Search PubMed⌕ Search

Biomedical subjects

W E Winter

Publications and source records attributed to W E Winter.

At least 37 records · Page 2Linked to original sources
PubMed1996

Type I insulin-dependent diabetes mellitus: a model for autoimmune polygenic disorders.

Insulin-dependent diabetes mellitus (IDD) affects between one in 250 and one in 500 Americans. The inheritance of IDD is non-Mendelian and polygenic. Genetic susceptibility predominantly results from specific alleles in the HLA complex and insulin gene region. Autoimmune destruction of pancreatic beta cells leads to profound insulinopenia (Atkinson and Maclaren, 1990). Without insulin treatment, fatal diabetic ketoacidosis results. Even with insulin treatment, after 10 to 20 years of IDD, devastating micro- and macrovascular complications lead to significant morbidity and premature mortality (Rosenbloom, 1983). In order to prevent this catastrophic disease and its consequences, we must understand the pathogenesis and immunogenetics of insulitis (the histologic lesion characteristic of IDD), whose ultimate expression is beta cell necrosis (Cudworth, 1978; Cahill and McDevitt, 1981; Eisenbarth, 1986). Current advances include recognition of new IDD-autoantigens (e.g., glutamic acid decarboxylase), susceptibility genes (e.g., HLA-DQB1*0201 and 0302), and the development of trials to prevent IDD through tolerization to IDD-autoantigens (e.g., insulin) (Maclaren, 1993; Winter et al., 1993). Unlocking the genetic mechanisms responsible for IDD can also reveal more general mechanisms involved in other organ-specific autoimmune diseases.

Alleles↗
PubMed1993

The genetics of autoimmune diabetes. Approaching a solution to the problem.

Molecular genetics has had a substantial impact on our understanding of inherited susceptibility to insulin-dependent diabetes mellitus. Alleles at the HLA-DQA1 and DQB1 loci appear to have the greatest influence on diabetogenesis. Other promising loci are present on chromosome 11 in the vicinity of the insulin gene. We have sought not only to improve our prediction of insulin-dependent diabetes mellitus but also to reveal the underlying immune and nonimmune defects that predispose to autoimmune beta-cell destruction. Continued advances in the field of genetics will aid in the prevention of insulin-dependent diabetes mellitus, which is our ultimate goal.

Diabetes Mellitus, Type 1↗
PubMed1993

Insulin-dependent diabetes in the NOD mouse model. II. Beta cell destruction in autoimmune diabetes is a TH2 and not a TH1 mediated event.

Type I, insulin-dependent diabetes (IDD) in both man and animals results from a specific autoimmune destruction of the pancreatic beta cells involving both humoral and cellular immune mechanisms. The pathognomonic histologic lesion, termed insulitis, is an inflammatory and immune cell infiltrate of the pancreatic islet cells. While recent histological and flow cytometric analyses have identified the cell composition of the infiltrate, the presence of a cell population may not reflect the functional reactivities important for beta cell destruction. In the present study, we have investigated the possible functional reactivities of islet-infiltrating mononuclear cell populations by measuring increased cytokine mRNA usage. Results indicate that 1) cytokine mRNA profiles exhibited by islet-infiltrating cells of female and male NOD mice were quite similar with the exception of IL-6 expression and the marked differences in the levels of IL-2 receptor and IL-1 alpha mRNA, 2) CD4+ T lymphocytes expressed IL-4, presumably IL-5, and occasionally IL-10 mRNA but no detectable IL-2 mRNA, 3) CD8+ T lymphocytes exhibited TNF-beta, perforin and high levels of IFN-gamma, and 4) IL-7 was expressed in the islet at very high levels. These findings, together with our earlier flow cytometric analyses of the islet-infiltrating cells, have permitted construction of a detailed model for the natural history of autoimmune diabetes. Interestingly, this model, based on a TH2- and not a TH1-mediated scheme, questions the more popular concepts currently thought to form the bases of the autoimmune reactions underlying IDD.

Animals↗
PubMed1993

Insulin-dependent diabetes in the NOD mouse model. I. Detection and characterization of autoantibody bound to the surface of pancreatic beta cells prior to development of the insulitis lesion in prediabetic NOD mice.

Type I, insulin-dependent diabetes (IDD) results from an autoimmune response against the insulin producing pancreatic beta cells. This autoimmune reaction involves both humoral and cell-mediated factors; nevertheless, the relative role of each remains unresolved. Furthermore, while adoptive transfer experiments have provided evidence for the role of T cells in beta cell destruction, the specific events which initiate leukocyte migration into the islets (insulitis) are unknown. Earlier studies indicated that NOD pancreatic beta cells may bind small amounts of autoantibody. Because of the possible importance of an early humoral response to the initiation of insulitis and subsequent disease, we have investigated a number of aspects of this phenomenon to determine the nature and specificity of the early autoantibodies as well as the time at which autoantibody binds to beta cells. Results of this study demonstrate that NOD/Uf mice are sensitized to islet-cell associated antigens, including GAD, prior to the first appearance of insulitis; that a small percentage of the beta cells of NOD/Uf mice have autoantibody bound to their surface prior to insulitis; that sera collected from preinsulitis NOD/Uf mice contain autoantibodies which will bind to beta cells of both IDD-prone and IDD-resistant mice; and that the autoantibodies which bind pancreatic beta cells are predominantly IgM with lesser amounts of IgG and IgA. These findings suggest that, in the natural course of IDD, insulitis may develop in response to an initial autoantibody-mediated injury of beta cells.

Animals↗
PubMed1993

Pediatric approach to prevention of coronary heart disease.

Management of children with hypercholesterolemia has proven to be a controversial issue. The appropriate approach is to test those at highest risk for premature coronary heart disease most likely to benefit from intervention. Recommendations are reviewed in the context of the National Cholesterol Education Program Expert Panel on Blood Cholesterol Levels in Children and Adolescents. An overview is provided of the problem of preventing coronary heart disease through childhood intervention.

Adolescent↗
PubMed1992

Kanamycin inhibits cochlear-renal ODC in neonatal rats.

Ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, is important in development and regeneration. We hypothesize that aminoglycoside inhibition of ODC mediates developmental hypersensitivity to aminoglycoside ototoxicity. Kanamycin effects on ODC activity (decarboxylation of ornithine) in vitro were determined in the postmitochondrial fraction of cochlear and renal homogenates from 11-day-old rats. Kanamycin inhibited cochlear and renal ODC by an uncompetitive mechanism. For the cochlear enzyme, the inhibitor constant (Ki) for kanamycin was 99 +/- 25 mumol/L; for the renal enzyme, the Ki = 1.5 +/- 0.1 mmol/L. In vivo effects of kanamycin on cochlear, renal, brain ODC activity were determined in rats treated with kanamycin (400 mg/kg/day, intramuscularly) or saline during postnatal days 11 through 20, the hypersensitive period for ototoxicity. Rats were killed on postnatal days 12, 14, 16, and 20 and ODC was assayed. Kanamycin significantly inhibited ODC in the lateral wall-organ of Corti and kidney (ANOVA alpha = 0.05), but had no effect on cochlear nerve and no consistent inhibitory effect in the brain. These results suggest that ODC is a potential target of kanamycin in susceptible tissues and may be a contributing factor in developmental sensitivity to the drug by inhibiting repair and developmental processes mediated by ODC.

Animals↗
PubMed1992

T cell receptor beta diversity and joining segments in the NOD mouse.

Pancreatic beta-cell autoantigen recognition by the immune system appears to be a critical event in the evolution of insulin dependent diabetes. Immune recognition involves antigen presentation by macrophages and subsequent antigen-peptide-class II MHC recognition by T cell receptors (TCR). Using the NOD mouse as a model for human IDD, we hypothesized that germline variability in the D beta nod and/or J beta nod segments could contribute to beta cell autoimmunity by influencing the specific peptides that are recognized. As an initial approach to our hypothesis, we sought to compare these segments to other strains of mice in search of genetic polymorphisms as reported in NZW mice. The germ line TCR beta nod gene did not display evidence of an expansion or contraction in the number of D beta nod or J beta nod segments at the level of resolution provided by restriction fragment length polymorphism analysis. The absence of such polymorphisms suggests that D beta nod or J beta nod segments are not different from nonautoimmune strains of mice.

Animals↗
PubMed1992

Encainide-induced diabetes: analysis of islet cell function.

OBJECTIVE: The purpose of this study was to gain insight into the mechanisms responsible for encainide-induced diabetes. Specifically, we sought to determine if absolute insulinopenia was present or whether encainide-induced diabetes was metabolically more like type II than type I diabetes. RESEARCH DESIGN AND METHODS: Islet function was assessed in a 65 year old white male with encainide-induced diabetes. After 6 months of encainide treatment and 2 months duration of diabetes, C-peptide, glucagon, and glucose levels were measured at baseline and at 30 minute intervals for 120 minutes following an oral mixed meal. These measurements allowed assessment of islet beta and alpha cell function in comparison to control data from our laboratory. RESULTS: In this patient with encainide-induced diabetes, basal and peak C-peptide concentrations were similar to controls although peak C-peptide occurred substantially later than in controls. At peak glucose, the patient's C-peptide/glucose ratio was low indicating relative (but not absolute) insulinopenia. At baseline, glucagon was relatively depressed. Following Sustacal, there was an increase in glucagon of 100% over baseline compared to a mean glucagon rise in controls of only 8%. There was no serological evidence for autoimmune diabetes as islet cell autoantibodies were absent. CONCLUSIONS: Similar to other forms of diabetes, encainide-induced diabetes is a bihormonal disorder. The metabolic pattern was more like type II than type I diabetes with C-peptide secretion in the normal range, yet persistent hyperglycemia that suggests relative insulinopenia and concurrent insulin resistance.

Aged↗
PubMed1990

Immunogenetic analysis of beta-cell autoimmunity in NOD mice. Relationship of insulitis to T-lymphocyte-receptor beta nod and A beta nod genes.

An early molecular event in the evolution of insulin-dependent diabetes in humans and NOD mice appears to involve the interaction of MHC class II molecules, beta-cell autoantigen-derived peptides, and receptor molecules of helper T lymphocytes. To examine the influence of T-lymphocyte-receptor beta-genes on the development of beta-cell autoimmunity, (NOD x NZW)F1 x NOD backcrossed (BC) mice were studied for the development of insulitis, because insulitis is the pathognomonic histological lesion of autoimmune diabetes. Heterozygosity for H-2nod was permissive for the development of pancreatic interstitial inflammation and peri-islet insulitis, whereas homozygosity for H-2nod was highly associated with insulitis. However, (NOD x NZW)F1 x NOD BC mice developed insulitis regardless of homozygosity or heterozygosity for T-lymphocyte receptor beta nod. Therefore, in our study, T-lymphocyte receptor beta nod did not function as an autosomal-recessive beta-cell autoimmunity gene.

Animals↗
PubMed1989

Natural history of incidental hyperglycemia and glycosuria of childhood.

We prospectively followed 29 children and adolescents over a 1- to 8-year period who were referred for evaluation of hyperglycemia (in the absence of diabetes) or glycosuria found on routine screening or during acute illness. On initial examination, four subjects had islet cell autoantibodies, 4 of 22 had an abnormal intravenous glucose tolerance test result, 6 of 22 had low first-phase insulin release on intravenous glucose tolerance testing, and 10 of 20 had impaired glucose tolerance on oral glucose tolerance testing. On follow-up, insulin-dependent diabetes had developed in two of the four subjects with islet cell autoantibodies. The other two subjects with islet cell antibodies have had persistently abnormal glucose tolerance on both oral and intravenous glucose tolerance testing and have low first-phase insulin responses. Diabetes has developed in none of 25 subjects without islet cell antibodies, although two have persistently abnormal glucose tolerance or insulinopenia. All five subjects with islet cell antibodies or human leukocyte antigen DR3/DR4 with initial impaired glucose tolerance have either acquired diabetes or have abnormal glucose tolerance. In contrast, only one of five subjects with initial impaired glucose tolerance but lacking these markers has persistent glucose intolerance. We conclude that in the absence of islet cell antibodies or human leukocyte antigen DR3/DR4 heterozygosity, incidental hyperglycemia or glycosuria is unlikely to be associated with progression or diabetes.

Adolescent↗
PubMed1988

Thymosin and the spontaneously diabetic BB rat.

The biological basis for autoimmunity and immunoincompetence in the BB rat has yet to be localized. In spite of normal thymic histology, thymocyte subsets and blastogenesis, thymus gland products (thymosins) have yet to be studied. In the present report, thymus gland function was studied by measuring thymosin alpha 1 levels at one time point in the BB rat compared with control rates, and BB rat responses to exogenous thymosin (Thymosin fraction 5) were observed. At five months of age, BB rats had thymosin alpha 1 levels comparable to Lewis and Wistar furth rats. Thymosin fraction 5 increased the ratio of peripheral blood W3/25 positive to OX8 positive cells, but otherwise had no effect on the BB rats' T-cell immunodeficiency, or frequencies of tissue autoantibodies or insulin-dependent diabetes. Although B-lymphocyte counts were normal in BB rats, splenocyte responses to B-lymphocyte mitogens were depressed. However, thymosin fraction 5 improved the BB rat B-lymphocyte blastogenesis to near normal for Mycoplasma neurolyticum. Coupled with our previous work, our results suggest that the immune derangement in the BB rat resides outside the thymus.

Animals↗
PubMed1988

Dietary protein restriction reduces the frequency and delays the onset of insulin dependent diabetes in BB rats.

Environmental agents have been implicated in the pathogenesis of insulin dependent diabetes (IDD). These studies were designed to learn if dietary protein influences the development of IDD in the BB rat. Specifically, analysis involved the effects of substituting a modified, semi-synthetic diet (AIN-76) containing soy protein as the sole protein source for the standard chow containing a mixture of animal and non-animal protein. IDD was less frequent (73% vs. 38%, P less than or equal to 0.01), and the onset of diabetes was retarded (110 +/- 11.0 vs. 92 +/- 15.5 days, P less than or equal to 0.01) in rats fed the study diet versus standard chow, respectively. The frequency of thyroid collodal autoantibodies was also significantly decreased in rats fed the study diet (56% vs. 23%, P less than or equal to 0.04), whereas frequencies of smooth muscle and gastric parietal cell autoantibodies were less frequent, but not significantly so. Lymphocyte counts and subsets were unaffected. In non-diabetic rats at greater than 180 days of age, insulitis was less severe in the experimental group. These findings suggested that dietary protein may influence the development of IDD in the BB rat.

Animals↗
PubMed1987

Maturity-onset diabetes of youth in black Americans.

Twelve of 129 black patients with youth-onset diabetes were identified as having an unusual clinical course, with apparent insulin dependence at the time of presentation followed by absence of dependence months to years later. This atypical form of diabetes was found in at least two generations in 9 of the 12 families of the propositi. Fourteen of the diabetic relatives, as well as the 12 propositi, were studied. Islet-cell autoantibodies were not found in any of the patients, and thyroid microsomal auto-antibodies were found in only one. The frequencies of the insulin-dependent-diabetes-associated antigens HLA-DR3 and DR4 were not increased among the propositi, and diabetes did not cosegregate with HLA haplotypes in the informative families. Insulin secretion, as measured by C-peptide responses to a liquid mixed meal (Sustacal), was intermediate between secretion in nondiabetic controls and that in patients with classic insulin-dependent diabetes. Peripheral-blood monocytes expressed increased numbers of insulin receptors as well as decreased empty-site affinities. The atypical form of diabetes in black Americans can be distinguished from classically defined insulin-dependent diabetes and may be best classified as a form of maturity-onset diabetes of youth.

Adult↗