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E A M Gale

Publications and source records attributed to E A M Gale.

17 recordsLinked to original sources
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↗
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↗
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↗
PubMed2002

A missing link in the hygiene hypothesis?

The incidence of childhood Type I (insulin-dependent) diabetes mellitus has risen in parallel with that of childhood asthma, and the hygiene hypothesis proposes that this is due to reduced stimulation of the immune system by early intercurrent infection. If so, this protective effect is probably mediated by regulatory T lymphocytes. Co-evolutionary partners might have contributed to the development of this form of response, and parasites and the indigenous biota of the gut are plausible candidates. Helminths inhibit the development of atopic disease via induction of regulatory T cells and secretion of Il-10, and pinworms inhibit diabetes development in the non-obese diabetic (NOD) mouse. The most successful human helminth of the western world is the pinworm Enterobius vermicularis, and some 50% of young children in Europe and North America may have been infested around the middle of the twentieth century. Pinworms are benign, usually asymptomatic, and may have immunomodulatory properties that protect against the development of immune-mediated disorders including diabetes and asthma. Their decline in response to improved living conditions might explain a number of features of the epidemiology of childhood atopy and diabetes. The proposed role would be one of immunomodulation rather than disease induction, possibly mediated by interaction with other influences upon the development of the mucosal immune system. This hypothesis could be tested in case-control studies by the development of serological markers or skin testing. If confirmed, identification of the underlying mechanisms could open the way to new forms of immune intervention.

Animals↗
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↗