Immunosuppressive therapy in insulin dependent diabetes.
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Adolescent↗
Biomedical subjects
W E Winter
Publications and source records attributed to W E Winter.
Restriction-fragment-length polymorphisms of 5'-flanking region of insulin I gene in BB and other rat strains. Absence of association with IDDM.
Because the 5'-flanking hypervariable region of the human insulin gene may be associated with insulin-dependent diabetes mellitus (IDDM), we examined the spontaneously diabetic BB rat and other rat strains for polymorphisms of the two rat insulin genes, the localization of such polymorphisms, and their possible association with IDDM. By use of restriction-fragment-length polymorphism analysis, we found that the transcribed portion of the insulin I gene, its 3'-flanking region, and the insulin II gene were not polymorphic. However, four alleles of the insulin I gene were identified, two of which (IA and IB) were found in BB rats. Alleles IA and IB varied in their 5'-flanking regions, yet neither was associated with IDDM in the BB rat.
Alleles↗
Is insulin-dependent diabetes mellitus a preventable disease?
Despite improvements in the ongoing care of individuals with insulin-dependent diabetes, the disease continues to produce significant morbidity and mortality, especially early in life, in individuals developing insulin-dependent diabetes in childhood or adolescence. In order to have a major impact on disease outcome, the best therapeutic approach is disease prevention. Because insulin-dependent diabetes results from autoimmune pancreatic beta cell destruction, the disease may be amenable to immunological intervention with immunotherapy. This is particularly exciting as we develop tools, such as islet cell autoantibody determinations, that allow diagnosis of individuals prior to clinical presentation. It is during this time-period when immune manipulation may be most efficacious in preventing further beta cell destruction, and otherwise eventual insulin dependence. As such trials are highly experimental, they must be conducted only in research centers staffed by physicians and scientists with expertise in diabetes, autoimmunity, and immunology.
Autoantibodies↗
Bovine albumin antibodies in NOD mice.
Sera from NOD mice were studied for the presence of bovine serum albumin (BSA) antibodies using an ELISA assay. NOD mice had higher levels of BSA binding and higher frequencies of BSA antibodies than did control mice. Furthermore, diabetic NOD mice had higher BSA binding, and higher frequencies of BSA Ab than did nondiabetic NOD mice. These findings are indicative of an exaggerated immune response in NOD mice to BSA that may be associated with diabetes.
Animals↗
Congenital pancreatic hypoplasia: a syndrome of exocrine and endocrine pancreatic insufficiency.
We describe two brothers with small size at birth, early-onset insulin-dependent diabetes, and pancreatic exocrine insufficiency. In contrast to the findings in pancreatic aplasia, their serum C-peptide and glucagon levels were measurable. These findings, in concert with their clinical courses, are consistent with the diagnosis of congenital pancreatic hypoplasia.
Adult↗
Are insulin autoantibodies markers for insulin-dependent diabetes mellitus?
Recent studies have shown that insulin autoantibodies occur in patients with newly diagnosed insulin-dependent diabetes mellitus (IDDM) before exogenous insulin treatment. Our study was designed to test the hypothesis that insulin autoantibodies, like cytoplasmic islet cell antibodies (ICAs), can identify individuals with ongoing autoimmune beta-cell destruction and increased risk of IDDM development. Insulin autoantibodies detected by use of a radioligand-binding assay were found in 1.4% of normal controls, 4% of first-degree relatives of IDDM patients, and in 37% of newly diagnosed IDDM patients. A strong positive correlation between insulin autoantibodies and ICAs was observed. HLA typing of insulin-autoantibody-positive first-degree relatives of IDDM patients, as well as in the general population, revealed a strong association with HLA-DR3 and/or-DR4, suggesting that insulin autoantibodies are restricted to persons genetically susceptible to IDDM. In an ongoing study of beta-cell function in ICA-positive nondiabetic individuals, the additional presence of insulin autoantibodies significantly increased the likelihood of beta-cell dysfunction. After intravenous glucose stimulation, insulinopenia was present in 70% of ICA and insulin-autoantibody-positive individuals in contrast to only 23% of ICA-positive, insulin-autoantibody-negative persons. These data document a significant association between insulin autoantibodies and ICAs and support the contention that insulin autoantibodies, like ICAs, are markers of ongoing beta-cell destruction.
Autoantibodies↗
Type I insulin dependent diabetes: an autoimmune disease that can be arrested or prevented with immunotherapy?
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Autoantibodies↗
Familial DiGeorge syndrome with tetralogy of Fallot and prolonged survival.
Two brothers with DiGeorge syndrome had tetralogy of Fallot with pulmonary valve atresia, illustrating similarity of the type of congenital heart disease (CHD) within affected families; the specific type of CHD differs between families. The late recognition of hypocalcemia in the older brother and his survival to age 21 years emphasizes the need to consider. DiGeorge syndrome in patients of all ages with hypocalcemia and congenital heart disease.
Adult↗
Pancreatic alpha cell autoantibodies and glucagon response to arginine.
The frequency and significance of cytoplasmic pancreatic alpha cell autoantibodies (ACA) were investigated in 2102 healthy controls, 879 patients with insulin-dependent diabetes mellitus (IDDM) who were negative for islet cell autoantibodies (ICA), and 1567 relatives of IDDM patients. ACA were found in approximately 1 in 200 people of all ages and were not significantly associated with IDDM, the IDDM-associated HLA phenotypes DR3 and DR4, or thyrogastric or adrenal autoantibodies. Of 11 ACA-positive patients studied by arginine stimulation tests, none had frank glucagon deficiency. Thus, ACA do not appear to be associated with defective alpha cell function or with IDDM.
Adrenal Glands↗
Autosomal dominant hypoparathyroidism with variable, age-dependent severity.
Hypoparathyroidism (hypocalcemia, hyperphosphatemia, mild hypomagnesemia, and inappropriately low serum C-terminal parathyroid hormone concentration) was found in six members of a family representing three successive generations. No patient had aortic arch or conotruncal malformations, lymphopenia, or features of type I or type II autoimmune polyglandular syndromes. Two individuals had transient neonatal seizures without further difficulties despite persistent hypocalcemia. None of the four affected adults has had major complications of hypoparathyroidism (mental retardation, cataracts, or seizures). We believe that persistence of hypoparathyroidism after resolution of neonatal hypocalcemic seizures should prompt a survey of the family for hypoparathyroidism.
Adult↗
Solitary central maxillary incisor associated with precocious puberty and hypothalamic hamartoma.
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Anodontia↗
Flow cytometric enumeration of mononuclear cell populations infiltrating the islets of Langerhans in prediabetic NOD mice: development of a model of autoimmune insulitis for type I diabetes.
Type I, insulin-dependent diabetes (IDD) in man and the NOD (non-obese diabetic) mouse is believed to result from an autoimmune destruction of pancreatic beta (beta) cells. In both species the pathologic correlate of this destruction is a peri- and intra-islet immune cell infiltrate, referred to as insulitis, easily recognized histologically. Although histologic studies of insulitis have established the autoimmune nature of IDD, controversy remains concerning the phenotypes and especially function of the islet-infiltrating immune cells. In the present study, we reveal a new protocol which permits enumeration of islet-infiltrating leukocytes using flow cytometry (FACS). Using this technique, we have analyzed systematically the changes in major leukocyte phenotypes during the development of the insulitis lesion. Results indicate that: 1) the first islet-infiltrating leukocytes are class II+, Ig- monocytes and CD8+ T lymphocytes, 2) after a slight decrease in the CD8+ cell population, an influx of CD4+ T lymphocytes occurs, accompanied by increasing numbers of CD8+ T cells, as well as IgM+ and IgG+ B lymphocytes, 3) whereas all the IgM+ B cells appear to be CD5+, between 70-95% of IgG+ B cells express CD5, and 4) throughout the response, the class II+, IgG-cell population remains relatively constant. These data, together with our previous work showing that autoantibody binds to pancreatic beta cells prior to leukocytic infiltration, permit construction of a working model for the natural history of insulitis in the NOD mouse. Briefly, the initial cellular response against the beta cell, which begins between 5-7 weeks of life, appears to be a local inflammation in which class II-positive macrophages and CD8-positive cells (possibly with antibody-dependent cell-mediated cytotoxic potential) infiltrate the islet. Finally, T helper cells are activated, traffic briefly through the islet, and elicit a B lymphocyte and T killer cell invasion of the islet that ultimately leads to beta cell necrosis.
Animals↗