https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(13)60591-7.pdf

Type 1 Diabetes

Insulin-Dependent Diabetes Mellitus

https://www.farm.ucl.ac.be/Full-texts-FARM/des-Rieux-2006-1.pdf

Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach.

INSULIN-DEPENDENT diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice results from the T-lymphocyte-mediated destruction of the insulin-producing pancreatic β-cells and serves as a model for human IDDM1. Whereas a number of autoantibodies are associated with IDDM2, it is unclear when and to what β-cell antigens pathogenic T cells become activated during the disease process. We report here that a T-helper-1 (Thl) response to glutamate decarboxylase develops in NOD mice at the same time as the onset of insulitis. This response is initially limited to a confined region of glutamate decarboxylase, but later spreads intramolecularly to additional determinants. Subsequently, T-cell reactivity arises to other β-cell antigens, consistent with intermolecular diversification of the response. Prevention of the spontaneous anti-glutamate decarboxylase response, by tolerization of glutamate decarboxylase-reactive T cells, blocks the development of T-cell autoimmunity to other β-cell antigens, as well as insulitis and diabetes. Our data suggest that (1) glutamate decarboxylase is a key target antigen in the induction of murine IDDM; (2) autoimmunity to glutamate decarboxylase triggers T-cell responses to other β-cell antigens, and (3) spontaneous autoimmune disease can be prevented by tolerization to the initiating target antigen.

Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes.

Insulin-dependent diabetes mellitus (IDDM) is a chronic disorder that results from autoimmune destruction of the insulin-producing pancreatic beta cells. Much has been learned during the past decade about the underlying genetics, natural history, and pathogenesis of IDDM. In this review, we shall describe some of this new information and discuss how it might be used to prevent the disease. Epidemiology IDDM occurs most frequently in persons of northern European descent. Among other racial groups, such as blacks, Native Americans, and Asians, the disease is less common1. The incidence ranges from a low of 1 to 2 per 100,000 per . . .

The Pathogenesis of Insulin-Dependent Diabetes Mellitus

Nonobese diabetic (NOD) mice spontaneously develop an autoimmune form of diabetes associated with insulitis. A number of immunomodulatory therapies have been investigated as a treatment for the disease process. Oral administration of the autoantigens myelin basic protein and collagen type II suppresses experimental models of encephalomyelitis and arthritis. We have now found that oral administration of insulin delays the onset and reduces the incidence of diabetes in NOD mice over a 1-year period in animals administered 1 mg of porcine insulin orally twice a week for 5 weeks and then weekly until 1 year of age. As expected, orally administered insulin had no metabolic effect on blood glucose levels. The severity of lymphocytic infiltration of pancreatic islets was also reduced by oral administration of insulin. Furthermore, splenic T cells from animals orally treated with insulin adoptively transfer protection against diabetes, demonstrating that oral insulin administration generates active cellular mechanisms that suppress disease. These results show that oral insulin affects diabetes and the pancreatic cellular inflammatory process in the NOD mouse and raise the possibility that oral administration of insulin or other pancreatic autoantigens may provide a new approach for the treatment of autoimmune diabetes.

https://www.pnas.org/content/pnas/88/22/10252.full.pdf

L Davidson

Papers

Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin.