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Biomedical subjects

R D Leslie

Publications and source records attributed to R D Leslie.

At least 19 recordsLinked to original sources
PubMed1995

Effects of type 1 diabetes mellitus on cardiac function: a study of monozygotic twins.

OBJECTIVE: To investigate left ventricular size and function in type 1 diabetes and their relation with diabetes duration, glycaemic control, autonomic dysfunction, and complications of diabetes. DESIGN: Cross sectional study using a pulsed wave Doppler echocardiogram to assess left ventricular dimensions, wall thickness, and transmitral blood flow velocity signals. PATIENTS: 40 monozygotic twin pairs (23 male, mean age 26 years) discordant for type 1 diabetes and 40 non-diabetic singleton controls with no clinical evidence of cardiac ischaemia. RESULTS: For all Doppler echocardiographic measurements there were strong correlations between monozygotic twins but not between twins and control subjects. Left ventricular dimensions, wall thickness and systolic function, peak E velocity, and the velocity integrals of early left ventricular filling were similar in all three groups. Peak A velocity and the velocity integrals of late ventricular filling (mean (SD)) were greater in diabetic twins (45 (12) v 38 (8) cm/s, P = 0.002; and 32 (11) v 26 (6), P = 0.0002). Diabetic twins had lower E/A ratio (1.59 (0.39) v 1.83 (0.39), P < 0.001), greater atrial filling fraction to total diastolic filling (28 (6) v 25 (5)%, P = 0.002), and prolonged isovolumic relaxation time (72 (12) v 63 (9) ms, P < 0.001). The differences in Doppler findings between diabetic and non-diabetic twins were related to disease duration whereas the prolongation of the isovolumic relaxation time was related to cardiac autonomic dysfunction. CONCLUSIONS: These results show that twins with type 1 diabetes have left ventricular diastolic dysfunction related to diabetes duration and cardiac autonomic dysfunction but not to glycaemic control or microvascular complications. In addition, genetic factors contribute to left ventricular dimension and function.

Adolescent↗
PubMed1994

Immunodominant epitopes of glutamic acid decarboxylase 65 and 67 in insulin-dependent diabetes mellitus.

To find the dominant epitopes of a major autoantigen in insulin-dependent diabetes mellitus (IDDM), glutamic acid decarboxylase (GAD), we studied the reactivity of peripheral blood T lymphocytes with peptides covering both major isoforms. A significant response to GAD 65 or GAD 67 peptides was detected in 13 of 15 IDDM patients and in 9 of 10 normal controls. Controls most frequently recognised the central region of GAD 65 (residues 161-243). IDDM patients preferentially recognised residues 473-555 (p < 0.03). T-cell responses to GAD 67 peptides were similar in IDDM patients and controls. T lymphocytes from IDDM patients recognise a distinct dominant epitope of GAD, which may be an important target for the disease process.

Adolescent↗
PubMed1994

Importance of persistent cellular and humoral immune changes before diabetes develops: prospective study of identical twins.

OBJECTIVES: To determine the pattern of cellular and humoral immune changes associated with insulin dependent diabetes before diabetes develops. DESIGN: Prospective study over 10 years of 25 non-diabetic identical twins of patients with insulin dependent diabetes. The non-diabetic twins were followed up either till they developed diabetes or to the end of the study. SETTING: Teaching hospital. SUBJECTS: 25 non-diabetic identical cotwins of patients with diabetes; 46 controls of the same sex and similar age tested over the same period. Of the 25 twins (total follow up 144 patient years), 10 developed diabetes (prediabetic twins); the remainder were followed up for a mean of 7.7 years. MAIN OUTCOME MEASURES: Results of glucose tolerance tests or fasting blood glucose concentrations at each sample point. Measurements of activated T lymphocytes, expressing the HLA-DR antigen, islet cell antibodies, and insulin autoantibodies in samples. RESULTS: All 10 prediabetic twins had both cellular and humoral changes initially and in most samples before diabetes was diagnosed (activated T lymphocytes in 39/40, islet cell antibodies in 45/47, and insulin autoantibodies to islet cells and insulin were detected infrequently (in 8/54, 6/69, and 0/69 samples, respectively). The combination of cellular and humoral (islet cell antibodies or insulin autoantibodies) immune changes were detected in all 10 of the prediabetic twins but in only one of the 15 non-diabetic twins (P < 0.001). The positive predictive value in this cohort of increased percentages of activated T cells and the presence of antibodies to islet cells or insulin on two consecutive occasions was 100%. CONCLUSION: Most of the twins had cellular or humoral immune changes at some stage. A combination of cellular and humoral immune changes and their tendency to persist is highly predictive of insulin dependent diabetes and distinguishes twins who develop diabetes from those who do not.

Adolescent↗
PubMed1994

Twin studies in auto-immune disease.

Immune-mediated diseases affect up to 5% of the population and are a major cause of morbidity and mortality. These diseases can be organ specific, such as insulin-dependent diabetes (IDDM) and non-organ specific, such as Rheumatoid Arthritis (RA). Identical and non-identical twins have been used to establish whether these diseases are determined by genetic or environmental factors. The results of these studies have been collated in a new section of the Mendel Institute in Rome. Diseases included in these studies included IDDM, RA, Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS) and Myasthenia. Striking differences in concordance rates between identical and non-identical twins in all these studies suggest that genetic factors are important in causing these diseases. All the diseases are known to be associated with HLA genes on chromosome 6 which may account for some or all of the genetic susceptibility. However, in the majority of pairs the affected twin has an unaffected co-twin. These observations suggest that non-genetically determined factors, probably environmental factors and not somatic mutations, are critical. The study of unaffected co-twins, who are at high disease-risk, has allowed the identification of changes which precede and predict the clinical disease. The immune-mediated destruction in many of these diseases is probably caused by T-lymphocytes. Twin studies have shown the importance of genetic factors in determining T-cell responses. Identical twins should, therefore, provide the perfect test bed to assess the role of T-cells in immune-mediated diseases.

Autoimmune Diseases↗
PubMed1994

Infections and diabetes: mechanisms and prospects for prevention.

Infections remain a serious hazard for the diabetic patient. Good metabolic control is a major factor in limiting the development and spread of infections and, most importantly, the development of diabetic complications which predispose to infections. In some patients recurrent infections can pose a problem, particularly if there is evidence of secondary immunodeficiency. In these patients adjuvant therapies, including Biological Responses Modifiers (BRMS) should be considered. Several factors could predispose diabetic patients to infections. These factors include: genetic susceptibility to infection; altered cellular and humoral immune defense mechanisms; local factors including poor blood supply and nerve damage, and alterations in metabolism associated with diabetes. In the context of a diabetic patient all or some of these factors may operate. The purpose of this review is to assess the relative contribution of these potential mechanisms in leading to infection in patients with diabetes.

Adult↗
PubMed1994

Exercise electrocardiography and aortic Doppler velocimetry in asymptomatic identical twins discordant for type 1 (insulin dependent) diabetes.

OBJECTIVE: To determine the influence of insulin dependent diabetes on the prevalence of myocardial ischaemia and on global left ventricular systolic performance. DESIGN: Stress treadmill electrocardiograms and simultaneous Doppler measurement of aortic maximum acceleration were obtained during exercise on symptom free subjects. The electrocardiograms were scored blindly according to the Minnesota code. PARTICIPANTS: 39 identical twin pairs (22 male) discordant for insulin dependent diabetes and 39 non-diabetic controls of similar age and sex were examined. The twins and controls had a mean age of 37 (range 25-69) with a mean (SD) duration of diabetes in the diabetic twin of 17 (7) years. Those selected were normotensive and had no renal impairment. RESULTS: Systolic blood pressure was significantly higher in the diabetic twins than in their non-diabetic cotwins both at rest (p < 0.05) and at peak exercise (p < 0.01). Electrocardiographic evidence of ischaemia was not correlated within twin pairs and was found in similar numbers of diabetic twins, their non-diabetic cotwins, and control subjects. Abnormal electrocardiograms were found in a similar number of diabetic twins (23%), non-diabetic cotwins (18%), and controls (15%). There was a significant correlation in Doppler measurements of global left ventricular systolic function within the identical twins; no significant difference was found for these Doppler measurements in the diabetic twins, non-diabetic cotwins, or controls. CONCLUSION: Exercise characteristics and cardiac function seem to be subject to shared genetic or shared environmental influences or both, whereas electrocardiographic features of ischaemia seem to be environmentally determined. In a selected cohort of diabetic identical twins without evidence of nephropathy there was no evidence that diabetes influenced the prevalence of myocardial ischaemia or global left ventricular systolic function.

Adult↗
PubMed1994

Increased expression of T-cell markers of immunological memory associated with protection from type I diabetes. A study of identical twins.

Disturbances in the balance of CD4+ helper T-lymphocytes expressing the surface molecules CD45RA and CD45R0, which define naive and memory populations, respectively, are present at diagnosis of type I diabetes. In a prospective study over 10 years, these subsets were analyzed in samples obtained from 18 identical twins of patients with type I diabetes, 8 of whom became diabetic (prediabetic twins), whereas the rest remained nondiabetic after at least 8 years follow-up and are now unlikely to develop the disease (diabetes-protected twins). At the beginning of the study, percentage levels of naive (CD45RA+) CD4+ lymphocytes were significantly elevated in prediabetic twins compared with diabetes-protected twins (P < 0.05) and remained so throughout the study (P < 0.01). Percentage levels of naive cells in diabetes-protected twins were significantly reduced compared with control subjects both at the beginning and throughout the study (P < 0.05, P < 0.01, respectively). In contrast, diabetes-protected twins at the beginning of the study had elevated percentage levels of memory (CD45R0+) CD4+ lymphocytes that persisted throughout the study compared with prediabetic twins (P < 0.05 for both). Percentage levels of memory cells in prediabetic twins were significantly reduced compared with control subjects both at the beginning and throughout the study (P < 0.01, P < 0.05, respectively). Increased percentage levels of a population of CD4+ lymphocytes coexpressing CD45RA and CD45R0 were seen in both twin groups compared with control subjects at entry into and during the study (P < 0.05 for all), but persisted only in the prediabetic twins.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Risk factors for cardiovascular disease in IDDM. A study of identical twins.

Patients with insulin-dependent diabetes mellitus (IDDM) have an excess mortality, predominantly attributable to cardiovascular disease. To determine the effect of IDDM on potential risk factors for cardiovascular mortality, we studied subjects from the British Diabetic Twin Study Group. Forty-five identical twin pairs discordant for IDDM were recruited in addition to 45 matched nondiabetic singleton control subjects. All were selected to be normotensive and to have normal albumin excretion rates. Four variables differed significantly between the diabetic twins and their nondiabetic identical co-twins: diabetic twins had higher systolic blood pressure (sBP) ([mean +/- SD] 127 +/- 17 vs. 123 +/- 18 mmHg, P < 0.05), high-density lipoprotein (HDL) cholesterol (1.36 +/- 0.31 vs. 1.25 +/- 0.29 mM, P < 0.05) and fibrinogen (3.23 +/- 0.81 vs. 2.98 +/- 0.71 mg/ml, P < 0.05) but lower factor VII (114 +/- 34 vs. 122 +/- 31%, P < 0.05). All four of these risk factors were significantly correlated (P < 0.001) within the identical twin pairs, as were the other risk factors. These significant correlations within twins for the risk factors studied reflects the impact of shared genetic and environmental influences. IDDM affects sBP, HDL cholesterol, fibrinogen, and factor VII, but only sBP and fibrinogen are affected adversely.

Adult↗
PubMed1994

Early environmental events as a cause of IDDM. Evidence and implications.

Insulin-dependent diabetes mellitus (IDDM) is caused by destruction of the insulin-secreting beta-cells of the islets of Langerhans. It is proposed that the disease is caused by nongenetic, probably environmental, factors operating in a genetically susceptible host to initiate a destructive immune process. These environmental factors may operate over a limited period in early childhood to induce the immune process that destroys the islet beta-cell. Thereafter, there is a long prodrome before the onset of clinical diabetes, during which clinical, immune, and metabolic changes can be detected. If these proposals are correct, epidemiological studies should focus on environmental events in early childhood that might induce, or accelerate, the disease process. Moreover, it should be possible to identify, from an early age, changes in the prediabetic period that persist to diagnosis and have predictive value. The variable age of presentation of IDDM may, therefore, reflect different rates of disease progression rather than different ages of exposure to the critical environmental events. Those patients in whom the disease process is slow could present with IDDM as adults, develop diabetes that does not require insulin treatment, or even fail to develop diabetes altogether. These proposed features, if confirmed, would have important implications for the prediction of IDDM and raise the possibility that modulation of the destructive immune process could prevent progression to clinical diabetes.

Adolescent↗
PubMed1994

Type I diabetes masquerading as type II diabetes. Possible implications for prevention and treatment.

Type I diabetes is probably due to the immune-mediated destruction of islet insulin-secreting beta-cells. This chronic destructive process is associated with both cellular and humoral immune changes in the peripheral blood that can be detected months, even years, before the onset of clinical diabetes. Throughout this prediabetic period, metabolic changes, including altered glucose tolerance and reduced insulin secretion, deteriorate at variable rates toward full-blown diabetes. The ability to predict subsequent clinical diabetes in those nondiabetic individuals with immune and metabolic changes has led to attempts to prevent the disease onset by therapeutic intervention. A small fraction of individuals with immune changes develop clinical diabetes that does not require insulin treatment. The onset of diabetes in these cases is usually in adult life, and because their diabetes is, at least initially, not insulin-dependent, they appear clinically to have type II diabetes. Such patients probably have the same disease process as patients with type I diabetes in that they have similar human leukocyte antigen (HLA) genetic susceptibility as well as autoantibodies to islet antigens. It is proposed that non-insulin-dependent diabetic patients who have markers that characterize individuals at risk of type I diabetes may be suitable candidates for those same therapeutic strategies that seek to prevent progression to insulin-dependence or even to reestablish normal glucose tolerance.

Autoimmunity↗
PubMed1994

Relationship between dairy product consumption and incidence of IDDM in childhood in Italy.

OBJECTIVE: To test the hypothesis that the consumption of dairy products, including fluid cows' milk and cheese, is related to the incidence of insulin-dependent diabetes mellitus (IDDM), we correlated incidence rates in children 0-14 years of age with cows' milk and cheese consumption in nine regions of a single country, Italy. RESEARCH DESIGN AND METHODS: Data on the incidence of IDDM were derived from the only nine Italian regions where primary and secondary sources of ascertainment were available for 1991. Data on fluid cows' milk and cheese consumption in the corresponding year in each region were obtained from the National Institute of Statistics. RESULTS: The correlation between fluid milk consumption and incidence of IDDM in Italy was 0.84 (P < 0.004, Poisson regression analysis). Cheese consumption was not related to IDDM incidence. CONCLUSIONS: The results indicate that there is a relationship, even in a single country, between dairy product consumption and the incidence of IDDM that is confined to fluid milk consumption. Cows' milk may contain a triggering factor for the development of diabetes, but the high incidence of IDDM in Sardinia and in other countries worldwide cannot be explained simply by the quantity of fluid cows' milk consumed.

Adolescent↗
PubMed1994

CD5+ B-cells at the onset of type I diabetes and in the prediabetic period.

OBJECTIVE: B-cells expressing CD5 are associated with the production of autoantibodies and are present at increased levels in several autoimmune diseases. The aim of this study was to investigate the relationship of these cells to the development of type I diabetes and the presence of organ and non-organ-specific autoantibodies. RESEARCH DESIGN AND METHODS: We measured percentage levels of CD5+ B-cells in patients with recent-onset (n = 34) and long-standing (n = 21) type I diabetes and in a cohort of 18 identical twins of patients with type I diabetes studied prospectively, 8 of whom became diabetic (prediabetic twins) during the study; the rest remained nondiabetic after at least 7 years and are now unlikely to develop the disease. Forty-seven healthy individuals were studied as control subjects. RESULTS: Percentage levels of total B-cells (CD20+) and the proportion expressing CD5 were increased in patients with recent-onset (P < 0.001 for both) but not long-standing type I diabetes compared with control subjects. Percentage levels of CD20+ B-cells were increased in prediabetic twins throughout the prediabetic period (P < 0.05), and there was an increased proportion of CD5-expressing B-cells that failed to reach statistical significance (P = 0.08). Percentage levels of CD20+ B-cells and the proportion expressing CD5 were normal throughout the study in twins remaining nondiabetic. No relationship between percentage levels of CD5+ B-cells and islet cell antibody, thyroid autoantibodies, or non-organ-specific autoantibodies was found. CONCLUSIONS: These results show an increase in B-cell percentage levels at the diagnosis of type I diabetes, which is because of an expansion of the CD5+ subset. These changes are also evident in twins throughout the prediabetic period, which suggests that they are related to the processes that lead to diabetes.

Adult↗
PubMed1993

Information on type 1 diabetes mellitus and QT interval from identical twins.

To determine whether QT interval is influenced by genetic factors and whether QT-interval prolongation occurs in type 1 diabetes or is related to diabetic autonomic neuropathy, QT intervals were measured, and autonomic function was assessed in 44 pairs of identical twins who were discordant for type 1 diabetes. Twins were compared with 44 normal control subjects of similar age and sex. QT intervals were corrected for heart rate (QTc). QTc in diabetic twins correlated with that in their nondiabetic co-twins (r = 0.41; p = 0.006). Diabetic twins had significantly longer QTc than did their nondiabetic co-twins and control subjects (416 +/- 18 vs 407 +/- 16 and 403 +/- 19 ms, respectively; p < 0.005). A greater number of abnormal autonomic function tests were detected in diabetic twins than in their nondiabetic co-twins and control subjects (8 vs 2 and 0%, respectively; p < 0.01). Diabetic twins with disease duration > 14 years (n = 22) had longer QTc than did their nondiabetic co-twins (420 +/- 17 vs 402 +/- 14 ms; p < 0.0005). Twins with diabetes for > 14 years had a greater frequency of abnormal autonomic function tests than did those with diabetes < 14 years (15 vs 2%; p < 0.001). QTc did not correlate with autonomic function in diabetic twins. It is concluded that QT interval is influenced by genetic factors, and in type 1 diabetes, QTc can be prolonged independently of autonomic neuropathy.

Adolescent↗