Polly J Bingley

Islet autoantibody markers in IDDM : risk assessment strategies yielding high sensitivity

SummaryIdentification of islet autoantigens offers the possibility that antibody tests other than islet cell antibodies may be used for assessing risk of insulin-dependent diabetes mellitus (IDDM). The aim of this study was to determine the combination of islet autoantibody markers that could identify most future cases of IDDM. Islet cell antibodies, antibodies to glutamic acid decarboxylase (GAD)65, 37,000/ 40,000 Mr islet tryptic fragments, carboxypeptidase-H, and islet cell autoantigen (ICA)69 were measured in sera from 100 newly-diagnosed IDDM patients, 27 individuals prior to onset of IDDM, and 83 control subjects. Islet cell antibodies were detected in 88 % of IDDM patients and 81 % with pre-IDDM, GAD65 antibodies in 70 % of IDDM patients and 89 % with pre-IDDM, and antibodies to 37,000/40,000 Mr islet tryptic fragments in 54 % of IDDM patients and in 48 % with pre-IDDM. The latter were found only in conjunction with islet cell antibodies and were more frequent in young onset cases. All 20 IDDM patients and the 3 pre-IDDM subjects who had islet cell antibodies without GAD65 antibodies had antibodies to 37,000/40,000 Mr islet tryptic fragments, and all but one had disease onset before age 15 years. No sera strongly immunoprecipitated in vitro translated ICA69 or carboxypeptidase-H; 4 % of patients had anti-ICA69 and 11 % anti-carboxypeptidase-H levels above those of the control subjects. The findings suggest that none of the single antibody specificities are as sensitive as islet cell antibodies, but that a combination of GAD65 antibodies and antibodies to 37,000/40,000 Mr islet tryptic fragments has the potential to identify more than 90 % of future cases of IDDM. Such a strategy could eventually replace islet cell antibodies in population screening for IDDM risk assessment.

Presentation and progress of childhood diabetes mellitus: a prospective population-based study

SummaryWe 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. Despite recent developments in diabetes management and a high level of clinical ommitment at participating centres, ketoacidosis remains a common presentation of childhood diabetes, and hypoglycaemia is unacceptably frequent in the years following diagnosis. Greater public and medical awareness of the presenting features of diabetes in young children is needed to reduce the frequency of ketoacidosis at presentation, while hypoglycaemia remains a major obstacle to good glycaemic control.

Loss of regular oscillatory insulin secretion in islet cell antibody positive non-diabetic subjects

SummaryBasal insulin secretion was compared in nine islet-cell antibody positive, non-diabetic first-degree relatives of children with Type 1 (insulin-dependent) diabetes mellitus and nine normal control subjects matched for age, sex and weight. Acute insulin responses to a 25 g intravenous glucose tolerance test were similar in the two groups (243 (198–229) vs 329 (285–380) mU·l−1·10min−1, mean (±SE), p=0.25). Fasting plasma insulin was assayed in venous samples taken at one min intervals for 2 h. Time series analysis was used to demonstrate oscillatory patterns in plasma insulin. Autocorrelation showed that regular oscillatory activity was generally absent in the islet-cell antibody positive group, whereas a regular 13 min cycle was shown in control subjects (p< 0.0001). Fourier transformation did, however, show a 13 min spectral peak in the islet-cell antibody positive group, consistent with intermittent pulsatility. We conclude that overall oscillatory patters of basal insulin secretion are altered in islet-cell antibody positive subjects even when the acute insulin response is within the normal range.

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

SummaryWe 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 37k-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. In contrast, the presence of the “whole” or “mixed” ICA staining pattern or of 37k-antibodies can identify a high risk of progression to IDDM within this polyendocrine population and may indicate the rate of metabolic deterioration.

Nicotinamide and insulin secretion in normal subjects

SummaryNicotinamide has been given both before and after clinical onset of Type 1 (insulin-dependent) diabetes mellitus in an attempt to prolong beta-cell survival. Nicotinic acid, structurally similar to nicotinamide, induces insulin resistance and increases insulin secretion in healthy individuals. It is not known if nicotinamide has similar effects. Since insulin secretion, as measured by the acute insulin response to intravenous glucose, is used to predict diabetes and to monitor therapy, the effects of nicotinamide must be established before trials in individuals at high risk of progression to Type 1 diabetes can be interpreted. Intravenous tolerance tests were performed according to the ICARUS standard protocol in 10 healthy, adult subjects (age 32±5.7 years) before and after 14 days of treatment with nicotinamide 25 mg · kg−1 · day−1. The acute insulin response after nicotinamide did not differ from the control study, whether measured as the incremental 0–10 min insulin area (278±142 vs 298±130mU · l−1 · 10 min−1) or as the 1±3 min insulin level (78±39 vs 81±44 mU/l). The late insulin response was equally unaffected, as were basal insulin (5.2±1.6 vs 5.6±2.1 mU/l) and glucose (5.0±0.4 vs 4.9±0.2 mmol/l) levels and glucose disposal rates (1.98±0.88 vs 2.04±0.68%/min). Nicotinamide does not affect insulin secretion and glucose kinetics in normal subjects, confirming its suitability for trials designed to delay or prevent the onset of Type 1 diabetes.

Early T-cell defects in pre-type 1 diabetes

Alterations of lymphocyte subsets have been recently reported in pre-type 1 diabetes but the relation with other immunological markers, in particular islet cell antibodies (ICA), is still unknown. In the present study, we have investigated prospectively changes of lymphocyte subsets in 86 first-degree relatives of patients affected by type 1 diabetes and correlated such modifications with ICA titres. Among individuals with persistent ICA, 8 had ICA titres of more than 20 JDF units, 14 had ICA titres between 5 and 20 JDF units and 64 had ICA titres between 0 and 5 JDF units. First-degree relatives with ICA titres of more than 20 JDF units had significantly decreased proportions of CD3 cells. This reduction was predominantly in the CD4 subset, giving rise to a decreased CD4/CD8 lymphocyte ratio. Those with ICA titres between 5 and 20 JDF units showed abnormalities in both CD3 and CD4 lymphocytes, but not in CD4/CD8 lymphocyte ratio. Further characterization of the CD4 cell subset was performed using three other monoclonal antibodies, CD45RO (UCHL1), CD45RA and CD29, phenotyping memory T-cells, the inducer cells of suppressor function and helper-inducer cells, respectively. The proportions of total CD45RO and CD45RA were not significantly different among first-degree relative with distinct ICA titres in a cross-sectional studt, whereas a trend towards a reduced proportion of CD4/ CD45RA cells was observed. The longitudinal study demonstrated that individuals potentially susceptible to the development of type 1 diabetes and who possess high titres of ICA have impairment of CD4/CD8 lymphocyte ratio, mainly due to a reduction in the CD4 subset. This alteration may contribute to the initial generation of the autoimmune response towards beta cells. All the calculations were made using minimum median and maximum value analyses.

Low interleukin-2 receptor levels in serum of patients with insulin-dependent diabetes.

Interleukin-2 receptors are released in the circulation in response to antigenic or mytogenic stimulation of T-lymphocytes. Abnormal serum interleukin-2 receptor levels have been found in young children with type 1 diabetes and “prediabetes.” We measured interleukin-2 receptor levels in 17 patients with newly diagnosed type 1 diabetes, 21 patients with long-standing type 1 diabetes, 19 patients with long-standing type 2 diabetes, 19 islet-cell antibody positive nondiabetic polyendocrine patients, 12 islet-cell antibody-positive first-degree relatives of patients with type 1 diabetes and compared the results to age- and sex-matched normal controls. We found significantly lower interleukin-2 receptor levels in patients with newly diagnosed and long-standing type 1 diabetes compared to normal controls (87 ± 11 and 93 ± 11 vs. 142 ± 25 and 132 ± 40 U/ml, P < 0.001 and P < 0.01). There were no significant differences in interleukin-2 receptor levels between prediabetic groups and normal controls or patients with long-standing type 1 or type 2 diabetes. There was no correlation between glycosylated hemoglobin, blood glucose levels, and interleukin-2 receptor in the groups with long-standing type 1 or type 2 diabetes. We conclude that patients with type 1 diabetes have low interleukin-2 receptor serum levels. This phenomenon is acquired close to disease onset and is unlikely to be an early markers of type 1 diabetes.

Epidemiology of Type 1 diabetes

In the 1930s Himsworth noted that diabetic patients fell into two main types. Older, heavier patients tended to have less severe clinical manifestations at onset and relatively large doses of insulin were needed to render them hypoglycaemic. In contrast, young, thin patients proved much more sensitive to insulin. From this simple clinical observation he correctly deduced that there were two main types of diabetes, characterized respectively by insulin deficiency and insulin resistance.’ In 1951 Lister et al coined the terms Type 1 and Type 2 diabetes to describe them. Even so, the heterogeneity of diabetes went largely unrecognised until the HLA associations of Type 1 diabetes were described in the 1970s. Since then detailed knowledge of the genetics, pathogenesis and epidemiology of Type 1 diabetes has rapidly outstripped understanding of these areas in Type 2 diabetes, to the extent that the definition of the latter is largely negative, resting as it does on the absence of hallmarks of Type 1 diabetes.2 The WHO Study Group preferred the terms IDDM and NIDDM, pointing out that these are clinically descriptive, whereas the terms Type 1 and Type 2 imply different pathogenetic mechanisms. They went on to propose that the differing terminologies should be ‘regarded as completely synonymous with IDDM and NIDDM, respectively (i.e. carrying no etiopathogenic implications)‘. We consider it a mistake to conflate the terms in this way; the term ‘Type 1’ is useful precisely because of its detailed connotations.