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Biomedical subjects

E A Gale

Publications and source records attributed to E A Gale.

At least 19 recordsLinked to original sources
PubMed1997

Rising incidence of insulin dependent diabetes in children aged under 5 years in the Oxford region: time trend analysis. The Bart's-Oxford Study Group.

OBJECTIVES: To monitor incidence of insulin dependent diabetes in children in Oxford health region since 1985, and to look for any evidence of disproportionate increase in children aged under 5. DESIGN: Primary ascertainment of cases of childhood diabetes was by prospective registration of all patients with insulin dependent diabetes diagnosed before age 15 years between 1985 and 1996 and resident in Oxford region at time of diagnosis. This was supplemented by examination of centralised hospital discharge records and death certificates. Secondary case ascertainment was by postal surveys of general practitioners in 1987 and 1996. SETTING: Area formerly administered by Oxford Regional Health Authority. SUBJECTS: 1037 children presenting with insulin dependent diabetes under age of 15 years. MAIN OUTCOME MEASURES: Incidence of insulin dependent diabetes in children aged 0-4, 5-9, and 10-14 years during 1985-95. RESULTS: Overall incidence of diabetes in children aged 0-15 was 18.6 cases/100000/year and showed an annual increase of 4% from 1985 to 1996. This was mainly due to a rapid increase in children aged 0-4 years, in whom there was an annual increase of 11% (95% confidence interval 6% to 15%, P < 0.0001), while the annual increase in those aged 5-9 was 4% (0 to 7%, P = 0.05) and in those aged 10-14 was 1% (-2% to 4%, P = 0.55). CONCLUSIONS: Incidence of insulin dependent diabetes in children aged under 5 years has risen markedly in the Oxford region over the past decade. The cause of the increase is unknown, but environmental influences encountered before birth or in early postnatal life are likely to be responsible.

Adolescent↗
PubMed1997

Population based study of prevalence of islet cell autoantibodies in monozygotic and dizygotic Danish twin pairs with insulin dependent diabetes mellitus.

OBJECTIVE: To study the comparative importance of environment and genes in the development of islet cell autoimmunity associated with insulin dependent diabetes mellitus. DESIGN: Population based study of diabetic twins. SETTING: Danish population. SUBJECTS: 18 monozygotic and 36 dizygotic twin pairs with one or both partners having insulin dependent diabetes. MAIN OUTCOME MEASURES: Presence of islet cell antibodies, insulin autoantibodies, and autoantibodies to glutamic acid decarboxylase (GAD65) in serum samples from twin pairs 10 years (range 0-30 years) and 9.5 years (2-30 years) after onset of disease. RESULTS: In those with diabetes the prevalence of islet cell antibodies, insulin autoantibodies, and autoantibodies to glutamic acid decarboxylase in the 26 monozygotic twins was 38%, 85%, and 92%, respectively, and in the dizygotic twins was 57%, 70%, and 57%, respectively. In those without diabetes the proportions were 20%, 50%, and 40% in the 10 monozygotic twins and 26%, 49%, and 40% in the 35 dizygotic twins. CONCLUSION: There is no difference between the prevalence of islet cell autoantibodies in dizygotic and monozygotic twins without diabetes, suggesting that islet cell autoimmunity is environmentally rather than genetically determined. Furthermore, the prevalence of islet cell antibodies was higher in the non-diabetic twins than in other first degree relatives of patients with insulin dependent diabetes. This implies that the prenatal or early postnatal period during which twins are exposed to the same environment, in contrast with that experienced by first degree relatives, is of aetiological importance.

Adolescent↗
PubMed1997

A novel micro-assay for insulin autoantibodies.

Insulin autoantibodies (IAA) are established markers of Type 1 diabetes and are widely used for the prediction of this disease. Standard assays require relatively large serum volumes for reliable measurement of IAA, limiting their use in young children. We have developed a novel small volume assay which is suitable for screening large numbers of samples. For reasons of economy we have adopted a two-stage strategy in which all samples are screened for insulin binding and those with raised levels are quantified in an assay using competitive displacement. Using this assay 126 out of 241 (52%) newly diagnosed IDDM patients (median age 10.2, range 1.3-20.7 years) had IAA levels above the 99th centile of 2860 schoolchildren (median age 11.3, range 9.0-13.8 years), including 81 out of 117 (69%) patients below the age of 10 years. The assay compared well overall when measuring IAA in direct comparison with a conventional assay. We conclude that reliable measurement of IAA is possible on less than 50 microl of serum using this novel assay and that this should facilitate large scale screening, particularly in young children.

Adolescent↗
PubMed1997

Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers.

Strategies for assessing risk of progression to IDDM, based on single and combined autoantibody measurement, were evaluated in 2,855 schoolchildren (median age 11.4 years) and 256 children with newly diagnosed IDDM (median age 10.2 years), recruited to a population-based study in the Oxford region. In 256 children with IDDM, levels of antibodies > or =97.5th centile of the schoolchild population were found in 225 (88%) for islet cell antibodies (ICAs), in 190 (74%) for antibodies to GAD, in 193 (75%) for antibodies to protein tyrosine phosphatase IA-2 (IA-2), and in 177 (69%) for autoantibodies to insulin (IAAs). Estimates of risk of progression to IDDM within 10 years, derived by comparing the distribution of antibody markers in the two populations (schoolchildren and children with IDDM), were 6.7% (ICAs), 6.6% (GAD antibodies), 5.6% (IA-2 antibodies), and 4.8% (IAAs) for schoolchildren with levels above the 97.5th centile, increasing to 20, 23, 24, and 11%, respectively, for antibody levels >99.5th centile. Most children with IDDM had multiple antibody markers, and 89% of those diagnosed over age 10 years had > or =2 antibodies above the 97.5th centile, as compared against 0.7% of schoolchildren, in whom this combination gave a 27% 10-year estimated risk of IDDM. Risk increased but sensitivity fell as combined antibody thresholds were raised, or the number of antibodies above the threshold was increased. Strategies based on detection of > or =2 antibodies with primary testing for GAD and IA-2 antibodies and second line testing for ICAs and/or IAAs were evaluated. Detection of at least two markers selected from GAD antibodies > or =97.5th centile and/or IA-2 antibodies > or =99.5th centile and/or ICAs > or =97.5th centile identified 0.25% of schoolchildren and 83% of children with newly diagnosed IDDM, with an estimated risk of 71% (95% CI 57-91). Although confirmation from prospective studies is still needed, this analysis suggests that antibody combinations can predict diabetes in the general population.

Adolescent↗
PubMed1996

Molecular mechanisms of beta-cell destruction in IDDM: the role of nicotinamide.

Autoimmune processes are involved in pancreatic beta-cell destruction in type 1 diabetes. Autoantibodies including islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA), and antibodies directed against the 37/ 40 K antigen appear in the circulation years before clinical onset and permit increasingly precise disease prediction. A cellular immune response causes pancreatic infiltration, while macrophages and Th-cells appear to be implicated-via local release of cytokines-in beta-cell destruction. Generation of free radicals, DNA strand breaks, activation of the enzyme poly (ADP-ribose) polymerase (PARP), and depletion of intracellular nicotinamide adenine dinucleotide (NAD) appear to be common factors in beta-cell death, whether mediated by oxygen radicals, nitric oxide, or streptozotocin. Nicotinamide, a soluble B group vitamin which offers protection against these toxic stimuli, is at high doses a free radical scavenger, a potent inhibitor of PARP, and protects against depletion of intracellular NAD. A sound scientific rationale therefore exists for its use in human prediabetes, and promising pilot studies have been performed in ICA-positive first-degree relatives and school children. No serious side effects have been reported from its use at the doses proposed in man or other species. There is therefore a sound case for submitting this agent to a controlled clinical trial.

Diabetes Mellitus, Type 1↗
PubMed1995

The 'dawn phenomenon' in adolescents with insulin dependent diabetes mellitus: possible contribution of insulin-like growth factor binding protein-1.

OBJECTIVE: Insulin resistance increases during adolescence, and is exaggerated in patients with insulin dependent diabetes mellitus (IDDM). A relative deficiency of insulin-like growth factor-I (IGF-I) may contribute to this increased insulin requirement. Two mechanisms have been proposed: (a) increased GH secretion, caused by failure of IGF feedback control, leading to increased insulin resistance and (b) lack of insulin-like action of the IGFs which is reinforced by high plasma levels of IGFBP-1, an inhibitor of IGF action. The contribution of these two mechanisms to the 'dawn phenomenon' is assessed. DESIGN: The two possible mechanisms were studied during the dawn rise of glucose in pubertal adolescent patients with IDDM. Two overnight studies were performed in each subject. Patients remained on the same insulin regimen throughout. SUBJECTS: Twenty-two diabetic adolescent subjects, aged (mean +/- SEM) 14.0 +/- 0.4 years, duration of IDDM 7.9 +/- 0.8 years, were recruited. Pubertal status was: group 1 (breast stage 1-2; testicular volume < 4-8 ml) 3 male and 4 female, group 2 (breast stage 3; testicular volume 10-12 ml) 0 male 4 female, group 3 (breast stage 4-5; testicular volume 15-25 ml) 4 male and 7 female. Height standard deviation score (mean +/- SD) (-0.02 +/- 0.99) and daily insulin dose (50.4 +/- 3.1 U/day) did not change between studies. There were no differences in HbA1 (study A 11.26 +/- 0.45%, study B 11.09 +/- 0.42%). METHODS: The subjects were admitted for the two studies 0.3 +/- 0.03 years apart. Blood samples were taken via an indwelling cannula every 20 minutes between 1900 and 0700 h. MEASUREMENTS: GH was assayed every 20 minutes, IGFBP-1, glucose and free insulin every hour and IGF-I at 0700 h. GH, IGFBP-1, IGF-I and free insulin were measured by radioimmunoassay. IGFBPs were also analysed by Western ligand blotting techniques. GH profiles were analysed by Pulsar and results compared by paired Student's t-test. The relations between the dawn rise in glucose and the changes in IGFBP-1, GH and free insulin were examined by multiple linear regression analysis. RESULTS: Serum IGFBP-1 levels rose overnight in the two studies (study A, from 9 +/- 1 at 2200 to 59 +/- 9 micrograms/l at 0700 h; study B, from 10 +/- 1 at 2100 to 64 +/- 14 micrograms/l at 0700 h) whilst insulin levels fell from 47 +/- 5 at 2200 to 16 +/- 2 mU/l at 0700 h (study A) and from 45 +/- 5 at 2000 to 14 +/- 2 mU/l at 0700 h (study B). Glucose levels fell from 16.0 +/- 1.0 to 9.3 +/- 0.9 mmol/l at 0400 h, and then rose to 11.9 +/- 1.1 mmol/l at 0700 h during study A, and from 13.4 +/- 1.3 to 10.1 +/- 1.1 mmol/l at 0400 h and then rose to 13.5 +/- 1.0 mmol/l at 0700 h during study B. There were no differences in GH secretion between studies (mean GH levels (mean +/- SD) (study A, 15.7 +/- 6.6 mU/l; study B, 16.2 +/- 7.1 mU/l; correlation within subjects between studies r = 0.77, P < 0.001), sum of GH peaks (study A, 189.9 +/- 90.3 mU/l; study B, 185.8 +/- 100.2 mU/l; r = 0.57, P = 0.006)). Mean GH levels varied with pubertal stage (group 1, 12.1 +/- 1.5 mU/l; group 2, 23.3 +/- 2.1 mU/l; group 3, 15.3 +/- 1.2 mU/l). Serum IGF-I levels were not different (study A, 203 +/- 12 micrograms/l; study B, 218 +/- 13 micrograms/l). REGRESSION ANALYSIS: The change in plasma glucose between 0200 and 0700 h in both studies related to free insulin, IGFBP-1 and the sum of the GH levels over the preceding hour (log glucose = 7.87 + 5.32 log IGFBP-1 (P = 0.0001) - 5.05 log free insulin (P = 0.0001) - 1.44 log GH (P = 0.004); R2 = 72%). Mean overnight GH levels did not predict the morning rise in plasma glucose. CONCLUSION: The morning rise of IGFBP-1 and plasma glucose appear to be related in this group of subjects with IDDM and this was a consistent finding in the two studies. This relation was additive to the effect of insulin deficiency.

Adolescent↗
PubMed1994

Slow metabolic deterioration towards diabetes in islet cell antibody positive patients with autoimmune polyendocrine disease.

We studied metabolic progression to IDDM in a cohort of adults who are ICA-positive and have associated autoimmune endocrine disease or circulating organ-specific autoantibodies (the Polyendocrine Study). Of the 186 individuals recruited 27 developed overt diabetes after a median follow-up of 4.5 years (range 0.4-12). Of these, eight patients did not require insulin treatment until at least 6 months after clinical diagnosis, with an interval of 1.8 years (1.2-5.7). An IVGTT was performed in 38 subjects and 23 had sequential studies. Of the initial 38 subjects six developed diabetes and only three showed a loss of FPIR to glucose (below the first percentile of a normal control group) before clinical onset of the disease. An additional three subjects showed a loss of the FPIR, and all still have normal glucose tolerance after median follow-up of 28 months (22-95). A "whole" or "mixed" pattern of islet cell staining was found in five of the six patients who developed diabetes and antibodies against an islet 37 k-antigen were detectable in four patients, all of whom required insulin soon after diagnosis. A beta-cell "selective" ICA staining pattern was seen in 14 of 17 subjects who did not develop diabetes and the "mixed" pattern in only three. None of this group had detectable 37 k-antibodies. We conclude that metabolic deterioration is slow in polyendocrine patients, and that the IVGTT has less prognostic significance in this group than in first degree relatives of patients with IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Presentation and progress of childhood diabetes mellitus: a prospective population-based study. The Bart's-Oxford Study Group.

We surveyed the clinical presentation, initial management and subsequent course of a prospectively registered, population-based cohort of 230 patients with Type 1 (insulin-dependent) diabetes mellitus diagnosed before age 21 years in the Oxford Regional Health Authority area in 1985 and 1986. Clinical details from the time of diagnosis were available on 219 patients. Thirty-four (16%) were in severe ketoacidosis with pH less than 7.10 or plasma bicarbonate less than 10 mmol/l, and 21 (10%) had mild to moderate ketoacidosis with pH 7.10-7.35 or plasma bicarbonate 10-21 mmol/l. One child died in ketoacidosis. Presentation in severe ketoacidosis was most common in children under age 5 years (p < 0.05), and ketoacidosis of any degree was less frequent in older children (0.05 < p < 0.01) and those with a parent or sibling with diabetes (p < 0.01). Within 4 years of diagnosis, 55 of 211 patients (26%) experienced severe hypoglycaemia, which in 31 (15%) led to one or more admissions. Readmission for unstable glycaemic control excluding acute hypoglycaemia occurred at least once within 1 year of diagnosis in 13% and within 4 years in 28%, and was more common in girls, in children aged less than 10 years at diagnosis, and those with a history of severe hypoglycaemia. A second cohort of 97 similar patients was recruited in 1990. The rates of admission at diagnosis (79%), severe ketoacidosis (13%) and mild to moderate ketoacidosis (13%) did not differ from the 1985/1986 cohort.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Do we know how to screen for gestational diabetes? Current practice in one regional health authority.

To review current practice for screening and diagnosis of gestational diabetes (GDM) in the North East Thames health region, clinical directors and other relevant individuals in all 17 obstetric units within NE Thames were interviewed personally. Additional information was obtained from local midwives, diabetologists, and chemical pathologists. Thirteen centres had a formal policy for screening and diagnosis of GDM. One centre ran two policies. Six of 18 centres performed a routine blood glucose (BG) screen on all pregnant women, proceeding to OGTT either on the basis of raised BG alone (3 centres), or on the basis of raised BG and/or clinical risk factors (3 centres). Of the remainder, 10 performed a diagnostic test (OGTT or equivalent) in all those with risk factors, and 2 via an intermediate screening BG. The choice and interpretation of screening and diagnostic tests varied considerably. Six centres used random BG, with cut-off ranging from > 5.8 mmol l-1 to > 9.0 mmol l-1, one used a single fasting BG > 5.0 mmol l-1, and another a 50 g oral glucose challenge (1 h level > 8.0 mmol l-1). Diagnosis of GDM was based on a 75 g (13 centres) or a 50 g OGTT (2 centres), while 1 used a standard mixed meal, and another a timed post-prandial glucose sample. Timing of tests ranged from booking to 36 weeks gestation and the diagnostic cut-off levels for GDM varied (fasting: 5.0-8.0 mmol l-1; 2 h: 6.0-10.1 mmol l-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes, Gestational↗
PubMed1994

New approach for in vivo detection of insulitis in type I diabetes: activated lymphocyte targeting with 123I-labelled interleukin 2.

Insulitis is considered the histopathological hallmark of type I (insulin-dependent) diabetes. In the non-obese diabetic (NOD) mouse, diabetes has never been observed in the absence of insulitis. The in vivo detection of insulitis could be of relevance for early prediction of diabetes. As approximately 15% of islet-infiltrating lymphocytes express interleukin 2 receptors, we have labelled recombinant interleukin 2 with 123I and used this radiopharmaceutical to detect insulitis by gamma camera imaging. We studied 71 prediabetic NOD and 27 normal Balb/c mice. Labelled alpha-lactalbumin was used as the control protein. In the first set of experiments we studied the tissue distribution of radiolabelled interleukin 2 in isolated organs from animals sacrificed at different time points. Higher radioactivity was detected in the pancreas of NOD mice injected with labelled interleukin 2, as compared to NOD mice receiving labelled alpha-lactalbumin (p < 0.003 at 20 min: p < 0.001 at 40 min; p < 0.001 at 60 min) or Balb/c mice injected with labelled interleukin 2 (p < 0.05 at 40 min; p < 0.001 at 60 min). In another set of experiments, gamma camera images have been acquired after injection of 123I-labelled interleukin 2. Radioactivity in the pancreatic region of prediabetic NOD and Balb/c mice showed similar kinetics to those observed by single organ counting, with higher accumulation in the pancreatic region of NOD mice (p < 0.04 after 22-45 min in NOD mice vs Balb/c mice).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives.

Prediction of insulin-dependent diabetes mellitus (IDDM) is still largely based on islet cell antibodies (ICAs), but it may be improved by combined analysis with other humoral markers. We examined autoantibodies to insulin (IAAs), glutamic acid decarboxylase (GAD), and M(r) 37,000 and M(r) 40,000 fragments of islet antigens (37 and 40 kDa) together with ICA subtypes in 101 family members with ICAs > or = 10 Juvenile Diabetes Foundation units (JDF U) followed for up to 14 years, of whom 18 have developed IDDM. Life-table analysis showed a 43% risk of IDDM within 10 years for those with ICAs > or = 10 JDF U, rising to 53% for those with ICAs > or = 20 JDF U. The risk for ICAs > or = 10 JDF U was 62% in the family members in the youngest age quartile (< 13.2 years) and fell with increasing age to 4% in those > 40.7 years of age (P = 0.03). ICAs > or = 10 JDF U combined with IAAs gave a risk of 84% (P = 0.03 compared with IAA-), and ICAs > or = 10 JDF U combined with GAD antibodies gave a risk of 61% (P = 0.018). The risk for ICAs > or = 10 JDF U with antibodies to 37-kDa antigen was 76% (P < 0.0001). Risk increased with the number of autoantibodies, from 8% for ICAs alone to 88% with > or = 3 autoantibodies (14 cases detected) (P < 0.0001). The increased risk associated with multiple antibodies was observed independent of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Double blind clinical and laboratory study of hypoglycaemia with human and porcine insulin in diabetic patients reporting hypoglycaemia unawareness after transferring to human insulin.

OBJECTIVES: To compare awareness of hypoglycaemia and physiological responses to hypoglycaemia with human and porcine insulin in diabetic patients who reported loss of hypoglycaemia awareness after transferring to human insulin. DESIGN: Double blind randomised crossover study of clinical experience and physiological responses during slow fall hypoglycaemic clamping with porcine and human insulin. SETTING: Clinical investigation unit of teaching hospital recruiting from diabetes clinics of five teaching hospitals and one district general hospital. SUBJECTS: 17 patients with insulin dependent diabetes mellitus of more than five years' duration who had reported altered hypoglycaemia awareness within three months of transferring to human insulin. MAIN OUTCOME MEASURES: Glycaemic control and frequency of hypoglycaemic episodes during two months' treatment with each insulin. Glucose thresholds for physiological and symptomatic responses during clamping. RESULTS: Glycaemic control did not change with either insulin. 136 hypoglycaemic episodes (eight severe) were reported with human insulin and 149 (nine severe) with porcine insulin (95% confidence interval -4 to 2.5, p = 0.63). 20 episodes of biochemical hypoglycaemia occurred with human insulin versus 18 with porcine insulin (-0.8 to 1, p = 0.78). During controlled hypoglycaemia the mean adrenaline response was 138 nmol/l/240 min for both insulins; neurohormonal responses were triggered at 3.0 (SE 0.2) versus 3.1 (0.2) mmol/l of glucose for adrenaline and 2.5 (0.1) versus 2.5 (0.1) mmol/l for subjective awareness. CONCLUSIONS: These data suggest that human insulin per se does not affect the presentation of hypoglycaemia or the neurohumoral, symptomatic, and cognitive function responses to hypoglycaemia in insulin dependent diabetic patients with a history of hypoglycaemia unawareness.

Adult↗