Immune Cell Infiltration, Cytokine Expression, and β-Cell Apoptosis During the Development of Type 1 Diabetes in the Spontaneously Diabetic LEW.1AR1/Ztm-iddm Rat

Abstract

The IDDM (LEW.1AR1/Ztm-iddm) rat is a type 1 diabetic animal model characterized by a rapid apoptotic pancreatic β-cell destruction. Here we have analyzed the time course of islet infiltration, changes in the cytokine expression pattern, and β-cell apoptosis in the transition from the pre-diabetic to the diabetic state. Transition from normoglycemia to hyperglycemia occurred when β-cell loss exceeded 60–70%. At the early stages of islet infiltration, macrophages were the predominant immune cell type in the peripherally infiltrated islets. Progression of β-cell loss was closely linked to a severe infiltration of the whole islet by CD8⁺ T-cells. With progressive islet infiltration, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were expressed in immune cells but not in β-cells. This proinflammatory cytokine expression pattern coincided with the expression of inducible nitric oxide synthase (iNOS) and procaspase 3 in β-cells and a peak apoptosis rate of 6.7%. Islet infiltration declined after manifestation of clinical diabetes, yielding end-stage islets devoid of β-cells and immune cells without any sign of cytokine expression. The observed coincidence of IL-1β and TNF-α expression in the immune cells and the induction of iNOS and procaspase 3 mRNA expression in the β-cells depicts a sequence of pathological changes leading to apoptotic β-cell death in the IDDM rat. This chain of events provides a mechanistic explanation for the development of the diabetic syndrome in this animal model of human type 1 diabetes.