Insulitis and mechanisms of disease resistance: studies in an animal model of insulin dependent diabetes mellitus

Insulin dependent diabetes mellitus (IDDM) is an autoimmune disease characterised by extreme insulin deficiency due to an overall decrease in the mass of properly functioning β-cells. This reduction occurs as a result of insulitis, the outcome of which will depend upon the intensity of the cytotoxic attack and the ability of β-cells to resist and repair immune mediated cell damage. To further elucidate the relationship between the insulitis process and β-cell defence and repair mechanisms in the prevention of diabetes we have studied a unique subgroup of diabetes prone (DP) BB/S rats which have demonstrated an ability to recover from IDDM (BB/S-R). Animals were diagnosed as diabetic at 115 days of age, subsequently receiving insulin therapy (1.49+/-0.1 IU/day) for a total of 19.7 days during 1 to 4 episodes of IDDM. Following a prolonged symptom-free period of 90 days, an IPGTT revealed that BB/S-R rats possessed normal glycaemic control. Islets were isolated from the BB/S-R rats and their glucose-stimulated insulin response was shown to be comparable to Wistar control islets . Furthermore, control and BB/S-R islets showed both a similar structural integrity and insulin content. BB/S-R islets cultured for 24 hr in IL-1β (10^-13 M) maintained a significant insulin secretory response to glucose in contrast to Wistar controls in which the response was completely inhibited. Nitrite production was induced by IL-1β, in a dose-dependent manner, in control islets whereas there was no significant increase in production in the islets of BB/S-R rats. These findings suggest that previous immune directed ß-cell attack may induce a state of increased resistance to subsequent deleterious effects of cytokine-mediated cytotoxicity. Overall therefore, the present study shows how the ”recovered” BB/S-R rat model provides a unique opportunity to assess the direct effects of insulitis on pancreatic islets and how this interaction may subsequently determine disease outcome.