Infant feeding and autoimmune diabetes.
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Animals↗
Biomedical subjects
D J Becker
Publications and source records attributed to D J Becker.
Progression to insulin-requiring diabetes in seronegative prediabetic subjects: the role of two HLA-DQ high-risk haplotypes.
AIMS/HYPOTHESIS: Most Caucasians with Type I (insulin-dependent) diabetes mellitus develop an autoimmune form of diabetes known as Type IA diabetes, based on the presence of humoral responses to islet autoantigens. Alleles at the HLA locus account for the strongest susceptibility to this form of diabetes, which requires insulin therapy. Because a number of patients who develop insulin-requiring diabetes are islet autoantibody negative, the HLA class II haplotypes, DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302, were evaluated to assess whether they are an independent risk factor for progression to insulin requirement in first-degree relatives of Type I diabetic patients. METHODS: Both HLA-DQ genotyping and islet cell autoantibody assessment (insulin, GAD65, IA-2 autoantibodies and cytoplasmic islet cell antibodies) were evaluated prospectively in 74 relatives of Type I diabetic patients who developed diabetes treated with insulin (prediabetics) and in 426 control subjects who did not develop insulin-requiring diabetes. Based on the presence of DQA1*0501-DQB1*0201 and/or DQA1*0301-DQB1*0302, the number of HLA-DQ high-risk haplotypes was assigned as 0, 1 or 2. RESULTS: A higher prevalence of 2 HLA-DQ high-risk haplotypes was present in seronegative prediabetic subjects as compared to non-diabetic autoantibody negative first-degree relatives (33.3 % vs 10.1 % respectively; p < 0.05). Moreover, in seronegative relatives who developed insulin-requiring diabetes, the presence of 2 HLA-DQ high-risk haplotypes conferred an increased cumulative risk of developing insulin requirement of 27 % at 12.5 years of follow-up, compared to a risk of 6 % for non-diabetic relatives who were antibody-negative and had 0 or 1 HLA-DQ high-risk haplotypes (Log rank p = 0.01). CONCLUSION/INTERPRETATION: These data provide evidence for a phenotype, which is associated with the absence of conventional islet autoantibodies at initial screening, while usually remaining seronegative, and the presence of 2 HLA-DQ high-risk haplotypes with progression to clinical Type I diabetes after a prolonged follow-up. Given the fact that in humans the highest risk-conferring locus associated and linked to the disease is the HLA cluster, and that HLA-DQ molecules play a key role in the development of autoimmune diabetes, our observations imply that as yet unidentified immunologic abnormalities could well exist in seronegative relatives at risk of developing clinical diabetes and carrying 2 HLA-DQ high-risk haplotypes.
Adolescent↗
T cells of multiple sclerosis patients target a common environmental peptide that causes encephalitis in mice.
Multiple sclerosis (MS) is a chronic autoimmune disease triggered by unknown environmental factors in genetically susceptible hosts. MS risk was linked to high rates of cow milk protein (CMP) consumption, reminiscent of a similar association in autoimmune diabetes. A recent rodent study showed that immune responses to the CMP, butyrophilin, can lead to encephalitis through antigenic mimicry with myelin oligodendrocyte glycoprotein. In this study, we show abnormal T cell immunity to several other CMPs in MS patients comparable to that in diabetics. Limited epitope mapping with the milk protein BSA identified one specific epitope, BSA(193), which was targeted by most MS but not diabetes patients. BSA(193) was encephalitogenic in SJL/J mice subjected to a standard protocol for the induction of experimental autoimmune encephalitis. These data extend the possible, immunological basis for the association of MS risk, CMP, and CNS autoimmunity. To pinpoint the same peptide, BSA(193), in encephalitis-prone humans and rodents may imply a common endogenous ligand, targeted through antigenic mimicry.
Adult↗
Type I diabetes and multiple sclerosis patients target islet plus central nervous system autoantigens; nonimmunized nonobese diabetic mice can develop autoimmune encephalitis.
Type I diabetes and multiple sclerosis (MS) are distinct autoimmune diseases where T cells target either islet or CNS self-proteins. Unexpectedly, we found that autoreactive T cells in diabetic patients, relatives with high diabetes risk, nonobese diabetic (NOD) mice, and MS patients routinely target classical islet as well as CNS autoantigens. The pathogenic potential of CNS autoreactivity was testable in NOD mice. Pertussis holotoxin, without additional Ags or adjuvants, allowed development of an NOD mouse-specific, autoimmune encephalitis with variable primary-progressive, monophasic, and relapsing-remitting courses. T cells from diabetic donors transferred CNS disease to pertussis toxin-pretreated NOD.scid mice, with accumulation of CD3/IFN-gamma transcripts in the brain. Diabetes and MS appear more closely related than previously perceived. NOD mouse-specific, autoimmune encephalitis provides a new MS model to identify factors that determine alternative disease outcomes in hosts with similar autoreactive T cell repertoires.
Acute Disease↗
Type 1 diabetes intervention trials.
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Journal Article↗
Lipid and blood pressure treatment goals for type 1 diabetes: 10-year incidence data from the Pittsburgh Epidemiology of Diabetes Complications Study.
OBJECTIVE: Subjects with type 1 diabetes are at high risk for many long-term complications, including early mortality and coronary artery disease (CAD). Few data are available on which to base goal levels for two major risk factors, namely blood pressure and lipid/lipoproteins. The objective of this study was to determine at which levels of LDL and HDL cholesterol, triglycerides, and blood pressure the relative risks of type 1 diabetic complications increase significantly. RESEARCH DESIGN AND METHODS: Observational prospective study of 589 patients with childhood-onset type 1 diabetes (<17 years) aged > or =18 years at baseline; 10-year incidence of mortality, CAD, lower-extremity arterial disease, proliferative retinopathy, distal symmetric polyneuropathy, and overt nephropathy. Relative risks were determined using traditional groupings of blood pressure and lipid/lipoproteins, measured at baseline, using the lowest groupings (<100 mg/dl [2.6 mmol/l] LDL cholesterol, <45 mg/dl [1.1 mmol/l] HDL cholesterol, <100 mg/dl [1.1 mmol/l] triglycerides, <110 mmHg systolic blood pressure, and <80 mmHg diastolic blood pressure) as reference. Adjustments for age, sex, and glycemic control were examined. RESULTS: Driven mainly by strong relationships (RR range 1.8-12.1) with mortality, CAD, and overt nephropathy, suggested goal levels are as follows: LDL cholesterol <100 mg/dl (2.6 mmol/l), HDL cholesterol >45 mg/dl (1.1 mmol/l), triglycerides <150 mg/dl (1.7 mmol/l), systolic blood pressure <120 mmHg, and diastolic blood pressure <80 mmHG: Age, sex, and glycemic control had little influence on these goals. CONCLUSIONS: Although observational in nature, these data strongly support the case for vigorous control of lipid levels and blood pressure in patients with type 1 diabetes.
Adult↗
Peptide dose, MHC affinity, and target self-antigen expression are critical for effective immunotherapy of nonobese diabetic mouse prediabetes.
Cross-reactive T cells that recognize both Tep69 (dominant nonobese diabetic (NOD) T cell epitope in ICA69 (islet cell autoantigen of 69 kDa)) and ABBOS (dominant NOD T cell epitope in BSA) are routinely generated during human and NOD mouse prediabetes. Here we analyzed how systemic administration of these mimicry peptides affects progressive autoimmunity in adoptively transferred and cyclophosphamide-accelerated NOD mouse diabetes. These models were chosen to approximate mid to late stage prediabetes, the typical status of probands in human intervention trials. Unexpectedly, high dose (100 microg) i.v. ABBOS prevented, while Tep69 exacerbated, disease in both study models. Peptide effects required cognate recognition of endogenous self-Ag, because both treatments were ineffective in ICA69null NOD congenic mice adoptively transferred with wild-type, diabetic splenocytes. The affinity of ABBOS for NOD I-A(g7) was orders of magnitude higher than that of Tep69. This explained 1) the expansion of the mimicry T cell pool following i.v. Tep69, 2) the long-term unresponsiveness of these cells after i.v. ABBOS, and 3) precipitation of the disease after low dose i.v. ABBOS. Disease precipitation and prevention in mid to late stage prediabetes are thus governed by affinity profiles and doses of therapeutic peptides. ABBOS or ABBOS analogues with even higher MHC affinity may be candidates for experimental intervention strategies in human prediabetes, but the dose translation from NOD mice to humans requires caution.
Adoptive Transfer↗
Measurement of T-cell autoreactivity in autoimmune diabetes.
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Autoimmune Diseases↗
Are predictors of coronary heart disease and lower-extremity arterial disease in type 1 diabetes the same? A prospective study.
In the Type 1 diabetes population, coronary heart disease (CHD) and lower-extremity arterial disease (LEAD) are the two common macrovascular complications leading to early mortality and morbidity. However, it is not clear if these two complications share the same risk factors. The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study prospectively examined and compared the risk factors for LEAD and CHD (including CHD morbidity and mortality). EDC subjects (332 men and 325 women), all diagnosed at Children's Hospital of Pittsburgh between 1950 and 1980, were first examined at baseline (1986-1988), and then biennially, for diabetes complications and their risk factors. Data used in the current analysis were from the first 6 years of follow-up, 98% provided at least some follow-up data for these analyses. CHD was defined as the presence of angina (diagnosed by the EDC examining physician) or a history of confirmed myocardial infarction or CHD death. An ankle-to-arm ratio of less than 0.9 at rest was considered to be evidence of LEAD. Among 635 subjects without CHD at baseline, 57 developed CHD (1.69/100 person-years), and among 579 without LEAD at baseline, 70 developed LEAD (2.31/100 person-years). CHD incidence rate was slightly higher in males, while LEAD incidence rate was slightly higher in females. Compared to non-incident cases, subjects who developed either complication were older, had a longer diabetes duration, higher LDL and total cholesterol, and were more likely to be hypertensive. In multivariate analyses, hypertension, low HDL cholesterol level, high white cell count, depression, and nephropathy were the independent risk factors for CHD (including morbidity and mortality). For LEAD, higher HbA1 level, higher LDL cholesterol level and smoking were the important contributing factors. In conclusion, the risk factor patterns differ between the two vascular complications. Glycemic control does not predict CHD overall but does predict LEAD, while hypertension and inflammatory markers are more closely related to CHD than to LEAD.
Arteries↗
Hypoglycemia: a complication of diabetes therapy in children.
Hypoglycemia is the most common acute complication in insulin-treated type 1 diabetic patients. Most surveys have demonstrated that the tighter the glycemic control, and the younger the patient, the greater the frequency of both mild and severe hypoglycemia. However, people in poor metabolic control, with high glycosylated hemoglobin levels, are not protected from experiencing severe hypoglycemia. Focusing on the pediatric population, we review new or controversial issues surrounding the prevalence of hypoglycemia, its causes, its consequences and preventive strategies, and discuss possible mechanisms underlying the variability of responses to hypoglycemia.
Brain↗
Therapeutic controversy: prevention and treatment of diabetes in children.
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Adolescent↗
Coronary calcium in adults with type 1 diabetes: a stronger correlate of clinical coronary artery disease in men than in women.
We studied the relationship of coronary artery calcification (CAC), a marker of coronary atherosclerosis, with prevalent clinical coronary artery disease (CAD) and established cardiovascular disease (CVD) risk factors in a type 1 diabetic population. At the 10-year follow-up examination of the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study cohort, 302 adults (mean age 38.1 +/- 7.8 years) received electron beam tomography (EBT) scanning of the heart and a clinical examination. Clinical CAD was defined as a confirmed history of myocardial infarction (MI), angiographic stenosis > or =50%, Pittsburgh EDC Study physician-diagnosed angina, or ischemic electrocardiogram (ECG). CAC correlated with most CVD risk factors. CAC had 84 and 71% sensitivity for clinical CAD in men and women, respectively, and 100% sensitivity for MI or obstructive CAD. A CACS cut point of 400 was the most efficient coronary calcium correlate of CAD. In subjects with angina only, CAC sensitivity was 83% in men and 46% in women. In logistic regression, CAC, ECG R-R variation, peripheral vascular disease, and Beck Depression Inventory independently correlated with prevalent CAD in men and overall. Except for CAC, the same variables independently correlated with CAD in women, and age also entered the model. CAC was an independent correlate of MI or obstructive CAD in both sexes and was the strongest independent correlate in men, but CAC was not independently associated with angina and ischemic ECG in either sex. It is concluded that EBT-detected CAC is strongly correlated with CAD in type 1 diabetes-particularly in men.
Adult↗
A nonlinear analytical model of the autonomic basis of heart rate variability (HRV).
The sinoatrial (SA) node is responsible for the initiation of cardiac contractions, and integrates charge across its cell membranes on a beat-to-beat basis mainly through the regulation of slow calcium-sodium channels. The time constant (slope) of this integrator and the firing threshold (voltage) of the SA nodal cells are influenced by inputs from both sympathetic and parasympathetic autonomic neural pathways converging on the heart. A model has been developed in Matlab that accounts for cumulative autonomic effects on the SA node's integrator and non-cumulative effects on it's firing threshold, and includes an assessment of the contribution of noise to both sub-systems. Using the model, an assessment of the effect of an arbitrary number of autonomic inputs is made on the beat-to-beat variability of heart rate. Additionally, the contribution of noise and nonlinear fast channel effects are considered. Assignment of particular autonomic control frequencies results in physiologically realistic heart rate versus time outputs. Physiological heart rate variability modes such as autonomic control spectra in heart rate, mode-locking, and other complex behaviors can be demonstrated. The results of this model may then be compared with physiological data in which autonomic inputs are controlled by paced breathing or other physiological stimulus.
Autonomic Nervous System↗
Persistent T cell anergy in human type 1 diabetes.
An anergic phenotype has been observed in nonobese diabetic (NOD) mice and some autoreactive T cells from patients with type I diabetes. To better understand this phenomenon, we measured T cell proliferative responses to 10 diabetes-associated and up to 9 control Ags/peptides in 148 new diabetic children, 51 age- and MHC (DQ)-matched siblings (sibs), 31 patients with longstanding diabetes, and 40 healthy controls. Most (78-91%) patient and sib responses to glutamate decarboxylase of 65 kDa (GAD65), islet cell cytoplasmic autoantibody (ICA) 69, diabetes-associated T cell epitopes in ICA69 (Tep69), and heat shock protein (Hsp) 60 involved anergic T cells that required exogenous IL-2 to proliferate. Responses to proinsulin, IA-2 (and tetanus toxoid) required no IL-2 and generated sufficient cytokine to rescue anergic T cell responses. Most new patients (85%) had autoreactive T cells, three quarters targeting more than half of the diabetes Ags. Only 7.8% of the sibs and none of the controls had such multiple T cell autoreactivities, which thus characterize overt disease. Multiple anergic and nonanergic T cell autoreactivities were sustained during 2 yr follow-up after onset and in patients with longstanding (3-26 yr) diabetes. Activated patient T cells survived severe IL-2 deprivation, requiring 20-100 times less IL-2 than normal T cells to escape apoptosis. Diabetic T cell anergy thus persists for decades and is Ag and host specific but not related to disease course. Rescue by IL-2 from bystander T cells and high resistance to apoptosis may contribute to this persistence. These data explain some of the difficulties in the routine detection of disease-associated T cells, and they emphasize challenges for immunotherapy and islet transplantation.
Adolescent↗
Leukocyte adhesion deficiency type II.
Leukocyte adhesion deficiency type II (LAD II) is a rare disorder characterized by recurrent infections, persistent leukocytosis, and severe mental and growth retardation. LAD II neutrophils are deficient in expression of selectin ligand activity, and exhibit a correspondingly diminished ability to roll on endothelium and to traffic to inflammatory sites in vivo. LAD II patients exhibit a deficiency in the expression of cell surface fucosylated glycan structures that include the H and Lewis blood group determinants and the sialyl Lewis x epitope, yet the corresponding fucosyltransferase activities responsible for synthesis of these structures are expressed at normal levels. The molecular defect in LAD II has been localized to the pathway that synthesizes GDP-fucose from GDP-mannose. However, the two known component enzymes in this GDP-fucose biosynthetic pathway are normal in sequence and in expression levels in LAD II cells. The genetic lesion in LAD II that accounts for the generalized fucosylation defect in LAD II patients remains to be determined.
ABO Blood-Group System↗
Antibodies to oxidized LDL and LDL-containing immune complexes as risk factors for coronary artery disease in diabetes mellitus.
Several groups have published results from clinical studies supporting the involvement of anti-modified LDL antibodies as risk factors for the initiation or progression of cardiovascular disease. However, the data published so far are judged inconclusive because of several contradictory observations concerning the correlation between clinical evidence of arteriosclerosis and the levels of antibodies to oxidized LDL (oxLDL Ab). We have previously reported that oxLDL Ab exist both in free form and as antigen-antibody complexes (LDL-IC) in patients with insulin-dependent diabetes mellitus (IDDM). The presence of LDL-IC in IDDM patients has important implications: it may interfere with the assay of oxLDL antibodies and the levels of LDL-IC may correlate better with the development of arteriosclerosis than the levels of free oxLDL antibodies. To clarify these questions baseline samples collected from 49 IDDM patients, who subsequently developed coronary artery disease (CAD) during an 8-year follow-up period, were compared to baseline samples from 49 age-, sex-, and duration-matched control IDDM subjects who remained free of clinical CAD during an identical follow-up period. The levels of free oxLDL antibody were significantly lower in the patients who developed CAD. The same patients had significantly higher concentrations of total cholesterol, apolipoprotein B, and IgA in immune complex-enriched polyethylene glycol (PEG) precipitates. The concentration of IgG was also higher in PEG precipitates from patients who developed CAD, but did not reach statistical significance. This indicates that patients who develop CAD had higher levels of circulating LDL-IC, a fact that could not be deduced from the measurement of free oxLDL antibody concentrations. A linear regression analysis of the correlation between the concentrations of total cholesterol in PEG precipitates, taken as a surrogate measurement of PEG-precipitated oxLDL-IC, and the concentration of free oxLDL antibody in serum showed a statistically significant negative correlation (r = -0.229, P = 0. 024). Our results support the conclusion that oxLDL-IC may be a risk factor for the development of macrovascular disease in IDDM patients. We also have demonstrated that circulating oxLDL-IC interfere with the assay of free oxLDL antibodies.
Adult↗
Intensive diabetes therapy in childhood: is it achievable? Is it desirable? Is it safe?
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Child↗
Hypoglycemia in children with type 1 diabetes mellitus. Risk factors, cognitive function, and management.
This article examines the relationship between hypoglycemia and brain function in children with type 1 diabetes. Hypoglycemic episodes occurring in the first 5 years of life may permanently disrupt cognitive function in a subset of children with diabetes, and a single acute episode of hypoglycemia may produce a transient reduction in mental efficiency, alter the electroencephalogram, and increase regional cerebral blood flow. Because iatrogenic development of hypoglycemic unawareness and autonomic failure are the most likely mediators of moderately severe hypoglycemia, medical management efforts should be directed at the prevention of frequently recurring, mild hypoglycemia.
Adolescent↗