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D Elleri,
J M Allen,
J Harris,
K Kumareswaran,
M Nodale,
L Leelarathna,
C L Acerini,
A Haidar,
M E Wilinska,
N Jackson,
A M Umpleby,
M L Evans, D B Dunger,
R Hovorka
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ABSTRACT: AIMS/HYPOTHESIS: Successful postprandial glycaemia management requires understanding of absorption patterns after meals containing variable complex carbohydrates. We studied eight young participants with type 1 diabetes to investigate a large low-glycaemic-load (LG) meal and another eight participants to investigate a high-glycaemic-load (HG) meal matched for carbohydrates (121 g). METHODS: On Visit 1, participants consumed an evening meal. On follow-up Visit 2, a variable-target glucose clamp was performed to reproduce glucose and insulin levels from Visit 1. Adopting stable-label tracer dilution methodology, we measured endogenous glucose production on Visit 2 and subtracted it from total glucose appearance measured on Visit 1 to obtain meal-attributable glucose appearance. RESULTS: After the LG meal, 25%, 50% and 75% of cumulative glucose appearance was at 88 ± 21, 175 ± 39 and 270 ± 54 min (mean ± SD), whereas glucose from the HG meal appeared significantly faster at 56 ± 12, 100 ± 25 and 153 ± 39 min (p < 0.001 to 0.003), and resulted in a 50% higher peak appearance (p < 0.001). Higher apparent bioavailability by 15% (p = 0.037) was observed after the LG meal. We documented a 20 min deceleration of dietary mixed carbohydrates compared with dietary glucose for the HG meal and a twofold deceleration for the LG meal. CONCLUSIONS/INTERPRETATION: Absorption patterns may be influenced by glycaemic load and/or meal composition, affecting optimum prandial insulin dosing in type 1 diabetes.
Diabetologia 02/2013; · 6.81 Impact Factor
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ABSTRACT: Aims/hypothesis. Early detection of risk of microalbuminuria could prevent early renal damage. We investigated whether urine retinol binding
protein and N-acetyl-glucosaminidase could predict the risk of microalbuminuria in a large cohort of children followed from diagnosis of
Type I (insulin-dependent) diabetes mellitus. Methods. Subjects under 16 years of age within a georaphically defined region were recruited at diagnosis of Type I (insulin-dependent)
diabetes mellitus. Annually, albumin-, retinol binding protein- and N-acetyl-glucosaminidase- to creatinine ratios were each measured in 3 urine samples. Results. A total of 511 subjects were followed for a median of 6 years (range: 1–14). Microalbuminuria (males: ≥ 3.5 mg/mmol; females:
≥ 4.0 mg/mmol, in 2 out of 3 urines) developed in 78 subjects (36 male). The cumulative probability of microalbuminuria was
40 % after 12 years duration of diabetes. Retinol-binding-proteinuria (men: ≥ 21 μg/mmol; women ≥ 33 μg/mmol) developed in
217 subjects (152 men). The cumulative probability of retinol-binding-proteinuria was 67 % after 12 years duration of diabetes.
The cumulative probability of retinol-binding-proteinuria was 40 % before the onset of microalbuminuria and 59 % in subjects
who did not subsequently develop microalbuminuria. Retinol-binding-proteinuria developed at a higher rate with increasing
HbA1 c than microalbuminuria. N-acetyl-glucosaminidase-uria (males: ≥ 56 μmol-pnp · h–1· mmol–1; females: ≥ 46 μmol-pnp · h–1· mmol–1) developed in 477 subjects. The cumulative probability of N-acetyl-glucosaminidase-uria was 98 % after 10 years of diabetes duration. The cumulative probability of N-acetyl-glucosaminidase-uria was 73 % in the years before the onset of microalbuminuria and 97 % in subjects without microalbuminuria.
The probability of N-acetyl-glucosaminidase-uria was 99 % with an HbA1 c greater than or equal to 14.5 %. Conclusions/interpretation. Raised amounts of urine retinol binding protein and N-acetyl-glycosaminidase are related to HbA1 c and the duration of diabetes. They occur in the majority of subjects and are not early markers for the risk of microalbuminuria.
[Diabetologia (2001) 44: 224–229]
Diabetologia 04/2012; 44(2):224-229. · 6.81 Impact Factor
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ABSTRACT: There are limited data on growth hormone-binding protein (GHBP) and free GH levels during the physiological challenge of a prolonged fast. Our aim was to explore the relationships between GHBP, free GH, total GH and non-esterified fatty acid (NEFA) levels during overnight and 24-hour fasts in healthy young adults.
We measured nocturnal levels of GHBP at three time-points (22:00, 03:00, 08:00), NEFA every 60 min and ultra-filtered free GH and total GH at 15-minute intervals for 10 h (22:00-08:00) during an overnight and a 24-hour fast in 7 female and 4 male normal-weight subjects aged 24.8 years (range: 22.8-26.9) with BMI 22.5 kg/m² (range: 18-27).
Spontaneous free and total GH levels were closely related during the overnight and 24-hour fasts (r=0.99, p<0.0001 and r=0.99, p<0.0001 respectively). 24 h of fasting led to an increase in levels of basal free GH (p=0.03), mean free GH (p=0.04), mean total GH (p=0.04) and NEFA (p<0.0001) whilst GHBP levels remained similar (p=0.8). Percentage free (over total) GH was similar during the overnight and prolonged fasts (p=0.3). There were no associations between levels of NEFA and free (r=0.24, p=0.5) or total GH (r=0.20, p=0.6).
A 24-hour fast led to parallel increases in free and total GH levels whilst there was no discernable change in GHBP levels or the fraction of free GH. This suggests that GHBP plays a role in limiting variations of circulating free GH levels. NEFA levels increased during the prolonged fast but they were not correlated with free or total GH levels.
Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society 03/2012; 22(2):76-81. · 2.35 Impact Factor
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H R Murphy,
D Elleri,
J M Allen,
J Harris,
D Simmons,
G Rayman,
R C Temple,
A M Umpleby, D B Dunger,
A Haidar,
M Nodale,
M E Wilinska,
R Hovorka
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ABSTRACT: Although maternal hyperglycaemia is associated with increased risk of adverse pregnancy outcome, the mechanisms of postprandial hyperglycaemia during pregnancy are poorly understood. We aimed to describe glucose turnover in pregnant women with type 1 diabetes, according to stage of gestation (early vs late gestation).
The rates of systemic glucose appearance (R(a)) and glucose disposal (R(d)) were measured in ten pregnant women with type 1 diabetes during early (12-16 weeks) and late (28-32 weeks) gestation. Women ate standardised meals--a starch-rich 80 g carbohydrate dinner and a sugar-rich 60 g carbohydrate breakfast--and fasted between meals and overnight. Stable-label isotope tracers ([6,6-(2)H(2)]glucose and [U-(13)C]glucose) were used to determine R(a), R(d) and glucose bioavailability. Closed-loop insulin delivery maintained stable glycaemic conditions.
There were no changes in fasting R(a) (10 ± 2 vs 11 ± 2 μmol kg(-1) min(-1); p = 0.32) or fasting R(d) (11 ± 2 vs 11 ± 1 μmol kg(-1) min(-1); p = 0.77) in early vs late gestation. There was increased hepatic insulin resistance (381 ± 237 vs 540 ± 242 μmol kg(-1) min(-1) × pmol/l; p = 0.04) and decreased peripheral insulin sensitivity (0.09 ± 0.04 vs 0.05 ± 0.02 μmol kg(-1) min(-1) per pmol/l dinner, 0.11 ± 0.05 vs 0.07 ± 0.03 μmol kg(-1) min(-1) per pmol/l breakfast; p = 0.002) in late gestation. It also took longer for insulin levels to reach maximal concentrations (49 [37-55] vs 71 [52-108] min; p = 0.004) with significantly delayed glucose disposal (108 [87-125] vs 135 [110-158] min; p = 0.005) in late gestation.
Postprandial glucose control is impaired by significantly slower glucose disposal in late gestation. Early prandial insulin dosing may help to accelerate glucose disposal and potentially ameliorate postprandial hyperglycaemia in late pregnancy.
ISRCTN 62568875
Diabetes UK Project Grant BDA 07/003551. H.R. Murphy is funded by a National Institute for Health Research (NIHR) research fellowship (PDF/08/01/036). Supported also by the Juvenile Diabetes Research Foundation (JDRF), Abbott Diabetes Care (Freestyle Navigator CGM and sensors free of charge), Medical Research Council Centre for Obesity and Related Metabolic Diseases and NIHR Cambridge Biomedical Research Centre.
Diabetologia 11/2011; 55(2):282-93. · 6.81 Impact Factor
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ABSTRACT: Asymmetric dimethylarginine (ADMA) is an independent risk factor for cardiovascular disease and its concentrations are increased in several diseases, including diabetes. However, there is limited information on this plasma marker in young people, particularly in those with Type 1 diabetes. The aim of the present study was therefore to perform a longitudinal evaluation of plasma ADMA and of its determinants in young people with childhood-onset Type 1 diabetes.
For measurement of ADMA using mass spectrometry, 1018 longitudinal stored blood samples were available from 330 young people with Type 1 diabetes followed in the Oxford Regional Prospective Study. Additional data concerning annual assessments of HbA(1c) , height, weight, insulin dose and three early morning urine samples for measurement of the albumin/creatinine ratio were available.
ADMA levels were significantly higher in males than in females (mean ± SD: 0.477 ± 0.090 vs. 0.460 ± 0.089 μmol/l, P=0.002) and declined with chronological age (estimate ± SE: -0.0106 ± 0.0008, P<0.001). A significant inverse association was detected between ADMA and HbA(1c) (estimate ± SE:-0.0113 ± 0.001, P<0.001). ADMA levels were lower in subjects developing microalbuminuria (mean ± SD: 0.455 ± 0.093 vs. 0.476 ± 0.087 μmol/l, P=0.001) than in subjects with normoalbuminuria, but this difference disappeared after adjusting for HbA(1c) .
In this longitudinal study, ADMA concentrations decreased with age and were significantly higher in males and lower in subjects developing microalbuminuria. These associations were largely explained by a paradoxical negative association between HbA(1c) and ADMA. We suggest that chronic hyperglycaemia might down-regulate mechanisms implicated in ADMA production or stimulate its metabolism confounding short-term associations with complications risk.
Diabetic Medicine 02/2011; 28(6):685-91. · 2.90 Impact Factor
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ABSTRACT: We assessed an extended interruption of subcutaneous insulin delivery during overnight closed-loop glucose control in children and adolescents with Type 1 diabetes (T1D).
In seven young subjects with T1D [age 14.2+/-2.1 years, diabetes duration 6.9+/-4.0 years, glycated haemoglobin (HbA1c) 8.0+/-1.5%, body mass index (BMI) 21.4+/-4.0 kg/m2, total daily insulin dose 0.9+/-0.2 units/kg/day; mean+/-sd) participating in overnight closed-loop glucose control studies, insulin delivery was interrupted for at least 90 min on the basis of predicted hypoglycaemia, low prevailing glucose levels or a too-steep decline in glucose levels.
Insulin delivery was interrupted for 165 (105, 210) min [median, interquartile range (IQR)]. Plasma glucose was 6.2+/-3.2 mmol/l at the time of interruption and 5.5+/-2.0 mmol/l 105 min later (P=0.15, paired t-test). Plasma glucose declined during the first hour of the interruption at a rate of 0.02+/-0.03 mmol/l per min and reached a nadir of 5.2+/-2.7 mmol/l; 105 min after the interruption, plasma glucose was increasing at a rate of 0.01+/-0.03 mmol/l per min. When insulin delivery restarted, plasma glucose was 6.4+/-2.2 mmol/l and peaked at 7.9+/-2.1 mmol/l in 60 min (P=0.01). Physiological levels of plasma insulin were measured throughout with a nadir of 119+/-78 pmol/l.
A prolonged interruption of insulin delivery during overnight closed-loop glucose control to prevent hypoglycaemia was not associated with an increased risk of hyperglycaemia in young people with T1D.
Diabetic Medicine 04/2010; 27(4):480-4. · 2.90 Impact Factor
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ABSTRACT: The incidence of type 1 diabetes (T1D) is increasing worldwide, particularly in children, and is associated with a significant burden, mainly related to the development of vascular complications. The prevention and treatment of microvascular complications, which include nephropathy, retinopathy and neuropathy, are of paramount importance to decrease the associated mortality and morbidity.
A literature search was performed on Medline and articles on microvascular complications, with particular emphasis on the increasing incidence of childhood T1D and its implications on prevention and treatment of complications, were selected.
The incidence of childhood T1D is increasing. Early identification of subjects at risk for long-term complications and early implementation of preventive and therapeutic strategies are fundamental in order to reduce the burden associated with microvascular complications of diabetes. Improving glycaemic control is the principle way of preventing and treating T1D complications.
In adults with T1D and microvascular complications, treatment with anti-hypertensive drugs and statins is increasingly common, whereas there are no definitive indications for treatment with these drugs in children and adolescents with early signs of complications.
There is growing interest in the development of new preventive and therapeutic strategies targeting specific pathways implicated in the pathogenesis of microvascular complications.
Investigations to clarify genetic and environmental factors implicated in the pathogenesis of microvascular complications could lead to the identification of biochemical markers with high predictive values, to be used as a guide for screening and intervention programmes.
British Medical Bulletin 01/2010; 94:145-64. · 4.54 Impact Factor
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ABSTRACT: Using compartment modelling, we assessed the time delay between blood glucose and sensor glucose measured by the Guardian RT continuous glucose monitoring system in young subjects with Type 1 diabetes (T1D).
Twelve children and adolescents with T1D treated by continuous subcutaneous insulin infusion (male/female 7/5; age 13.1 +/- 4.2 years; body mass index 21.9 +/- 4.3 kg/m(2); mean +/- sd) were studied over 19 h in a Clinical Research Facility. Guardian RT was calibrated every 6 h and sensor glucose measured every 5 min. Reference blood glucose was measured every 15 min using a YSI 2300 STAT Plus Analyser. A population compartment model of sensor glucose-blood glucose kinetics was adopted to estimate the time delay, the calibration scale and the calibration shift.
The population median of the time delay was 15.8 (interquartile range 15.2, 16.5) min, which was corroborated by correlation analysis between blood glucose and 15-min delayed sensor glucose. The delay has a relatively low intersubject variability, with 95% of individuals predicted to have delays between 10.4 and 24.3 min. Population medians (interquartile range) for the scale and shift are 0.800 (0.777, 0.823) (unitless) and 1.66 (1.47, 1.84) mmol/l, respectively.
In young subjects with T1D, the total time delay associated with the Guardian RT system was approximately 15 min. This is twice that expected on physiological grounds, suggesting a 5- to 10-min delay because of data processing. Delays above 25 min are rarely to be observed.
Diabetic Medicine 01/2010; 27(1):117-22. · 2.90 Impact Factor
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ABSTRACT: The endogenous secretory receptor for advanced glycation end products (esRAGE) appears to work as a scavenger for AGEs and it has been implicated in the pathogenesis of diabetic complications. The aim of the present study was to perform a longitudinal evaluation of esRAGE in young people with Type 1 diabetes (T1D) in relation to the development of microalbuminuria (MA).
Serum esRAGE levels were measured in longitudinally collected blood samples from 49 T1D patients with MA (MA+) and 49 matched normoalbuminuric patients (MA-), followed in the Oxford Regional Prospective Study. esRAGE levels were compared between MA+ and MA- subjects in relation to the time of MA onset.
Overall, esRAGE levels were significantly lower in MA+ than in MA- subjects (0.727 +/- 0.396 vs. 0.936 +/- 0.433 ng/ml; P = 0.015). These differences between the two groups were present both before (0.725 +/- 0.410 vs. 0.956 +/- 0.505 ng/ml, P = 0.038) and after the onset of MA (0.750 +/- 0.433 vs. 0.948 +/- 0.418 ng/ml, P = 0.04). In a longitudinal analysis there was no effect of age, duration, glycated haemoglobin (HbA(1c)) or body mass index standard deviation scores on esRAGE levels (all P > 0.05). In a Cox model, esRAGE levels significantly contributed to the probability of developing MA [Exp(B)(95% confidence interval): 0.34(0.12-0.98); P = 0.04), independently of HbA(1c).
In this longitudinal study of young people with T1D, esRAGE levels were reduced in MA+ subjects, even before the onset of MA, and appeared to be related to its development, thus suggesting a potential role of esRAGE in the pathogenesis of this complication. Diabet. Med. 26, 815-819 (2009).
Diabetic Medicine 08/2009; 26(8):815-9. · 2.90 Impact Factor
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ABSTRACT: Insulin-like growth factor-1 is a major childhood growth factor and promotes pancreatic islet cell survival and growth in vitro. We hypothesised that genetic variation in IGF1 might be associated with childhood growth, glucose metabolism and type 1 diabetes risk. We therefore examined the association between common genetic variation in IGF1 and predisposition to type 1 diabetes, childhood growth and metabolism.
Variants in IGF1 were identified by direct resequencing of the exons, exon-intron boundaries and 5' and 3' regions in 32 unrelated type 1 diabetes patients. A tagging subset of these variants was genotyped in a collection of type 1 diabetes families (3,121 parent-child trios). We also genotyped a previously reported CA repeat in the region 5' to IGF1. A subset of seven tag single nucleotide polymorphism (SNPs) that captured variants with minor allele frequency (MAF) > or =0.05 was genotyped in 902 children from the Avon Longitudinal Study of Parents And Children with data on growth, IGF-1 concentrations, insulin secretion and insulin action.
Resequencing detected 27 SNPs in IGF1, of which 11 had a MAF > 0.05 and were novel. Variants with MAF > or = 0.10 were captured by a set of four tag-SNPs. These SNPs showed no association with type 1 diabetes. In children, global variation in IGF1 was weakly associated with IGF-1 concentrations, but not with other phenotypes. The CA repeat in the region 5' to IGF1 showed no association with any phenotype.
Common genetic variation in IGF1 alters IGF-1 concentrations but is not associated with growth, glucose metabolism or type 1 diabetes.
Diabetologia 06/2008; 51(5):811-5. · 6.81 Impact Factor
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ABSTRACT: Concordance with growth hormone (GH) therapy in 75 children was objectively assessed using data on GP prescriptions over 12 months. 23% missed >2 injections/week. Lower concordance was associated with longer duration on GH therapy (p<0.005), lack of choice of delivery device (p<0.005) and short prescription durations (p<0.005), and predicted lower height velocities (p<0.05).
Archives of Disease in Childhood 03/2008; 93(2):147-8. · 2.88 Impact Factor
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ABSTRACT: The long-acting insulin analogue glargine reduces nocturnal hypoglycaemia and stabilizes morning blood glucose levels in patients with Type 1 diabetes (T1DM) on multiple injection therapy. However, young children may not tolerate such intensive insulin regimens. We investigated the effects of glargine in various three-injections-daily insulin combinations on 24-h glucose control in prepubertal children.
Seventeen T1DM prepubertal children (10 boys), median age 10.2 years (range 6.0-12.4), glycated haemoglobin (HbA(1c)) 8.8% (6.8-11.5) were recruited to a randomized, open-label, cross-over study. After a 2-week run-in period (with NPH pre-bed), every child underwent three different 3-week treatment blocks in random order. All treatment blocks included glargine pre-bed, but used different morning insulins: block 1, soluble only; block 2, soluble + NPH; block 3, aspart + NPH. Continuous glucose monitoring was performed for 3 days at the end of the run-in and each treatment block.
Compared with the run-in period on NPH, the three glargine treatment blocks were associated with lower (P < 0.0001) and less variable (P < 0.05) pre-breakfast glucose levels, and with an 8-15% reduction in total daily insulin dose (P < 0.0001). Risk of nocturnal hypoglycaemia detected by continuous glucose monitoring varied significantly between the three glargine treatment blocks, and was lowest when children were given aspart + NPH in the morning (block 3).
Insulin glargine pre-bed can be used in three-injections-daily regimens in prepubertal children to lower and stabilize pre-breakfast glucose levels. However, to avoid the risk of nocturnal hypoglycaemia, the pre-bed glargine dose should be lowered by giving a further long-acting insulin, such as NPH, in the morning.
Diabetic Medicine 01/2008; 24(12):1406-11. · 2.90 Impact Factor
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Diabetologia 11/2007; 50(10):2218-20. · 6.81 Impact Factor
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ABSTRACT: Size at birth and patterns of postnatal weight gain have been associated with adult risk for the development of type 2 diabetes in many populations, but the putative pathophysiological link remains unknown. Studies of contemporary populations indicate that rapid infancy weight gain, which may follow fetal growth restriction, is an important risk factor for the development of childhood obesity and insulin resistance. Data from the Avon Longitudinal Study of Pregnancy and Childhood shows that rapid catch-up weight gain can lead to the development of insulin resistance, as early as 1 year of age, in association with increasing accumulation of central abdominal fat mass. In contrast, the disposition index, which reflects the beta-cells ability to maintain insulin secretion in the face of increasing insulin resistance, is much more closely related to ponderal index at birth than postnatal catch-up weight gain. Infants with the lowest ponderal index at birth show a reduced disposition index at aged 8 years associated with increases in fasting NEFA levels. The disposition index is also closely related to childhood height gain and insulin-like growth factor-I (IGF-I) levels; reduced insulin secretory capacity being associated with reduced statural growth, and relatively short stature with reduced IGF-I levels at age 8 years. IGF-I may have an important role in the maintenance of beta-cell mass, as demonstrated by recent studies of pancreatic beta-cell IGF-I receptor knock-out and adult observational studies indicating that low IGF-I levels are predictive of subsequent risk for the development of type 2 diabetes. However, as insulin secretion is an important determinant of IGF-I levels, cause and effect may be difficult to establish. In conclusion, although rapid infancy weight gain and increasing rates of childhood obesity will increase the risk for the development of insulin resistance, prenatal and postnatal determinants of beta-cell mass may ultimately be the most important determinants of an individual's ability to maintain insulin secretion in the face of increasing insulin resistance, and thus risk for the development of type 2 diabetes.
Proceedings of The Nutrition Society 09/2007; 66(3):451-7. · 2.77 Impact Factor
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C C Dupuis,
H L Storr,
L A Perry,
J T F Ho,
L Ahmed,
K K Ong, D B Dunger,
J P Monson,
A B Grossman,
G M Besser,
M O Savage
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ABSTRACT: Paediatric Cushing's disease is frequently associated with abnormal puberty. We addressed the hypothesis that prepubertal patients show excessive virilization and pubertal patients show suppression of LH and FSH secretion.
Serum androstenedione (A4), dehydroepiandrosterone sulphate (DHEAS), testosterone (T), and sex hormone binding globulin (SHBG) were determined at diagnosis and converted to standard deviation scores. LH, FSH concentrations were also determined. Severity of CD was assessed from the sleeping midnight cortisol concentration. Puberty was staged and excessive virilization defined as advance in pubic hair stage for breast stage or testicular volume (TV).
Twenty-seven CD patients (17 male, 10 female), median age 13.4 years (range 5.9-17.8) were studied.
In the CD group as a whole, A4, DHEAS, T standard deviation scores (SDS) values were normal. SHBG SDS values (n = 19) were low (median -1.93, -4.32-0.86) correlating with BMI (r = -0.49). A4, DHEAS, T, SHBG, LH and FSH did not correlate with midnight cortisol, but A4 and T SDS correlated with ACTH at 09.00 h (both r = 0.51). Thirteen patients (11 male, 2 female) had excessive virilization with increased A4 (P = 0.033), DHEAS (P = 0.008), testosterone (P = 0.033) and decreased SHBG (P = 0.004) compared with subjects without excessive virilization. Pubertal boys (TV > or = 4 ml) (n = 7) and girls (breasts > or = stage 2) (n = 8) had low median LH and FSH. Boys had an LH concentration of 1.2 mU/l (0.3-3.5), FSH, 0.9 mU/l (0.2-6.4) and median T SDS, -1.95 (-3.8-4.65), while girls had an LH concentration of 1 mU/l (0.3-7.4).
Many patients had abnormal puberty and excessive virilization associated with increased adrenal androgens and decreased SHBG. Pubertal patients had low LH and FSH suggesting impaired pituitary-gonadal axis function.
Clinical Endocrinology 06/2007; 66(6):838-43. · 3.17 Impact Factor
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ABSTRACT: HLA haplotypes DRB1*03_DQB1*02 and DRB1*04_DQB1*0302, and allelic variation of the T cell regulatory gene cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) and of the T cell activation gene protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (PTPN22) have been associated with type 1 diabetes and autoimmune thyroid disease. Using thyroid peroxidase autoantibodies (TPOAbs) as an indicator of thyroid autoimmunity, we assessed whether the association of these loci is different in type 1 diabetes patients with TPOAbs than in those without.
TPOAbs were measured in 4,364 type 1 diabetic patients from across Great Britain, 67% of whom were aged under 18 years. These patients and 6,866 geographically matched control subjects were genotyped at CTLA4, PTPN22, HLA-DRB1 and HLA-DQB1.
TPOAbs were detected in 462 (10.6%) of the type 1 diabetic patients. These patients had a stronger association with CTLA4 (odds ratio [OR] = 1.49 for the G allele of the single nucleotide polymorphism rs3087243; 95% CI = 1.29-1.72) than did the TPOAbs-negative patients (p = 0.0004; OR = 1.16; 95% CI = 1.10-1.24) or type 1 diabetes patients overall (OR = 1.20; 95% CI = 1.13-1.27). The ratio of women:men was higher (1.94:1) in this subgroup than in type 1 diabetes patients without TPOAbs (0.94:1; p = 1.86 x 10(-15)). TPOAbs status did not correlate with age at diagnosis of type 1 diabetes or with PTPN22 (Arg620Trp; rs2476601).
Our results identify a subgroup of type 1 diabetic patients that is sensitive to allelic variation of the negative regulatory molecule CTLA-4 and indicate that TPOAbs testing could be used to subclassify type 1 diabetes patients for inclusion in genetic, biological or clinical studies.
Diabetologia 05/2007; 50(4):741-6. · 6.81 Impact Factor
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ABSTRACT: To determine whether higher than average albumin excretion during early puberty identifies subjects who will subsequently develop microalbuminuria (MA) and clinical proteinuria.
Longitudinal data from the Oxford Regional Prospective Study of Childhood Diabetes (ORPS; n = 554, median duration of follow-up 10 years; range 3.0-16.7) with assessment of albumin/creatinine ratios in three early morning urine samples collected annually. An albumin excretion phenotype was derived from longitudinal data, for each individual, defining deviation from the mean of regression models, including covariates gender, age, duration of diabetes and age at assessment. Tracking of the phenotypes was confirmed in a second independent cohort from Perth, Australia.
The albumin excretion phenotype showed reasonable correlation between age 11-15 years and age 16-18 years in both cohorts, indicative of good 'tracking'. In the ORPS cohort, tertiles of the albumin excretion phenotype at aged 11-15 years were predictive of subsequent risk for the development of MA. All of the subjects developing clinical proteinuria had an albumin excretion phenotype in the upper tertile or an HbA(1c) > 9% at aged 11-15 years.
Identification of adolescents at risk of diabetic nephropathy using an albumin excretion phenotype is feasible. When combined with elevated HbA(1c), it may identify subjects for trial of early intervention with angiotensin-converting enzyme inhibitors/angiotensin-II receptor antagonists and statins to improve long-term prognosis in these subjects where sustained improvement in glycaemic control may be difficult to achieve.
Diabetic Medicine 02/2007; 24(2):131-6. · 2.90 Impact Factor
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Diabetologia 02/2007; 50(1):212-3. · 6.81 Impact Factor
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ABSTRACT: Cerebral oedema complicating diabetic ketoacidosis (DKA) remains the major cause of morbidity and mortality in children with type 1 diabetes, but its aetiology remains unknown. Our objective was to determine the impact of baseline biochemical factors and of treatment-related variables on risk of the development of cerebral oedema in children with DKA.
This was a national UK case-control study. Through the British Paediatric Surveillance Unit we identified 43 cases of cerebral oedema. Through a parallel reporting system, we also identified 2,940 episodes of DKA and selected 169 control subjects on the basis of comparable age, sex, numbers of new or known cases of diabetes and date of admission. Baseline biochemical data and treatment-related variables were extracted from the clinical notes of cases and control subjects.
Allowing for differences in age, sex and new or known diabetes, cases were more acidotic at diagnosis of DKA (odds ratio [OR] for events in the least acidotic compared with the most acidotic tertile=0.02 [95% CI: 0.002-0.15], p<0.001). In addition, cases had higher potassium and urea levels at baseline. Calculated osmolality and baseline glucose were not significantly different. After allowing for severity of acidosis, insulin administration in the first hour (OR 12.7 [1.41-114.5], p=0.02) and volume of fluid administered over the first 4 h (OR 6.55 [1.38-30.97], p=0.01) were associated with risk. Low baseline plasma sodium and an elevated p(a)CO(2) also contributed to risk in the final regression model. Bicarbonate administration was not associated with increased risk of an event when corrected for acidosis.
In this case-control study of DKA, baseline acidosis and abnormalities of sodium, potassium and urea concentrations were important predictors of risk of cerebral oedema. Additional risk factors identified were early administration of insulin and high volumes of fluid. These observations should be taken into account when designing treatment protocols.
Diabetologia 09/2006; 49(9):2002-9. · 6.81 Impact Factor
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ABSTRACT: Size at birth is said to be a highly heritable trait, with an estimated 30-70% of the variability a result of genetics. Data from family studies may be confounded, however, by potential interactions between fetal genes and the maternal uterine environment. Overall, the maternal environment tends to restrain fetal growth, and this is most evident in first pregnancies. Restraint of fetal growth appears to be inherited through the maternal line. Potential genetic candidates include the mitochondrial DNA 16189 variant, and common variants of exclusively maternally expressed genes, such as H19, which have been associated with size at birth. Maternal blood glucose levels and blood pressure are also correlated with size at birth, but the degree to which these changes relate to genetic variation in the mother is unclear. Elegant studies in mouse knockout models and rare genetic variants in humans have highlighted the importance of insulin-like growth factor I (IGF-I), IGF-II, insulin and their respective receptors in determining fetal growth. However, data linking common variation in the genes that regulate these proteins and receptors with size at birth are few and inconsistent. Interestingly, common variation in the insulin gene (INS) variable number tandem repeats, which regulates the transcription of insulin and IGF-II, has been associated with size at birth, largely in second and subsequent pregnancies, where maternal restraint is least evident. This suggests that fetal genes, and in particular paternally expressed genes, may have significant effects on fetal growth during pregnancies where maternal restraint of fetal growth is less evident.
Hormone Research 02/2006; 65 Suppl 3:34-40. · 2.48 Impact Factor
