction means a loss of 0.5-0.6 is required to be relatively certain of definite percentage fat reduction.
Archives of Disease in Childhood 06/2007; 92(5):399-403. · 2.88 Impact Factor
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ABSTRACT: To estimate the incidence of type 2 diabetes in children <17 years of age and to investigate the relationship of diabetes with increasing childhood obesity in the U.K. and the Republic of Ireland (ROI).
Active monthly reporting of cases by consultant pediatricians occurred through the framework of the British Pediatric Surveillance Unit, with additional reports from specialist diabetes nurses. All children <17 years of age and diagnosed by their clinician as having non-type 1 diabetes from 1 October 2004 to 31 October 2005 were included.
A total of 168 confirmed cases of non-type 1 diabetes were reported, resulting in a national incidence (excluding the ROI) of 1.3 x 100,000(-1) x year(-1). Of these, 40% were diagnosed with type 2 diabetes giving a minimum incidence of 0.53 x 100,000(-1) x year(-1). Children of ethnic minorities were greatly overrepresented, with those of black and South-Asian origin (England data only) having an incidence of 3.9 and 1.25 x 100,000(-1) x year(-1), respectively, compared with 0.35 x 100,000(-1) x year(-1) in those defined as white. Of those diagnosed with type 2 diabetes, 95% were overweight and 83% obese according to International Obesity Task Force guidelines. Eighty-four percent had a family history of type 2 diabetes.
Type 2 diabetes is still less common than type 1 diabetes in U.K. children. However, compared with previous prevalence data, the frequency of type 2 diabetes appears to be increasing. Incidence among ethnic minorities is far higher than in whites, as previously described in the U.S. Increased adiposity and family history of type 2 diabetes were strongly associated with the diagnosis of type 2 diabetes in U.K. children.
Diabetes care 05/2007; 30(5):1097-101. · 8.09 Impact Factor
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ABSTRACT: The elevation of free fatty acids (FFAs), observed in childhood obesity results in intramyocellular lipid (IMCL) accumulation with consequent insulin resistance. Using in vitro differentiated myotubes from normal weight pre-pubertal children (n = 8), we examined the effects of saturated (palmitate) and unsaturated (oleate) FFAs on insulin-stimulated AKT phosphorylation (pAKT) and IMCL accumulation. Palmitate decreased pAKT (Mean [SEM] % change pAKT with palmitate 750 microM vs. control; pThr308 site -50.5% [28.7] and pSer473 site -38.7% [11.7]; P < 0.001) with no effect on IMCL formation. Equimolar bromopalmitate did not effect pAKT and blocking ceramide production abolished the palmitate-induced reduction in signalling, suggesting that ceramide synthesis is critical for palmitate's actions. Oleate did not effect pAKT (1,000 microM oleate; pSer473 site -3.4% [11.4]; P = NS) but increased IMCL accumulation (+32.3% [7.1%]; P < 0.001). Co-administration of oleate diminished the reduction in pAKT seen with palmitate (+36.4% [23.6] vs. -13.3% [13.6]; P = 0.28), with similar IMCL levels to oleate alone. Co-administration also caused a significant reduction in 14C-ceramide synthesis from 14C-palmitate (101.6 [21.6] vs. 371.5 [122.4] DPM/mg protein; P < 0.001). In summary, palmitate appears to cause insulin resistance in children's myotubes via its metabolism to ceramide, and this process appears unrelated to IMCL formation and is ameliorated by oleate.
Journal of Cellular Physiology 04/2007; 211(1):244-52. · 3.87 Impact Factor
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Julian P H Shield
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ABSTRACT: It has become increasingly apparent over the last few years that the seemingly ubiquitous auto-immune aetiology to pre-pubertal diabetes does not apply to those diagnosed under 6 months of age. In this age group, disease appears, in the vast majority of cases, to be conferred by single gene disorders mainly related to pancreatic development. The unravelling of these disorders has resulted in a far greater understanding of pancreatic development and some startling changes in treatment, resulting in improved quality of life and diabetes control. The progress made in our scientific and clinical understanding of these extremely rare diseases is a perfect example of how studying seemingly rare illnesses can improve our overall knowledge of much more common conditions.
Hormone Research 02/2007; 67(2):77-83. · 2.48 Impact Factor
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ABSTRACT: There is an unexplained excess of type 1 diabetes and other organ-specific autoimmune diseases in children with Down's syndrome, but the immunogenetic characteristics of diabetes in Down's syndrome have not been investigated. We studied the frequency of islet autoantibodies in 106 children with Down's syndrome and no history of autoimmunity and analyzed HLA class II genotypes in 222 children with Down's syndrome, 40 children with Down's syndrome and type 1 diabetes, 120 age- and sex-matched children with type 1 diabetes, and 621 healthy control subjects. Co-occurrence of at least two islet autoantibody markers was observed in 6 of 106 nondiabetic children with Down's syndrome compared with 13 of 2,860 healthy age-matched children (P < 0.001). There was an excess of diabetes-associated HLA class II genotypes in children with Down's syndrome and type 1 diabetes compared with age- and sex-matched healthy control subjects (P < 0.001). Down's syndrome children with type 1 diabetes were, however, less likely to carry the highest risk genotype DR4-DQ8/DR3-DQ2 than children with type 1 diabetes from the general population (P = 0.01) but more likely to carry low-risk genotypes (P < 0.0001). The frequency of subclinical islet autoimmunity is increased in Down's syndrome, and susceptibility to type 1 diabetes in Down's syndrome is partially HLA mediated. Other factors, possibly including genes on chromosome 21, may increase the penetrance of type 1 diabetes in Down's syndrome.
Diabetes 11/2006; 55(11):3185-8. · 8.29 Impact Factor
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ABSTRACT: Adiponectin is an adipocyte-specific protein with insulin-sensitizing properties. Several studies have examined the expression of adiponectin mRNA or tissue/secreted protein levels in fat obtained from adults, but none has assessed tissue levels in childhood.
Paired subcutaneous (Sc) and visceral (V) fat samples were obtained from 12 normal-weight children.
Mature adipocytes were isolated and total adiponectin levels determined by ELISA. Insulin sensitivity and lipid parameters were assessed in fasting blood samples taken at the time of biopsy collection.
A positive correlation was seen between the adiponectin concentration within the Sc and V mature adipocytes derived from each child (r = 0.924; P < 0.001). After logarithmic transformation of the Sc and V adiponectin concentrations (log-Sc and log-V) to render the data Gaussian, both log-Sc and log-V were found to be lower in those children with higher body mass index sd score (r = -0.621 and r = -0.357 respectively), although this reached statistical significance only in the Sc adipocytes (P = 0.03). Age was not related to either log-Sc or log-V adiponectin levels, although a significant negative association was seen with serum adiponectin (r = -0.589; P = 0.04). Log-Sc or log-V did not correlate with serum adiponectin concentrations, markers of insulin sensitivity, or circulating lipid levels.
These data indicate a relationship between total adiponectin levels in different tissue compartments, suggesting either some form of interaction or coregulation by systemic factors, possibly related to body size/fat mass. Serum concentrations of total adiponectin were inversely related to age but showed no relationship with either tissue levels or body mass index sd score.
Journal of Clinical Endocrinology & Metabolism 02/2006; 91(1):332-5. · 6.50 Impact Factor
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Julian P H Shield
Hormone Research 02/2006; 66(1):43-4. · 2.48 Impact Factor
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Anna L Gloyn,
Frank Reimann,
Christophe Girard,
Emma L Edghill,
Peter Proks,
Ewan R Pearson,
I Karen Temple,
Deborah J G Mackay, Julian P H Shield,
Debra Freedenberg,
Kathryn Noyes,
Sian Ellard,
Frances M Ashcroft,
Fiona M Gribble,
Andrew T Hattersley
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ABSTRACT: Neonatal diabetes can either remit and hence be transient or else may be permanent. These two phenotypes were considered to be genetically distinct. Abnormalities of 6q24 are the commonest cause of transient neonatal diabetes (TNDM). Mutations in KCNJ11, which encodes Kir6.2, the pore-forming subunit of the ATP-sensitive potassium channel (K(ATP)), are the commonest cause of permanent neonatal diabetes (PNDM). In addition to diabetes, some KCNJ11 mutations also result in marked developmental delay and epilepsy. These mutations are more severe on functional characterization. We investigated whether mutations in KCNJ11 could also give rise to TNDM. We identified the three novel heterozygous mutations (G53S, G53R, I182V) in three of 11 probands with clinically defined TNDM, who did not have chromosome 6q24 abnormalities. The mutations co-segregated with diabetes within families and were not found in 100 controls. All probands had insulin-treated diabetes diagnosed in the first 4 months and went into remission by 7-14 months. Functional characterization of the TNDM associated mutations was performed by expressing the mutated Kir6.2 with SUR1 in Xenopus laevis oocytes. All three heterozygous mutations resulted in a reduction in the sensitivity to ATP when compared with wild-type (IC(50) approximately 30 versus approximately 7 microM, P-value for is all <0.01); however, this was less profoundly reduced than with the PNDM associated mutations. In conclusion, mutations in KCNJ11 are the first genetic cause for remitting as well as permanent diabetes. This suggests that a fixed ion channel abnormality can result in a fluctuating glycaemic phenotype. The multiple phenotypes associated with activating KCNJ11 mutations may reflect their severity in vitro.
Human Molecular Genetics 04/2005; 14(7):925-34. · 7.64 Impact Factor
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ABSTRACT: Transient neonatal diabetes mellitus (TNDM) is associated with overexpression of an imprinted locus on chromosome 6q24; this locus contains a differentially methylated region (DMR) consisting of an imprinted CpG island that normally allows expression only from the paternal allele of genes under its control. Three types of abnormality involving 6q24 are known to cause TNDM: paternal uniparental disomy of chromosome 6 (pUPD6), an isolated methylation defect of the imprinted CpG island at chromosome 6q24 and a duplication of 6q24 of paternal origin. A fourth group of patients has no identifiable anomaly of 6q24. Bisulphite sequencing of the DMR has facilitated the development of a diagnostic test for TNDM based on ratiometric methylation-specific polymerase chain reaction. We have applied this method to 45 cases of TNDM, including 12 with pUPD6, 11 with an isolated methylation mutation at 6q24, 16 with a duplication of 6q24 and six of unknown aetiology, together with 29 normal controls. All were correctly assigned. The method is therefore capable of detecting all known genetic causes of TNDM at 6q24, although pUPD6 and methylation mutation cases are not distinguished from one another. In addition, we have carried out bisulphite sequencing of the DMR to compare its methylation status between six TNDM patients with a known methylation mutation, six patients with no identifiable 6q24 mutation and six normal controls. Whereas methylation mutation patients showed a near-total absence of DNA methylation at the TNDM locus, the patients with no identified molecular anomaly showed no marked methylation variation from controls.
Human Genetics 04/2005; 116(4):255-61. · 5.07 Impact Factor
