Beta-cell autoimmunity

Graves, P.M., etal. Prospective study of enteroviral infections and development of beta-cell autoimmunity. Diabetes autoimmunity study in the young (DAISY), Diabetes Res. Clin. 

The exact mechanisms of tacrolimus-induced diabetes are unknown. In one renal transplant patient with genetic susceptibility, tacrolimus was associated with insulin-dependent diabetes mellitus and the simultaneous occurrence of anti-glutamic acid decarboxylase antibody (54). Within 2 months after conversion from tacrolimus to ciclosporin, the antibody was no longer detected and the patient s insulin requirements fell dramatically. Tacrolimus-induced direct beta cell toxicity, with subsequent development of beta cell autoimmunity, was therefore suggested as a possible mechanism in patients with genetic susceptibility for type I diabetes. 

Kimpimaki T, Kupila A, Hamalainen AM, Kukko M, Kulmala P, Savola K, Simell T, Keskinen P, llonen J, Simell O, Knip M (2001) The first signs of beta-cell autoimmunity appear in infancy in genetically susceptible children from the general population the Finnish Type 1 Diabetes Prediction and Prevention Study. J Clin Endocrinol Metab, 86 4782—4788. 

Does nitric oxide mediate autoimmune destmction of beta-cells Possible therapeutic interventions in IDDM, Diabetes 41 (1992), p. 897-903... 

The etiology of type 1 diabetes is autoimmune destruction of the pancreatic beta cells, which is initiated by an event such as viral infection and progresses to the point of frank symptoms during childhood and the teenage years. 

Sigurdsson, E., and Baekkeskov, S. (1990). The 64-kDa beta cell membrane autoantigen and other target molecules of humoral autoimmunity in insulin-dependent diabetes mellitus. Curr. Top. Microbiol. Immunol. 164, 143-168. 

As indicated earlier, most cases of type 1 diabetes are caused by an autoimmune response that selectively attacks and destroys pancreatic beta cells in susceptible individuals. Therefore, drugs that suppress this autoimmune response may be helpful in limiting beta cell destruction, thereby decreasing the severity of this disease.4,41 Several immunosuppressants have been investigated as a way to potentially minimize beta cell loss from the autoimmune reactions underlying type 1 diabetes some immunosuppressants that have been considered for this situation include cyclosporine, azathioprine, cyclophosphamide, methotrexate, and glucocorticoids.11 The pharmacology of these immunosuppressants is discussed in more detail in Chapter 37. 

Yoon JW, Jun HS. Autoimmune destruction of pancreatic beta cells. Am J Ther. 2005 12 580-591. 

Cyclosporine is used to a somewhat lesser extent in treating autoimmune diseases, but it may be helpful in conditions such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, and glomerulonephri-tiS.i5,32,63 as discussed in Chapter 32, cyclosporine has also been used in the early stages of type 1 diabetes mellitus to help control immune-mediated destruction of pancreatic beta cells, thus decreasing the severity of this disease in some patients.9... 

Aniano, K. and Yoon, J. W. (1990). Studies on autoimmunity for initiation of beta-cell destruction. V. Decrease of macrophage-dependent T lymphocytes and natural killer cytotoxicity in silica-treated BB rats.Diabetes 39, 590-596. 

Bach, J. F. (1995). Insulin-dependent diabetes mellitus as a beta-cell targeted disease of immunoregulation. J. Autoimmun. 8, 439 463. 

Hotta, M., Tashiro, F., Ikegami, H., Niwa, H., Ogihara, T., Yodoi, J. and Miyazaki, J. (1998). Pancreatic beta cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and Streptozotocin-induced diabetes. J. Exp. Med. 188, 1445-1451. 

Kurrer, M. O., Pakala, S. V., Hanson, H. L. and Katz, J. D. (1997). Beta cell apoptosis in T cell-mediated autoimmune diabetes. Proc. Natl. Acad. Sci. USA 94, 213-218. 

A deficiency in insulin production results in a condition called diabetes mellitus. Approximately 6.2 percent of the population in the United States is affected with diabetes. Type 1 diabetics account for 10 percent of those individuals suffering from diabetes mellitus. It is also known as juvenile diabetes and generally develops in young people, typically between the ages of ten and fifteen years, as a result of an autoimmune disorder. Why the body s immune system turns on itself, attacking and destroying beta cells, the pancreatic cells in which insulin is synthesized, is not clear. The unfortunate consequence is insulin deficiency. 

Metabolic disorders are common, especially diabetes mellitus, a disorder of the glucose control. Most serious is type 1 diabetes, where the beta cells are destructed, typically by an autoimmune reaction, so the patient must be given insulin the rest of his/her life. Untreated it can lead to death within some months to a few years. It attacks mainly younger adults or children. The second, called type 2 diabetes, affects older people, typically in their 60s and typically obese. The disease is a combination of a decreased insulin production and an impaired glucose disposal. It evolves slowly and many patients can, at least in the beginning, be controlled with diet and exercise. 

Alba A, Puertas MC, Carrillo J, Planas R, Ampudia R, Pastor X, Bosch F, Pujol-Borrell R, Verdaguer J, Vives-Pi M. IFN beta accelerates autoimmune type 1 diabetes in nonobese diabetic mice and breaks the tolerance to beta cells in nondiabetes-prone mice. J Immunol 2004 173 6667-75. 

In a study using a competitive radiobinding assay, as many as 43% of patients with rheumatoid arthritis using penicillamine had autoantibodies against insulin (132). These antibodies did not appear to affect pancreatic beta-cells, as the response to intravenous glucose was normal and there were no episodes of hypoglycemia. Other sulfhydryl compounds that have occasionally been reported to cause autoimmune hypoglycemia are tio-pronin, pyritinol, and thiamazole (methimazole) (133). 

Type 1 diabetes is characterized by a near-absolute insulin deficiency at diagnosis or soon thereafter. The beta cells of the pancreas are no longer able to secrete insulin due to autoimmune destruction. Therefore, people with type 1 diabetes require exogenous administration of insulin for survival. People with type 2 diabetes may require insulin therapy when diet, exercise, and the oral agents are no longer enough to provide adequate glucose control. 

Type 1 diabetes is due to autoimmune destruction of pancreatic islet beta cells causing loss of insulin. Type 2 diabetes is due to the combination of cellular resistance to insulin and beta cell failure. Tissue lesions are common to both types of diabetes, and chronic hyperglycemia (or a closely related metabolic abnormality) is responsible for diabetic complications including diabetic nephropathy. 

The influence of antioxidants (e.g. vitamin E or a-tocopherol, vitamin C or ascorbic acid, and carotenoids, including P-carotene and lycopene) on autoimmune diseases has not been extensively studied. There is some evidence that damage induced by reactive oxygen species contributes to the destruction of pancreatic beta cells, brain tissue, and joints seen in diabetes mellitus type 1, multiple sclerosis, and rheumatoid arthritis, respectively. However, there are few prospective studies of antioxidant intake and risk of autoimmune diseases. Although there is some evidence of a reduced risk of rheumatoid arthritis and lupus with higher intake or serum levels of antioxidants, there are inconsistent findings with respect to which antioxidants or foods are involved (Comstock et al., 1997 Knekt et al., 2000 Cerhan et al., 2003). Only one prospective study of antioxidants and risk of multiple sclerosis is available, and that study reported no association with intakes of vitamin C, vitamin E, or carotenoids (Zhang et al., 2001). 

Diabetes mellitus type 1 (T1D). Autoimmune form of diabetes mellitus caused by immune-mediated destruction of insulin-producing beta cells in the pancreas with irreversible loss of insulin production. Islet cell autoantibodies and autoantibodies directed against glutamic acid decarboxylase, insulin, and the IA2-antigen are diagnostic markers for T1D as well as risk markers for the development of this disease. 

Glutamic acid decarboxylase (GAD). Main autoantigen in -diabetes mellitus type 1 and stiff-person syndrome (a neurological autoimmune disease). Localized in pancreatic beta cells and GABA-ergic neurons. 

Roep BO, van den Engel NK, van Halteren AG, et al. Modulation of autoimmunity to beta-cell antigens by proteases. Diabetologia, 2002 45(5) 686-692. 

Much has been learned about insulin because of its relationship with diabetes. In classical, type I diabetes (or insulin-dependent diabetes), the individual does not make insulin, or at least not enough of it. This is usually caused by destruction of the beta cells of the islets of Langerhans in the pancreas from a type of autoimmune disease. The only remedy for type I diabetes is regular insulin injections, and insulin is produced for this purpose by recombinant DNA technology (Chapter 13). 

Vidalain P-0, Azocar O, Lamouille B, Astier A, Rabourdin-Combe C, Servet-Delprat C (2000) Measles virus induces functional TRAIL production by human dendritic cells. J Virol 74 556-559 von Herrath MG, Efrat S, Oldstone MB, Horwitz MS (1997) Expression of adenoviral E3 transgenes in beta cells prevents autoimmune diabetes. Proc Natl Acad Sci USA 94 9808-9813 Wadell G (1990) In Zuckerman AJ, Banatvala JE, Pattison JR (eds) Adenoviruses. Wiley, New York, pp 267-297... 

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