Effects of growth hormone treatment on neutrophil count in children born small for gestational age.
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Child↗
Biomedical subjects
David B Dunger
Publications and source records attributed to David B Dunger.
Sex-discordant associations with adiponectin levels and lipid profiles in children.
In adults, lower circulating levels of the adipocyte-derived hormone adiponectin are associated with obesity, type 2 diabetes, and cardiovascular disease risks. Its use as a risk marker in children is less clear. In 839 children aged 8 years from a representative birth cohort, circulating adiponectin levels were associated with body weight, BMI, waist circumference, and fasting and 30-min insulin levels, but the associations were opposite in boys, with positive associations, and girls, with inverse associations (P = 0.008-0.00001 for interaction with sex). Girls had overall higher adiponectin, higher total cholesterol, lower HDL cholesterol, and higher triglyceride levels than boys, even after adjustment for BMI. With increasing BMI, girls showed steeper declines in HDL cholesterol (P = 0.01 for interaction) and adiponectin levels (P = 0.0005 for interaction) and a steeper increase in triglyceride levels (P = 0.009 for interaction) compared with boys. In conclusion, plasma adiponectin is not a simple marker of central fat and insulin sensitivity in children. With increasing BMI, decreasing adiponectin levels in girls could contribute to their faster deterioration in lipid profiles in comparison with boys. Our data suggest a complex age- and sex-related regulation of adiponectin secretion or clearance.
Adiponectin↗
Effects of recombinant human IGF-I/IGF-binding protein-3 complex on glucose and glycerol metabolism in type 1 diabetes.
Recombinant human IGF-I (rhIGF-I) complexed with its natural binding protein IGF-binding protein (IGFBP)-3 (rhIGF-I/IGFBP-3) is a novel formulation that has been shown to improve insulin sensitivity in type 1 diabetes, yet the mechanisms are not clear. We used stable isotopes to investigate the effects of rhIGF-I/IGFBP-3 on glucose and glycerol metabolism in type 1 diabetes. Fifteen subjects (age 13-24 years; 10 males) were studied on three occasions in random order. Each study period lasted for two days, and an injection of either placebo or rhIGF-I/IGFBP-3 (0.1-0.8 mg x kg(-1) x day (-1)) was given subcutaneously at 6:00 p.m. on days 1 and 2. Following the second injection, the subjects were kept euglycemic overnight by a variable rate insulin infusion, followed by a 4-h, two-step (insulin 0.6 and 1.5 mU x kg(-1) x min (-1)) hyperinsulinemic-euglycemic clamp. During the overnight basal steady state, rhIGF-I/IGFBP-3 dose-dependently reduced endogenous glucose production rate (R(a)) (P = 0.004), while peripheral glucose uptake (R(d)) was not different from placebo. The increase in glucose R(d) during hyperinsulinemic clamp was greater following rhIGF-I/IGFBP-3 than placebo, both during the first (P = 0.008) and second step (P = 0.008) of the clamp. No significant differences were found in glycerol R(a), a measure of lipolysis, between rhIGF-I/IGFBP-3 and placebo. In conclusion, rhIGF-I/IGFBP-3 enhances glucose metabolism by controlling both endogenous glucose output and peripheral glucose uptake.
3-Hydroxybutyric Acid↗
Individual igf-I responsiveness to a fixed regimen of low-dose growth hormone replacement is increased with less variability in obese compared to non-obese adults with severe growth hormone deficiency.
BACKGROUND/AIMS: Decreased GH and IGF-I levels and increased GH responsiveness are frequently reported in obesity. As GH-deficient adults are commonly obese, the role of obesity in affecting hepatic responsiveness of IGF-I generation to GH stimulation is unclear in severe GH-deficient states. To address this question, we challenged a cohort of severely GH-deficient non-obese and obese adults with a fixed low GH dose (0.2 mg/day), and examined the relationship of body mass index (BMI) with IGF-I response. METHODS: 12 non-obese (6 males, median BMI 24.7 kg/m2) and 14 obese (7 males, median BMI 45.2 kg/m2) adults with severe GH deficiency were studied for 8 weeks. Blood samples were collected at baseline, and weeks 4 and 8. RESULTS: There was a larger increment and reduced variability of IGF-I levels in obese compared to non-obese GH-deficient adults at week 8, but not at week 4. A similar but smaller increment and less variability was observed with IGFBP-3. Increment IGF-I positively correlated with baseline BMI at weeks 4 (r=0.49, p<0.02) and 8 (r=0.47, p<0.02). No gender differences were observed with the IGF-I and IGFBP-3 response. CONCLUSIONS: This study demonstrates that there is a larger increment and deceased individual variability of IGF-I to the low GH replacement dose in obese compared to non-obese adults with severe GH deficiency, regardless of gender. The positive association of IGF-I increment with BMI implies a greater impact of obesity rather than GH deficiency in enhancing hepatic sensitivity to GH. These findings, thus, question the reliability of interpreting single serum IGF-I levels in non-obese adults with severe GH deficiency treated with low GH replacement doses.
3-Hydroxybutyric Acid↗
Genetic variation in the type 2 insulin-like growth factor receptor gene and disparity in childhood height.
OBJECTIVE: The type 2 insulin-like growth factor receptor (IGF2R) is thought to regulate insulin-like growth factor-II (IGF-II) bioavailability by degrading it in the lysosomes after uptake. We hypothesised that polymorphisms in the IGF2R gene could alter size at birth and childhood growth. DESIGN AND METHODS: The hypothesis was tested in a normal birth cohort (Avon Longitudinal Study of Parents and Children) by genotyping the IGF2R gene gly1619arg polymorphism, which causes a non-conservative amino acid change in the IGF-II binding region, using PCR and restriction fragment length polymorphism analysis. RESULTS: The IGF2R gly1619arg genotype was not associated with any measure of size at birth, but A/A homozygotes grew more slowly, as determined by their change in height standard deviation scores (SDS) over the first three years (-0.70 (0.72); n = 12), than G/G homozygotes (0.00 (1.09); n = 561) (p = 0.03). They remained shorter during childhood and by the age of 7 years respective height SDS were: 0.73 (1.02) (n = 12) and 0.01 (0.99) (n = 634) (p = 0.01). These height differences persisted after adjusting for parental heights and gender. There were no detectable differences in weights at 7 years. CONCLUSION: Allelic variation in the gly1619arg SNP of the IGF2R gene is associated with disparity in childhood stature which could reflect altered binding of IGF-II to its receptor.
Alleles↗
Common polymorphism in H19 associated with birthweight and cord blood IGF-II levels in humans.
BACKGROUND: Common genetic variation at genes that are imprinted and exclusively maternally expressed could explain the apparent maternal-specific inheritance of low birthweight reported in large family pedigrees. We identified ten single nucleotide polymorphisms (SNPs) in H19, and we genotyped three of these SNPs in families from the contemporary ALSPAC UK birth cohort (1,696 children, 822 mothers and 661 fathers) in order to explore associations with size at birth and cord blood IGF-II levels. RESULTS: Both offspring's and mother's H19 2992C>T SNP genotypes showed associations with offspring birthweight (P = 0.03 to P = 0.003) and mother's genotype was also associated with cord blood IGF-II levels (P = 0.0003 to P = 0.0001). The offspring genotype association with birthweight was independent of mother's genotype (P = 0.01 to P = 0.007). However, mother's untransmitted H19 2992T allele was also associated with larger birthweight (P = 0.04) and higher cord blood IGF-II levels (P = 0.002), suggesting a direct effect of mother's genotype on placental IGF-II expression and fetal growth. The association between mother's untransmitted allele and cord blood IGF-II levels was more apparent in offspring of first pregnancies than subsequent pregnancies (P-interaction = 0.03). Study of the independent Cambridge birth cohort with available DNA in mothers (N = 646) provided additional support for mother's H19 2992 genotype associations with birthweight (P = 0.04) and with mother's glucose levels (P = 0.01) in first pregnancies. CONCLUSION: The common H19 2992T allele, in the mother or offspring or both, may confer reduced fetal growth restraint, as indicated by associations with larger offspring birth size, higher cord blood IGF-II levels, and lower compensatory early postnatal catch-up weight gain, that are more evident among mother's smaller first-born infants.
Birth Weight↗
Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms.
As part of an ongoing search for genes associated with type 1 diabetes (T1D), a common autoimmune disease, we tested the biological candidate gene IL2RA (CD25), which encodes a subunit (IL-2R alpha) of the high-affinity interleukin-2 (IL-2) receptor complex. We employed a tag single-nucleotide polymorphism (tag SNP) approach in large T1D sample collections consisting of 7,457 cases and controls and 725 multiplex families. Tag SNPs were analyzed using a multilocus test to provide a regional test for association. We found strong statistical evidence in the case-control collection (P=6.5x10(-8)) for a T1D locus in the CD25 region of chromosome 10p15 and replicated the association in the family collection (P=7.3x10(-3); combined P=1.3x10(-10)). These results illustrate the utility of tag SNPs in a chromosome-regional test of disease association and justify future fine mapping of the causal variant in the region.
Case-Control Studies↗
Effects of obesity on growth and puberty.
Nutrition is an important regulator of the tempo of human growth. Infancy may represent a critical "window" where variations in nutrition have longer-term consequences for growth and development. Rapid weight gain during infancy is associated with accelerated growth and early pubertal development. Rapid weight gain in infancy is also associated with the development of insulin resistance and an exaggerated adrenarche. Such circulating hormonal changes, together with elevated leptin levels and integral effects of fat cells on hormone action through local 11beta-steroid dehydrogenase and aromatase activity could effect rate of progression of pubertal development in obese subjects. The secular trends in growth and maturation are partly attributed to changing nutrition. Recent data suggest that age at menarche may be static, but there is a debate as to whether the first signs of puberty are being seen much earlier in obese girls. Rapid early weight gain, obesity and early development may have implications for later health through the development of PCOS and overall association with cancer risk.
Adolescent↗
Endocrine and metabolic consequences of intrauterine growth retardation.
Size at birth and early infancy growth rates have been linked to long-term risks for diseases, such as type 2 diabetes and cardiovascular disease. These associations could be explained by permanent programming of metabolic responses and selective survival of those genetically predisposed to such adaptations. These epidemiologic associations may also affect long-term disease risk in short small-for-gestational age children, who are often treated with growth hormone. Study of the mechanisms and genetic factors involved in the association between small size at birth, rapid postnatal weight gain, and adult disease may promote the early identification of subjects with the highest disease risk and new opportunities to develop targeted early interventions.
Disease↗
Assessing the validity of the association between the SUMO4 M55V variant and risk of type 1 diabetes.
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Age of Onset↗
Increasing urine albumin excretion is associated with growth hormone hypersecretion and reduced clearance of insulin in adolescents and young adults with type 1 diabetes: the Oxford Regional Prospective Study.
HYPOTHESIS: We previously described lower insulin-like growth factor I (IGF-I) levels in association with increased microalbuminuria (MA) risk in type 1 diabetic subjects followed from diabetes diagnosis through puberty into adulthood. By inference lower IGF-I levels may be associated with higher GH levels and changes in insulin sensitivity. METHODS: To test this hypothesis, microalbuminuric subjects (MA+, n = 14) from the same cohort had overnight GH levels measured during euglycaemia (5 mmol/l, 01:00-07:30 h) maintained by a variable rate insulin infusion followed by a 2-step hyperinsulinaemic, euglycaemic clamp study using [6.6 2H2] glucose, and were compared to MA- controls (MA-, n = 14), matched for age (median 19.3 years, range 15.8-30.5), sex, duration of diabetes (11.1 years, range 5.1-16.4). RESULTS: In MA+ cases GH levels, measured by the Pulsar programme, were higher (baseline; 1.8 +/- 1.4 vs. 0.7 +/- 0.5 ng/ml, P = 0.02, mean; 3.8 +/- 1.3 vs. 2.6 +/- 1.6 ng/ml, P = 0.03, maximum; 16.7 +/- 7.0 vs. 12.3 +/- 5.4, P = 0.02), despite similar HbA1(c) levels (9.8%vs. 9.6%, P = 0.6) and body or truncal fat mass. Fourier transform revealed increased GH pulse amplitude at all periodicities and overnight insulin clearance was reduced (11.7 +/- 6.9 vs. 20.1 +/- 6.5 ml/kg/min, P < 0.02). In multiple regression analysis, urine albumin excretion was associated with higher GH levels and reduced insulin clearance, independent of HbA1(c) and body composition. In female cases (n = 9), dextrose requirements were reduced during the first step of the euglycaemic clamp (1.7 +/- 0.8 vs. 2.7 +/- 1.4, P < 0.05) but no such differences existed in males or in the rate of glucose production or disposal. CONCLUSION: The development of MA during puberty and young adulthood is associated with higher GH levels and abnormalities in insulin metabolism, particularly in females. These data extend support for our previous findings indicating a role for the GH/IGF-I axis in the pathogenesis of MA.
Adolescent↗
Improvement in insulin sensitivity without concomitant changes in body composition and cardiovascular risk markers following fixed administration of a very low growth hormone (GH) dose in adults with severe GH deficiency.
OBJECTIVE: Untreated GH-deficient adults are predisposed to insulin resistance and excess cardiovascular mortality. We showed previously that short-term treatment with a very low GH dose (LGH) enhanced insulin sensitivity in young healthy adults. The present study was therefore designed to explore the hypothesis that LGH, in contrast to the standard GH dose titrated to normalize serum IGF-I levels (SGH), may have differing effects on insulin sensitivity, body composition, and cardiovascular risk markers [lipid profile, C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and adiponectin] in adults with severe GH deficiency. PATIENTS AND METHODS: In this 12-month open, prospective study, 25 GH-deficient adults were randomized to receive either a fixed LGH (0.10 mg/day, n = 13) or SGH (mean dose 0.48 mg/day, n = 12), and eight age- and body mass index (BMI)-matched GH-deficient adults acted as untreated controls. Fasting blood samples were collected at baseline and at months 1, 3, 6, 9 and 12. Assessments of insulin sensitivity, using the hyperinsulinaemic euglycaemic clamp technique, and body composition, using dual-energy X-ray absorptiometry, were performed at baseline and at month 12. RESULTS: The LGH decreased fasting glucose levels (P < 0.01) and enhanced insulin sensitivity (P < 0.02), but body composition, nonesterified fatty acid (NEFA) levels and cardiovascular risk markers were unchanged. The SGH did not modify insulin sensitivity, decreased truncal fat mass (P < 0.05), CRP (P < 0.05) and IL-6 (P < 0.05) levels, and increased NEFA levels (P < 0.05). No changes were observed with the untreated controls. CONCLUSION: Our data indicate that, in contrast to the SGH, fixed administration of the LGH enhances insulin sensitivity with no apparent effects on body composition, lipolysis and other surrogate cardiovascular risk markers in adults with severe GH deficiency. Thus, the LGH may potentially be a beneficial replacement dose in reducing type 2 diabetes risk in adults with severe GH deficiency.
Adult↗
The relationship between microalbuminuria and glomerular filtration rate in young type 1 diabetic subjects: The Oxford Regional Prospective Study.
BACKGROUND: The purpose of this study was to examine the relationship between glomerular filtration rate (GFR) measured at 5 years' diabetes duration and annual urine albumin excretion in a prospective cohort of children with type 1 diabetes (T1DM). METHODS: Three hundred and eight children were followed from diagnosis of T1DM [aged 9.8 years (range 0.4-15.9) for a median duration of 10.9 years (6.0-17.8) with annual assessments comprising measurement of HbA1(c) and 3 urine samples for albumin:creatinine ratio (ACR). GFR was measured in all children at 5 years' diabetes duration. RESULTS: Two hundred forty-three (78.8%) subjects were normoalbuminuric (MA-) for the duration of the study. At 5 years: 35 (11.4%) subjects had MA (MA+) and 30 (9.7%) subjects were normoalbuminuric but developed MA during subsequent follow-up annual assessments (future MA+). In the future MA+ group compared to the MA+ and MA- groups; GFR was higher (167 vs. 134 vs. 139 mL/min/1.73 m(2), P < 0.002); the prevalence of hyperfiltration (GFR >125 mL/min/1.73 m(2)) was greater (97 vs. 57 vs. 64%, P= 0.006) and HbA1c levels were higher (11.4 vs. 10.8 vs. 9.7%, P < 0.001). The probability (Cox Model) of having hyperfiltration at 5 years' duration was related to puberty (a 1.7-fold increased risk with puberty onset) and poor glycemic control (a 10% increased risk for a 1% increase in HbA1c). Comparing subjects with and without hyperfiltration, prior to the first GFR measurement no difference in ACR levels existed; however, after this time median ACR levels were significantly greater [1.2 (0.1-86.4) vs. 0.9 (0.1-71.6) mg/mmol, P= 0.003], independent of age and HbA1c levels. The probability of developing MA between 5 and 10 years' duration was associated with poor glycemic control (a 30% increased risk for a 1% increase in HbA1c) and higher GFR at 5 years (22% increased risk for a 10 mL/min/1.73 m(2) rise in GFR). CONCLUSION: Glomerular hyperfiltration is associated with puberty and increasing ACR levels and is predictive of MA independent of HbA1c. This suggests that factors other than poor glycemic control may be involved in the pathogenesis of early diabetic nephropathy and early intervention with medical therapy to reduce GFR may be beneficial even before onset of MA.
Adolescent↗
Childhood and adolescent diabetes.
Circulating levels of insulin-like growth factor-I (IGF-I) and its principal binding protein IGFBP-3 are reduced, whereas those of the inhibitory binding protein, IGFBP-1, tend to be high in children and adolescents with type 1 diabetes mellitus (T1DM). These abnormalities are thought to arise because of relative portal hypoinsulinaemia and partial resistance at the hepatic growth hormone (GH) receptor. During adolescence, reductions in IGF-I and IGF bioactivity lead to feedback for GH hypersecretion and the elevated GH and low IGF-I levels lead to an increase of the normal insulin resistance encountered during puberty. Low IGF-I levels, but in particular elevated GH levels, have been implicated in the pathogenesis of diabetic microangiopathic complications, in particular, renal hypertrophy, glomerular hyperfiltration and the development of microalbuminuria. Early study of IGF-I replacement with recombinant human IGF-I (rhIGF-I) demonstrated, in the short term, reductions in GH hypersecretion with improved insulin sensitivity and, in the longer term, reductions in insulin requirements and improvements in HbA1c levels. However, larger doses of rhIGF-I were associated with retinopathy either due to rapid improvements in glycaemic control or direct effects of high levels of 'free' IGF-I. More recently, pilot studies using the combination of rhIGF-I/rhIGFBP-3 have confirmed the physiological efficacy of IGF-I replacement in T1DM. The combined treatment is better tolerated and may result in reduced tissue exposure to high levels of 'free' IGF-I. Longer term clinical studies with this IGF-I/IGFBP-3 combination are needed.
Adolescent↗
The relationship of disordered eating habits and attitudes to clinical outcomes in young adult females with type 1 diabetes.
OBJECTIVE: To describe the clinical outcomes of adolescent and young adult female subjects with type 1 diabetes in relation to the disturbance of eating habits and attitudes over 8-12 years. RESEARCH DESIGN AND METHODS: Patients were recruited from the registers of pediatric and young adult diabetes clinics (including nonattenders) and interviewed in the community. A total of 87 patients were assessed at baseline (aged 11-25 years), and 63 (72%) were reinterviewed after 8-12 years (aged 20-38 years). Eating habits and attitudes were assessed by a semistructured research diagnostic interview (Eating Disorder Examination). RESULTS: Clinical eating disorders ascertained from the interview and/or case note review at baseline or follow-up were found in 13 subjects (14.9% [95% CI 8.2-24.2]), and an additional 7 subjects had evidence of binging or purging, bringing the total affected to 26%. Insulin misuse for weight control was reported by 31 (35.6% [25.7-46.6]) subjects. Overall outcome was poor; serious microvascular complications were common and mortality was high. There were significant relationships between disordered eating habits, insulin misuse, and microvascular complications. CONCLUSIONS: Although the cross-sectional prevalence of clinical eating disorders in young women with diabetes is modest, the cumulative incidence of eating problems continues to increase after young adulthood, and this is strongly associated with poor physical health outcomes. The combination of an eating disorder and diabetes puts patients at high risk of mortality and morbidity. Better methods of detection and management are needed.
Adolescent↗
Cross-sectional associations of diet and insulin-like growth factor levels in 7- to 8-year-old children.
BACKGROUND: The insulin-like growth factors (IGF) are polypeptide hormones which are associated with several adult diseases including cancer and coronary heart disease. The dietary determinants of circulating levels of components of the IGF system are of interest, as these may mediate some of the effects of diet on later health. However, few studies have examined the relationship between diet and IGF levels in children. OBJECTIVE: To investigate associations between diet and IGF-I and IGFBP-3 levels in 7- to 8-year-old children. METHODS: This study used subjects participating in the Avon Longitudinal Study of Parents and Children. Diet was assessed using a 3-day unweighed food diary. Confounding variables considered were maternal education, housing tenure, birthweight, and body mass index. RESULTS: Complete information on dietary intakes, IGF levels, and all confounding variables were available for 521 children (287 boys). IGF-I was positively associated with intakes of protein, magnesium, zinc, calcium, potassium, and phosphorus, and IGFBP-3 was positively associated with energy. The IGF-I/IGFBP-3 ratio was positively associated with intakes of protein, zinc, and phosphorus. There was some evidence that the dietary determinants of the IGF system differed between the sexes. None of the foods examined were strongly associated with IGF levels, in particular, there was no association with red meat or vegetable intake. CONCLUSION: These data suggest that the IGF axis in children is affected by diet. This may provide a mechanism whereby childhood diet could have a long-term effect on risk of chronic disease.
Child↗
Type 1 diabetes in children: a review.
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Blood Glucose↗
A family with severe insulin resistance and diabetes due to a mutation in AKT2.
Inherited defects in signaling pathways downstream of the insulin receptor have long been suggested to contribute to human type 2 diabetes mellitus. Here we describe a mutation in the gene encoding the protein kinase AKT2/PKBbeta in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Expression of the mutant kinase in cultured cells disrupted insulin signaling to metabolic end points and inhibited the function of coexpressed, wild-type AKT. These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans.
Active Transport, Cell Nucleus↗