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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 1 diabetes mellitus has received much attention recently as a potential target for the emerging science of stem cell medicine. In this autoimmune disease, the insulin-secreting beta-cells of the pancreas are selectively and irreversibly destroyed by autoimmune assault. Advances in islet transplantation procedures now mean that patients with the disease can be cured by transplantation of primary human islets of Langerhans. A major drawback in this therapy is the availability of donor islets, and the search for substitute transplant tissues has intensified in the last few years. This review will describe the essential requirements of a material designed as a replacement beta-cell and will look at the potential sources of such replacements. These include embryonic stem (ES) cells and multipotent adult stem/progenitor cells from a range of tissues including the pancreas, intestine, liver, bone marrow and brain. These stem cell populations will be evaluated and the different experimental approaches that have been employed to derive functional insulin-expressing cells will be discussed. The review will also look at the capability of human ES (hES) cells generated by somatic cell nuclear transfer and some adult stem cell populations such as bone marrow-derived stem cells, to offer autologous transplant material that would remove the need for immunosuppression. In patients with Type 1 diabetes, auto-reactive T-cells are programmed to recognise the insulin-producing beta-cells. As a result, for therapeutic replacement tissues, it may be more sensible to derive cells that behave like beta-cells but are immunologically distinct. Thus, the potential of cells derived from non-beta-cell origin to avoid the autoimmune response will also be discussed. Finally, the review will summarise the future prospects for stem cell therapies for diabetes and will highlight some of the problems that may be faced by researchers working in this area, such as malignancy, irreproducible differentiation strategies, immune-system rejection and social and ethical concerns over the use of hES cells.
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PMID:Diabetes mellitus: a potential target for stem cell therapy. 1822 Aug 71

Autoimmunity is mediated by a variety of mechanisms, molecular and cellular events, and responses. Predisposition to a given autoimmune response requires the requisite allele(s) that controls antigen presentation by antigen-presenting cells for T cell recognition. Some autoimmune responses emerge following infection by a pathogen, whose protein(s) possess structural similarities in some of its epitopes to regions on proteins of the host. Thus, antibodies evoked against a pathogen might cross-react with a self-protein and act as autoantibodies, and the involved autoantigen then provides a source for persistent stimulation. Proteins to which the immune system is ordinarily self-tolerant might, if altered, elicit autoimmune responses. Ways in which self-proteins can be altered include mutations and altered expression, posttranslational modification, covalent modifications, denaturation, native disorder or misfolding. Sequestered proteins normally sheltered from immune recognition become immunogenic and targets of immune effector functions, once exposed to the immune system. Other alterations can occur because of disruption in the levels or activity of regulatory proteins. These include certain alleles of the cytotoxic T lymphocyte-associated antigen-4 gene (possibly a nonspecific exacerbating molecule of disease risk in several autoimmune diseases), the lymphoid protein tyrosine phosphatase nonreceptor type 22 gene (associated with type 1 diabetes and other autoimmune diseases), TNF-alpha (involved in chronic inflammation, autoimmunity and malignancies) and the FOXP3 gene (expressed by CD4+C25+ regulatory T cells), whose mutations can cause immune dysregulation, polyendocrinopathy and X-linked inheritance syndromes of systemic autoimmunity. An autoimmune response can also arise from natural antibodies or autoantibodies that occur independently of known immunization and are able to bind to microbial antigens, altered proteins as well as self-antigens. Natural autoantibodies possess in general a low intrinsic affinity for antigen, but can function as templates for the generation of pathogenic autoantibodies, that emerge through a process of clonal selection entailing somatic hypermutation and class switch DNA recombination, as driven by antigen.
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PMID:Molecular mechanisms of autoimmunity. 1832 81

The active metabolite of vitamin D3 - 1,25-(OH)2D3 - exerts most of its physiological and pharmacological actions through its nuclear receptor (VDR), regulating the transcriptional machinery of a variety of cell types. Basic research motivated by the detection of VDR in numerous target cells, has indicated potential therapeutic applications of VDR ligands in osteoporosis, cancer, secondary hyperparathyroidism and autoimmune diseases such as psoriasis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes and multiple sclerosis. In recent years vitamin D analogs, particularly calcipotriol and tacalcitol, have been used as topical therapeutic agents in vitiligo, an autoimmune pigmentary disorder characterized by aberrant loss of functional melanocytes from involved epidermis. The presence of cytotoxic T cells targeting melanocyte antigens and imbalance of the cytokine network were described as characteristics of the disease, eventually leading to melanocyte damage and death. Vitamin D ligands are designed to target the local immune response in vitiligo, acting on specific T cell activation, mainly by inhibiting the transition of T cells from early to late G1 phase and by inhibiting the expression of several pro-inflammatory cytokines genes, such as those encoding tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma). Vitamin D(3) compounds are known to influence melanocyte maturation and differentiation and also to up-regulate melanogenesis through pathways activated by specific ligand receptors, such as endothelin receptor and c-kit. In this review we summarize the complex pathogenetic rationale of vitamin D analogs in vitiligo depigmentation. Understanding the cellular and molecular mechanisms through which vitamin D targets the epidermal melanin unit is of great interest for identification of new effective therapeutic combination(s) that might induce repigmentation in vitiligo.
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PMID:Cellular and molecular mechanisms involved in the action of vitamin D analogs targeting vitiligo depigmentation. 1839 27

Emerging evidence has suggested environmental factors such as infections and xenobiotics and some dietary proteins and peptides in the pathogenesis of many autoimmune diseases. Considering the fact that autoantibodies can often be detected prior to the onset of a disease, in this study an enzyme immunoassay was used for measurement of antibodies against different highly purified antigens or synthetic peptides originating not only from human tissue, but also from cross-reactive epitopes of infectious agents, dietary proteins and xenobiotics. The measurement of antibodies against a panel of antigens allows for identification of patterns or antibody signatures, rather than just one or two markers of autoimmunity, thus establishing the premise for increased sensitivity and specificity of prediction, as well as positive predictive values. This panel of different autoantibodies was applied to 420 patients with different autoimmune diseases, including pernicious anemia, celiac disease, thyroiditis, lupus, rheumatoid arthritis, osteoarthritis, Addison's disease, type 1 diabetes, cardiovascular disease and autoimmunity, which are presented in this article. In all cases, the levels of these antibodies were significantly elevated in patients versus controls. Antibody patterns related to neuroautoimmune disorders, cancer, and patients with somatic hypermutation will be shown in a subsequent article. We believe that this novel 96 antigen-specific autoantibody or predictive antibody screen should be studied for its incorporation into routine medical examinations. Clinicians should be aware that the detection of antibodies should not automatically mean that a patient will definitely become ill, but would rather give a percentage of risk for autoimmune disease over subsequent months or years.
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PMID:Antibodies as predictors of complex autoimmune diseases. 1854 71

Relations of obesity and type 2 diabetes to urinary tract cancer were described. Occurrence of kidney cancer is more often in both obesity and type 2 diabetes. Bladder cancer has no relation to obesity but is more common in type 2 diabetic patients. Inverted relations were found in prostatic cancer. This disease is more common in obese patents but less common in type 2 diabetes. Diabetics are partly protected to this disease. Physical activity decreases the risk of kidney and bladder cancer but has no relation to bladder cancer. Urinary tract cancers have no relation to type 1 diabetes. We have found 3.9 time higher risk of kidney cancer in Czech diabetic patients.
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PMID:[Tumours of kidneys, urinary bladder and prostate in obesity and diabetes]. 1863 Jun 27

The prevalence of overweight (body mass index, BMI, between 25 and 30 kg/m2) and obesity (BMI of 30 kg/m2 or higher) is increasing rapidly worldwide, especially in developing countries and countries undergoing economic transition to a market economy. One consequence of obesity is an increased risk of developing type II diabetes. Overall, there is considerable evidence that overweight and obesity are associated with risk for some of the most common cancers. There is convincing evidence of a positive association between overweight/obesity and risk for adenocarcinoma of the oesophagus and the gastric cardia, colorectal cancer, postmenopausal breast cancer, endometrial cancer and kidney cancer (renal-cell). Premenopausal breast cancer seems to be inversely related to obesity. For all other cancer sites the evidence of an association between overweight/obesity and cancer is inadequate, although there are studies suggesting an increased risk of cancers of the liver, gallbladder, pancreas, thyroid gland and in lymphoid and haematopoietic tissue. Far less is known about the association between diabetes mellitus type I (also called insulin dependent diabetes mellitus or juvenile diabetes), type II diabetes (called non-insulin dependent diabetes mellitus or adult onset diabetes mellitus) and cancer risk. The most common type of diabetes mellitus, type II, seems to be associated with liver and pancreas cancer and probably with colorectal cancer. Some studies suggest an association with endometrial and postmenopausal breast cancer. Studies reporting on the association between type I diabetes mellitus, which is relatively rare in most populations and cancer risk are scanty, but suggest a possible association with endometrial cancer. Overweight and obesity, as well as type II diabetes mellitus are largely preventable through changes in lifestyle. The fundamental causes of the obesity epidemic-and consequently the diabetes type II epidemic-are societal, resulting from an environment that promotes sedentary lifestyles and over-consumption of energy. The health consequences and economic costs of the overweight, obesity and type II diabetes epidemics are enormous. Avoiding overweight and obesity, as well as preventing type II diabetes mellitus, is an important purpose to prevent cancer and other diseases. Prevention of obesity and type II diabetes should begin early in life and be based on the life-long health eating and physical activity patterns. Substantial public investments in preventing overweight, obesity and type II diabetes mellitus are both appropriate and necessary in order to have a major impact on their adverse health effects including cancer.
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PMID:Obesity and diabetes epidemics: cancer repercussions. 1863 86

The association of high levels of autoantibodies to glutamic acid decarboxylase (GAD-ab) and stiff-person syndrome (SPS) is well known. However, the full spectrum of neurological syndromes associated with GAD-ab is not well established. In addition, these patients usually present type 1 diabetes mellitus (DM1) that could justify the presence of high GAD-ab levels. To clarify these issues, we reviewed the clinical and immunological features of patients in whom high GAD-ab levels were detected in a reference centre for DM1 and for the detection of antineuronal antibodies in suspected paraneoplastic neurological syndromes (PNS). High GAD-ab levels were defined as values > or =2000 U/ml by radioimmunoassay. Intrathecal synthesis (IS) of GAD-ab was calculated in paired serum/CSF samples. Values higher than the IgG index were considered indicators for positive GAD-ab-specific IS. High GAD-ab levels were identified in 61 patients, 22 (36%) had SPS, 17 (28%) cerebellar ataxia, 11 (18%) other neurological disorders (epilepsy -- four, PNS -- four; idiopathic limbic encephalitis -- two; myasthenia gravis -- one), and 11 (18%) isolated DM1. Patients with SPS and cerebellar ataxia had the same frequency of female gender (86% vs 94%), DM1 (59% vs 53%), CSF oligoclonal bands (35% vs 69%). Three of the four PNS patients, with paraneoplastic encephalomyelitis, a predominant gait cerebellar ataxia, and limbic encephalitis, had neuroendocrine carcinomas. GAD expression was confirmed in the two tumours in which the study was done. The fourth patient presented with paraneoplastic cerebellar degeneration antedating a lung adenocarcinoma. The frequency of increased IS of GAD-ab was 85% in SPS, 100% in cerebellar ataxia, and 86% in other neurological disorders. In conclusion, our study emphasizes that high GAD-ab levels associate with other neurological disorders besides SPS. Cerebellar ataxia, the second most common syndrome associated with high GAD-ab levels, shares with SPS the same demographic, clinical and immunological features. The demonstration of an increased IS of GAD-ab is important to confirm that the GAD autoimmunity is related to the neurological syndrome particularly when there is a concomitant DM1 that could justify the presence of high GAD-ab levels. Lastly, in patients who develop neurological syndromes that suggest a PNS, the finding of GAD-ab does not rule out this possibility and appropriate studies should be done to confirm an underlying cancer.
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PMID:Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. 1879 17

The vitamin D endocrine system is essential for calcium and bone homeostasis. The precise mode of action and the full spectrum of activities of the vitamin D hormone, 1,25-dihydroxyvitamin D [1,25-(OH)(2)D], can now be better evaluated by critical analysis of mice with engineered deletion of the vitamin D receptor (VDR). Absence of a functional VDR or the key activating enzyme, 25-OHD-1alpha-hydroxylase (CYP27B1), in mice creates a bone and growth plate phenotype that mimics humans with the same congenital disease or severe vitamin D deficiency. The intestine is the key target for the VDR because high calcium intake, or selective VDR rescue in the intestine, restores a normal bone and growth plate phenotype. The VDR is nearly ubiquitously expressed, and almost all cells respond to 1,25-(OH)(2)D exposure; about 3% of the mouse or human genome is regulated, directly and/or indirectly, by the vitamin D endocrine system, suggesting a more widespread function. VDR-deficient mice, but not vitamin D- or 1alpha-hydroxylase-deficient mice, and man develop total alopecia, indicating that the function of the VDR and its ligand is not fully overlapping. The immune system of VDR- or vitamin D-deficient mice is grossly normal but shows increased sensitivity to autoimmune diseases such as inflammatory bowel disease or type 1 diabetes after exposure to predisposing factors. VDR-deficient mice do not have a spontaneous increase in cancer but are more prone to oncogene- or chemocarcinogen-induced tumors. They also develop high renin hypertension, cardiac hypertrophy, and increased thrombogenicity. Vitamin D deficiency in humans is associated with increased prevalence of diseases, as predicted by the VDR null phenotype. Prospective vitamin D supplementation studies with multiple noncalcemic endpoints are needed to define the benefits of an optimal vitamin D status.
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PMID:Vitamin D and human health: lessons from vitamin D receptor null mice. 1869 80

Spinal epidural lipomatosis (SEL) is accumulation of unencapsulated fat tissue within the epidural space of the spinal canal. The most common cause of SEL is corticosteroid therapy, whereas most of the non-corticosteroid-dependent cases are idiopathic. If unrecognized, it may result in diagnostic confusion with other neuropathic or myelopathic conditions. We report 2 cases of SEL. The first case is of a 30-year-old man who received corticosteroid therapy for an acute and probably immune-mediated demyelinating process. Subsequently, the addition of compressive effects of SEL resulted in diagnostic confusion and initial workup at other centers for spinal cord malignancy and vascular malformation. The patient's symptoms improved after decompression surgery. The second case is of a 63-year-old woman with a history of type 1 diabetes mellitus that presented with increasing numbness in the lower extremities. She was initially diagnosed with diabetic neuropathy; however, the presence of myelopathic signs led to further investigation and diagnosis of SEL. Decompression surgery resulted in improvement of symptoms.
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PMID:Myeloneuropathic presentation of spinal epidural lipomatosis. 1907 99

Genotoxic air pollution is ubiquitous in urban and industrial areas. A variety of studies has linked human exposure to air pollution with a number of different somatic cell endpoints including cancer. However, the potential for inducing mutations in the human germline remains unclear. Sentinel animal studies of germline mutations at tandem-repeat loci (specifically minisatellites and expanded simple tandem repeats) have recently provided proof of principle that germline mutations can be induced in vertebrates (birds and mice) by air pollution under ambient conditions. Although humans may also be susceptible to induced germline mutations in polluted areas, uncertainties regarding causative agents, doses, and mutational mechanisms at repetitive DNA loci currently preclude extrapolation from animal data to the evaluation of human risk. Nevertheless, several recent studies have linked air pollution exposure to DNA damage in human sperm, indicating that our germ cells are not impervious to the genotoxic effects of air pollution. Thus, both sentinel animal and human studies have raised the possibility that ambient air pollution may increase human germline mutation rates, especially at repetitive DNA loci. Given that some human genetic conditions appear to be modulated by length mutations at tandem-repeat loci (e.g. HRAS1 cancers, type 1 diabetes, etc.), there is an urgent need for extensive study in this area. Research should be primarily focused upon: (1) the direct measurement of mutation frequencies at repetitive DNA loci in human male germ cells as a function of air pollution exposure, (2) large-scale epidemiology studies of inherited disorders and tandem-repeat associated genetic conditions and air pollution, and (3) the characterization of mutational mechanisms at hypervariable tandem-repeat loci.
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PMID:Air pollution and mutations in the germline: are humans at risk? 1911 82


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