Insulin autoantibodies

In a randomized trial in 74 patients with chronic hepatitis C treated with interferon alfa-2b and ribavirin, plus placebo or amantadine, two developed glutamic acid decarboxylase (GAD) autoantibodies, but none developed IA-2 or insulin autoantibodies (543). One had an increased titer of GAD autoantibodies during a first sequence of interferon alfa monotherapy, then a further rise during subsequent combination therapy, and finally developed diabetes mellitus after 5 months of treatment. The authors suggested that repetitive treatment with interferon alfa could increase the risk of type 1 diabetes in patients previously positive for islet antibodies. 

Vardi P, Brik R, Barzilai D, Lorber M, Scharf Y. Frequent induction of insulin autoantibodies by D-penicillamine in patients with rheumatoid arthritis. J Rheumatol 1992 19(10) 1527-30. 

Qll There is both a genetic and environmental component in type 1 diabetes. The pathological basis of the condition is autoimmune destruction of the pancreatic islet cells, which is said to be associated with genetic and environmental factors such as viral infection. It has been shown that antibodies to islet cells and insulin autoantibody (IAA) can exist for years before the occurrence of symptoms, possibly as a result of the autoimmune processes the IAA may form during the process of active islet and /1-cell destruction. Both insulin and glucagon play a role in the development of hyperglycaemia and hyperketonaemia, since both a- and /1-cell functions are abnormal in diabetes. Both a lack of insulin and a relative excess of glucagon coexist in type 1 diabetes, and so the metabolic abnormalities that occur are likely to be caused by both hormones. 

Type-I diabetes is the result of an immunologically mediated genetically programmed destruction of the B-cells. This process may require many years and can be documented by several humoral and cellular immunological abnormalities preceding the clinical onset of the disease. Islet cell surface antibodies (ICA) and insulin autoantibodies (IAA) are often detected years before overt clinical symptoms start. A florid insulitis, however, has mainly been observed only close to the time of diagnosis (Bottazzo et al., 1985). 

Insulin autoantibodies also occur in 30-40% of IDDM children at presentation and in their high-risk siblings, and may be a marker for the prediabetic stage of IDDM. Insulin autoantibodies can develop and may cause a syndrome of postprandial glucose intolerance combined with fasting hypoglycaemia. 

Insulin autoantibodies are antibodies that develop spontaneously without prior administration of exogenous insulin. These have been reported in various groups of patients, including some with Graves disease treated with methimazole (Hirata et al., 1974) and others treated with hydralazine or procainamide (Blackshear et al., 1983), penicillamine (Benson et al., 1985) or a-mercaptopropionylglycine (Ichihara et al., 1977). In certain cases, no... 

Insulin autoantibodies (lAAs) are present in more than 90% of children who develop type 1 diabetes before age 5, but in fewer than 40% of individuals developing dia-betes after age 12. Their frequency in healthy people is similar to tliat of ICA. A radioisotopic method that calculates the displaceable insulin radiohgand binding after the addition of excess nonradiolabeled insulin is recommended for lAA. Results are positive when concentrations exceed the mean +2 (or 3) standard deviations (SD) of healthy controls. An important caveat is that insulin antibodies develop after insrdin therapy, even in those persons who use human insulin. 

The pathogenesis of type I diabetes is autoimmune destruction of the cells of the pancreas. The factor or factors that trigger this autoimmune response are unknown. Predisposing factors appear to include certain major histocompatibility complex haplotypes and autoantibodies to various islet cell antigens. The progression of the autoimmune response is characterized by lymphocytic infiltration and destruction of the pancreatic cells resulting in insulin deficiency. Type I diabetes mellitus constitutes about 10% of cases of diabetes mellitus. 

Dobersen, M. J., Scharff, J. E., Ginsberg-Fellner, F., Notkins, A. L. (1980). Cytotoxic autoantibodies to beta cells in the serum of patients with insulin-dependent diabetes mellitus. N. Engl. ]. Med. 303, 1493-1498. 

Yamamoto T, Sato T, Mori T, Yamakita T, Hasegawa T, Miyamoto M, Hosoi M, Ishii T, Yoshioka K, Tanaka S, Fujii S. Clinical efficacy of insulin-like growth factor-1 in a patient with autoantibodies to insulin receptors a case report. Diabetes Res Clin Pract 2000 49(l) 65-9. 

In three middle-aged patients, diabetes was diagnosed after 3-7 months of treatment with interferon alfa-2b and ribavirin, and two presented with severe ketoacidosis (534,535). There was a family history of diabetes in one patient and two had high titers of glutamic acid decarboxylase antibodies before treatment. One patient never had diabetes-related serum autoantibodies before or after interferon alfa therapy. All three required permanent insulin treatment despite withdrawal of interferon alfa. 

In patients with chronic hepatic B or C the respective prevalences of pancreatic autoantibodies increased from 2% and 3% at baseline to 5% and 7% after interferon (544). In all, 31 published cases of type 1 diabetes mellitus attributed to interferon alfa treatment were detailed, mostly in patients with hepatitis C. Irreversible diabetes required permanent insulin treatment in all but eight cases. At least one marker of pancreatic autoimmunity was positive in nine of 18 patients before treatment, and in 23 of 30 patients at the onset of diabetes. In accordance with these results and the likelihood of a genetic predisposition, the authors recommended screening for islet cell and glutamic acid decarboxylase autoantibodies before and during interferon alfa treatment. However, owing to the low number of reported cases and the paucity of studies that have examined the relation between pancreatic autoimmunity and the occurrence of diabetes, further research on the predictive potential of such a systematic investigation is warranted. 

Autoimmune polyglandular syndrome with progressive thyroid autoimmunity, type 1 diabetes mellitus, amenorrhea, and adrenal insufficiency has been reported in a 51-year-old woman treated with interferon alfa for chronic hepatitis C (545). Pancreas and pituitary gland autoantibodies, which were undetectable before interferon alfa treatment, were present at the time of diagnosis. After withdrawal, she recovered normal thyroid function, but was still insulin dependent with amenorrhea and adrenal insufficiency. 

Daw, K., Ujihara, N., Atkinson, M.A. and Powers, A.C. (1996) Glutamic acid decarboxylase autoantibodies in stiff man syndrome and insulin-dependent diabetes mellitus exhibit similarities and differences in epitope recognition. J. Immunol., 156, 818-825. 

Autoimmune diseases have been reported to be more frequent in human subjects treated with several recombinant cytokines [38], For instance, increased titers or the new occurrence of autoantibodies have been observed in hepatitis C patients treated with the recombinant interferons-alpha (IFNa). Quite a few clinical case reports describe the development of organ-specific as well as systemic autoimmune diseases including systemic lupus erythematosus, insulin-dependent type I diabetes mellitus, autoimmune thrombocytopenia, autoimmune hemolytic anemia, myasthenia gravis, and autoimmune thyroiditis in patients under IFNa therapy. Although the mechanism involved is not fully elucidated, the available data support the pathogenic potential of IFNa in autoimmunity [31]. In contrast, autoimmune effects associated with IFNp therapy are thought to be of lesser concern based on the current clinical evidence [38], Thyroid autoimmunity in contrast to other autoimmune diseases is frequent in patients treated with recombinant interleukin-2 (rIL-2). Thus, among 281 previously euthyroid cancer patients treated with rIL-2, up to 41%... 

Selinger, S., Tsai, J., Pulini, M., Saperstein, A., Taylor, S. Autoimmune thrombocytopenia and primary biliary cirrhosis with hypoglycemia and insulin receptor autoantibodies. Ann. Intern. Med. 1987 107 686 - 688... 

Kuglin, B., Cries, F. A., and Kolb, H. (1988). Evidence of IgG autoantibodies against human proinsulin in patients with IDDM before insulin treatment. Diabetes 37, 130-132. 

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