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R D Leslie

Publications and source records attributed to R D Leslie.

At least 19 recordsLinked to original sources
PubMed2004

Lack of effect of vitamin D administration during pregnancy and early life on diabetes incidence in the non-obese diabetic mouse.

BACKGROUND AND AIMS: Several studies have suggested that vitamin D supplementation in early life may reduce the risk of developing type 1 diabetes in later life. The non-obese diabetic (NOD) mouse is a model of spontaneous type 1 diabetes currently used for testing hypothesis/compounds aimed at disease prevention. In this study, we tested the effect of vitamin D (16 IU by gavage) on diabetes incidence in NOD/Ba mice treated from conception with olive oil containing vitamin D via maternal dosing up to 10 weeks of age and followed up until 32 weeks of age. METHODS: Twelve breeding pairs were administered olive oil containing vitamin D during pregnancy, 15 days following the birth of the pups and for the next 10 weeks subsequently. The same breeding pairs were bred again after a clearance period of 15 days using a control solution to produce a control litter. This control group received a control solution for the same period of time. Diabetes incidence, degree of insulitis, and insulin content in the pancreas were investigated in the two groups. RESULTS: 12 vitamin D-treated NOD mice developed diabetes compared to 15 animals in the control group (Log rank test p = 0.899, NS). There were no significant differences between the groups in diabetes incidence, time of onset of the disease, degree of insulitis, or the insulin content in the pancreas. CONCLUSION: Vitamin D administered in utero and in the early stages of life at the dosage used does not change the incidence of diabetes or modify the disease process that leads to beta cell destruction in the NOD mouse.

Animals↗
PubMed2001

Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States.

AIMS: To determine the risk, hazard rate and factors affecting progression to diabetes in monozygotic twins of patients with Type I (insulin-dependent) diabetes mellitus. METHODS: Prospective analysis was done of two cohorts of non-diabetic monozygotic twins of patients with Type I diabetes from Great Britain (n = 134) and the United States (n = 53). RESULTS: The diabetes-free survival analysis was similar between both cohorts (p = 0.6). The combined survival analysis (n = 187, median follow-up = 17.7 years, range = 0.01-57) at 40 years of discordance estimated a 39% probability of diabetes for the initially discordant twin. Survival analysis with left truncation of data estimated that probability to be 50%. For twins who became concordant (n = 47), the median discordance time was 4.2 years (range 0.4 to 39), exceeding 15 years in 23.4%. Twins of probands diagnosed at 24 years of age or younger had a 38% probability of diabetes by 30 years of discordance, compared with 6% for twins of probands diagnosed after 24 years of age (p = 0.004). The twins of probands diagnosed before 15 years of age had the highest diabetes hazard rate in the first discordance year, decreasing thereafter. By survival analysis, diabetes risk was higher in twins who were heterozygous for DR3-DQ2 and DR4-DQ8 than in twins with neither DR3-DQ2 nor DR4-DQ8 (p < 0.05). CONCLUSION/INTERPRETATION: Monozygotic twins of patients with Type I diabetes from two different countries had similar rates of progression to diabetes. Whereas most twins did not develop diabetes, 25% of the twins who progressed did so after more than 14 years of discordance. An age-related heterogeneity was observed, with higher progression to diabetes for twins of patients diagnosed at a younger age.

Adolescent↗
PubMed2001

HbA(1c) levels are genetically determined even in type 1 diabetes: evidence from healthy and diabetic twins.

HbA(1c), a measure of blood glucose regulation, reflects glucose levels in the preceding months. In diabetes, HbA(1c) levels predict the risk of microvascular complications. The aim of this study was to determine whether genetic factors could influence HbA(1c) levels in normal subjects and type 1 diabetic patients. We performed a classical twin study of HbA(1c) in healthy nondiabetic female twins and 42 monozygotic (MZ) and 47 dizygotic (DZ) pairs. Interclass correlations (r) were higher in MZ (r = 0.77) compared with DZ (r = 0.53) twin pairs, suggesting a substantial genetic effect; this was confirmed by quantitative genetic model fitting. Additive genetic effects (heritability) explained 62% (95% CI 47-75) of population variance in HbA(1c); the remainder was attributable to the influence of unique environment (23% [15-36]) and age (14% [5-28]). Multivariate modeling showed that genetic factors also have a substantial influence on fasting glucose levels (51%). However, HbA(1c) heritability could not be explained by genes in common with fasting glucose. In the patients with type 1 diabetes, HbA(1c) levels were correlated in 33 MZ twins concordant for diabetes (r = 0.68; P < 0.001) but also in 45 MZ twins discordant for the disease (r = 0.52; P < 0.001). These significant correlations for HbA(1c) in both concordant and discordant pairs indicate a diabetes-independent familial effect. Thus, HbA(1c) levels are largely genetically determined and independent of the genes influencing fasting glucose. Even in type 1 diabetes, familial (i.e., diabetes-independent) factors influence protein glycation, implying that familial factors may explain, in part, the risk for microvascular complications, as indicated by high HbA(1c) levels.

Adult↗
PubMed2001

Concordance for type 1 diabetes in identical twins is affected by insulin genotype.

OBJECTIVE: Monozygotic twins are usually discordant (only one twin affected) for type 1 diabetes. Discordance for disease between such twins implies a role for nongenetically determined factors but could also be influenced by a decreased load of diabetes susceptibility genes. The aim of this study was to determine whether two susceptibility genes were less prevalent in discordant twins compared with concordant twins. RESEARCH DESIGN AND METHODS: We studied 77 monozygotic twin pairs (INS), 40 concordant and 37 discordant, for type 1 diabetes at polymorphism of the insulin gene region on chromosome 11 p and HLA-DQBI. RESULTS: The disease-associated INS genotype (Hph I) was identified in 87.5% of the concordant twins but only in 59.5% (P = 0.005) of the discordant twins. Neither DQB1*0201 nor DQB1*0302 was seen in 2 of 40 (5%) concordant twins compared with 8 of 37 (22%) discordant twins (P = 0.04). No statistical differences were seen between concordant and discordant twins at individual alleles of DQB1. Combining insulin and DQ data, 5% of concordant twins compared with 32.4% of discordant twins had neither DQB1*0201/DQB1*0302 nor the high-risk Hph I INS "++" genotype (P = 0.002). CONCLUSIONS: We conclude that the possession of the high-risk Hph I insulin genotype increases the likelihood of identical twins being concordant for type 1 diabetes and that the "load" of both major histocompatibility complex (MHC) and non-MHC susceptibility genes has an impact on the disease penetrance of type 1 diabetes.

Adolescent↗
PubMed2000

Effects of acute hyperglycaemia on cardiac function: an echocardiographic study of monozygotic twins.

BACKGROUND: A major cause of morbidity in type I diabetes is congestive heart failure due predominantly to left ventricular diastolic dysfunction. The mechanism of diastolic dysfunction remains unknown and does not relate to blood pressure, microvascular complications and glycated haemoglobin. Hyperglycaemia is the hallmark of diabetes and is a potential determinant of left ventricular diastolic dysfunction. OBJECTIVE: To determine whether acute hyperglycaemia can induce changes in left ventricular diastolic function in normal subjects similar to those observed in insulin-dependent diabetes mellitus (IDDM). DESIGN: Cross-sectional study. SETTING: London teaching hospital. SUBJECTS: Sixteen twins from eight identical twin pairs discordant for IDDM (age 18-38 years, five male) were studied; none had a history or evidence of myocardial ischaemia, valvular or primary heart muscle disease, systemic hypertension or nephropathy. INTERVENTIONS: Non-diabetic twins underwent a hyperglycaemic clamp at 10 mmol/l. MAIN OUTCOME MEASURES: Doppler echocardiography was performed in basal condition in identical twin pairs discordant for IDDM and repeated in the non-diabetic twins during hyperglycaemia. Blood glucose, insulin and catecholamines were measured at baseline and during hyperglycaemia. RESULTS: Transmitral Doppler E/A velocity ratio was significantly lower in diabetic than non-diabetic twins at baseline (1.44 (0.38) vs. 1.51 (0.19), P<0.05). Glucose infusion in the non-diabetic twins resulted in an increase in their E/A ratio (1.51 (0.19) vs. 1.82 (0. 47), P<0.05) due to an increase in E velocity (68 (12) to 64.7 (10. 7), P<0.05) and a decrease in the peak A velocity (42.7 (3.85) to 38. 0 (4.1), P<0.05). No significant changes were observed in peak E velocity or isovolumic relaxation time in the non-diabetic twins between baseline and hyperglycaemia. CONCLUSIONS: The alterations in left ventricular diastolic function induced by acute hyperglycaemia and consequent increase in plasma catecholamines do not mimic those demonstrated in IDDM patients.

Adolescent↗
PubMed2000

Immune reactivity to glutamic acid decarboxylase 65 in stiffman syndrome and type 1 diabetes mellitus.

BACKGROUND: The immune response to an isoform of glutamic acid decarboxylase (GAD), GAD65, is associated with two clinically distinct diseases, stiff-man syndrome (SMS) and type 1 (insulin-dependent) diabetes mellitus. We sought to identify differences in the cellular and humoral immune responses to GAD in these two diseases. METHODS: We compared T-cell responses in 14 SMS patients with axial disease and 17 patients with type 1 diabetes. FINDINGS: Peripheral blood T cells of eight SMS patients recognised different immunodominant epitopes of GAD65 compared with T cells from 17 patients with type 1 diabetes. GAD regions 81-171 and 313-403 induced a dominant T-cell response in six of eight patients with SMS but in only one of 17 patients with type 1 diabetes (p=0.001). No SMS patients responded dominantly to GAD fragments 161-243 and 473-555 compared with ten patients with type 1 diabetes (p=0.008). GAD antibodies were detected in 11 of 14 SMS patients (seven with diabetes) and 11 of 17 patients with type 1 diabetes; IgG1 was dominant in both groups. SMS patients, however, were more likely than patients with diabetes to have isotypes other than IgG1 (p=0.03), in particular, IgG4 or IgE isotypes, which were not detected in patients with type 1 diabetes (p=0.012). INTERPRETATION: Our findings indicate differences between patients with SMS and type 1 diabetes in cellular (epitope recognition) and humoral (isotype pattern) responses to GAD65. Thus the same autoantigen can elicit distinct immune responses in patients with SMS, even when associated with diabetes, compared with patients with type 1 diabetes.

Adolescent↗
PubMed2000

Twins: mirrors of the immune system.

Twin studies are a powerful tool to assess genetic and nongenetic factors in multifactorial, immune-mediated diseases. Here, Marco Salvetti and colleagues review important results from such studies and highlight their potential value. Future developments that should help to realize the potential of twin studies are discussed.

Humans↗
PubMed2000

Nitric oxide synthesis and isoprostane production in subjects with type 1 diabetes and normal urinary albumin excretion.

The role of nitric oxide (NO) and free radicals in the development of microvascular disease in type 1 diabetes remains unclear. We have measured NO and isoprostane (a stable marker of in vivo lipid peroxidation) production in 13 type 1 diabetic subjects with normal urinary albumin excretion and 13 healthy volunteers. Whole-body NO synthesis was quantified by measuring the urinary excretion of 15N-nitrate after the intravenous administration of L-[15N]2-arginine. The urinary excretion of the major urinary metabolite of 15-F2t-isoprostane (8-iso-prostaglandin-F2alpha), 2,3-dinor-5,6-dihydro-F2t-IsoP, was quantified as a marker of in vivo lipid peroxidation. Whole-body NO synthesis was significantly higher in diabetic subjects compared with control subjects (342 vs. 216 nmol 15N-nitrate/mmol creatinine [95% CI of the difference 45-207], P = 0.005). This increase was not explained by a difference in renal function between the 2 groups. There was no difference in 2,3-dinor-5,6-dihydro-F2t-IsoP excretion between diabetic subjects and control subjects (44.8+/-7.8 vs. 41.4+/-10.0 ng/mmol creatinine, mean +/- 95% CI). However, there was an inverse correlation between NO synthesis and free radical activity in subjects with diabetes (r = -0.62, P = 0.012) that was not observed in control subjects (r = 0.37, P = 0.107). We conclude that whole-body NO synthesis is higher in type 1 diabetic subjects with normal urinary albumin excretion than in control subjects. The inverse correlation between isoprostane production and NO synthesis in diabetic subjects is consistent with the hypothesis that NO is being inactivated by reactive oxygen species.

Adult↗
PubMed2000

Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes: isotype restriction and polyclonality.

OBJECTIVE: To determine the isotypes and clonality of antibodies to GAD (GADA) and IA-2 (IA-2A) in patients with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied the following consecutive series of patients who attended a diabetes center for antibodies to GADA and IA-2A: 52 newly diagnosed type 1 diabetic patients, 199 type 2 diabetic patients, 200 control patients, and a cohort of 34 nondiabetic identical twins of patients with type 1 diabetes (15 of whom developed diabetes) who were followed prospectively. RESULTS: GADA or IA-2A were detected in 37 (71%) type 1 diabetic patients compared with only 10 (5%) type 2 diabetic patients (P<0.0001). Both GAD and IA-2 antibodies, regardless of the type of diabetes, were usually subclass restricted to IgG1 and were polyclonal. IgM, IgG3, and IgE isotypes were also detected, but all isotypes of GADA and IA-2A were less prevalent than IgG1 (P<0.017 for either antibody). There was no evidence of spreading or switching of isotypes before the onset of type 1 diabetes. CONCLUSIONS: These observations suggest that the pathogenesis of antigen-specific antibodies in type 1 and type 2 diabetes is similar and probably involves a chronic nonrandom antigen-driven polyclonal B-cell activation that is consistent with a Th1-type immune response.

Adult↗
PubMed1999

Concordance rate for type II diabetes mellitus in monozygotic twins: actuarial analysis.

To determine the concordance rate for Type II (non-insulin-dependent) diabetes mellitus in monozygotic twin pairs, initially ascertained discordant for diabetes, we carried out a prospective study on 44 non-diabetic subjects, each of whom had a sibling twin with diabetes (21 men, 23 women, median age 55 years, interquartile range 47-65). The subjects were referred as discordant for Type II diabetes. The twin pairs were part of the British Diabetic Twin Study and ascertained between May 1968 and January 1998. These subjects underwent an OGTT at time of referral and periodically thereafter. The mean follow-up was 8 years (range 0-18 years) and data were collected until January 1996. The percentage of twins who developed Type II diabetes was assessed by standard actuarial life-table methods and the pairwise concordance rate, that is the proportion of concordant pairs over the sum of concordant and discordant pairs, was calculated. The observed rates of concordance for Type II diabetes at 1, 5, 10, and 15 years follow-up were 17, 33, 57, and 76%, respectively. The concordance rate for any abnormality of glucose metabolism (either Type II diabetes or impaired glucose tolerance) at 15 years follow-up was 96%. The concordance rate for Type II diabetes in monozygotic twins is very high even in twins initially ascertained discordant for diabetes.

Actuarial Analysis↗
PubMed1999

Cytokine secretion patterns in twins discordant for Type I diabetes.

AIMS/HYPOTHESIS: The search for T-cell reactions that are associated with disease in Type I (insulin-dependent) diabetes mellitus is severely hampered because control groups cannot be matched for relevant immune response genes. We therefore compared T-cell responses between identical twins discordant for Type I diabetes. METHODS: Pairs of monozygotic twins (n = 17) discordant for Type I diabetes were studied. Cultures were set up from whole blood immediately after sampling and cells were challenged with human recombinant hsp60, with the mitogen phytohaemagglutinin or with the staphylococcal superantigen. Supernatants were removed after 48 or 96 h and analysed for T-helper1 type cytokines interferon-gamma, TNFalpha and T-helper2 type cytokines IL-4, IL-10 by sandwich-ELISA. RESULTS: The height of the T-helper1 type cytokine response to hsp60, phytohaemagglutinin or staphylococcal enterotoxin B did not show disease association, i. e. it was similar between discordant twins. In contrast, the production of T-helper2 type cytokines differed between discordant twins. The IL-10 response to hsp60 was higher in twins at low disease risk (islet cell antibody-negative) than in their diabetic cotwins (p < 0.01), as was the IL-4 response to phytohaemagglutinin (p < 0.05). No difference was seen in the cytokine response between islet cell antibody-positive twins and their diabetic cotwins. CONCLUSIONS/INTERPRETATION: The data indicate an association between T-helper2 type cytokine secretion patterns and disease or disease risk.

Adolescent↗
PubMed1999

Antibodies to GAD65 and a tyrosine phosphatase-like molecule IA-2ic in Filipino type 1 diabetic patients.

OBJECTIVE: Type 1 diabetes is more prevalent in Europeans than it is in Asians. The disease is associated with autoantibodies to GAD65 and a protein tyrosine phosphatase-like molecule (IA-2). The frequency of GAD antibodies in Asian patients with type 1 diabetes may be lower than that in Europeans. No data are available on IA-2 antibodies in Asians. We tested antibodies to GAD65 and IA-2ic (the intracellular fragment containing the antibody epitope) in Filipino diabetic patients because this population has mixed European and aboriginal racial origins. RESEARCH DESIGN AND METHODS: A cross-sectional study of antibodies to GAD65 and IA-2ic was performed on a consecutive series of 91 type 1 diabetic patients, 74 type 2 diabetic patients, and 100 control subjects attending a diabetes clinic in Manila, the Republic of the Philippines. All subjects were <40 years of age, with a mean age +/- SD of 24.8+/-9.8, 34.3+/-5.8, and 25.8+/-8.0 years, respectively. Diagnosis of type 1 diabetes was determined clinically and confirmed by baseline C-peptide. RESULTS: Of 91 type 1 diabetic patients, antibodies to GAD65 were detected in 25 (27.4%), but antibodies to IA-2ic were found in only 8 (8.8%) (P = 0.002); neither autoantibody was detected in either the type 2 diabetic or control subjects. Of the 25 recently diagnosed type 1 diabetic patients (disease duration <2.0 years), autoantibodies to GAD65 were detected in 14 (56%), but those to IA-2ic in only 4 (16%) (P = 0.007); GAD65 antibodies were detected in only 4 (6%) of 66 patients with a longer disease duration (P = 0.0004). Comparison with recently diagnosed European type 1 diabetic patients of age and disease duration similar to that of the Filipinos indicated that IA-2ic antibodies, unlike GAD antibodies, were significantly less prevalent in Filipino type 1 diabetic patients (P = 0.0007). CONCLUSIONS: This is the first study investigating the prevalence and pattern of humoral immune response in type 1 diabetic patients from the Philippines. Antibodies to IA-2ic, unlike GAD antibodies, were infrequent. Patterns of immune responses to type 1 diabetes-associated antigens may differ worldwide, with important implications for prediction of the disease and the potential for antigen-specific therapy.

Adult↗
PubMed1998

IA-2 and IA-2beta: the immune response in IDDM.

Pancreatic islet cell autoantigens associated with insulin-dependent diabetes mellitus (IDDM) include a recently identified family of protein tyrosine phosphatase-like molecules, notably IA-2 and IA-2beta. IA-2 is a 979 amino acid transmembrane protein located on human chromosome 2q35, whereas IA-2beta is 986 amino acids long located on human chromosome 7q36. Comparison of human IA-2 and IA-2beta showed 74% identity within the intercellular domains, but only 27% indentify within the extracellular domains. These IA-2 molecules are expressed predominantly in cells of neuroendocrine origin, particularly pancreatic islets and brain. Radioimmunoprecipitation with recombinant IA-2 and IA-2beta has been used to measure autoantibodies to these molecules and their intracellular fragments. Autoantibodies to IA-2 are detected in the majority (60% to 80%) of newly diagnosed IDDM patients and in less than 2% of controls. The major antigenic determinants of both IA-2 and IA-2beta reside within the C-terminus of their intracellular domains. In first-degree relatives of IDDM patients, the presence of autoantibodies to IA-2 is predictive of IDDM and in combination with autoantibodies to glutamic acid decarboxylase (GAD) the positive predictive value is in the 50% range. The role of IA-2 and IA-2beta in the pathogenesis of IDDM is still unclear. Identification of these antigens has extended our ability to predict the disease and may be valuable in the search for antigen-specific therapies to prevent IDDM.

Animals↗
PubMed1998

Metabolic and immune parameters at clinical onset of insulin-dependent diabetes: a population-based study. IMDIAB Study Group. Immunotherapy Diabetes.

The age at diagnosis of insulin-dependent diabetes mellitus (type I DM) varies between childhood and adulthood. The aim of this study was to define the immunologic and metabolic characteristics of the disease according to the age at which it is diagnosed. We evaluated the residual beta-cell function (basal and stimulated C-peptide) and frequency of two major islet cell-related autoantibodies, glutamic acid decarboxylase (GAD) and tyrosine phosphatase-like molecule (IA-2ic), at the onset of type I DM. A population-based study was performed with 235 consecutive cases of recent-onset (<4 weeks) type I DM (ages 5 to 45 years) diagnosed in the Lazio region of central Italy. Five age groups were considered: patients diagnosed between ages 5 and 7 years (n = 10), 7 and 10 years (n = 38), 10 and 17 years (n = 94), 17 and 20 years (n = 17), and 20 and 45 years (n = 76). Patients diagnosed before puberty had significantly reduced C-peptide secretion compared with patients diagnosed at a later age (P < .02). Glycosylated hemoglobin (HbA1c) did not differ at diagnosis between the different age groups. Patients diagnosed at puberty or after required significantly less insulin compared with younger patients (P < .04). GAD antibodies were found in 65% and IA-2ic antibodies in 59% of patients. GAD antibodies tended to be more frequent in patients diagnosed after age 17 compared with younger patients (P = .05), while IA-2ic antibodies were not age-related. These data suggest that (1) the extent of beta-cell damage differs between patients diagnosed before and after puberty, the process being more destructive in children less than 7 years of age, when C-peptide levels are the lowest; and (2) residual beta-cell function at diagnosis is not influenced by the presence or absence of islet cell-related antibodies. These findings have implications for trials in type I DM diagnosis aimed at protecting beta cells from end-stage destruction and in attempts to prevent the disease in susceptible individuals.

Adult↗
PubMed1998

Evidence that the age at diagnosis of IDDM is genetically determined.

OBJECTIVE: The aim of this study was to determine the impact of genetic or environmental factors on the age or time of onset of IDDM by studying pairs of twins and siblings concordant for the disease. RESEARCH DESIGN AND METHODS: From 404 twin pairs referred to a diabetic twin study, we selected pairs concordant for IDDM: 1) 116 identical pairs with an index twin diagnosed diabetic under age 60 years and 2) 12 identical and 12 nonidentical matched twin pairs. From 972 families referred to a population-based diabetic family study, we selected sibling pairs with IDDM: 33 pairs with an index case diagnosed diabetic under age 21 years. Twin and sibling pairs were analyzed for intraclass correlations for age and time of diagnosis. RESULTS: Of twins concordant for IDDM, the age at diagnosis correlated 1) in 116 identical pairs (R = 0.94; P < 0.000001) and 2) more closely in 12 identical twins (R = 0.96, P < 0.000001) than 12 nonidentical twins (R = 0.59, P = 0.046). Of 33 sibling pairs with IDDM, the age, but not the time, of diagnosis was correlated (R = 0.53, P = 0.0016). CONCLUSIONS: Correlations within pairs of twins and siblings for age, not time, at diagnosis suggest that much of the variability of the age at diagnosis of IDDM is genetically determined.

Adolescent↗