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P J Bingley

Publications and source records attributed to P J Bingley.

At least 19 recordsLinked to original sources
PubMed2006

An association analysis of the HLA gene region in latent autoimmune diabetes in adults.

AIMS/HYPOTHESIS: Pathophysiological similarities between latent autoimmune diabetes in adults (LADA) and type 1 diabetes indicate an overlap in genetic susceptibility. HLA-DRB1 and HLA-DQB1 are major susceptibility genes for type 1 diabetes but studies of these genes in LADA have been limited. Our aim was to define patterns of HLA-encoded susceptibility/protection in a large, well characterised LADA cohort, and to establish association with disease and age at diagnosis. MATERIALS AND METHODS: Patients with LADA (n = 387, including 211 patients from the UK Prospective Diabetes Study) and non-diabetic control subjects (n = 327) were of British/Irish European origin. The HLA-DRB1 and -DQB1 genes were genotyped by sequence-specific PCR. RESULTS: As in type 1 diabetes mellitus, DRB1 0301_DQB1 0201 (odds ratio [OR] = 3.08, 95% CI 2.32-4.12, p = 1.2 x 10(-16)) and DRB1 0401_DQB1 0302 (OR = 2.57, 95% CI 1.80-3.73, p = 4.5 x 10(-8)) were the main susceptibility haplotypes in LADA, and DRB1 1501_DQB1 0602 was protective (OR = 0.21, 95% CI 0.13-0.34, p = 4.2 x 10(-13)). Differential susceptibility was conferred by DR4 subtypes: DRB1 0401 was predisposing (OR = 1.79, 95% CI 1.35-2.38, p = 2.7 x 10(-5)) whereas DRB1 0403 was protective (OR = 0.37, 95% CI 0.13-0.97, p = 0.033). The highest-risk genotypes were DRB1 0301/DRB1 0401 and DQB1 0201/DQB1 0302 (OR = 5.14, 95% CI 2.68-10.69, p = 1.3 x 10(-8); and OR = 6.88, 95% CI 3.54-14.68, p = 1.2 x 10(-11), respectively). These genotypes and those containing DRB1 0401 and DQB1 0302 associated with a younger age at diagnosis in LADA, whereas genotypes containing DRB1 1501 and DQB1 0602 associated with an older age at diagnosis. CONCLUSIONS/INTERPRETATION: Patterns of susceptibility at the HLA-DRB1 and HLA-DQB1 loci in LADA are similar to those reported for type 1 diabetes, supporting the hypothesis that autoimmune diabetes occurring in adults is an age-related extension of the pathophysiological process presenting as childhood-onset type 1 diabetes.

Adult↗
PubMed2006

Type 1 diabetes risk assessment: improvement by follow-up measurements in young islet autoantibody-positive relatives.

AIMS/HYPOTHESIS: Combinations of autoantibody characteristics, including antibody number, titre, subclass and epitope have been shown to stratify type 1 diabetes risk in islet autoantibody-positive relatives. The aim of this study was to determine whether autoantibody characteristics change over time, the nature of such changes, and their implications for the development of diabetes. METHODS: Five-hundred and thirteen follow-up samples from 141 islet autoantibody-positive first-degree relatives were tested for islet autoantibody titre, IgG subclass, and GAD and IA-2 antibody epitope. All samples were categorised according to four risk stratification models. Relatives had a median follow-up of 6.8 years and 48 developed diabetes during follow-up. Survival analysis was used to determine the probability of change in risk category and of progression to diabetes. RESULTS: For each stratification model, the majority of relatives (71-81%) remained in the same risk category throughout follow-up. In the remainder, changes occurred both from lower to higher and from higher to lower risk categories. For all four models, relatives aged < 15 years were more likely to change risk category than those aged >15 years (0.001 < p < 0.03). Relatives whose autoantibody status changed from low- to high-risk categories had a higher risk of diabetes than relatives who remained in low-risk categories, and inclusion of autoantibody status during follow-up improved diabetes risk stratification in Cox proportional hazards models (p < 0.001). CONCLUSIONS/INTERPRETATION: Changes in islet autoantibodies are relevant to pathogenesis, and are likely to signal alterations in the disease process. Detection of changes through follow-up measurement will improve diabetes risk stratification, particularly in young individuals.

Adolescent↗
PubMed2006

Progression to type 1 diabetes in islet cell antibody-positive relatives in the European Nicotinamide Diabetes Intervention Trial: the role of additional immune, genetic and metabolic markers of risk.

AIMS/HYPOTHESIS: To examine the role of additional immune, genetic and metabolic risk markers in determining risk of diabetes in islet cell antibody (ICA)-positive individuals with a family history of type 1 diabetes recruited into the European Nicotinamide Diabetes Intervention Trial. METHODS: Five hundred and forty-nine first-degree relatives with confirmed ICA levels > or =20 Juvenile Diabetes Foundation units (mean age 15.9 years; interquartile range 10.4-33.7 years) were recruited from 20 countries. OGTTs and IVGTTs were performed at baseline, antibodies to glutamate decarboxylase (GADA), protein tyrosine phosphatase (IA-2A) and insulin (IAA) were determined by RIA, and HLA class II genotyping was performed by PCR of sequence-specific oligonucleotides. RESULTS: One hundred and fifty-nine participants developed diabetes within 5 years. Univariate analysis showed that the cumulative risk of development of diabetes within 5 years varied according to age, relationship to the proband, positivity for IAA, IA-2A and GADA, number and combination of islet antibodies, HLA class II genotype, baseline glucose tolerance, and first-phase insulin secretion, but not gender or incidence of childhood type 1 diabetes in the background population. Children aged < or =10 years had a 59% risk of diabetes within 5 years, compared with 11% in those > or =25 years (p<0.0001). Using multivariate analysis, independent determinants were age, first-phase insulin response, baseline glucose tolerance and number of additional antibody markers, but not antibody type or genotype. Individuals <25 years with two or more additional antibodies at baseline had a 62% risk of diabetes within 5 years and these combined criteria identified 81% of the cases in the whole cohort. CONCLUSIONS/INTERPRETATION: We suggest that screening and recruitment for future intervention trials should be limited to family members aged <25 years, and should be based on islet autoantibodies alone.

Adolescent↗
PubMed2006

GAD antibodies in probands and their relatives in a cohort clinically selected for Type 2 diabetes.

AIMS: A subset of patients who present as if they have Type 2 diabetes have positive pancreatic autoantibodies, and have been referred to as having latent autoimmune diabetes in adults (LADA). We assessed the prevalence and clinical characteristics of patients with glutamic acid decarboxylase antibodies (GADA) in a cohort clinically selected for Type 2 diabetes and determined the presence of diabetes and GADA in their first-degree relatives. METHODS: GADA were measured in 2059 subjects, not known to be related, and clinically selected as having Type 2 diabetes for genetic studies. Clinical characteristics were compared in GADA positive and GADA negative subjects. Diabetes and GAD antibody status were compared in 208 first-degree relatives of GADA positive and GADA negative probands. RESULTS: Of the subjects, 136 (7%) were GADA positive. Compared with the GADA negative subjects, they were slimmer (P < 0.001), diagnosed at a younger age (P = 0.011) and progressed to insulin faster (P < 0.001). Thirty-three per cent of GADA positive subjects had a first-degree relative with diabetes compared with 42% of GADA negative subjects (P = 0.034). The overall prevalence of GADA was similar in the first-degree relatives of GADA positive and GADA negative probands (4 v 5%), and 19 of 22 (86%) diabetic relatives of GADA positive probands were GADA negative. CONCLUSION: Despite clinically selecting a Type 2 diabetes cohort, 7% were GADA positive with an altered phenotype. These GADA positive patients had a strong family history of non-autoimmune diabetes. This suggests that, in this subgroup of patients, autoimmune pancreatic beta-cell destruction occurs on a background of Type 2 diabetes genetic susceptibility.

Adult↗
PubMed2005

Continuing metformin when starting insulin in patients with Type 2 diabetes: a double-blind randomized placebo-controlled trial.

AIMS: To test the effect of continuing metformin on weight gain and glycaemic control in patients with poorly controlled Type 2 diabetes who need to start insulin. METHODS: Patients with Type 2 diabetes on maximum tolerated oral agents referred for insulin conversion were recruited from hospital diabetes clinics into a double-blind randomized placebo-controlled trial. The 183 participants received metformin or placebo, titrated up to 2 g a day or maximum tolerated dose, with insulin started according to local practice. The main outcome measures were weight change over 12 months, HbA1c, insulin dose, frequency of hypoglycaemia, treatment satisfaction, and well-being. RESULTS: Over 12 months, metformin was associated with less weight gain than placebo [mean 6.1 kg vs. 7.6 kg; adjusted difference 1.5 kg (95% confidence interval 0.2-2.9); P=0.02], a greater reduction in HbA1c[1.5% vs. 1.3%; adjusted difference 0.5% (0.1-0.9); P=0.02] and a lower insulin requirement [62 units vs. 86; adjusted difference 25 units (15-34); P<0.001], but also more hypoglycaemia [relative risk of any episode 1.24 (1.02-1.1); P=0.03]. Treatment satisfaction improved more in patients on metformin than on placebo (P<0.001), as did the positive well-being score (P=0.02). CONCLUSIONS: Metformin decreases weight gain, lowers insulin requirement, and improves glycaemic control, and should be continued in patients with Type 2 diabetes who transfer to insulin.

Cholesterol↗
PubMed2004

European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes.

BACKGROUND: Results of studies in animals and human beings suggest that type 1 diabetes is preventable. Nicotinamide prevents autoimmune diabetes in animal models, possibly through inhibition of the DNA repair enzyme poly-ADP-ribose polymerase and prevention of beta-cell NAD depletion. We aimed to assess whether high dose nicotinamide prevents or delays clinical onset of diabetes in people with a first-degree family history of type 1 diabetes. METHOD: We did a randomised double-blind placebo-controlled trial of nicotinamide in 552 relatives with confirmed islet cell antibody (ICA) levels of 20 Juvenile Diabetes Federation (JDF) units or more, and a non-diabetic oral glucose tolerance test. Participants were recruited from 18 European countries, Canada, and the USA, and were randomly allocated oral modified release nicotinamide (1.2 g/m2) or placebo for 5 years. Random allocation was done with a pseudorandom number generator and we used size balanced blocks of four and stratified by age and national group. Primary outcome was development of diabetes, as defined by WHO criteria. Analysis was done on an intention-to-treat basis. FINDINGS: There was no difference in the development of diabetes between the treatment groups. Of 159 participants who developed diabetes in the course of the trial, 82 were taking nicotinamide and 77 were on placebo. The unadjusted hazard ratio for development of diabetes was 1.07 (95% CI 0.78-1.45; p=0.69), and the hazard ratio adjusted for age-at-entry, baseline glucose tolerance, and number of islet autoantibodies detected was 1.01 (0.73-1.38; p=0.97). Of 168 (30.4%) participants who withdrew from the trial, 83 were on placebo. The number of serious adverse events did not differ between treatment groups. Nicotinamide treatment did not affect growth in children or first-phase insulin secretion. INTERPRETATION: Large-scale controlled trials of interventions designed to prevent the onset of type 1 diabetes are feasible, but nicotinamide was ineffective at the dose we used.

Autoimmune Diseases↗
PubMed2004

Mortality of South Asian patients with insulin-treated diabetes mellitus in the United Kingdom: a cohort study.

AIMS: To investigate mortality in South Asian patients with insulin-treated diabetes and compare it with mortality in non South Asian patients and in the general population. METHODS: A prospective cohort study was conducted of 828 South Asian and 27 962 non South Asian patients in the UK with insulin-treated diabetes diagnosed at ages under 50 years. The patients were followed for up to 28 years. Ethnicity was determined by analysis of names. Standardized mortality ratios (SMRs) were calculated, comparing mortality in the cohort with expectations from the mortality experience of the general population. RESULTS: SMRs were significantly raised in both groups of patients, particularly the South Asians, and especially in women and subjects with diabetes onset at a young age. The SMRs for South Asian patients diagnosed under age 30 years were 3.9 (95% CI 2.0-6.9) in men and 10.1 (5.6-16.6) in women, and in the corresponding non South Asians were 2.7 (2.6-2.9) and 4.0 (3.6-4.3), respectively. The SMR in women was highly significantly greater in South Asians than non South Asians. The mortality in the young-onset patients was due to several causes, while that in the patients diagnosed at ages 30-49 was largely due to cardiovascular disease, which accounted for 70% of deaths in South Asian males and 73% in females. CONCLUSIONS: South Asian patients with insulin-treated diabetes suffer an exceptionally high mortality. Clarification of the full reasons for this mortality are needed, as are measures to reduce levels of known cardiovascular disease risk factors in these patients.

Adult↗
PubMed2003

The prevalence of insulin autoantibodies at the onset of Type 1 diabetes is higher in males than females during adolescence.

AIMS/HYPOTHESIS: The incidence of Type 1 diabetes shows little sex bias up to age 15 years, but more males are diagnosed in early adult life. Humoral responses to the beta cell antigen insulin could help to reveal the mechanism underlying this difference. We therefore determined the influence of sex on the prevalence of insulin autoantibodies (IAA) at diagnosis. METHODS: IAA were measured by radiobinding assay in 598 patients with newly diagnosed Type 1 diabetes (aged 10.5, range 0.8-20.7 years, 333 male), and analysed according to age, sex and HLA class II genotype. RESULTS: Overall, 74% of males and 65% of females had IAA above the 97.5(th) centile of 2860 schoolchildren ( p=0.028). IAA prevalence was similar in males and females under the age of 15 (0-4 yr, 95% vs 88%; 5-9 yr, 76% vs 73%; 10-14 yr, 67% vs 58%), but male excess was seen between 15 and 21 years (66% vs. 32%, p(corr)=0.016). HLA class II genotype was available for 426 patients. IAA prevalence in DR4 homozygous patients was 87%, in DR4 heterozygous patients 72% and in DR4 negative patients 55% ( p<0.001). Multivariate analysis showed independent association of IAA with age ( p<0.001), number of DR4 alleles ( p<0.001) and male sex ( p=0.002). CONCLUSIONS/INTERPRETATION: The prevalence of IAA in patients with newly diagnosed Type 1 diabetes is higher in males than females between 15 and 21 years of age. The lower prevalence of IAA in adolescent females implies sex-specific modulation of the autoimmune process during puberty.

Adolescent↗
PubMed2003

Three generations of autoimmune diabetes: an extended family study.

AIMS/HYPOTHESIS: One in four children with Type 1 diabetes in a population-based family study has an affected grandparent. We set out to study the clinical and immune features of diabetes in the grandparents' generation, and to examine sharing of HLA class II susceptibility haplotypes between grandparent and grandchild. METHODS: Of 5855 grandparents in the Bart's-Oxford family study, 428 (7.3%) were known to have diabetes. Clinical data and samples were collected from 115 of 213 surviving affected grandparents and from 219 unaffected grandparents within the same families. Samples were tested for ICA and autoantibodies to GAD and IA-2, and typed for HLA-DRB1-DQA1-DQB1. Transmission of HLA class II haplotype from affected and unaffected grandparents to the diabetic proband was compared. RESULTS: Of 115 affected grandparents studied, the median age at diagnosis was 61 years and at analysis was 73 years; 70% were diet or tablet treated and 30% were on insulin. One or more islet autoantibodies were found in 26% and 66% had one or both of the high risk HLA class II susceptibility haplotypes DRB1*03-DQA1*0501-DQB1*0201 or DRB1*04-DQA1*0301-DQB1*0302. In 79 informative families the HLA class II haplotype of the affected grandparent was transmitted to the proband more frequently than expected overall (59%, p=0.02), and in the insulin-treated subgroups (65%, p=0.03). CONCLUSION/INTERPRETATION: A total of 7.3% of grandparents reported a clinical diagnosis of diabetes and 2.2% had features of Type 1 diabetes. Genetic susceptibility was shared between grandparents with diabetes and their affected grandchildren. Diabetes in the grandparents of children with Type 1 diabetes often has an autoimmune basis, even when it presents late in life and does not require insulin treatment.

Aged↗
PubMed2003

Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes.

AIMS/HYPOTHESIS: Although ischaemic heart disease is the predominant cause of mortality in older people with diabetes, age-specific mortality rates have not been published for patients with Type 1 diabetes. The Diabetes UK cohort, essentially one of patients with Type 1 diabetes, now has sufficient follow-up to report all heart disease, and specifically ischaemic heart disease, mortality rates by age. METHODS: A cohort of 23,751 patients with insulin-treated diabetes, diagnosed under the age of 30 years and from throughout the United Kingdom, was identified during the period 1972 to 1993 and followed for mortality until December 2000. Age- and sex-specific heart disease mortality rates and standardised mortality ratios were calculated. RESULTS: There were 1437 deaths during the follow-up, 536 from cardiovascular disease, and of those, 369 from ischaemic heart disease. At all ages the ischaemic heart disease mortality rates in the cohort were higher than in the general population. Mortality rates within the cohort were similar for men and women under the age of 40. The standardised mortality ratios were higher in women than men at all ages, and in women were 44.8 (95%CI 20.5-85.0) at ages 20-29 and 41.6 (26.7-61.9) at ages 30-39. CONCLUSIONS/INTERPRETATION: The risk of mortality from ischaemic heart disease is exceptionally high in young adult women with Type 1 diabetes, with rates similar to those in men with Type 1 diabetes under the age of 40. These observations emphasise the need to identify and treat coronary risk factors in these young patients.

Adolescent↗
PubMed2002

Islet autoantibodies, nationality and gender: a multinational screening study in first-degree relatives of patients with Type I diabetes.

AIMS/HYPOTHESIS: First-degree relatives of patients with Type I (insulin-dependent) diabetes mellitus diagnosed at 20 years of age or under were screened for islet cell antibodies (ICA) in the course of recruitment to an international diabetes prevention trial. Our aim was to evaluate the influence of age, gender, proband characteristics and nationality on the prevalence of ICA and co-existence of autoantibodies to GAD, IA-2 and insulin. METHODS: A central laboratory screened samples from 10 326 non-diabetic relatives who were aged less than 40 years, from eight European countries for ICA. Antibodies to GAD and IA-2 were measured in all samples with ICA of 10 JDF units or more. RESULTS: Overall, 8.9 % of relatives had ICA of 10 JDF units or more, 3.8 % with ICA of 20 JDF units or more. Of 921 relatives with ICA of 10 JDF units or more, 29 % had co-existing antibodies to GAD or IA-2 or both. ICA of 10 JDF units or more were more prevalent in males (10.8 %) than females (7.3 %). ICA with GAD or IA-2 antibodies or both were also more common in males (3.4 %) than females (1.9 %) and in relatives under 20 years of age (3.5 % vs 1.5 %). Multiple regression analysis showed nationality to be a determinant of ICA of 10 JDF units or more but not of ICA of 20 JDF units or more or of ICA with co-existing islet antibodies, and confirmed the importance of age and gender as determinants of islet autoimmunity. CONCLUSIONS/INTERPRETATION: Relatives from different European countries have similar rates of islet autoimmunity despite wide variation in the background incidence of childhood diabetes, and male excess is equally evident in all populations. The male excess of ICA and islet autoimmunity over 10 years of age reflects the higher male incidence of Type I diabetes in this age group, and suggests that boys may be more likely than girls to develop islet autoimmunity during adolescence.

Adolescent↗
PubMed2002

Diabetes in the parents of children with Type I diabetes.

AIMS/HYPOTHESIS: Previous studies have reported an excess of Type II (non-insulin-dependent) diabetes mellitus in parents of children with Type I (insulin-dependent) diabetes mellitus. We set out to characterise the clinical and immunogenetic features of diabetes in parents of affected children, and to test the hypothesis that there is no excess of Type II diabetes within this population. METHODS: Clinical details were collected from 3164 parents of 1641 children with Type I diabetes participating in the Bart's-Oxford study of childhood diabetes. Islet cell antibodies, antibodies to GAD and IA-2, and HLA class II genotype were determined in a subset of this group. Individuals were assigned a classification of Type I diabetes on the basis of clinical features and measurement of islet autoantibodies. RESULTS: Of 184 parents with diabetes, 138 (75 %) were on insulin. At least one islet autoantibody was detected in 90 (59 %) of 152 parents tested, and of 116 who were HLA-typed, 23 (20 %) had the highest risk genotype HLA-DRB1(*)03-DQA1*0501-DQB1(*)0201 / DRB1*04-DQA1(*)0301-DQB1*0302. Of 46 non-insulin-treated parents, 12 had islet autoantibodies. Of all parents, 141 (4.5 %) were therefore classified as having Type I diabetes, and 31 (0.98 %) as Type II diabetes; 12 could not be classified because of missing data or samples. CONCLUSION/INTERPRETATION: Autoimmune diabetes can present late and without immediate need for insulin treatment in parents of children with the disease. Previous studies have categorised this as Type II diabetes. Our study suggests that there is no excess of non-autoimmune diabetes in the families of children with Type I diabetes.

Adolescent↗
PubMed2001

A comparison of the prevalence of islet autoantibodies in children from two countries with differing incidence of diabetes.

AIMS/HYPOTHESIS: To examine the prevalence of sub-: clinical islet autoimmunity in children from two countries with a twofold to threefold difference in incidence of childhood Type I (insulin-dependent) diabetes mellitus. METHODS: Sera were collected from 2,860 English and 3,053 Lithuanian non-diabetic schoolchildren according to the same protocol. Occult diabetes was excluded by blood glucose measurement. Antibodies to GAD and the protein tyrosine phosphatase IA-2 were measured with standardised radiobinding assays in a single laboratory. Islet cell antibodies and insulin autoantibodies were additionally measured in all samples with GAD and/or IA-2 antibody levels above the 97.5th centile of the English schoolchildren. RESULTS: Of Lithuanian schoolchildren 2.7 % had GAD antibodies above the 97.5th centile of the English schoolchildren but only 0.2 % had antibodies to IA-2 above this threshold (p < 0.001). Islet cell and/ or insulin autoantibodies above the 97.5th centile were found in 22 Lithuanian and 16 English schoolchildren and the overall prevalence of two or more antibodies on or above the 97.5th centile was similar [0.7 % (0.5-1.1) vs 0.6 % (0.4-1.0)] in the two cohorts. CONCLUSION/INTERPRETATION: The prevalence of multiple antibody markers was similar in the cohorts from the two populations, despite the two to three-fold difference in incidence of diabetes. The unexpectedly high prevalence of subclinical islet autoimmunity suggests that the incidence of diabetes in Lithuania is likely to increase in the near future.

Adolescent↗
PubMed2001

Update on major trials for the prevention of type 1 diabetes mellitus: the American Diabetes Prevention Trial (DPT-1) and the European Nicotinamide Diabetes Intervention Trial (ENDIT).

The general population risk of developing type 1 diabetes mellitus (DM), 1/300, is magnified 15-20 fold in first-degree relatives of affected individuals. Because a combination of immunologic, metabolic, and genetic markers can be used to predict the disease, multicenter prevention trials in the US (DPT-1) and Europe (ENDIT) were initiated in relatives. In the DPT-1 over 80,000 relatives under 45 years of age will be screened for ICA and then 'staged' to assess risk. High-risk subjects (>50% over 5 yr) are randomized either to 4 days intravenous insulin infusion annually followed by b.i.d. low doses of subcutaneous ultralente insulin, or to close observation. To date (September 2000), 331/340 (97%) high-risk subjects have been enrolled with the intention of detecting a 35% decrease in disease over 5 years (80% power). 280/490 (57%) of intermediate risk subjects (25-50% over 5 yr) have been randomized to oral insulin or placebo. A 50% treatment difference is sought. Anticipated enrolment for the high-risk arm will be completed by year 2001, and by 2003 for the oral arm. The ENDIT study will prospectively address whether nicotinamide will reduce the rate of progression to DM in relatives. 40,000 first-degree relatives (5-40 yr) have been screened with 552 subjects (ICA titers > or = 20 JDF U) randomized to nicotinamide or placebo. This study is designed with 90% power to detect a 35% reduction in disease (placebo group estimated at 40% risk over 5 years). Analysis of data is expected in 2003.

Diabetes Mellitus, Type 1↗