Experiments by nature: lessons on type 1 diabetes

Abstract

The etiology and pathogenesis of type 1 diabetes (T1D) - one of the most frequent chronic, life-debilitating diseases in humans - have long fascinated endocrinologists, pathologists and biologists alike. Currently conventional wisdom portrays T1D as a chronic T cell-mediated autoimmune disease that leads to the specific destruction of pancreatic insulin-producing β cells. The process of β cell destruction is accompanied (or preceded) by the production of autoantibodies (autoAb) to β cell antigens (i.e. insulin, GAD65, IA-2 and ZnT8). These autoAb have proved to be instrumental in identifying subjects at risk of developing the disease prior to overt hyperglycemia, and they help to distinguish T1D from T2D patients (who have no autoAb), but are not deemed to be pathogenic. This review will examine to which extent this well-established disease-dogmas are sustained by experiments by nature, which should not suffer from the common biases and errors of experiments by humans.

Type 1 diabetes

“…50 Experiments, such as the transfer of type 1 diabetes following non-T-cell depleted allogeneic bone-marrow transplantation, 51 development of type 1 diabetes in an individual with B-lymphocyte and antibody deficiency, 52 and inherited genetic defects of T-lymphocyte function causing type 1 diabetes 53 highlight the crucial role of T cells in the pathophysiology of type 1 diabetes. 54 Almost all studies of peripheral autoimmunity in people with type 1 diabetes show overlap of phenotypes seen in the general population, and the proportion of islet autoreactive cells present in the periphery is often tiny (only a few cells among millions of non-autoreactive cells). As a result, connecting the population of autoreactive immune cells that is detectable in blood to the disease process in islets has been difficult.…”

Rats deficient in the GAD65 isoform exhibit epilepsy and premature lethality

“…62 In addition, GAD65 autoantibodies were detected in type 1 diabetes as well as in anti-GAD65 Ab-associated cerebellar ataxia, the latter of which is characterized by motor dysfunction. 16,63 It is of interest to note that GAD67 is rarely autogenic, despite its high sequence identity with GAD65. Certain GAD65 autoantibodies, such as mAB b78, inhibited GAD65 catalytic activity in vitro 64 and internalization of these antibodies was detected in neurons.…”

Antibodies against H1N1 influenza virus cross‐react with α‐cells of pancreatic islets

“…The model portrays the destruction of β‐cells by mistakenly activated T cells. Although very popular, the model is rather tedious, and failed to be confirmed by neither animal experiments, nor in the clinical efforts to rescue the damaged pancreatic islets by immune inhibitors. Given the hallmark of type 1 diabetes is the loss of pancreatic β‐cells, if their precursor cells, that is, α‐cells, are not affected in the process of the disease, then the damaged β‐cells should be able to be restored when an immunosuppressant is applied.…”